Individual Differences in Cardiovascular Response

to Stress

PERSPECTIVES ON INDIVIDUAL DIFFERENCES

CECIL R. REYNOLDS, Texas A&M Uni1Je1'8ity, CoUege Station ROBERT T. BROWN, University of Nurth Carolina, Wilmi1/{/ton

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INDMDUAL DIFFERENCES IN CARDIOVASCULAR RESPONSE TO STRESS

Edited by J. Rick Turner, Andrew Sherwood, and Kathleen C. Light

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Individual Differences in Cardiovascular Response

to Stress

Edited by

J. Rick Turner Andrew Sherwood

and

Kathleen C. Light University of Norllt Carolina at Chapel HiU

Chapel HiU, Nurth Carolina

Springer Science+Business Media, LLC

Library of Congress Catalog1ng-tn-Publteat ton Data

I n d i v i d u a l d i f f e r e n c e s in c a r d i o v a s c u l a r response to s t r e s s / e d i t e d by J. Rick Turner, Andrew Sherwood, and Kathleen C. Light.

p. cm. — ( P e r s p e c t i v e s on i n d i v i d u a l d i f f e r e n c e s ) I n c l u d e s b i b l i o g r a p h i c a l r e f e r e n c e s and index.

1. Cardiovascular system—Pathophysiology. 2. S t r e s s (Physiology) 3. S t r e s s (Psychology) I . Turner, J. Rick. I I . Sherwood, Andrew. I I I . L i g h t , Kathleen C. IV. S e r i e s . [DNLM: 1. Cardiovascular System—physlopatholDgy.

2. I n d i v i d u a l i t y . 3. S t r e s s , P s y c h o l o g i c a l — p h y s i o p a t h o l o g y . WG 100 139] RC669.9.I53 1992 616.1* 08—dc20 DNLM/DLC • for Library of Congress 92-49958

CIP

ISBN 978-1-4899-0699-1 ISBN 978-1-4899-0697-7 (eBook) DOI 10.1007/978-1-4899-0697-7

© Springer Science+Business Media New York 1992 Originally published by Plenum Press, New York in 1992

Softcover reprint of the hardcover 1st edition 1992

All rights reserved

No part of this book may be reproduced, stored in a retrieval system, or transmitted in any form or by any means, electronic, mechanical, photocopying, niim)nTming,

recording, or otherwise, without written permission from the Publisher

To the Memory of

Paul A Obrist

Contributors

Bruce S. Alpert, Department of Pediatrics, University of Tennessee, Memphis, Tennessee 38103

Norman B. Anderson, Departments of Psychiatry and Psychology, Social and Health Sciences, Duke University, Durham, North Carolina 27710

James A. Blumenthal, Departments of Psychiatry and Psychology, Duke University Medical Center, Durham, North Carolina 27710

Ronald Bulbulian, Department of Health, Physical Education, and Recrea­tion, University of Kentucky College of Education, Lexington, Kentucky 40536-0219

Robyn Cheung, Department of Behavioral Science, University of Kentucky College of Medicine, Lexington, Kentucky 40536-0086

Joel E. Dimsdale, Department of Psychiatry, University of California at San Diego, La Jolla, California 92093

Roger B. Fillingim, Department of Psychiatry, Duke University Medical Center, Durham, North Carolina 27710

Gregory A. Harshfield, Department of Pediatrics, University of Tennessee, Memphis, Tennessee 38103

B. Kent Houston, Department of Psychology, University of Kansas, Law­rence, Kansas 66045-2160

vii

viii CONTRIBUTORS

Kathleen C. Light, Department of Psychiatry, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599-7175

William R. Lovallo, Department of Psychiatry and Behavioral Sciences, Uni­versity of Oklahoma Health Sciences Center, and Veterans Affairs Medical Center, Oklahoma City, Oklahoma 73190

James A. McCubbin, Department of Behavioral Science, University of Ken­tucky College of Medicine, Lexington, Kentucky 40536-0086

Maya McNeilly, Department of Psychiatry, Duke University Medical Center, Durham, North Carolina 27710

Paul J. Mills, Department of Psychiatry, University of California at San Diego, La Jolla, California 92093

Thomas B. Montgomery, Department of Medicine, University of Kentucky College of Medicine, Lexington, Kentucky 40536-0086

Hector Myers, Department of Psychology, University of California at Los Angeles, and Department of Psychiatry, Charles R. Drew University of Medicine and Science, Los Angeles, California 90024

Derrick A. Pulliam, Department of Pediatrics, University of Tennessee, Mem­phis, Tennessee 38103

RichardJ. Rose, Department of Psychology, Indiana University, Bloomington, Indiana 47405

Andrew Sherwood, Department of Psychiatry, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599-7175

Catherine M. Stoney, The Miriam Hospital and Brown University School of Medicine, Division of Behavioral Medicine, Providence, Rhode Island 02906

J. Rick Turner, Department of Psychiatry, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599-7175; present address: School of Public Health, University of California at Berkeley, Berkeley, California 94720

Lorenz J. P. van Doomen, Division of Psychophysiology, Free University of Amsterdam, Amsterdam, The Netherlands 1081 HV

CONTRIBUTORS ix

Dawn K. Wilson, Department of Pediatrics, University of Tennessee, Mem­phis, Tennessee 38103

John F. Wilson, Department of Behavioral Science, University of Kentucky College of Medicine, Lexington, Kentucky 40536-0086

Michael F. Wilson, Department of Medicine, University of Oklahoma Health Sciences Center, and Veterans Affairs Medical Center, Oklahoma City, Oklahoma 73190

Preface

The study of cardiovascular responses to psychosocial stress is one of the major avenues of investigation in the rapidly growing field of cardiovascular behav­ioral medicine. It has become apparent that the magnitudes, and indeed pat­terns, of cardiovascular responses to stress exhibit marked variation among individuals. Although all individual difference phenomena are of intrinsic in­terest to experimental behavioral scientists, this particular individual variation dimension has attracted additional scrutiny because of hypothesized links be­tween large-magnitude stress responses and the later development of cardio­vascular disease. In recent years, it is this possibility that has motivated a large proportion of the numerous investigations conducted to delineate various char­acteristics of stress responses, such as their stability across time and situation, their genetic and environmental determinants, and their association with other hypothesized influences on cardiovascular pathophysiology.

The invitation to prepare this volume, afforded to the authors by series editor Robert T. Brown, came at an opportune time in the development of this research field. Following seminal research by Paul Obrist and his contempo­raries in the 19708 and 1980s, the rigorous execution of many experiments has demonstrated the reproducibility of individual differences in stress responses. Now, the next generation of scientists is in the enviable position of being able to start to test some of the hypotheses linking behaviorally elicited cardiovas­cular excitation with cardiovascular morbidity. This book aims to present a sample of this research to interested behavioral scientists from a variety of disciplines.

The following chapters, then, describe the relationship among stress, car­diovascular response, and potential disease outcomes. The book is divided into three parts. The first provides an introduction to the assessment of both in­laboratory and ambulatory (those occurring during people's naturalistic daily activities) stress responses. Both conceptual and methodological issues are introduced, and the mechanisms by which the cardiovascular system is mobil­ized during psychological stress are discussed. The second part examines the

xi

xii PREFACE

detenninants of individual differences in stress responses. Contained within this section are investigations of the influence of genetic inheritance, environ­ment, personality, race, gender, and age. The potentially moderating influence of aerobic exercise and associated clinical implications are also discussed. Final­ly, the third part focuses on the psychophysiological processes by which re­sponses to stress may be translated over time into cardiovascular disease. The roles of endogenous opioids and salt are examined, and a biobehavioral model of hypertension development is presented. The final chapter of the volume evaluates present evidence concerning the degree to which present-day stress responses predict future cardiovascular pathology; if they do so well, interven­tion and thus preventive medicine may be viable.

A major goal of the volume is to emphasize the interdependence and mutual elucidation of all topics discussed A complete understanding of biobe­havioral interactions, and any possible pathogenic consequences, requires that all useful avenues of inquiry and investigative techniques are combined appro­priately in integrative research strategies. Contained within the volume's chapters are, for example, discussions of recent advances in the conceptualiza­tion of relevant issues, the measurement techniques of cardiovascular psycho­physiology, the experimental paradigms of behavioral medicine (such as inter­personal stressors and tasks suitable for large-scale studies of heterogeneous subject samples), and the analytical techniques of behavioral genetics. Re­search approaches combining several of these advances, among others, seem crucial in an area in which associations and interactions among different influences are so important. In this way, although we do not yet have all the answers, perhaps we may be able to start asking the right questions.

We express sincere thanks to chapter authors for their promptness and their willingness to comply with editorial requests; to series editor Robert Brown and to Eliot Werner at Plenum for advice throughout the project; and to Dot Faulkner for secretarial assistance.

Chapel Hill, Narth Carolina

J. Rick Turner Andrew Sherwood Kathleen C. Light

Contents

Part One. CARDIOVASCULAR REACTIVITY: LABORATORY AND AMBULATORY ASSESSMENT PROCEDURES

Chapter One. A Conceptual and Methodological Overview of Cardiovascular Reactivity Research. . . . . . . . . . . . . . . . . . . . . . . . . . 3

Andrew Sherwood and J. Rick Turner

Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3 The Biological Perspective.................................... 4 Assessment of Reactivity. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7 Individual Differences........................................ 10 Psychosomatic Aspects of Cardiovascular Reactivity. . . . . . . . . . . . . 14 Temporal Stability. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 17 Situational Stability. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 19 Summary and Future Directions. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 25 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 27

Chapter Two. Sympathetic Nervous System Responses to Psychosocial Stressors. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 33

Paul J. Mills and Joel E. Dimsdale

Introduction. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 33 Considerations of Catecholamine Physiology. . . . . . . . . . . . . . . . . . . . 33 Individual Variability in Catecholamine Responses to Stressors . . . 34 New Frontiers. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 38 Summary.... ... .... ................ ....... ....... ....... ... 44 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 45

xiii

xiv CONTENTS

Chapter Three. Individual Differences in Ambulatory Blood Pressure Patterns. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 51

Gregory A HarshjWld and Derrick A PuUiam

Introduction. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 51 What Is a ''Typical'' ABP Pattern? ........ . . . . . . . . . . . . . . . . . . . . 51 Factors Associated with Individual Differences in ABP

Patterns. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 52 Summary and Conclusions. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 58 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 58

Chapter Four. The Ecological Validity of Laboratory Stress Testing.................................................... 63

Lorenz J. P. van Doornen and J. Rick Turner

Introduction. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 63 Lab Reactivity and Self-Monitored Casual Blood Pressure....... 65 Lab Reactivity and Average Ambulatory Levels. . . . . . . . . . . . . . . . . 66 Studies Predicting Both Real-Life Variability and/or Average

Levels................................................... 68 Studies Measuring Ambulatory Blood Pressure Invasively on a

Beat-by-Beat Basis. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 73 Studies Predicting the Response to a Well-Defined Real-Life

Stressor. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 75 Discussion. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 77 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 81

Part Two. DETERMINANTS OF INDIVIDUAL DIFFERENCES IN CARDIOVASCULAR RESPONSES DURING STRESS

Chapter Five. Genes, Stress, and Cardiovascular Reactivity. . . . . . . . 87

Richard J. Rose

Introduction. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 87 Differential Reactivity: G x E Interaction. . . . . . . . . . . . . . . . . . . . . . 89 Selective Transaction: G x E Correlation .. .. .. . .. .. .. .. . .. .. .. 95 Summary. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 100 References................................................. 100

CONTENTS xv

Chapter Six. Personality Characteristics, Reactivity, and Cardiovascular Disease . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 103

B. Kent Houston

Introduction................................................ 103 Personality Characteristics Affecting the Appraisal Process ...... 106 Personality Characteristics Influencing Emotional Arousal ....... 107 Personality Characteristics Influencing Motivational Arousal...... 111 Characteristics Modulating Emotional and Motivational

Arousal .................................................. 113 MultifacetedConstructs ...................................... 114 Issues in Conducting Research on Personality and Reactivity. . . . . 117 References. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 118

Chapter Seven. Toward Understanding Race Difference in Autonomic Reactivity: A Proposed Contextual Model. . . . . . . . . 125

Norman B. Aru.imson, Maya McNeilly, and Hector Myers

Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 125 Black-White Differences in Reactivity.......................... 126 Predictors of Reactivity among Blacks. . . . . . . . . . . . . . . . . . . . . . . . . 128 Summary of Research Findings. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 130 Augmented Reactivity in Blacks: A Contextual Model. . . . . . . . . . . . 130 Testing the Contextual Model: Directions for Research . . . . . . . . . . 139 Summary and Conclusions.................................... 139 References................................................. 140

Chapter Eight. The Role of Reproductive Hormones in Cardiovascular and Neuroendocrine Function during Behavioral Stress........................................... 147

Catherine M. Stoney

Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 147 Sex Differences in Adult Stress Responses . . . . . . . . . . . . . . . . . . . .. 148 Investigations of Individuals through Their Reproductive

Lives.................................................... 150 Investigations of Individuals Receiving Exogenous Hormones. . . . . 157

xvi CONTENTS

Conclusions................................................. 160 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 160

Chapter Nine. The Role of Cardiovascular Reactivity in Hypertension Risk.......................................... 165

WiUiam R. Lovallo and Michael F. Wilson

Introduction............................ .................... 165 Background Issues . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 165 Tasks and Response Types in Studies of Reactivity.............. 166 Rationale for Behavioral Studies of Reactivity in High-Risk

Normotensives. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 169 Parental History of Hypertension............................. 169 Cardiovascular Function in PH + and PH - Persons. . . . . . . . . . . . . 170 Borderline Hypertension. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 174 Longitudinal Studies of Borderline Hypertensives and Other

High-Risk Groups. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 177 Summary................................................... 180 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 181

Chapter Ten. Stress Reactivity in Childhood and Adolescence. . . . .. 187

Bruce S. Alpert and Dawn K Wilson

Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 187 Individual Differences in Genetic Background. . . . . . . . . . . . . . . . . .. 189 Environmental Factors and Reactivity......................... 193 Personality Factors and Reactivity............................ 196 Conclusions. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 198 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 198

Chapter Eleven. Does Aerobic Exercise Reduce Stress Responses? .. 203

Roger B. FiUingim and James A. Blumenthal

Introduction and Objectives .................................. 203 Methodological Issues. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 204 Cross-Sectional Studies of Physical Fitness and Cardiovascular

Reactivity. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 208

CONTENTS xvti

Longitudinal Studies of Physical Fitness and Cardiovascular Reactivity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 210

Effects of Acute Aerobic Exercise on Cardiovascular Reactivity. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 212

Concluding Comments and Future Directions. . . . . . . . . . . . . . . . . .. 213 References................................................. 214

Part Three. CARDIOVASCULAR STRESS RESPONSES AND CARDIOVASCULAR DISEASE

Chapter Twelve. Endogenous Opioids and Stress Reactivity in the Development of Essential Hypertension. . . . . . . . . . . . . . . . . . . . .. 221

James A McCubbin, Robyn Cheung, Thomas B. Montgomery, Ronald Bulbulian, and John F. Wilson

Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 221 Stress Reactivity and the Developmental Etiology of Essential

Hypertension. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 222 Stress Reactivity and the Endogenous Opioid Neuropeptides ..... 224 Experimental Studies of Individual Differences in Inhibitory

Opioid Tone . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 225 Discussion. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 238 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 240

Chapter Thirteen. Differential Responses to Salt Intake-Stress Interactions: Relevance to Hypertension . . . . . . . . . . . . . . . . . . . .. 245

Kathleen C. Light

Introduction. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 245 The Influence of Sodium Excretion and Retention on Blood

Pressure . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 246 Stress Exposure Alters Sodium Excretion in Animal Models. . . . . . 248 Stress Exposure Alters Sodium Excretion in Man. . . . . . . . . . . . . .. 250 Cardiovascular Responses on High- versus Low-Salt Diets. . . . . .. 255 Summary. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 259 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 261

xviii CONTENTS

Chapter Fourteen. A Biobehavioral Model of Hypertension Development. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 265

WiUiam R. Lovallo and Michael F. Wilson

A Model of Hypertension Development . . . . . . . . . . . . . . . . . . . . . . .. 265 Heritability of Resting Blood Pressure and Cardiovascular

Reactivity in Humans. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 274 Relationship between Cardiovascular Reactivity and

Hypertension Risk ........................................ 275 Implications . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 277 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 278

Chapter Fifteen. High Cardiovascular Reactivity to Stress: A Predictor of Later Hypertension Development. . . . . . . . . . . . . . 281

Kathleen C. Light, Andrew Sherwood, and J. Rick Turner

Introduction. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 281 High Pressor Response to the Cold Pressor Test Enhances

Risk of Hypertension. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 282 High Diastolic Pressure Reactivity to Mental Arithmetic

Predicts Early Hypertension ........... . . . . . . . . . . . . . . . . . . .. 283 High Heart Rate and Blood Pressure Reactivity as Predictors of

Resting and Ambulatory Blood Pressure on Follow-Up........ 286 Integration of Findings to Date and Recommendations for Future

Prospective Studies. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 287 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 292

Index .......................................................... 295

PART ONE

CARDIOVASCULAR REACTIVITY Laboratory and Ambulatory Assessment Procedures

CHAPTER ONE

A Conceptual and Methodological Overview of Cardiovascular

Reactivity Research

ANDREW SHERWOOD AND J. RICK TURNER

INTRODUCTION

Cardiovascular reactivity is a psychophysiological construct referring to the magnitude, patterns, and/or mechanisms of cardiovascular responses asso­ciated with exposure to psychological stress. It is a term that is used to refer to the propensity for an individual to exhibit an alteration in cardiovascular activity during exposure to some external, predominantly psychological stim­ulus, which may, or may not, elicit an active behavioral response. Hence, cardiovascular reactivity is assumed to be a behavioral trait. A key objective of this chapter is to review the available evidence relevant to this contention.

The magnitude of adjustment in one or more measures of cardiovascular function has been the attribute of an individual that has received the most attention to date in research investigating cardiovascular reactivity. Histor­ically, in large part owing to their relative ease of measurement, blood pressure and heart rate have been the primary indices of cardiovascular response. Systolic blood pressure and heart rate, and to a lesser extent diastolic blood

ANDREW SHERWOOD AND J. RICK TuRNER • Department of Psychiatry, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599-7175.

3

4 CHAPrERONE

pressure, provide convenient indices of cardiovascular arousal that are amen­able to quantification in terms of their deviations from some reference state. The reference state, or baseline, for the measurement of cardiovascular re­activity is generally one in which the individual is minimally stimulated by external events; in other words, it is a state of rest or relaxation. Thus, for example, an individual who shows an increase in heart rate of 20 bpm from resting baseline, when challenged to perform mental arithmetic computations, would be considered to evidence greater reactivity than an individual who showed an increase of only 5 bpm. Responses to a single psychological chal­lenge, however, may not provide a reliable assessment of the individual's pro­pensity to respond in other situations. AI; we shall discuss in this chapter, the optimal strategy for assessment of reactivity is an important but as yet un­resolved issue.

Individual differences in cardiovascular reactivity are of intrinsic interest to psychophysiologists, but it has been their predictive significance for future health outcomes, in the context of behavioral medicine, that has been the guiding influence in the development of this research field. Perhaps the most precise definition of cardiovascular reactivity has been offered by Manuck, Kasprowicz, and Muldoon (1990) in their review of potential associations be­tween reactivity and hypertension. Their definition emphasizes the unique information pertaining to physiological variability among individuals, gener­ated by exposure to a standardized behavioral stimulus. AI; they point out, resting baseline levels of physiological activity are positively correlated with levels observed during behavioral stimulation, but far from perfectly so: for instance, a resting baseline heart rate will provide a general guide to estimating an individual's heart rate during a Mental Arithmetic task, but this estimate will be far from precise. The individual's change in heart rate during the task is of course the other determinant of task heart rate, and it is this characteristic that reflects the cardiovascular reactivity of the individual. We shall provide an overview and some discussion of cardiovascular reactivity as a psychosomatic construct in relation to hypertensive disease.

THE BIOLOGICAL PERSPECTIVE

Cannon (1915) originally proposed that the sympathetic nervous system serves to mobilize the cardiovascular system in preparation for fight or flight. Research on the defense reaction in animals, stemming from the work of Hess (1949), has provided support for, and generated acceptance of, this notion. Hence, stimulation of the hypothalamic "defense area" in cats can produce flight or attack behavior accompanied by an increase in cardiac output that is distributed to the skeletal muscles. Moreover, at lower levels of brain stimula-

CARDIOVASCULAR REACTMTY RESEARCH 5

tion, only the cardiovascular responses occur, suggesting that these compo­nents subserve anticipated recourse to behavioral activity (Abrahams, Hilton, &. Zbrozyna, 1960, 1964). In humans, evidence from sports physiology is con­sistent with the foregoing viewpoint. Heart rates of athletes awaiting the start­ing signal of competitive track events are not only dramatically elevated above resting levels but are elevated as an inverse function of the distance involved in the race (McArdle, Foglia, & Patti, 1967). For example, heart rates in five athletes averaged 148 bpm immediately prior to a 60-yard dash but only 108 bpm prior to a 2-mile event. Clearly, the rapid onset of vigorous activity is much more crucial in a short-distance event, suggesting that the higher heart rates may have been at least partly attributable to the anticipatory psychological arousal.

A variety of stimuli, which may be generally considered to impose stress of a psychological nature, have been shown to be associated with increased cardiovascular activity. Such stimuli range from contrived laboratory tasks, such as aversive Reaction Time tasks (Obrist, Gaebelein, Teller, Langer, Grig­nolo, Light, & McCubbin, 1978), Mental Arithmetic tasks (Brod, Fencl, Hejl, & Jirka, 1959), and video games (Turner, Carroll, & Courtney, 1983) to inter­personal stressors as presented by interview procedures (Dimsdale, Stern, & Dillon, 1988) or public speaking (Gliner, Bunnell, & Horvath, 1982). The car­diovascular response pattern to such stressors frequently resembles the char­acteristic exercise response (as well as that of the defense reaction), with an increase in cardiac output distributed to the skeletal muscles (Brod et 01, 1959; Williams, Bittker, Buchsbaum, & Wynne, 1975). The apparent similarity be­tween the psychological stress and the exercise response, however, belies the somewhat different mechanisms involved in their mediation. Several studies have provided evidence that the sympathetic nervous system plays the primary role in mediating cardiovascular responses during psychological stress (Dims­dale & Moss, 1980; Langer, McCubbin, Stoney, Hutcheson, Charlton, & Obrist, 1985; Sherwood, Allen, Obrist, & Langer, 1986). Figure 1 illustrates cardiac output and total peripheral vascular resistance changes occurring during an aversive Reaction Time task compared to exercise on a bicycle ergometer in five healthy male adults. On the left-hand side of Figure 1, the similarity between the two responses is clearly evident, with cardiac output increasing and vascu­lar resistance decreasing. Following blockade of cardiac and vascular beta­adrenergic receptors with propranolol (4 mg, intravenously administered), however, as shown on the right-hand side of Figure 1, the characteristic re­sponse to the aversive Reaction Time task is completely abolished while the response to exercise is only marginally attenuated. These effects were inter­preted as reflecting intrinsic autoregulatory mechanisms of the heart and vas­culature maintaining blood flow needed to subserve the metabolic demands of active skeletal muscles during exercise; in contrast, during the aversive stres­sor, a similar hemodynamic response pattern was not secondary to metabolic

6 CHAP1'ER ONE

activity but was maintained by extrinsic sympathetic nervous system influences (Sherwood et al, 1986).

The available evidence, then, suggests that the sympathetically mediated exerciselike response patterns evident during exposure to some psychological stressors are anticipatory cardiovascular adjustments. Only a few psychophys­iological studies have attempted to evaluate the hypothesis that psychological determinants of cardiovascular arousal subserve motoric preparation, and these have generally yielded equivocal results (Greene, Lorys, & Webb, 1985; Sherwood, Allen, Murrell, & Obrist, 1988; Stem, 1976). Nonetheless, the biolog­ical argument is compelling, and it has been widely accepted that cardiovascular mobilization during psychological stress represents a psychophysiological reft.ex that evolved as an adaptive anticipatory response. For a more compre­hensive appreciation of the biological basis of human cardiovascular responses during psychological stress, readers are referred to articles by proponents of

50 CJ Intact _ Beta blockade

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FIGURE 1. Mean cardiac output and vascular resistance responses in five healthy male subjects during an aversive Reaction Time task (stress) and during bicycle exercise. Responses are shown with sympathetic innervations intact and following beta-adrenergic receptor blockade by intra­venous propranolol (4 mg). Data based on a study reported by Sherwood et al. (1986).

CARDIOVASCULAR REACTIVITY RESEARCH 7

the defense reaction as a useful explanatory model (Folkow, 1985; Henry, Stephens, & Ely, 1986).

ASSESSMENT OF REACTIVITY

PHYSIOLOGICAL MEASURES

Arterial blood pressure and heart rate have been the most widely reported measures of cardiovascular reactivity. Both measures can be recorded by non­invasive techniques. Systolic and diastolic blood pressure are typically mea­sured at the brachial artery, using an occlusion cuff to permit oscillometric determinations, or in conjunction with a stethoscope or microphone for the detection of Korotkoff sounds used in the auscultatory method (Geddes, 1970). Automated instruments adopting these techniques to derive systolic, mean, and diastolic pressures are commercially available for clinical and research applica­tions. More recent technological advances, which have allowed these instru­ments to be reduced in size, have led to the production of ambulatory blood pressure monitors, allowing subjects to go about their daily activities while periodic measurements are taken automatically. Heart rate recordings are usually derived from interheartbeat interval information available from record­ing the electrocardiogram (ECG) via electrodes adhered to the chest or limbs. Automated blood pressure monitors usually include measurement of heart rate, either from ECG signals or arterial pulse detection, during blood pressure measurement sequences.

Although some of the earliest reports of cardiovascular responses during stress included measurements of cardiac output, they did so using invasive procedures (Brod et al, 1959). Such procedures, however, are considered high­ly stressful in and of themselves, so much so that they served as the ex­perimental stressor in what were perhaps the first reports of cardiovascular reactivity (Hickman, Cargill, & Golden, 1948; Stead, Warren, Merrill, & Bran­non, 1945). It is obviously critical that measurement procedures in this field of research should be minimally stressful and preferably relatively unobtrusive so that normal behavior is unrestricted. In view of these concerns and the lack of availability of reliable noninvasive cardiac output measurement techniques, in addition to ethical issues surrounding the use of risky procedures in healthy subjects, studies reporting hemodynamic responses during psychological stress in humans were virtually nonexistent in the early stages of modern reactivity research. This situation changed when the technique of impedance cardiog­raphy was developed for noninvasive cardiac output measurement in the late 1960s (Kubicek, Karnegis, Patterson, Witsoe, & Mattson, 1966; Kubicek, Witsoe, Patterson, & From, 1969). Impedance cardiography offered a risk-free, continuous, and unobtrusive means of estimating cardiac output, requiring only the application of four disposable band-electrodes placed around the neck and

8 CHAPl'ER ONE

chest. Validation studies comparing impedance measures with accepted in­vasive standards have generated increasing empirical support for its use as a measure of cardiac output (Mohapatra, 1981). A landmark review of the tech­nique was published in the psychophysiological literature in 1978, summarizing that relative changes in cardiac output were of acceptable validity using impe­dance cardiography, though measures of absolute levels were not as valid (Miller & Horvath, 1978). Since that time, impedance cardiography has become increasingly used in cardiovascular reactivity research, recently prompting recommendations for methodological standardization iIi order to allow compa­rison of research findings (Sherwood, Allen, Fahrenberg, Kelsey, Lovallo, & van Doornen, 1990a).

In addition to cardiac output and stroke volume measurement, impedance cardiography permits assessment of several indices of myocardial contractility, including the systolic time intervals, preejection period, and left-ventricular ejection time. The cardiac preejection period is considered to provide a useful index of sympathetic nervous system influences on the myocardium and is thereby a valuable measure for reactivity research (Newlin & Levenson, 1979). Of equal-if not greater-importance, the measurement of cardiac output in conjunction with blood pressure recording permits an assessment of the hemo­dynamic basis of stress-related pressor responses. This is possible because mean arterial blood pressure (MAP) represents the product of cardiac output (CO) and the total peripheral resistance (TPR) of the systemic vasculature. Thus, simultaneous measurement of two of these three parameters (i.e., MAP and CO) permits derivation of the third (TPR). The hemodynamics of blood pressure elevations in the various stages of hypertension are well documented. In contrast, the hemodynamics of cardiovascular reactivity are just beginning to be understood. The hemodynamics of blood pressure responses vary mark­edly across individuals, as will be illustrated in the next section of this chapter. As will also become apparent in this and other chapters, hemodynamic response patterns that are characteristic of specific stressors, as well as of certain individuals, show promise of clarifying the possible link between cardiovascular reactivity and hypertension development.

STRESSORS

The most frequently applied strategy for the assessment of cardiovascular reactivity is through the administration of one or more stressors. The typical test environment is a quiet room in which the subject is instrumented for physiological measurement, with monitoring equipment and research person­nel usually in an adjacent room. Prior to stress testing, resting baseline in­formation is usually recorded. The so-called resting baseline levels, reported in most reactivity studies, do not meet stringent criteria such as those required in studies of basal metabolic rate. Since baseline levels following various rest periods are reported in reactivity research and since extraneous influences­such as previous substance ingestion, preceding activity level, and time of

CARDIOVASCULAR REACTIVITY RESEARCH 9

day-are also often variable, resting baseline cardiovascular measures are more appropriately considered as control levels, relatively low in stress. Most studies have used cardiovascular measures recorded following an initial period of relaxation, usually at least 10 minutes, but longer periods are preferable, especially if invasive procedures, such as venipuncture for blood sampling, are involved. Accepting the importance of baseline measures, some researchers have attempted to be more stringent in their baseline measurement proced­ures. For example, Obrist (1981) has evaluated various alternative means of baseline assessment, including the use of multiple session testing, with a special nonstress baseline measurement session scheduled for a separate day. For both practical reasons as well as a desire to achieve baseline and stress measures without possible influences from variations in the placement of physiological recording devices, however, most researchers use prestress task rest periods. A 30-minute pretask, postinstrumentation rest period appears to be an accept­able and replicable strategy (Schneiderman & McCabe, 1989).

A wide variety of tasks, each construed as consisting of some element of psychological stress, has been reported in cardiovascular reactivity research. Usually, tasks are chosen to elicit responses mediated by the sympathetic nervous system and resembling the defense reaction. Obrlst (1976) coined the now widely used term "active coping" to describe the behavioral challenges that tend to elicit such responses in humans. Such tasks typically demand active engagement of some behavioral skill and involve either a specified or implied objective for successful performance on the task. In his own research, aversive Reaction Time tasks involving threat of shock were extensively employed to study the active coping response (Obrlst, 1981). Various other tasks, including appetitive Reaction Time tasks (Light & Obrist, 1983), Mental Arithmetic (Brod et al., 1959), video games (Turner et al., 1983), Stroop color-word tests (Manuck & Proietti, 1982), and Raven's Matrices (Steptoe, Melville, & Ross, 1983), generally produce somewhat similar responses. Such tasks appear to evoke sympathetic nervous system responses that lead to stimulation of cardiac and vascular beta-adrenergic receptors. In contrast, other tasks that may typically involve more passive coping, passive sensory intake, or vigilance are more often associated with sympathetic activation leading to pressor responses mediated by the vasoconstrictive action of alpha-adrenergic receptor stimula­tion. The Cold Pressor test, involving application of iced water to some body part, usually the hand or foot, is the most widely studied stressor in this general category (Peckerman, Saab, McCabe, Skyler, Winters, Llabre, & Schneider­man, 1991). Interestingly, the relative contribution of alpha- and beta-adrener­gic mechanisms of stress-related effects on the cardiovascular system has itself become a widely used criterion for identifying and describing types of behav­ioral stressors. Perhaps due partly to a lack of clarity in the definition of the stressful nature of various tasks, many reactivity studies have omitted any clear rationale pertaining to the choice of specific stressors. There have been marked exceptions, however, generating a trend that is becoming more the rule as the psychophysiological attributes of various tasks become better defined. Thus, for

10 CHAPI'ER ONE

example, hostile individuals evidence greater reactivity when tasks include some degree of harassment (Suarez & Williams, 1990); borderline hyperten­sives tend to show sympathetic hyperresponsivity during active, but not pas­sive, coping tasks (Drummond, 19~); and racial differences in cardiovascular responses may be related to the adrenergic receptor types engaged during exposure to a given task (Anderson, Lane, Muranaka, Williams, & Houseworth, 1988).

Laboratory reactivity testing, by its nature, focuses on acute cardiovas­cular responses occurring during relatively brief exposure (typically from 3 to 15 minutes) to one or more contrived stressors. The advantage of using lab­oratory-based task-response assessment is the high degree of experimental control conveyed. Also, the laboratory environment allows for more extensive instrumentation of the subject and thereby more detailed assessment of the cardiovascular response. There is some concern, however, as to the ecological validity of cardiovascular reactivity assessment in the laboratory; in other words, are an individual's laboratory task responses representative of respon­ses to stressors encountered in rea1life? This question will be briefly addressed later in this chapter and then in detail in Chapter 4. While the relationship between lab and life responses is still being evaluated, there is a compelling case for adopting more naturalistic stressors in the laboratory. Dimsdale and colleagues (1988) have proposed a Stress Interview as a tool for assessing reactivity. In a similar vein, Ewart and Kolodner (1991) have reported en­couraging initial results from a Social Competence Interview designed to prov­ide a structured framework for subjects to recall and cognitively reexperience their recurring life problems. Simulated public speaking tasks are also emerg­ing as potent laboratory stressors (Girdler, Turner, Sherwood, & Light, 1990; Saab, Matthews, Stoney, & McDonald, 1989). More ambitiously, there have also been attempts to evaluate cardiovascular responses during marital and family interactions (Matthews, Woodall, & Lassner, 1990; Smith & Brown, 1991).

Despite the theoretical importance of establishing the external validity of laboratory reactivity testing, however, its value as a psychosomatic construct will be determined in large part empirically by long-term follow-up studies investigating health outcomes. The laboratory-based part of these studies will need to be carefully designed. AB we shall argue later in this chapter, reactivity testing by a battery of diverse stressors may be the optimum strategy for understanding the nature and pathological significance of cardiovascular re­activity.

INDIVIDUAL DIFFERENCES

MAGNITUDE OF BLOOD PRESSURE AND HEART RATE RESPONSES

One of the most striking characteristics of cardiovascular reactivity is the magnitude of individual differences observed in response to laboratory stres-

CARDIOVASCULAR REACTIVITY RESEARCH 11

sors. The phenomenon is illustrated by the data presented in Table 1, based on a study of 20 healthy young (18 to 25 years) adult male college students (Sherwood, Davis, Dolan, & Light, 1992). The values presented for blood pres­sure and heart rate responses represent average task levels minus resting baseline levels. In addition to the mean response for the group, the minimum and maximum responses observed demonstrate the variation or range of in­dividual differences in magnitude of responses observed among this relatively small sample. The five tasks are representative of the kinds of stressors used in laboratory reactivity testing. The Mental Arithmetic task required subjects to solve simple subtraction problems presented on a computer video display, with task difficulty kept constant across subjects by automatic adjustment of problem difficulty according to performance. The Reaction Time task required subjects to simply press a key as quickly as possible whenever they heard a loud tone, ostensibly in order to avoid the possibility of mild electric shock to the leg.

TABLE 1. Mean, Minimum, and Maximum Systolic Blood Pressure (SBP), Diastolic Blood Pressure (DBP), and Heart Rate (HR) Responses to a Series of Laboratory Stressors in 20 Healthy Young Male Adults (Adapted from Sherwood, Davis,

Dolan, & Light, 1992)

Task Mean Minimum Maximum

Mental Arithmetic SBP (mm Hg) 20 5 42 DBP(mmHg) 8 -1 28 HR (bpm) 22 5 47

Reaction Time SBP(mm Hg) 20 -1 41 DBP(mmHg) 3 -9 12 HR (bpm) 19 0 48

Speech Stressor SBP(mm Hg) 32 10 60 DBP(mmHg) 21 6 35 HR(bpm) 25 6 44

Mirror Trace SBP (mm Hg) 11 -5 31 DBP(mmHg) 8 -9 33 HR (bpm) 5 -9 18

Forehead Cold Pressor SBP (mm Hg) 20 5 34 DBP (mm Hg) 20 8 47 HR (bpm) -2 -15 16

12 CHAPl'ER ONE

The Speech Stressor task involved oral presentation of an article that subjects had previously read while three judges would view and evaluate their perfor­mance on a video monitor. The Mirror Trace task required subjects to simply trace, at their own speed, using a computer mouse, a shape displayed on a computer monitor, with a line generated on the screen representing the mirror image of mouse movements. Finally, the Cold Pressor task required subjects to passively tolerate an ice pack held against their forehead. These tasks, all of which lasted 3 minutes and were interspersed with recovery periods, are de­scribed in more detail by Sherwood, Davis, Dolan, and Light (1992). Again, it is striking that the blood pressure and heart rate responses to these stand­ardized laboratory stressors varied markedly across the individuals tested, even though they represented a highly homogeneous population sample.

HEMODYNAMIC RESPONSE PATl'ERNS

It is also evident from the data presented in Table 1 that there was some variation in the relative magnitude of blood pressure and heart rate responses typically associated with these tasks. For example, the Reaction Time task tended to evoke primarily systolic pressure and heart rate increases, with relatively little effect on diastolic pressure. In contrast, the Cold Pressor task evoked relatively large increases in diastolic pressure while heart rate changed minimally. AP. described earlier, these two tasks are not only in sharp contrast according to the active versus passive coping dimension but also in the sympa­thetic mechanisms mediating the responses. The Reaction Time task invokes primarily stimulation of beta-adrenergic receptors while the Cold Pressor task invokes primarily alpha-adrenergic receptors. Thus, based upon impedance cardiographic cardiac output response measures, the Reaction Time task was associated with an average increase in cardiac output of 38% and a decrease in total peripheral vascular resistance of 17%. AP. shown earlier (see Figure 1), this hemodynamic response pattern is a result of increased myocardial contractility via 131 receptor stimulation and decreased arterial resistance via ~ stimulation. In sharp contrast, cardiac output decreased an average of 8% during the Cold Pressor task while total peripheral resistance increased 37%. Though the re­sponse to the Cold Pressor task is thought to invoke central pain modulation mechanisms, the peripheral cardiovascular effects are primarily attrIbutable to the stimulation of vascular alpha-adrenergic receptors leading to a pressor response caused by vasoconstriction (peckerman et al, 1991). AP. can be seen from Table 1, the responses to the other tasks fall somewhere between the extremes represented by the Reaction Time and Cold Pressor tasks and prob­ably involve a combination of alpha and beta response mechanisms. Supporting this view, the relative contributions of norepinephrine (predominantly an alpha and 131 selective agonist) released from sympathetic nerves, circulating epi­nephrine (an alpha and beta nonselective agonist) and norepinephrine released from the adrenal medulla have been shown to vary across different kinds of

CARDIOVASCULAR REACTMTY RESEARCH 13

stressors (Dimsdale & Moss, 1980; Goldstein, Eisenhofer, Sax, Keiser, & Kopin, 1987; Ward, Mefford, Parker, Chesney, Taylor, Keegan, & Barchas, 1983; see also Chapter 2).

Though specific stressors can be characterized as tending to elicit certain hemodynamic response patterns, the individual differences in such responses for a given stressor can vary dramatically. Consequently, apparently similar cardiovascular responses to a stressor in terms of blood pressure can be asso­ciated with very different underlying hemodynamic mechanisms. For example, Figure 2 illustrates the similar blood pressure responses observed during a Mental Arithmetic task for two subjects, A and B, who were tested in our laboratory. Upon examining the cardiac output and vascular resistance respon­ses, also shown in Figure 2, it becomes clear, however, that these two subjects showed very different cardiovascular responses to the task. Subject A dis­played a response similar to the fight or flight response described earlier, with

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14 CHAPrERONE

cardiac output increasing and vascular resistance decreasing. This response was probably mediated predominantly via beta-adrenergic receptors. In con­trast, to the same Mental Arithmetic task, subject B showed an increase in vascular resistance and essentially no change in cardiac output. Presumably, alpha-adrenergic receptor activity was more involved in subject B's response. AB we shall see, such hemodynamic response patterns may be consistent char­acteristics of individuals.

PSYCHOSOMATIC ASPECTS OF CARDIOVASCULAR REACTIVITY

There has been much interest in the role of psychological factors in the etiology of cardiovascular disease. This has been especially so for hypertension, which develops slowly and rarely becomes manifest before the fourth decade of life. Thus, theoretically, there is ample opportunity for potentially deleterious effects of life stressors to take their toll in cardiovascular pathology. Psychoso­matic hypotheses of cardiovascular disease generally propose that the phys­iological concomitants of coping with life stressors may produce progressive alterations in cardiovascular physiology. Consequently, cardiovascular reac­tivity research, with its detailed focus on individual differences in acute phys­iological responses associated with stress, has become a field with major em­phasis on elucidating potential pathophysiological mechanisms within a psychosomatic disease model. Some postulated mechanisms are briefly con­sidered below.

PATHOPHYSIOLOGICAL MECHANISMS

The extent to which individuals vary in magnitude of blood pressure and heart rate responses during exposure to laboratory stressors was described earlier. Not surprisingly, large magnitude responses have been considered more likely to represent a risk factor for cardiovascular disease than small magnitude responses. Hence, in population samples exposed to stress tests, there have been numerous reports identifying "high versus low" and "hot versus cold" reactors in terms of the magnitude of blood pressure or heart rate responses relative to the test sample as a whole. The reasoning behind risk implication is that highly reactive individuals may be prone to frequently ex­hibit their characteristic large increases in blood pressure during everyday life. There is clear evidence that structural adaptations of the heart and vasculature associated with hypertension are secondary to increased arterial pressure lev­els (Folkow, 1982). Vascular hypertrophy is thought to be a self-reinforcing adaptation that regulates blood flow in the face of elevated pressure by in­creasing vascular resistance, but in doing so it contributes to further the pres­sure elevation. This slow but escalating process is known as the structural autoregulation theory of hypertension. Analogous to the skeletal muscle growth

CARDIOVASCULAR REACTMTY RESEARCH 15

induced by the repeated but intennittent stimulation of weight training, it is postulated that similarly repeated episodes of stress-induced pressor responses may be sufficient to trigger vascular smooth muscle growth and thus directly bear upon the structural autoregulatory process.

One concern with the focus of cardiovascular reactivity as a disease risk characteristic defined only in terms of blood pressure response magnitude is that exercise also increases blood pressure but is generally considered to be beneficial to cardiovascular health. So, more recent research concerned with pathophysiology has focused on the differences between exercise and psycho­logical stress responses. One obvious difference between the stress and ex­ercise response is that exercise blood pressure and flow increases subserve the increased metabolic demands of active skeletal muscles whereas muscle activity and metabolic requirements are minimal during typical psychological chal­lenge. The metabolically excessive nature of heart rate adjustments during stress was first noted in studies of pilots engaged in difficult training maneuvers (Blix, Stromme, & Ursin, 1974). Laboratory tasks such as video games have also been found to elicit metabolically excessive heart rate increase (Turner & Carroll, 1985; Turner, Carroll, Hanson, & Sims, 1988). Such heart rate respon­ses suggested that cardiac output may also be in excess of metabolic demands during psychological stress. This assumption was confirmed in a study that measured cardiac output and oxygen consumption during a shock avoidance task (Sherwood et 01., 1986). Additionally, the latter study also demonstrated that a foot Cold Pressor task, which was also characterized by metabolically excessive heart rate, was associated with metabolically normal levels of cardiac output (i.e., cardiac stroke volume decreased), indicating that only certain stressor characteristics may tend to elicit excessive blood flow increases. The importance of these findings is that they indicate that psychological stressors may generate physiological conditions prerequisite to transitory increases in vascular resistance via the mechanism of metabolic autoregulation (Guyton, Coleman, & Granger, 1972). Evidence from both animal studies (Forsyth, 1971) and in humans (Carroll, Cross, & Harris, 1991; Miller & Ditto, 1988) supports the view that the maintenance of blood pressure increases during stress may show a transition from myocardial to vascular control mechanisms over time. In human hypertension, there is evidence that its long-term progression may involve an early phase of blood pressure elevation due primarily to increased cardiac output, but progressively the pattern becomes reversed so that in established hypertension vascular resistance is elevated and cardiac output is normal or even low (Julius, Pascual, Sannerstedt, & Mitchell, 1971; Julius, Weber, & Egan, 1983). The evidence that acute psychological stress may en­gender a similar pattern of hemodynamic transition, albeit transient and re­versible, is a provocative finding in the search for pathophysiological mecha­nisms. The potential contribution of such metabolic autoregulation to the onset and progression of hypertension has been discussed (Coleman, Granger, & Guyton, 1971), but the connection between short-term metabolic autoregulation

16 CHAPl'ER ONE

and long-term structural autoregulation appears far less clear than their superficial resemblance.

Another attribute of psychological stress is the predominant role of sympa­thetic nervous system activation in cardiovascular response mediation, as was illustrated in Figure 1. Hence, stimulation of cardiac ~1 and vascular 13! adrenergic receptors tends to give rise to the characteristic fight or flight cardiovascular response. Besides sympathetic outflow, the sensitivity of the adrenergic receptors in target organs will determine the cardiovascular re­sponse pattern and magnitude. In the progression of hypertension, beta-adre­nergic receptors have been found to become progressively down-regulated, or desensitized (Bertel, Buhler, Kiowski, & Lutold, 1980). Such down regulation occurs as an adaptation to overstimulation by chronically elevated sympathetic tone (Trimarco, Volpe, Ricciardelli, Picotti, Galva, Petracca, & Condorelli, 1983). Therefore, in the presence of continued stimulation, ~1 receptor down regulation should progressively reduce cardiac output while ~2 receptor down regulation will lead to a progressive increase in vascular resistance. These effects are consistent with the hemodynamic transition seen in the progression of hypertension. In principle, it is possible that repeated sympathetic activation by psychological stress might produce similar receptor changes in the long term. We have recently initiated a research project to address this question.

With regard to the autoregulation and beta-receptor down regulation mechanisms, both would suggest that the beta-adrenergically mediated fight or flight pattern would be the more deleterious psychological stress response. There is evidence that black individuals may be predisposed to exhibit a greater alpha-adrenergic component in their stress responses, however (Anderson et al., 1988; Light & Sherwood, 1989; see also Chapter 7). Since hypertension is approximately twice as prevalent in the black population of the United States as in the white population, it is interesting to speculate that this response pattern to psychological stress may be of pathophysiological significance. If so, it would suggest that the fight or flight cardiovascular mobilization may be less damaging than blood pressure elevations produced primarily by vascular con­striction. Ultimately, longitudinal studies will provide the empirical basis for definitively assessing the issue of pathophysiological mechanisms. Meanwhile, it may not seem surprising if all of these mechanisms play some role in the multifactorial etiology of hypertension.

PSYCHOSOMATIC CONCEPTS

The notion that a physiological response pattern evoked during stress may be a stable characteristic of an individual has historical grounding in psychoso­matic models of disease. Individual response specificity is a descriptive term proposed by Engel and colleagues in relation to this idea and is contrasted with stimulus-response specificity (situational stereotypy), which refers to the ten­dency of a given stimulus to evoke a particular physiological response pattern

CARDIOVASCULAR REACTMTY RESEARCH 17

(Engel & Moos, 1967; Garwood, Engel, & Capriotti, 1982; Roessler & Engel, 1974). Exploring these concepts in cardiovascular reactivity research is crucial to our understanding of the potential role of reactivity in the etiology of car­diovascular disorders. AP. illustrated earlier, individuals exhibit striking differ­ences in their cardiovascular responses during exposure to the same stressors. These differences exist in terms of both the magnitude of blood pressure changes and the hemodynamic mechanisms underlying them. If certain re­sponse patterns are to be implicated in the development of slowly progressing cardiovascular disease, they should be expected to conform to the character­istics of an individual trait; in other words, individuals should show a propensity to exhibit a characteristic cardiovascular response pattern during exposure to various stressors encountered in everyday life. Manuck and colleagues have used the term idiosyncratic reactions to capture this concept in relation to cardiovascular reactivity (Manuck, Kasprowicz, Monroe, Larkin, & Kaplan, 1989). It is also evident, however, that specific stressors are associated with differential patterns of sympathetic activation and thereby with the elicitation of their own hemodynamic response characteristics. The question therefore arises as to what extent characteristic individual responses are modulated by the specific nature of stressors. This question will be addressed later in the section on situational stability, which reviews evidence of intertask consistency of individual responses to laboratory stressors as well as the generalization of these responses to real-life situations. Before considering that research, how­ever, evidence pertaining to another equally important dimension of reactivity as an idiosyncratic reaction, namely the temporal stability of cardiovascular responses, will be reviewed.

TEMPORAL STABILITY

If cardiovascular reactivity is to be viewed as a behavioral trait, individuals should show temporal stability of their characteristic responses, especially in association with repeated exposure to the same stressor. A number of in­vestigators have documented temporal stability of blood pressure and heart rate responses to behavioral challenges administered in a laboratory setting. Measures of temporal stability have been reported most frequently as simple correlation coefficients, depicting the degree of correspondence of reactivity assessed at an initial test session with that at a subsequent test session.

Manuck and colleagues investigated the temporal stability of reactivity during a concept formation task, with initial testing followed by a I-week and subsequently a IS-month retest session (Manuck & Garland, 1980; Manuck & Schaefer, 1978). For heart rate (HR) and systolic blood pressure (SBP) re­activity they found impressive stability over both the I-week (HR r = 0.69; SBP r = 0.68) and IS-month (HR r = 0.81; SBP r = 0.63) intervals. Diastolic blood

18 CHAPl'ER ONE

pressure reactivity, however, showed relatively poor stability over the same intervals (1 week, r = 0.46; 13 months, r = 0.24). Strikingly similar results to these initial reports have been found by other investigators using different laboratory tasks. For example, a highly significant correlation (r = 0.74) was found for heart rate reactivity associated with performance on a "space in­vaders" video game tested over a 20-month interval (Turner, Carroll, Sims, Hewitt, & Kelly, 1986). During an aversive Reaction Time task, heart rate and systolic pressure reactivity evidenced temporal stability over a 2.5-year interval (Allen, Sherwood, Obrist, Crowell, & Grange, 1987). Again, though, in the latter study, diastolic pressure reactivity did not exhibit test-retest reliability. Nu­merous other investigators have reported essentially similar findings for a variety of behavioral stressors (Lovallo, Pincomb, & Wllson, 1986; Matthews, Rakaczky, Stoney, & Manuck, 1987; van Egeren & Sparrow, 1989). Several factors may account for the evidence of lack of temporal stability of diastolic pressure responses. Speculatively, these may include the dependence upon complex cardiac and vascular interactions in determining diastolic pressure responses; the relatively smaller changes in diastolic pressure reported for many behavioral challenges; and the comparative difficulty in measurement of diastolic pressure compared to heart rate and systolic pressure measurement.

In contrast to the large number of studies that have examined temporal stability of blood pressure and heart rate responses, there are relatively few reports regarding hemodynamic response patterns. Two early reports found cardiac output responses to show good test-retest reliability. In one, which involved a I-week interval between tests in male college students, stability coefficients that were computed for cardiac output responses were significant for a Reaction Time task, a number-sequencing cognitive test, and a Cold Pressor test (Myrtek, 1985). Similar findings, reported in terms of correlation coefficients, were observed over a 3-month test-retest interval, in older 'men, for Reaction Time (r = 0.43) and video game (r = 0.58) tasks (McKinney, Miner, Ruddel, McIlvain, Witte, Buell, Eliot, & Grant, 1985). Since heart rate re­activity has been found to evidence impressive temporal stability and heart rate is a key determinant of cardiac output, it may not be surprising that cardiac output reactivity has been found to show good temporal stability. In both the study by Myrtek (1985) and by McKinneyet al (1985), however, stroke volume responses were also found to exhibit significant, though somewhat lower, test­retest stability.

At least one study has generated contrasting results compared to the former two. Fahrenberg and colleagues reported nonsignificant test-retest correlations for cardiac output responses to Mental Arithmetic and Cold Pres­sor tests administered to young adult males on four occasions: at initial testing and subsequently following 3 weeks, 3 months, and 1 year (Fahrenberg, Schnei­der, Foerester, Myrtek, & Muller, 1985). There is no obvious explanation for

CARDIOVASCULAR REACTIVITY RESEARCH 19

the latter finding, though methodological aspects of testing, including potential habituation to the tasks and measurement reliability, may have been contribut­ing variables.

With growing interest in the pathogenic significance of individual differ­ences in the hemodynamics of cardiovascular reactivity, two more recent stud­ies have evaluated the stability of cardiac and vascular contributions to pressor responses. One study involved 13 middle-aged Type A males who were tested twice on a competitive Reaction Time task over a 3-month interval (Sherwood, Turner, Light, & Blumenthal, 1990c). Test-retest correlations were significant for systolic pressure (r = 0.67), heart rate (r = 0.91), cardiac output (r = 0.81), stroke volume (r = 0.87), preejection period (r = 0.82), and total peripheral resistance (r = 0.68) but not for diastolic pressure (r = 0.31). The second study reported data from 39 college students tested over a 4-week interval on Mental Arithmetic and Mirror Trace tasks (Kasprowicz, Manuck, Malkoff, & Krantz, 1990). Generally, test-retest correlations were significant, though sometimes only marginally so, for blood pressure, cardiac, and vascular responses to the tasks. Interestingly, the more highly significant correlations reported by Sher­wood et al. (199Oc) were associated with lesser habituation of mean task re­sponses than in the latter study, supporting the possibility that response habit­uation may partly account for discrepant findings of studies investigating temporal stability. In a further post-hoc analysis of their data, Kasprowicz et al. (1990) identified well-differentiated subgroups of cardiac and vascular reactors. Individuals so identified showed impressive temporal stability of the hemody­namic adjustments underlying their pressor responses to the tasks. Collec­tively, these findings suggest that hemodynamic patterning may be more stable than blood pressure change.

SITUATIONAL STABILITY

The previous section described the cumulative evidence of the consistency across time of individual differences in cardiovascular stress responses. Atten­tion now turns to an examination of the evidence of consistency across different situations. Situational stability can be divided, both conceptually and descrip­tively, into two sections. The first, referred to as intertask consistency, concerns consistency of response between different stressors encountered typically in a single experimental session; psychophysiological studies are increasingly using multiple stressors, a development strongly endorsed by several prominent authors (Manuck et al., 1990; Pickering & Gerin, 1990). The second aspect of situational stability concerns the relationship between laboratory stress re­sponses and responses to real-world situations met during daily life. The term

20 CHAPTER ONE

laboratory-field generalization, or lab-life generalization, is often used in this context. Each of these aspects of situational stability will be considered in turn.

LABORATORY INTERTASK CONSISTENCY

Both the temporal stability and intertask consistency of stress responses can be regarded as meaningful individual difference dimensions (Manuck et al, 1990). While both dimensions are of interest in themselves, they assume added importance in theories of disease development because such consistency is a prerequisite if stress responses are to be implicated in the disease process. If exaggerated cardiovascular responses are indeed of etiological significance, it is reasonable to argue that a given individual should react in the same way to the same challenge met at different times and should react similarly to various different challenges.

Early evidence was reported by Manuck and Garland (1980), who found that heart rate and blood pressure changes during a concept formation task cOlTelated significantly with those seen during a serial subtraction Mental Arithmetic task. This finding was replicated by Manuck and Proietti (1982). Similarly, Light (1981) reported that heart rate and blood pressure during two different versions of a Reaction Time task (shock avoidance [aversive] and direct head-to-head competitive) were highly cOlTelated.

In a series of experiments conducted by Turner and by CalToll, the in­tertask consistency of heart rate responses to various stressors was explored (Turner, 1988). The majority of studies employed a video game in conjunction with either a Mental Arithmetic or a Reaction Time task. For example, in one study, 102 subjects completed the video game task and a Mental Arithmetic task; an intertask cOlTelation coefficient ofOAO (P<.OO1) was obtained. It may be noted here that while this coefficient was highly significant, its magnitude was somewhat less than values typically seen in examinations of temporal stability for either task and somewhat less than the values reported by Light (1981) and by Manuck and colleagues (1980, 1982) in their investigations of intertask consistency. As noted by Turner (1988), however, the combination of a video game task and a Mental Arithmetic task was different from the com­binations used by Light and by Manuck and colleagues; whereas they employed two cognitive tasks, the Mental Arithmeticlvideo game pairing comprises a cognitive task and a psychomotor task. Interestingly, when intertask con­sistency was assessed during two cognitive tasks, Mental Arithmetic and Raven's Matrices (Carroll et al, 1986), markedly greater consistency was found. Thus, evidence for intertask consistency of heart rate response was provided. It appeared that situational (i.e., task-specific) influences, however, may have been superimposed upon a predisposition to react in general to a greater or lesser extent during behavioral challenge; perhaps it is not un­reasonable to expect that individuals might be more readily engaged by some

CARDIOVASCULAR REACTIVITY RESEARCH 21

challenges than by others (Turner, 1989). This sentiment's implication for reactivity research is discussed later in this chapter.

In a more recent study (Turner, Girdler, Sherwood, & Light, 1990), 32 subjects completed four laboratory challenges, comprising two Speech tasks and two Mental Arithmetic tasks. Intertask consistency of reactivity scores was evaluated across all task pairings for systolic blood pressure, diastolic blood pressure, and heart rate. Significance was attained by all coefficients for all three parameters; coefficients ranged in magnitude from 0.38 to 0.85. It should be noted that the coefficients for diastolic blood pressure were smaller in magnitude than those for systolic blood pressure and heart rate. In the previous section addressing temporal stability, the lack of evidence for diastolic blood pressure stability was discussed. It is interesting to note that although statis­tical significance was obtained by evaluations of diastolic intertask consistency in this study, the evidence was less powerful than that for systolic blood pres­sure and heart rate, possibly for the same reasons suggested in the previous section.

Overall then, considerable evidence of intertask consistency has been documented for blood pressure and heart rate. Recently, as for temporal sta­bility, investigation of this dimension of reliability of response has focused on the underlying hemodynamic determinants of blood pressure. Three recent reports have examined the consistency shown by cardiac output and total peripheral resistance responses. Sherwood, Dolan, and Light (1990b) examined hemodynamic responses to active and passive coping stressors in a sample of 90 healthy male college students. They found that Reaction Time tasks, de­manding active coping responses, tended to raise blood pressure due primarily to augmented cardiac output while vascular resistance fell. During passive coping situations, which included passive participation with a partner in a Reaction Time task and exposure to an emotionally arousing film, cardiac output also tended to increase, but so too did vascular resistance, leading to a rise in blood pressure by their synergistic effects. Despite the variation in hemodynamic patterns associated with the different kinds of stressors, inter­task correlations of blood pressure, cardiac output, and vascular resistance responses during the active and passive coping stressors were significant (P<.OI) in 39 of 40 comparisons made. The consistency of hemodynamic re­sponse patterning suggested by these correlations was further explored by post-hoc classification of 30 high-myocardial reactors (pressor responses due to increased cardiac output) and 31 high-vascular reactors (pressor responses associated with vascular resistance increase), based upon their responses dur­ing a separate task. The contrasting hemodynamic response patterns exhibited by the two groups were preserved across the active and passive coping stres­sors, suggesting that the hemodynamic basis of reactivity is an individual characteristic only partially modified by coping demands of a situation. Second, Kasprowicz et a1 (1990), as noted in the previous section on temporal stability, examined the responses of 39 subjects to Mental Arithmetic and a mirror

22 CHAPl'ER ONE

tracing task on two occasions 4 weeks apart. Of present interest are their findings for intertask consistency. Significant, though modest, associations were found for blood pressure responses on both occasions of testing. For cardiac output and total peripheral resistance, however, significance was only obtained during the second testing session; no explanation for this intersession discrepancy is readily apparent. Third, in a report in which the intertask consistency of response of 36 subjects during four psychological stress condi­tions was examined, five out of six coefficients attained significance for both cardiac output and total peripheral resistance; coefficients ranged from 0.37 to 0.75 for the former parameter and from 0.38 to 0.76 for the latter (Turner, Sherwood, & Light, 1990).

Evidence is thus accumulating that hemodynamic responses to psycholog­ical and psychosocial stressors show the same intertask consistency as do blood pressure responses. It would appear that the hemodynamic patterns underly­ing blood pressure responses are themselves reliable individual difference characteristics.

LABORATORy-FIELD GENERALIZATION

The second aspect of situational stability is laboratory-field, or lab-life, generalization. This avenue of investigation is concerned with the relationship between responses seen in the laboratory and those evoked by naturalistic, or real-world, stressors that occur during people's everyday lives. As was noted earlier, in moving from the laboratory to the real world, we lose some of the tight experimental control available in the psychophysiological laboratory, but we gain ecological validity; everyday life does not consist entirely of Mental Arithmetic. Real-world investigation is of fundamental importance; if hyper­responsivity does playa role in the etiology of cardiovascular disease, it is in the arena of real-world behavioral challenge and everyday psychosocial interac­tions that these responses will take their toll (Turner, 1989). The usefulness of response measures in the laboratory is predicated in part on the assumption that they reflect responses to real-life behavioral events; however, the veracity of this assumption undoubtedly has limits that require experimental determina­tion (Light, 1987). In this context, studies of lab-life predictability are of par­ticular interest.

In one study discussed by Obrist and Light (1988), ambulatory heart rate data were collected from 18 subjects during two periods; these were attending a class (the low-stress period) and taking an examination (the high-stress period). These subjects had previously completed laboratory psychophysiolog­ical testing, and they were divided into high heart rate reactors and low heart rate reactors on the basis of their laboratory responses. The heart rates of the low reactors were similar during both real-world periods while the heart rates of the high reactors were appreciably greater during the high-stress period than during the low-stress period. Obrist and Light (1988) concluded that these

CARDIOVASCULAR REACTMTY RESEARCH 23

data suggested that the challenge of an examination influences heart rate "only in those individuals evidencing greater heart rate reactivity in the labora­tory."In a similar study (Turner, Carroll, Dean, & Harris, 1987), subjects completed laboratory testing and subsequently took part in a public speaking contest. Conclusions were strongly tempered by a very small sample size, but there was evidence that the extent of response during the debate was indicated by the magnitude of response to the standard laboratory stressors.

Not all studies, however, have provided evidence of lab-life generalization of response. Indeed, the somewhat confusing picture obtained by examining the current literature bears witness to the need for experimental and conceptual clarification. For example, Matthews, Manuck, and Saab (1986) found that reactions shown by adolescents immediately before and after a 5-minute speech in an English class were predictable. from the magnitude of reaction shown to laboratory stressors, and Steptoe, Melville, and Ross (1983) reported that individuals showing the greatest laboratory responses showed the highest self­determined blood pressure levels over a 14-day period. In contrast to these results, three recent studies have failed to find a relationship between lab and life responses, although they all reported associations between lab and life absolute levels (Fredrikson, Blumenthal, Evans, Sherwood, & Light, 1989; Harshfield, James, Schlussel, Yee, Blank, & Pickering, 1988; Turner et 01, 1990).

The issue of lab-life generalization is beset by methodological, statistical and conceptual difficulties (Manuck et 01, 1989). While Chapter 4 will address this issue in detail, we can note here that ambulatory monitoring studies will undoubtedly continue to be of great importance. At present, the technical aspects of real-world recording are under much greater control than our real­world behavioral assessment strategies; it is difficult to measure all the behav­ioral aspects of ambulatory subjects. Extraneous factors, such as proximity to meals, awakening, locomotion, and postural adjustments, all influence blood pressure (Manuck et 01, 1990). Second, the identification of specific instances of naturally occurring events that are psychologically similar to laboratory stres­sors is difficult. Calculation of reactivity scores is therefore particularly difficult, especially when the identification of suitable baseline periods is also problematic.

Nevertheless, ambulatory data have proved very interesting to date. Some investigators, such as Floras, Hassam, Jones, and Sleight (1987), have focused on variability, on the grounds that while specific individual stressors may be hard to pinpoint, the more reactive individual will probably display a greater range of values, the higher ones occurring during psychological challenge. In regard to absolute levels, this information too may be very helpful. Devereux and colleagues (Devereux, Pickering, Harshfield, Kleinert, Denby, Clark, Pregibon, Jason, Kleiner, Borer, & Laragh, 1983) have found that ambulatory levels during work correlate better with end-organ damage-left-ventricular hypertrophy-in hypertensives than clinical values or readings during quieter

24 CHAPrERONE

periods. In this sense, ambulatory data may indeed provide an independent prognostic indicator in the overall risk profile of the individuals. Chapter 3 focuses on ambulatory monitoring and gives examples of how this methodology can provide useful information over and above that collected in the laboratory.

EXTRANEOUS INFLUENCES ON SITUATIONAL STABILITY

A methodological problem in assessing the stability of individual differ­ences in reactivity during real-life situations is the contribution of extraneous factors such as level of physical activity and posture. Such factors are in­dependent determinants of blood pressure that may interact nonadditively with stress-related pressor events. Stressful activities encountered in a standing position may be associated with different cardiovascular responses than while sitting. Activity diaries, completed to correspond with ambulatory blood pres­sure measurements, are one means by which such influences can be taken into account. Laboratory reactivity testing, however, involves assessment in the seated posture, so it has remained unclear how information on postural status can be used to correct for postural effects.

In a recent study, we examined whether establishing resting baselines in different postures might improve our understanding of blood pressure re­activity across postures (Turner & Sherwood, 1991). In this laboratory study, we measured resting baseline cardiovascular measures while subjects were seated and while standing. A highly standardized, computer-based Mental Arithmetic task, based on that first proposed by Turner and colleagues (Tur­ner, Hewitt, Morgan, Sims, Carroll, & Kelly, 1986b), was employed in the study. Using a counterbalanced design, subjects were tested on the Mental Arithmetic task a total of four times, twice while seated and twice while standing. Resting baseline systolic pressure was slightly lower on average for the sitting baseline while in contrast diastolic pressure was significantly higher while standing. More importantly for our objectives, there was a substantial degree of variation between individuals in systolic and diastolic blood pressure differences between the two postural baselines. Therefore, we hypothesized that correlations be­tween blood pressure responses to the Mental Arithmetic task might be higher if the appropriate postural baseline was used to compute responses than always using a sitting baseline. In fact, the results were surprisingly the reverse of these expectations, with blood pressure reactivity correlations between sitting and standing postures higher when responses to the standing Mental Arith­metic task were computed as change scores from the sitting baseline. Thus, it appeared that blood pressure responses to the mental stressor in the standing position seemed to offset the individual differences associated with adjustment to standing per se. In other words, absolute blood pressure levels associated with Mental Arithmetic task performance across the two postures were more similar than the corresponding resting levels. Perhaps this finding may par-

CARDIOVASCULAR REACTIVITY RESEARCH 25

tially explain the closer correspondence of absolute blood pressure levels than response values for studies of laboratory-field generalization.

In the study described above, we also examined the stability of underlying hemodynamic responses across postures (Sherwood & Turner, in press). As might be expected from a consideration of the hydrostatic effects of gravity, resting blood pressure while standing was generally characterized by greater vascular resistance than while sitting. We examined stability of hemodynamic response patterns to the Mental Arithmetic task, with response levels derived from the corresponding postural baseline. In sharp contrast to the findings for blood pressure, cardiac output and vascular resistance responses were highly stable across postures. Speculatively, these results may suggest that the com­parative robustness of the hemodynamic determinants of pressor responses may be due to their closer reflection of sympathetic nervous system activation patterns and lesser susceptibility to extraneous influences. In terms of psycho­somatic models of reactivity in cardiovascular disease, our findings provide further evidence that the hemodynamics of pressor responses appear to display the characteristics of idiosyncratic responses.

SUMMARY AND FUTURE DIRECTIONS

Cardiovascular responses during psychologically stressful or challenging episodes are determined by the interaction of the individual with the environ­ment. We have seen how the nature of a given stressor can be a significant determinant of blood pressure responses and their underlying hemodynamic adjustments. At the same time, the available evidence of temporal and situa­tional stability suggests that cardiovascular responses are to some extent con­sistent characteristics of an individual. Thus, some individuals appear to be generally more reactive than others in terms of showing typically large mag­nitude blood pressure responses to a variety of stressful stimuli. In addition, the hemodynamic mechanisms responsible for stress-related pressor responses appear to be relatively stable individual characteristics that are only partially modified by specific situations. Therefore, cardiovascular reactivity exhibits attributes that are consistent with it being viewed as a psychophysiological trait.

Like other traits, it seems likely that cardiovascular reactivity may vary in strength or degree of robustness: individuals may vary in the temporal and/or situational stability of their characteristic responsiveness. Its assessment should thus attempt to provide some indication of these characteristics. This becomes especially important with regard to its use as a psychosomatic con­struct because the relationship between repeated acute cardiovascular respon­ses and long-term pathophysiological consequences is far from clear. In this regard, early approaches to assessment of reactivity by categorization of the

26 CHAPTER ONE

magnitude of blood pressure responses in terms of high and low reactors to a single stressor were of limited value. The limitations are present at two levels. First, the magnitude of blood pressure responses may be of only partial impor­tance to their potentially deleterious effects, with hemodynamic patterns and neurohumoral mechanisms also being important. Investigation of hemodynam­ic response patterns may well help to clarify the possible link between reactivity and disease. Second, responses to single stressors run a high risk of being nonrepresentative. Repeated testing over time provides a means of improving reliability of reactivity assessed by a single stressor. Furthermore, more recent trends in reactivity research have included more sophisticated and more ex­tensive physiological assessment during exposure to multiple laboratory stres­sors; in addition, ambulatory monitoring during real-life situations has some­times been included in research protocols.

Given the present stage of maturation of cardiovascular reactivity re­search, the selection of stress tests and physiological measures will probably continue to be driven by theories, specific objectives, and populations under test in a given stUdy. Nonetheless, there has been growing interest in the idea of developing multiple stressor reactivity assessment procedures that may pre­sent a standardized assessment technology, eventually permitting the collec­tion of epidemiological data. One research group has proposed a highly stan­dardized battery of computer-based cognitive tasks with this end in mind (Kamarck, Jennings, Debski, Glickman-Weiss, Johnson, Eddy, & Manuck, in press). While there are advantages to precise task standardization, it may be too early to decide what form such standardization should take. Ewart and Kolodner (1991) have likened the reactivity assessment problem to the psycho­metric assessment of other behavioral traits. They compare reactivity tasks to items on a scale, with each item (task) contributing distinct information about the underlying construct (reactivity). Thus, reactivity assessment using a bat­tery of diverse stressors may present a potentially more fruitful approach.

Such a reactivity assessment scale may need to be quite extensive. It might include one or more highly standardized cognitive tasks, controlling for difficulty, such as those used by Kamarck et al. (in press). Standardized tasks chosen to elicit responses via contrasting physiological mechanisms (e.g., alpha versus beta adrenergic) would also have an important place. Tasks such as the Cold Pressor or Mirror Trace would contrast well with an aversive Reaction Time task. Other tasks would be needed to tap more personalized aspects of individual stress, sacrificing some standardization at the benefit of improving ecological Validity. Harassment manipulations of existing tasks (Suarez & Wil­liams, 1990) and structured interview procedures such as proposed by the Stress Interview (Dimsdale et al., 1988) or the Social Competence Interview (Ewart & Kolodner, 1991) are tasks that might usefully serve the objective of detecting psychological elements contributing to reactivity. Inclusion of phys­ical stressors, such as isometric and dynamic exercise, may also contribute distinct and important information. By employing comprehensive assessment

CARDIOVASCULAR REACTIVITY RESEARCH 27

of this nature, it should be possible to extend our description of an individual's cardiovascular reactivity status in several ways. First, we would achieve more confidence in our descriptions of hyporeactivity and hyperreactivity and of cardiac and vascular reactors. A dimension of robustness of the reactivity trait, according to generalization of response characteristics across the range of tasks, may be a highly valuable risk marker. Moreover, the broad-ranging assessment strategy should provide a means of distinguishing the relative contribution of psychological and physiological aspects of the individual in the assessment of reactivity characterization. Thus, for example, it may be possible to subclassify hyperreactors into those who show primarily a physiological disturbance (i.e., hyperresponsive to all psychological and physical stressors) and those who are more psychologically reactive (i.e., hyperresponsive to only specific psychological stressors). Information of this kind is likely to improve our understanding of the potential contributions of cardiovascular reactivity to disease processes. Furthermore, it would promise to suggest what form of behavioral or pharmacological intervention might best benefit a particular individual at risk for cardiovascular disease.

ACKNOWLEDGMENT

Preparation of this chapter was supported by a grant funded by the National Institutes of Health (HL38950).

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30 CHAPTER ONE

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Manuck, S. B., Kasprowicz, A L., & Muldoon, M. F. (1990). Behaviorally evoked cardiovascular reactivity and hypertension: Conceptual issues and potential associations. Annals of Behav­ioral Medicine, 12, 17-29.

Matthews, K. A, Manuck, S. B., & Sash, P. G. (1986). Cardiovascular responses of adolescents during a naturally occurring stressor and their behavioral and psychophysiological predictors. Psychophysiology, 29, 198-209.

Matthews, K. A, Rakaczky, C. J., Stoney, C. M., & Manuck, S. B. (1987). Are cardiovascular responses to behavioral stressors a stable individual difference variable in childhood? Psycho­physiology, 24, 464-473.

Matthews, K. A, Woodall, M. S., & Lassner, J. (1990, April 19). Family resources associated with psychophysiological responses during conflict resolution. Paper presented at the Society of Behavioral Medicine annual meeting, Chicago.

Miller, J. C., & Horvath, S. M. (19'78). Impedance cardiogrsphy. Psychophysiology, 15, SO-91. Miller, S. B., & Ditto, B. (1988). Cardiovascular responses to an extended aversive video game task.

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Obrist, P. A (19'76). The cardiovascular-behavioral interaction-As it appears today. PsychophY8-iology, 19, 95-107.

Obrist, P. A (1981). Cardiovascular psychophysiology: A perspective. New York: Plenum Press. Obrist, P. A, & Light, K. C. (1988). Active-passive coping and cardiovascular reactivity: Interaction

with individual differences and types of baseline. In W. A Gordon, J. A Herd, & A Baum (Eds.), Perspectives on behavioral medicine (Vol. 3, pp. 109-126). San Diego: Academic Press.

Obrist, P. A, Gaebelein, C. J., Teller, S. E., Langer, A W., Grignolo, A, Light, K. C., & McCubbin, J. A (1978). The relationship among heart rate, carotid dP/dt, and blood pressure in humans as a function of the type of stress. Psychophysiology, 15, 102-115.

Peckerman, A, Sash, P. G., McCabe, P. M., Skyler, J. S., Wmters, R. W., Llabre, M. M., & Schneiderman, N. (1991). Blood pressure reactivity and the perception of pain during the forehead cold pressor test. Psychophysiology, 28, 485-495.

Pickering, T. G., & Gerin, W. (1990). Cardiovascular reactivity in the laboratory and the role of behavioral factors in hypertension: A critical review. Annals of Behavioral Medicine, 12, 3-16.

Roessler, R., & Engel, B. T. (19'74). The current status of the concepts of physiological response specificity and activation. IntemaJ:ional Juumal of Psychiatry and Medicine, 5, 359-366.

Saab, P. G., Matthews, K. A, Stoney, C. M., & McDonald, R. H. (1989). Premenopausal and

CARDIOVASCULAR REACTIVITY RESEARCH 31

postmenopausal women differ in their cardiovascular and neuroendocrine responses to beha­vioral stressors. Psyclwphysiology, 26, 270-280.

Schneiderman, N., & McCabe, P. M. (1989). Psychophysiologic strategies in laboratory research. In N. Schneiderman, S. M. Weiss & P. G. Kaufmann (Eds.), Handbook of research methods in cardiovascular behavimnl medicine (pp. 349-364). New York: Plenum Press.

Sherwood, A, & Turner, J. R. (in press). Postural stability of hemodynamic responses during mental challenge. Psyclwphysiology.

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Sherwood, A, Allen, M. T., Fahrenberg, J., Kelsey, R. M., Lovallo, W. R., & van Doornen, L. J. P. (1990a). Committee report: Methodological guidelines for impedance cardiography. Psycho­physiology, 27, 1-23.

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Sherwood, A, Turner, J. R., Light, K. C., & Blumenthal, J. A (199Oc). Temporal stability of the hemodynamics of cardiovascular reactivity. Internaticmal Journal of Psyclwphysiology, 10, 95-98.

Sherwood, A, Davis, M. R., Dolan, C. A, & Light, K. C. (1992). Effects of seif-challenge on cardiovascular reactivity. Internaticmal Journal of Psyclwphysiology, ItZ, 87-94.

Smith, T. W., & Brown, P. W. (in press). Cynical hostility, attempts to exert social control, and cardiovascular reactivity in married couples. Journal of Behavimnl Medicine.

Stead, E. A, Warren, J. V., Merrill, A J., & Brannon, E. S. (1945). The cardiac output in male subjects as measured by the technique of atrial catheterization. Normal values with ob­servation on the effects of anxiety and tilting. Journal of Clinical Investigaticm, tZ4. 326-331.

Steptoe, A, Melville, D. R., & Ross, A (1983). Behavioral response demands, cardiovascular reactivity, and essential hypertension. Psychosmnatic Medicine, 45, 33-48.

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Suarez, E. C., & Williams, R. B., Jr. (1990). The relation between dimensions of hostility and cardiovascular reactivity as a function of task characteristics. Psychosmnatic Medicine, 5tZ, 558-570.

Trimarco, B., Volpe, M., Ricciardelli, B., Picotti, G. B., Galva, M. D., Petracca, R., & Condorelli, M. (1983). Studies of the mechanisms underlying impairment of beta-adrenoceptor-mediated effects in human hypertension. Hypertension, 5, 584-590.

Turner, J. R. (1988). Inter-task consistency: An integrative re-evaluation. Psyclwphysiology, 25, 235-238.

Turner, J. R. (1989). Individual differences in heart rate response during behavioral challenge. Psyclwphysiology, 26, 497-505.

Turner, J. R., & Carroll, D. (1985). Heart rate and oxygen consumption during mental arithmetic, a video game, and graded exercise: Further evidence of metabolically-exaggerated cardiac adjustments? Psyclwphysiology, 2tZ, 261-267.

Turner, J. R., & Sherwood, A (1991). Postural effects on blood pressure reactivity: Implications for studies of laboratory-field generalization. Journal of Psychosmnatic Research, 95, 289-295.

Turner, J. R., Carroll, D., & Courtney, H. (1983). Cardiac and metabolic responses to "Space Invaders": An instance of metabolically -exaggerated cardiac adjustments? Psyclwphysiology, 20, 544-549.

Turner, J. R., Carroll, D., Sims, J., Hewitt, J. K., & Kelly, K. A (l986a). Temporal and inter-task

32 CHAPl'ER ONE

consistency of heart rate reactivity during active psychological challenge: A twin study. Physiology and Beha'lJinr, 38, 641-644.

Turner, J. R., Hewitt, J. K., Morgan, R. K., Sims, J., Carroll, D., & Kelly, K. A. (l986b). Graded mental arithmetic as an active psychological challenge. International Jquma/, of Psychuphys­iology, 3, 307-309.

Turner, J. R., Carroll, D., Dean, S., & Harris, M. G. (1987). Heart rate reactions to standard laboratory challenges and a naturalistic stressor. International Jquma/, of Psychuphysiology, 5,151-152.

Turner, J. R., Carroll, D., Hanson, J., & Sims, J. (1988). A comparison of additional heart rates during active psychological challenge calculated from upper body and lower body dynamic exercise. Psychuphysiology, 25, 209-216.

Turner, J. R., Girdler, S. S., Sherwood, A., & Light, K. C. (1990). Cardiovascular responses to behavioral stressors: Laboratory-field generalization and inter-task consistency. Jquma/, of Psychosorrwtic Research, 34, 581-589.

Turner, J. R., Sherwood, A., & Light, K. C. (1990). Generalization of cardiovascular response: Supportive evidence for the reactivity hypothesis. International Jquma/, of Psychuphysiol­ogy, 11, 207-212.

van Egeren, L. F., & Sparrow, A. W. (1989). Laboratory stress testing to assess real-life cardiovas­cular reactivity. Psychosorrwtic Medicine, 51, 1-9.

Ward, M. M., Mefford, I. N., Parker, S. D., Chesney, M. A., Taylor, C. B., Keegan, D. L., & Barchas, J. D. (1983). Epinephrine and norepinephrine responses in continuously collected human plasma to a series of stressors. Psychosomatic Medicine, 45, 471-486.

Williams, R. B., Bittker, F. E., Buchsbaum, M. S., & Wynne, L. C. (1975). Cardiovascular and neurophysiologic correlates of sensory intake and rejection. I. Effect of cognitive tasks. Psychuphysiology, 12, 427-432.

CHAPTER TWO

Sympathetic Nervous System Responses to Psychosocial Stressors

PAUL J. MILLS AND JOEL E. DIMSDALE

INTRODUCTION

Sympathetic nervous system (SNS) activity was initially inferred by responses of end organs such as sweat glands or heart rate . .Ai3 biochemical techniques developed, it became possible to monitor SNS activity as mirrored in the urine and later in plasma. Now a number of other options are available for such study, including direct recording from SNS nerve fibers and quantification of adre­nergic receptors. Regardless of the site of measurement, there is a great deal of variance in all SNS measures because the SNS is so exquisitely responsive to virtually all stimuli. In order to perceive individual differences or differences between tasks, the investigator must control for these perturbations of SNS activity.

This chapter reviews factors that are potential sources of variation in the study of catecholamine responses to stressors. It also considers some recently developed markers of SNS function that may be useful in further characterizing individual responses to behavioral stressors.

CONSIDERATIONS OF CATECHOLAMINE PHYSIOLOGY

Despite the fact that catecholamine studies have always faced limitations, such as tedious and often weakly reproducible assays, low physiological con-

PAUL J. MILLS AND JOEL E. DIMSDALE • Department of Psychiatry, University of California at San Diego, La Jolla, California 92093.

33

34 CHAPl'ER TWO

centrations (picogram range), and short half-life (1 to 2 minutes), plasma cat­echolamines are routinely taken as indices of sympathetic neural and adre­nomedullary activity. Historically, norepinephrine has been understood as a classic neurotransmitter of sympathetic nerve endings and epinephrine as a hormone coming exclusively from the adrenal medulla. Recent studies, how­ever, indicate that epinephrine is also produced and released from other tissue, including the kidney, atria, and red blood cells (Ziegler, Kennedy, & Elayan, 1989a,b).

Once plasma catecholamines are successfully measured, the interpretation of their value is far from straightforward. Venous and arterial norepinephrine levels, for example, reflect not only release but metabolic degradation, re­uptake, binding to postsynaptic receptors, diffusion, corelease with other vaso­active peptides, and regional and local circulation. Thus, catecholamine levels may only approximate the complex web of sympathetic activity, a web whose many threads are themselves subject to regulation. It is, in part, this innate complexity that underlies the variability of interindividual differences in cate­cholamine responses to stressors. As will be seen later, many of the recently developed SNS markers focus on studying these underlying components of catecholamine physiology.

INDMDUAL VARIABILITY IN CATECHOLAMINE RESPONSES TO STRESSORS

The history of progress in this field has included, among other things, the realization that SNS responsiveness is highly variable, being affected by both the internal and external environment of the individual. This section reviews several factors that have been examined as possible sources of catecholamine variation:

• Sodium, race, and hypertension • Anger, hostility, and Type A behavior • Meditation and relaxation • Age

• Caffeine • Antihypertensive therapy • Task setting and sample timing • Menstrual cycle

SODIUM, RACE, AND HYPERTENSION

The effects of sodium, race, and diagnosis of hypertension were examined on plasma catecholamine reactivity to a mental arithmetic stressor (Dimsdale, Ziegler, Mills, Delehanty, & Berry, 1990). No evidence was found that any of

SYMPATHETIC NERVOUS SYSTEM RESPONSES 35

these three variables had a significant bearing on norepinephrine or epineph­rine responses. Of three other studies comparing normotensive and hyper­tensive subjects (Eliasson, Hjemdahl, & Kahan, 1983; Lorimer, Macfarlane, Provan, Duffy, & Lawrie, 1971; Sullivan, Proeci, DeQuattro, Schoentgen, Lev­ine, van Der Meulen, & Bornheimer, 1981), none found significant differences in norepinephrine reactivity, and only one (Eliasson et al, 1983) found an increased epinephrine response in hypertensives compared to normotensive controls. One study (Tischenkel, Saab, Schneiderman, Nelesen, Pasin, Gold­stein, Spitzer, Woo-Ming, & Weidler, 1989) found no differences in plasma catecholamines between black and white normotensive in response to a struc­tured interview, a video game, or the cold pressor task.

Thus, while sodium (Kjeldsen, Os, Beckmann, Westheim, Hjermann, Leren, & Eider, 1986), hypertension (Goldstein, 1983), and race (Sever, Peart, Davies, Tunbridge, & Gordon, 1979) may have clear effects on resting plasma norepinephrine levels, there appear to be no effects of these variables on norepinephrine reactivity.

ANGER, HOSTILITY, AND TYPE A BEHAVIOR

The last few years mark an evolutionary period in understanding the relationship between behavior and sympathetic responses to psychosocial stressors. Much of this growth in understanding stems from research on Type A behavior. Although research findings on Type A and SNS responses to stress tended to be inconsistent, the emerging trend appears to be one of increased norepinephrine (but not epinephrine) reactivity to stressors in Type As (see DeQuattro, Loo, & Foti, 1985 and Harbin, 1989, for reviews). Perhaps more importantly, the path of Type A research yielded an impetus for further re­search on behavior and stress. Specifically, studies now suggest that the Type A SUbcomponents of anger and hostility are more related to pathogenic end­points and cardiovascular reactivity than the global Type A rating (Williams, 1987; see also Chapter 6). Similarly, in terms of catecholamine reactivity, suppressed anger and increased anxiety may be associated with increased plasma norepinephrine responses to a mental stressor (Sullivan et al, 1981). Conversely, the increased expression of anger-outward has been associated with decreased plasma norepinephrine responses to a mental stressor (Mills, Schneider, & Dimsdale, 1989).

What remains to be determined is whether the relationship between anger styles and norepinephrine reactivity in part underlies the suggested relation­ship between anger styles and cardiovascular morbidity.

MEDITATION AND RELAXATION

Although there are many studies examining the acute effects of meditation and relaxation on cardiovascular reactivity (see Jacob & Chesney, 1986, for a

36 CHAP1'ER TWO

review), there are few studies examining their effects on catecholamine re­activity. Morrell and Hollandsworth (1986) reported that compared to controls, subjects who practiced the relaxation response for 30 days had a greater plasma norepinephrine response to the stress of venipuncture. Similar results were found when examining plasma norepinephrine responses during handgrip (Hoffman, Benson, Arns, Stainbrook, Landsberg, Young, & Gill, 1982; Morrell and Hollandsworth, 1986). Interestingly, the cardiovascular response accom­panying this noradrenergic hyperactivation was blunted. Since adrenergic re­ceptor stimulation by norepinephrine usually raises cardiovascular responses, the authors interpreted these data as evidence for an adrenergic receptor desensitization associated with the behavioral technique (Hoffman et 01, 1982). A later study found direct support for this hypothesis. Subjects practicing meditation had significantly fewer high-affinity state lymphocyte beta-adrener­gic receptors than nonmeditating controls, indicating a reduced receptor sen­sitivity (Mills, Schneider, Hill, Walton, & Wallace, 1990). Together, the studies suggest that behavioral techniques are associated with alterations in certain components of sympathetic responsiveness to stressors.

AGE

Age has important effects on both the release of and response to norepi­nephrine. The resting levels of plasma norepinephrine in a 60-year-old man are approximately twice that of a 10-year-old child. In response to a mental stres­sor, older subjects will exhibit greater norepinephrine responses (approximate­ly 40% higher; Barnes, Rasking, Gumbrecht, & Halter, 1982). Similarly, in response to standing or a cold pressor task, an older person will have approx­imately twice the norepinephrine levels than a younger person (Lake, Ziegler, & Kopin, 1976; Palmer, Ziegler, & Lake, 1978). The data suggest that age influences sympathetic neural but not adrenomedullary responses since epi­nephrine responses show no significant age effects. Thus, age should be con­sidered a potentially important source of individual variation in norepinephrine reactivity studies.

CAFFEINE

Caffeine has appreciable cardiovascular and adrenomedullary effects (Lane, Adcock, Williams, & Kuhn, 1990; Lovallo, Pincomb, Sung, Passey, Sau­sen, & Wilson, 1989; Smits, Pieters, & Thien, 1986). Stress and caffeine seem to synergistically interact to enhance adrenomedullary responses as well. An equivalent caffeine consumption of 2 to 3 cups of coffee per day can more than double epinephrine and cortisol responses to psychological stressors (Lane et 01, 1990; Lovallo et 01, 1989; Pincomb, Lovallo, Passey, Bracket, & Wilson, 1987). On the other hand, norepinephrine reactivity does not appear to be

SYMPATHETIC NERVOUS SYSTEM RESPONSES 37

significantly altered. Since caffeine consumption is so common, careful attention should be given to its control in reactivity studies.

ANTIHYPERTENSIVE THERAPY

Certain antihypertensive therapies can alter plasma catecholamine re­sponses to psychosocial stressors. We recently reviewed the effects of beta­blockers on reactivity to psychosocial stressors and reported that although blood pressure reactivity was not affected, the majority of these therapeutic agents tend to increase catecholamine responses (Mills and Dimsdale, 1991). Most of the discrepancies in this literature can be accounted for by considering the intrinsic sympathomimetic activity (ISA) of the drug under study. ISA is a measure of how well the blocker (receptor antagonist) mimics receptor agonist properties. High lSA drugs, such as pindolol, tend to block the normal cate­cholamine increase to stress while drugs with no lSA, such as metoprolol and propranolol, tend to augment the response (Bonelli, 1982; Brisse, Tetsch, Schwill, & Bender, 1983; Dimsdale, Hartley, Ruskin, Greenblatt, & LaBrie, 1984; Trap-Jensen, Carlsen, Hartling, Svendsen, Tango, & Christensen, 1982). Drug lSA may work by stimulating clearance mechanisms. Neither drug se­lectivity (betal selective or nonselective) nor lipophilicity (lipophilic or hydro­philic) seems to influence catecholamine responsiveness. With these data in mind, the use of beta-blockers by subjects should be controlled for as a potential source of catecholamine variation.

There have been few if any studies on the effects of converting-enzyme inhibitors on sympathetic responses to psychological stressors. Studies using both handgrip (Niarchos, Pickering, Morganti, & Laragh, 1982) and upright posture (Morganti, Sala, Turolo, Palermo, & Zanchetti, 1985) as stimuli, how­ever, report no significant changes in plasma norepinephrine responsiveness.

TASK SETI'ING AND SAMPLE TIMING

The setting of the stressor has substantial effects on the character and magnitude of the SNS response. Dimsdale (1984) compared plasma catechol­amines obtained after a laboratory mathematics task and a naturalistic public speaking task. The math task led to increases of 80 and 42 pg/ml in norepi­nephrine and epinephrine, respectively, while public speaking led to increases of 300 and 75 pg/ml in norepinephrine and epinephrine, respectively. Goldstein et al (Goldstein, 1982) showed an average 24% (85 pg/ml) increase in norepi­nephrine and 308% (194 pg/ml) increase in epinephrine following a real-life stressor (dental surgery).

The timing of sample withdrawal also influences catecholamine measures in these settings. During the course of a IS-minute public speaking task, epi­nephrine increased rapidly in the initial three minutes but had returned to baseline levels by the time the speaker had finished speaking (Dimsdale &

38 CHAPl'ER TWO

Moss, 1980). Ward et a1 (Ward, Mefford, Parker, Chesney, Taylor, Keegan, & Barchas, 1983) examined plasma catecholamine responses to a series of five short-term laboratory stressors and reported that epinephrine reached its peak in the first two minutes of the task while norepinephrine reached its peak six to eight minutes later, often after the stressor was over. Thus, both the setting of the stressor (field versus laboratory) and the timing of sample acquisition clearly affect the nature of the derived catecholamine data.

MENSTRUAL CYCLE

Both resting (Goldstein, Levinson, & Keiser, 1983) and reactivity (Collins, Eneroth, & Landgren, 1985) values of the catecholamines may change during the different phases of the menstrual cycle. For studies employing women as subjects, investigators should therefore control for their subjects' menstrual phase (see also Chapter 8).

NEW FRONTIERS

Although advances in catecholamine measurement have greatly enhanced our understanding of sympathetic responsiveness to stressors, much of the variation in responsiveness remains unexplained. Consequently, other potential markers of SNS functioning are being explored. While not all of the measures we review have been studied within the context of reactivity to psychosocial stressors, many may prove useful in this area of research:

• Direct sympathetic nerve monitoring • Chromogranin A • N europeptide Y • Norepinephrine pharmacokinetics • Platelet catecholamines and pupil tone • Plasma renin • Plasma cyclic AMP • Adrenergic receptors

DIRECT SYMPATHETIC NERVE MONITORING

Since all chemical measures of SNS activity reflect the complex physiology of neuronal secretion, reuptake, clearance, and distribution, many investigators have searched for a direct electrical measure of SNS transmission. Although somewhat invasive, it is possible to measure SNS activity directly by placing an electrode on the sural or peroneal nerve (Hagbarth & Valbo, 1968). One of the vast paradoxes of this technique is that it reveals that SNS activity is highly differentiated and does not respond in the "all or none" fashion that was initially

SYMPATHETIC NERVOUS SYSTEM RESPONSES 39

suggested. Instead, SNS fibers in different regions of the body are activated by different stressors. This is frustrating to the cardiovascular-oriented research­er since SNS fibers to the heart are not accessible for human study.

Despite these limitations, there are data that such recordings can reflect individual differences in age (yamada, Mi~ima, Tochikubo, Matsukawa, & Ishii, 1989) or diagnosis of hypertension (Anderson, Sinkey, Lawton, & Mark, 1989). The technique has also proven useful in discerning the effects of mental stress on sympathetic neural activity (Figure 1; Anderson, Wallin, & Mark, 1987).

CHROMOGRANIN A

Because the SNS responds so quickly and because the fate of norepineph­rine released from the nerve is so complex (hectic even), many investigators have looked for some long-tenn measures of accumulated or integrated sympa­thetic activity. Obviously, such a measure would be useful in trait-oriented research and would be less useful in acute reactivity studies.

In the 1970s, there was initial enthusiasm for dopamine beta-hydroxylase (DBH) as such a marker. DBH is an enzyme involved in catecholamine syn­thesis. When the nerve fires and discharges norepinephrine into the synapse, a small amount of DBH is also released. What makes this potentially interest­ing is that DBH is not susceptible to reuptake, it has a long half-life, and it can be measured rather easily. Unfortunately, DBH levels did not track SNS firing

Control Stress Recovery

_ 1Jw.,.~Wi- 'II.~II III II I 11111 II . neurogram _ flMr~\w.J'~ ~~~~~

s sec MSNA

(bursts/min) 27 35 30

Integrated MSNA 371 941 525 (units)

HR (beats/min) 70 85 • BP (mmHg) 125185. i5 125177. iI5 120188 ••

FIGURE 1. Neurogram of leg muscle sympathetic nerve activity (MSNA) in one subject during control, stress, and recovery periods. Leg MSNA increased markedly during stress and remained elevated during recovery. Heart rate (HR) and blood pressure (BP) also increased during mental stress but returned promptly to control levels during recovery. (Reprinted with permission from Erling Anderson and the American Heart Association.)

40 CHAPTER TWO

that precisely. There were profound genetic differences in DBH levels regard­less of SNS activity.

More recently, chromogranin A (CgA), an acidic protein present in chromaffin tissue, has been characterized (O'Connor, Frigon, & Sokoloff, 1984). In response to large-scale perturbations of the SNS, CgA levels change ap­propriately. Short-term psychological stressors, however, do not lead to a measurable change in such levels (Dimsdale, O'Connor, Ziegler, & Mills, 1989). It remains to be seen if longer term stressors affect CgA levels or if trait characteristics are related to such levels. The ease of assay, the lack of require­ment for indwelling catheters for blood draw, and the small amount of plasma required for assay make CgA studies a potentially interesting opportunity for further research.

N EUROPEPTIDE Y

Neuropeptide Y (NPy) is a recently identified peptide (Tatemoto, 1982) that is stored in large vesicles and coreleased with norepinephrine from post­ganglionic sympathetic nerves. It is also coreleased with epinephrine from the adrenal medulla (Lundberg, Pernow, Franco-Cersceda, & Rudehill, 1987). NPY release usually occurs with high-frequency sympathetic activation. NPY can enhance norepinephrine responses, can inhibit nerve-stimulated norepi­nephrine release, and can serve as a vasoconstrictor in most vascular beds via specific high-affinity receptors. We know of no studies examining the effects of psychological stress upon NPY release. Studies using exercise have shown an increase in plasma NPY along with both plasma norepinephrine and epineph­rine (Lundberg, Martinsson, Hemsen, Theodorsson-Norheim, Svedenhag, Ekblom, & Hjemdahl, 1985; Pernow, Lundberg, Kaijser, Hjemdahl, Theo­dorsson-Norheim, Martinsson, & Pernow, 1986). One study did not find a significant increase in plasma NPY in response to a handgrip task despite a doubling of plasma norepinephrine (Pernow et aI,., 1986). This may imply that only substantial psychosocial stressors would be sufficient to stimulate NPY responses.

NOREPINEPHRINE PHARMACOKINETICS

Plasma norepinephrine reflects both release and uptake mechanisms, both of which can be quantified using pharmacokinetic techniques (Lake & Ziegler, 1985). The technique involves infusion of a trace amount of radiolabeled nore­pinephrine (3H-NE) and sampling the radiolabeled norepinephrine in plasma. The rates of norepinephrine clearance and release from plasma can be calcu­lated by the following formulae:

3H -NE infused per minute Clearance (liters/minute) = -------"-----

3H -NE per liter plasma

SYMPATHETIC NERVOUS SYSTEM RESPONSES 41

Release = clearance x plasma norepinephrine

Goldstein et al (Goldstein, Eisenhofer, Sax, Keiser, & Kopin, 1987) applied norepinephrine kinetic measures to study the role of norepinephrine during mental challenge. Venous norepinephrine did not increase significantly in re­sponse to the stressor nor did it relate to changes in systolic blood pressure or cardiac output. Arterial norepinephrine, on the other hand, did increase significantly but was only weakly associated with changes in systemic hemody­namics. Norepinephrine release, however, not only increased significantly (30%) in response to the task but, in contrast to either venous or arterial norepinephrine, showed strong relationships with blood pressure and cardiac output hemodynamics. Norepinephrine clearance was not affected by the task. Similar findings have been reported by Hjemdahl et al (Hjemdahl, 1989). A mental stressor (color word task) was associated with a 30% increase in nore­pinephrine release but not in norepinephrine clearance. Moreover, norepineph­rine release was correlated with sympathetic nerve activity.

Such findings may prove useful in explaining mechanisms underlying in­dividual variability in catecholamine responses to stressors. For example, Esler et al's studies of pharmacokinetics indicate that age (Esler, Skews, Leonard, Jackman, Bobika, & Korner, 1981a) and hypertension (Esler, Leonard, Jack­man, Bobik, & Skews, 1980; Esler, Jackman, Bobik, Leonard, Kelleher, Skews, Jennings, & Korner, 1981b) are associated with reduced norepinephrine clear­ance The finding that aging reduces clearance may help explain Barnes et al's (1982) findings of increased norepinephrine responsiveness to mental stress in older subjects, which were reviewed previously.

PLATELET CATECHOLAMINES AND PuPIL TONE

Two other indices of sympathetic tone are platelet catecholamine content and pupil tone. Blood platelets take up, concentrate, and store norepinephrine and epinephrine (Abrams & Solomon, 1969; Daprada & Picotti, 1979). Since platelet catecholamine content reflects the average circulating catecholamine levels over several days (Zweifler & Julius, 1982), this measure is believed to provide an index of chronic sympathetic activation.

Schneider et al (Schneider, Julius, Moss, Dielman, Zweifler, & Karunas, 1987) reported increased platelet epinephrine, but not norepinephrine, and greater pupil diameter in Type A subjects as compared to Type B subjects. The authors interpreted these data as support for the hypothesis that Type A individuals show enhanced sympathetic tone.

Pupillometry provides a measure of alpha-adrenergic tone outside of the vascular system (Lowenstein & Lowenfeld, 1969). The technique involves quan­tifying pupillary dilatation in response to an exogenous alpha-adrenergic ago­nist, such as phenylephrine. Lehmann, Goodale, and Benson (1986) used this technique to examine the effects of six weeks of practice of the relaxation

42 CHAPTER TWO

response. Compared to controls, the relaxation group showed a reduction in pupillary sensitivity to phenylephrine, suggesting a reduced end organ respon­sivity in the relaxation group. Schneider et al. (1987) found no difference between Type A and Type B subjects in the pupillary response to phenyleph­rine.

While platelet catecholamine concentrations probably have limited appli­cations in acute SNS reactivity studies, pupillometry may offer a relatively noninvasive measure of SNS tone suitable for acute evaluation.

PLASMA RENIN

Several studies indicate that mental stressors can increase plasma renin levels by 12 to 65% (Clamage, Vander, & Mouw, 1977; Heine & Weiss, 1987; Herrmann, Schonecke, Wagner, Rosenthal, & Schmidt, 1980). Some studies, however, have failed to show this effect (Esler & Nestel, 1973; Hjemdahl & Eliasson, 1979). All of these studies used subjects on unrestricted sodium diets. Given the profound effect of sodium on renin levels, Dimsdale et al. (Dimsdale, Ziegler, & Mills, 1990) reexamined the effects of stressors on renin responses but did so under conditions of controlled sodium intake. The results indicated that the stressors (a standing and a mathematics task) significantly elevated renin levels. This response, however, was evident only on a low (10 mEq), not high (200 mEq), sodium diet. Additionally, delta renin (response minus base­line) but not delta norepinephrine correlated with the blood pressure response to the stressors. These studies suggest that under high basal renin conditions, renin is responsive to stressors and that, perhaps via its indirect vasocon­strictive properties, renin plays a role in mediating end organ SNS responses to psychosocial stressors.

PLASMA CYCLIC AMP

Cyclic adenosine monophosphate (cAMP) serves as the second messenger for a variety of receptor systems, including the adrenergic. Several studies demonstrate sharp increases of up to 66% in plasma cAMP following mental stress (Eliasson et al., 1983; Hjemdahl & Eliasson, 1979; Larsson, Martinsson, Olsson, & Hjemdahl, 1989; Meyerhoff, Oleshansky, & Mougey, 1988). The increase in cAMP is correlated with the increase in epinephrine (Eliasson et al., 1983; Meyerhoff et al., 1988).

As with plasma catecholamines, the plasma cAMP response to mental stress seems to be similar for hypertensives and normotensives (Eliasson et al., 1983; Hjemdahl & Eliasson, 1979). In contrast, in response to a physical task, such as the handgrip, borderline hypertensives may exhibit a greater increase in cAMP (as well as plasma norepinephrine and epinephrine) when compared to normotensive controls (Nami, Bianchini, Aversa, Gragnani, Papini, Peruzzi, Lucani, Perrone, Johnson, & Gennarl, 1986).

SYMPATHETIC NERVOUS SYSTEM RESPONSES 43

We discussed earlier that catecholamine responses to stressors can be blocked by high ISA beta-blocking drugs, such as pindolol. Similarly, pindolol reduces the stress-induced increase of plasma cAMP, while metoprolol, a block­er with no ISA, does not (Brisse et al., 1983).

ADRENERGIC RECEPTORS

Many of the areas reviewed above, such as cAMP, norepinephrine kinetics, and pupillometry, implicitly examine adrenergic receptor function. Adrenergic receptors influence sympathetic responses to stress by mediating a host of catecholamine functions, including release, reuptake, and the eventual efficacy of catecholamines in stimulating end organ responses.

The last few years have seen an expansion of the use of these measures in behavioral research. There are several reasons for this. One is the development of highly specific radiolabeled receptor agonists and antagonists and the refinement of receptor binding techniques. Another, an especially important observation for human studies, is the recognition that certain peripheral blood cells can serve as models of human adrenergic receptor systems. Lymphocytes, for example, contain 132-adrenergic receptors, which can serve as models of human heart and lung beta-adrenergic receptors (Aarons, Nies, Gerber, & Molinhoff, 1983; Brodde, Beckeringh, & Michel, 1987; Liggett, Marker, Shah, Roper, & Cryer, 1988). Although the validity of the platelet ~-adrenergic receptor as a model of human alpha-adrenergic receptors is not as clearly demonstrated, it is often used in cardiovascular research (see Michel, Otto­Erich, & Insel, 1990, for a review).

The majority of studies examining the effects of stressors on adrenergic receptors have used physical stressors (see Mills & Dimsdale, 1988, for a review); only recently have psychosocial stressors been used (Freedman, Em­bury, Migaly, Keegan, Pandey, Javid, & Davis, 1990; Graafsma, van Tits, Westerhof, van Valderen, Lenders, Rodrigues de Miranda, & Thien, 1987; Graafsma, van Tits, van Heijst, Reyenga, Lenders, Rodrigues de Miranda, & Thien, 1989). Graafsma et al. (1987) demonstrated that a five-minute mental arithmetic task was sufficient to significantly increase lymphocyte beta-adre­nergic receptor density (Bmax) by an average 23%. Platelet alpha-adrenergic receptors were unchanged. No differences were noted between hypertensives and normotensives. Larsson, Martinsson, Olsson, & Hjemdahl (1989) demon­strated a 60% increase in lymphocyte beta-receptor density but no change in receptor sensitivity following 17 to 25 minutes of a color word test. This study shows that alterations in receptor density do not necessarily reflect alterations in functional responses. Since this phenomenon is absent in adrenalectomized subjects (Graafsma, Lenders, Peters, van Tits, Pieters, Rodrigues de Miranda, & Thien, 1988), epinephrine reactivity probably plays a crucial role in the process.

As to the exact mechanism(s) of the upregulation in receptor density,

44 CHAPl'ER TWO

Maisel, Harris, Reardon, and Michel (in press) and others (Landmann, Por­tenier, Staehelin, Wesp, & Box, 1988) suggest that the sympathetic activation of a stressor stimulates a redistribution of lymphocyte subsets: an approximate tripling of T 8uppressor/eytotoxie and natural killer cells, with only modest or no changes in T heJper cells. Since lymphocyte subsets differ in their beta-receptor properties (Khan, Sanson, Silverman, Engleman, & Melmon, 1986), the changes in Bmax following a stressor may simply reflect a change in cell subsets. Interestingly, as with the upregulation in Bmax following mental stress (Graafs­rna et 01., 1987), the subset redistribution following sympathetic activation is dependent on epinephrine responses (Maisel et al, in press).

The entire redistribution issue adds a note of caution to the use of per­ipheral cell receptors as markers of central receptors following SNS activation. Although peripheral lymphocyte beta receptors appear to be reasonable mod­els for central beta receptors under resting conditions, their utility as models following sympathetic activation is likely to be problematic.

In addition to the effects of stressors on receptors, several studies ex­amined the role that receptors play in stress responses. One study found that high cardiovascular reactivity to a mathematics challenge was related to base­line measures of high lymphocyte beta-adrenergic receptor density and high plasma catecholamines (Pacak, Nedvidkova, Horvath, Frantik, Husek, & Pa­covsky, 1989). A more recent study further examined this issue and found that lymphocyte beta-adrenergic receptor density and sensitivity (assessed by iso­proterenol-stimulated cAMP accumulation) accounted for nearly 50% of the variance in heart rate responses to a mathematics task (Mills, Dimsdale, Zieg­ler, Berry, & Bain, in press). When both receptor and nonreceptor variables (resting values of plasma catecholamines, blood pressure, and heart rate) were combined in a multiple regression, 76% of the heart rate response was pre­dicted (Figure 2).

Finally, Kahn, Perumal, Gully, Smith, Cooper, and Klein (1987) studied lymphocyte t3:!-adrenergic and platelet ~-adrenergic receptors in relation to Type A behavior. Type A was related to the ratio of az/t3:!-receptor density. The authors suggested that a preponderance of alpha-receptor-associated vasocon­striction and reduced beta-receptor-associated vasodilation may be related to increase autonomic responses to stressors seen in some individuals with Type A behavior.

It appears, therefore, that receptor measures, perhaps in combination with nonreceptor neurohormonal measures, may provide a reliable measure asso­ciated with reactivity to stressors.

SUMMARY

Much progress has been made in characterizing the rich diversity of SNS responses to psychosocial stressors; it requires considerable attention to re-

SYMPATHETIC NERVOUS SYSTEM RESPONSES 45

15

10

Delta Heart Rate (Actual) 5

o

-5+-~~--~~~~r-~~-.-------' -5 o 5 10 15

Delta Heart Rate (Predicted)

FIGURE 2. Plot showing the results of a multiple regression analysis employing receptor (lym­phocyte beta-adrenergic density and sensitivity) and nonreceptor (resting values of blood pressure, heart rate, and plasma catecholamines) measures as the independent variables and delta heart rate as the dependent variable. The regression predicted 76% of the variance in the heart rate response. (Reprinted with permission from the American Psychosomatic Society.)

liably control for the myriad of factors underlying this diversity. The advent of newer analytic techniques marks the promise of further progress in this field.

ACKNOWLEDGMENTS

Preparation of this paper was supported by grants MOI-RROO827, HL47074, HL36005, and HL40102.

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46 CHAPTER TWO

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CHAPI'ER THREE

Individual Differences in Ambulatory Blood Pressure Patterns

GREGORY A HARSHFIELD AND DERRICK A PULLIAM

INTRODUCTION

The development of ambulatory blood pressure (ABP) monitoring has provided the behavioral scientist with a methodology to identify and study factors re­sponsible for individual differences in systolic (S) and diastolic (D) blood pres­sure (BP) in the natural environment. Although ABP monitoring does not give the investigator the control over experimental conditions offered by traditional laboratory testing, it does provide a means to study the individual as he or she responds to the physical and psychological demands that they normally en­counter during the day. Furthermore, ABP monitoring provides a method to study the influence of these demands on systems that are important for the long-term regulation of BP, such as the renin-angiotensin system and the hypothalamo-pituitary-adrenal system.

WHAT IS A ''TYPICAL'' ABP PATTERN?

ABP patterns averaged across large numbers of subjects are character­ized by a peak in BP in the morning between 09:00 and 10:00 hours, a gradual decline until a second peak occurs in the early evening between 18:00 and 19:00

GREGORY A. HARSHFIELD AND DERRICK A. PuLLIAM • Department of Pediatrics, University of Tennessee, Memphis, Tennessee 38103.

51

52 CHAPTER THREE

hours, another sharper decline until the lowest BPs occur in the early morning between 03:00 and 04:00 hours, and a gradual increase until the time of awaken­ing (Bevan, Honour, & Stott, 1969; Floras, Hassan, Jones, & Sleight, 1987; Littler, West, Honour, & Sleight, 1978). The average difference in BP from peak to trough is 30 to 40 mm Hg for SBP and 20 to 30 mm Hg for DBP, depending, in part, on the initial level of BP. It is not unusual, however, to see differences as great as 100 mm Hg for SBP and 70 mm Hg for DBP.

From a behavioral perspective, the highest levels of BP averaged across large numbers of subjects occur at work, with lower levels at home, and the lowest levels during sleep (Harshfield, Pickering, Kleinert, Blank, & Laragh, 1982). It is important, however, to recognize that not all subjects display this pattern. In one study on 382 hypertensive patients (Harshfield, Pickering, Blank, & Laragh, 1986),34% of the subjects had their highest BPs in the clinic, 57% at work, and 10% at home, despite similar BPs during sleep.

FACTORS ASSOCIATED WITH INDIVIDUAL DIFFERENCES IN ABP PATTERNS

PHYSICAL AND PSYCHOLOGICAL DEMANDS

It has been clear from the initial intra-arterial ABP studies that differ­ences in activity patterns playa significant role in the determination of the ABP patterns. Acute changes in BP were reported during a number of different activities, including sleep, micturition, defecation, coitus (Littler et aL, 1978), and physical activity (Mann, Millar-Craig, Melville, Balasubramanian, & Raft­ery, 1979; Rowlands, Stallard, Watson, & Littler, 1980). More recent studies using noninvasive ABP recorders (Clark, Denby, Pregibon, Harshfield, Picker­ing, Blank, & Laragh, 1987; Van Egeren & Madarasmi, 1988) have extended these findings to include additional activities with primarily physical demands (e.g., walking, performing household chores, and so on) and those with primar­ily psychological demands (e.g., watching television, business meetings, and so forth). Additionally, further studies have found elevations in BP in response to emotional states. In one study, BP was elevated in subjects when they were happy, angry, or anxious (James, Yee, Harshfield, Blank, & Pickering, 1986) and in another study when they were worried, depressed, or hostile (Southard, Coates, Kolodner, Parker, Padgett, & Kennedy, 1986).

Further evidence for the importance of activity on BP patterns comes from studies on shift workers, in whom activity patterns are reversed. Sundberg et aL (Sundberg, Kohvakka, & Gordin, 1988) monitored the ABP patterns of seven shift workers on three consecutive days as they changed from a day shift to a night shift. The subjects had normal ABP patterns on the first day but totally reversed their patterns by the third day, with higher BPs at night during the working hours. Subsequent studies on larger sample sizes have found similar

AMBULATORY BLOOD PRESSURE 53

results (Baumgart, Walger, Fuchs, Dorst, Vetter, & Rahn, 1989b; Chau, Mal­lion, Gaudemaris, Ruche, Siche, Pelen, & Mathern, 1989).

AGE AND GENDER

Cross-sectional studies suggest that ABP levels increase with age, but patterns do not change (Drayer, Weber, DeYoung, & Wyle, 1982; Egger, Bianchetti, Gnadinger, Kobelt, & Oetliker, 1987; Watson, Stallard, Flinn, & Littler, 1980). The patterns of males and females are similar; however, males have higher levels of BP than females throughout the entire 24 hours (De Guademaris, Mallion, Battistella, Battistella, Siche, Blatier, & Francois, 1987).

BLOOD PRESSURE STATUS

Several early studies compared the ABP patterns of groups of normo­tensives and hypertensives to determine if there is a "hypertensive profile." These studies demonstrated that normotensives and hypertensives display similar patterns, except that hypertensives maintain a higher level of BP throughout both the day and night (Brunner, Waeber, & Nussberger, 1985; Horan, Kennedy, & Padgett, 1981; Pickering, Harshfield, Kleinert, Blank, & Laragh, 1982; Weber, Drayer, Nakamura, & Wyle, 1984). A further study demonstrated that normotensives and hypertensives had similar variability of BP over the course of a day (Harshfield, Pickering, James, & Blank, 1990d).

The only difference between hypertensives and normotensives demon­strated thus far is the pressor response exhibited by hypertensives, referred to as the ''white coat" effect (Pickering, James, Boddie, Harshfield, Blank, & Laragh, 1988). This has been investigated in detail by Mancia and colleagues (Mancia, Parati, Pomidossi, Casadei, Groppelli, Sposato, & Zanchetti, 1985). They measured intra-arterial BP on 16 hospitalized patients visited four times by a physician over a two-day period. BP increased during the first four minutes of the visit, when BP was also measured using standard techniques, and then declined throughout the rest of the visit. Similar results were found for each of the four visits, suggesting the doctor-elicited rise in BP persisted across time.

The percentage of individuals in a clinical population who display white coat hypertension has been investigated in two studies. One (Pickering et al., 1988) determined the percentage of patients clinically defined as hypertensive who had ABPs at or below the 90th percentile of a normotensive control group. A total of 21 % of borderline hypertensives and 5% of established hypertensives had ABP values in this range. A second study (White, 1986) supported these findings in patients who had elevated BPs when they were measured by a physician in the clinic but normal self-measured BPs at home. In this study, 68% of the patients had normal levels ofBP (defined as an average BP less than 130/80 mm Hg) once they left the physician's office.

54 CHAPrER THREE

RACE

Racial differences in casual BP are well documented (see Chapter 7). We and others have made the observation that black and white normotensive adults differ in their ABP patterns. One study from our laboratory at Drew University was performed on normotensive black adults (Harshfield, Hwang, & Grim, 1990b). In contrast to the patterns previously observed in white adults (see above), the black adults in this study had similar levels of BP both during the day and night. These findings were confirmed in preliminary studies from other laboratories. One study (Murphy, Nelson, & Elliott, 1988) compared the ABP patterns of 44 blacks to 37 whites. The average daytime BPs of the blacks and whites were equivalent. The blacks, however, had a significantly smaller noctur­nal decline than whites in both SBP (8% versus 14%) and DBP (8% versus 13%). In a second preliminary study (Murphy, Lang, Nelson, Bednarz, & Elliott, 1990), these investigators reported that the "elevated" nocturnal BPs in blacks were associated with greater left-ventricular mass, a measure of hypertensive target organ damage. A study from another laboratory (James, 1990) compared the ABP patterns of 27 black and 83 white women employed in clerical or technical positions at the same institution. The black and white women had similar levels of BP at work and at home. The black women, though, had significantly higher levels of BP at night (109/65 mm Hg versus 104/60 mm Hg).

We extended these findings to adolescents in a study from our laboratory at the University of Tennessee (Harshfield, Alpert, Willey, Somes, Murphy, & Dupaul, 1989). Black and white subjects had similar BPs while awake, with males having higher levels of SBP and comparable levels of DBP relative to females. The patterns while the adolescents were asleep were quite different. Black males had higher levels of SBP while asleep than: (1) white males; (2) white females; and (3) black females. Additionally, black adolescents as a group had higher levels of DBP at night than white adolescents.

AEROBIC FITNESS

Several cross-sectional studies have reported an inverse relationship be­tween physical activity and BP. More importantly, prospective studies have demonstrated that increasing the level of exercise reduces casual BP and BP reactivity (see Chapter 11). Based on these findings, we performed a cross­sectional study that examined the relationship between aerobic fitness and ABP patterns in normotensive adolescents (Harshfield, Dupaul, Alpert, Christman, Willey, Murphy, & Somes, 1990a). The results of this study suggested that aerobic fitness does influence ABP patterns, particularly in blacks. Unfit black subjects had more elevated levels of BP both while awake and asleep than: (1) fit black subjects; (2) unfit white subjects; and (3) fit white subjects.

AMBULATORY BLOOD PRESSURE 55

ELECTROLYTE INTAKE AND REGULATION

An association between electrolyte intake, regulation, and BP has often been demonstrated (see Chapter 13). Guyton has proposed that the purpose of the long-term control of BP is to maintain the osmolality of body fluids for the regulation of volume homeostasis (Guyton, 1987). This is accomplished by the renal-body fluid system (Guyton's terminology), which is based on two ob­servations. First, an increase in BP increases the kidney's excretion of both water (pressure diuresis) and sodium (pressure natriuresis), leading to de­creases in extracellular fluid volume and blood volume. The decrease in blood volume reduces cardiac output, which lowers BP. The second observation is that a drop in BP increases the kidney's reabsorption of both water and sodium. This increases extracellular fluid volume and blood volume. Increasing blood volume increases cardiac output, returning BP to normal.

There is considerable human and animal evidence that supports this model (Guyton, 1987) and has led to the identification of groups in whom the equilib­rium point for sodium balance is set at a higher level of BP. These are best demonstrated by the classic series of studies by Weinberger and colleagues (Weinberger, Miller, Luft, Grim, & Fineberg, 1986). Briefly, these studies demonstrated that blacks and individuals over the age of 40 have difficulty in excreting a large sodium load, resulting in elevated BPs maintained for a longer period of time in order to achieve sodium balance. Furthermore, the BP of these groups increases even in response to a lesser sodium load, characteristic of individuals refeITed to as salt-sensitive. Falkner and colleagues extended these findings to adolescents, demonstrating that subjects who were both salt-sen­sitive and had a family history of hypertension had the greatest responses to sodium loading (Falkner, Kushner, Khalsa, Canessa, & Katz, 1986). Addition­ally, the cOITelation between the change in BP and sodium excretion was negative and significant but only for salt-sensitive subjects (Falkner, 1990).

Results from one of our recent studies suggest that sodium intake is an important determinant of ABP profiles in children and adolescents (Harshfield, Alpert, Pulliam, Willey, Somes, & Stapleton, 1991). A significant interaction between race and sodium excretion was found for both casual SBP and SBP during sleep. For black subjects, the slope between BP and sodium excretion was positive and significant for casual SBP (b = 0.17) and SBP during sleep (b = 0.08). In contrast, sodium excretion was not related to either casual SBP or SBP during sleep for white subjects. Although the interaction between race and sodium excretion was not significant for SBP while awake, the slope be­tween sodium excretion and SBP was positive and significant for black subjects (b = 0.08) but not for white subjects. The results of this study support the research cited above that demonstrated a stronger relationship between casual BP and sodium in black subjects, extending these findings to BP both while awake and while asleep.

56 CHAPrER THREE

SYMPATHETIC NERVOUS SYSTEM

The influence of the sympathetic nervous system on ABP patterns has also been demonstrated in two clinical populations. Pheochromocytoma is a tumor of the adrenal medulla or sympathetic paraganglia that chronically or inter­mittently secretes epinephrine and norepinephrine. This results in hyperten­sion that is curable with treatment or removal of the tumor. As such, sympa­thetic nervous system activity is directly responsible for this form of hypertension. Two studies have examined the ABP patterns of subjects with pheochromocytoma, with discrepant results. In one (Littler & Honour, 1974), the BP of two of three patients remained at awake levels during sleep but declined significantly following the removal of the tumor. In the other study (Imai, Abe, Miura, Nihei, Sasaki, Minami, Munaka, Taira, Sekino, Yamakoshi, & Yoshinaga, 1988a), pheochromocytoma patients had a normal nocturnal de­cline in BP.

Heart transplant patients are a second group of patients with abnormal ABP patterns (Reeves, Shapiro, Thompson, & Johnson, 1986). Once again, the nocturnal BP is either similar to or higher than awake levels of BP in these patients. In part, this can be attributed to the loss of the sympathetic nervous system regulation resulting from cardiac denervation.

RENIN-ANGIOTENSIN SYSTEM

Renin is an enzyme that is secreted primarily from the kidneys in response to several factors, including an increase in sympathetic nervous system activity and a decrease in renal perfusion pressure. Renin converts angiotensin I into its active form, angiotensin II, which can raise BP by a variety of mechanisms (Hall, Guyton, Coleman, Woods, & Mizelle, 1987). These mechanisms include vasoconstriction of the resistance vessels, activation of the sympathetic nervous system, and potentiation of circulatory responses to sympathetic nervous sys­tem stimulation. Additionally, angiotensin II influences the control of volume homeostasis by activation of the thirst centers, by directly affecting the proxi­mal tubules to increase sodium reabsorption, and by stimulation of aldosterone secretion (see below).

Two studies examined the relationship between renin and ABP patterns in a hospital setting under ambulant conditions. The results of these studies are contradictory. The first (Watson et al, 1980) performed a log transformation on values of plasma renin activity and correlated these with the level and vari­ability of awake BP. Significant positive correlations were found but only after plasma renin activity was adjusted for age. In the second study (Chau, Cha­nudet, & Larroque, 1990) upright plasma renin activity was correlated with both the 24-hour mean BP and the difference in BP from awake to asleep. In contrast to the first study, the correlations were negative.

AMBULATORY BLOOD PRESSURE 57

In a recent study (Harshfield, Pulliam, Alpert, Stapleton, Willey, & Somes, 1990c), we examined the relationship between renin-sodium profiles and ABP patterns in healthy children and adolescents under normal conditions. We first developed a renin-sodium nomogram for children and adolescents similar to the nomogram developed by Laragh for hypertensive adults (Laragh, 1987). The subjects were then classified as low, intermediate, or high renin based on the relationship between their plasma renin activity and sodium excretion. All of the subjects had comparable casual SBP and DBP. The three groups also had comparable levels of SBP and DBP while they were awake. The subjects classified as high renin, however, had: (1) higher levels of SBP while asleep than subjects classified as low renin; (2) smaller declines in SBP from awake to asleep than subjects classified as intermediate renin; (3) higher levels of DBP at night than subjects classified as intermediate renin; (4) a tendency to show higher levels of DBP at night than subjects classified as low renin; and (5) greater variability of DBP at night than subjects classified as either inter­mediate or low renin.

HYPOTHALAMo-PlTUITARy-AnRENAL SYSTEM

The hypothalamo-pituitary-adrenal system is responsible for the regula­tion of a number of physiological and behavioral processes that either directly or indirectly influence BP (Guyton, 1986). Cushing's syndrome is a disease of this system that is caused by excessive secretion of cortisol by the zona fas­ciculata and zona reticularis of the adrenal cortex, resulting in excessive blood glucose concentration. This.in turn disrupts the normal circadian rhythm of the hypothalamo-pituitary-adrenal system, which may affect sympathetic nervous system activity. Three studies have reported that patients with Cushing's syndrome have abnormal ABP patterns (Baumgart, Walger, Dorst, Eiff, Rahn, & Vetter, 1989a; Imai, Abe, Sasaki, Minami, Nihei, Munakata, Murakami, Matsue, Sekino, Miura, & Yoshinaga, 1988b; Munakata, Imai, Abe, Sasaki, Minami, Sekino, & Yoshinaga, 1988). In each of these studies, the nocturnal BP of Cushing's patients either remained at, or increased above, awake levels.

Aldosterone is mineralocorticoid secreted from the zona glomerulosa of the adrenal cortex. At least three conditions lead to the secretion of aldosterone, including: (1) increased potassium ion concentration of the extracellular fluid; (2) increased circulating levels of angiotensin II (see above); and (3) decreased total body sodium. This can only occur in the presence of adrenocorticotropic hormone, however, aldosterone promotes sodium reabsorption at the level of the walls of the renal tubules and thereby increases extracellular fluid volume and BP, as described above.

Primary aldosteronism is a disease of the hypothalamo-pituitary-adrenal system that is due to a tumor of the zona glomerulosa. Three studie~ have performed ABP recordings on patients with primary aldosteronism, with con-

58 CHAP1'ER THREE

tradictory results. One study reported nonnal ABP patterns in these patients (Imai et al, 1988b) while two reported that nocturnal BP in these patients either remained at or increased above awake levels (Baumgart et al, 1989a; Tanaka, Natsume, SIu"bata, Nozawa, Kojima, Tsuchiya, Ashida, & Ikeda, 1983).

SUMMARY AND CONCLUSIONS

In summary, all of the factors responsible for individual differences in both casual BP and BP reactivity are potentially responsible for individual differ­ences in ABP patterns. Only a few of these factors have been investigated thus far, often with contradictory results.

Three lines of research have demonstrated the importance of continued studies in this area. First, several studies have demonstrated the superiority of ABP patterns over casual BP for the prediction of target organ changes, including left-ventricular mass (Pickering, Harshfield, Devereux, & Laragh, 1985), arterial distensibility (Asmar, BruneI, Pannier, Lacolley, & Safer, 1988), and levels of microalbumin (Giaconi, Levanti, Fommei, Innocenti, Seghieri, Palla, Palombo, & Ghione, 1989; Opsahl, Abraham, Halstenson, & Keane, 1988). Second, studies have found poor associations between ABP patterns and both casual BP and BP measured during either physical or psychological stress testing (Pickering & Gerin, 1988), suggesting these are not acceptable alter­natives to ABP monitoring. Finally, recent studies have demonstrated individ­ual differences in ABP patterns despite similar levels of casual BP (see above). These differences have helped to elucidate our understanding of the role that various mechanisms play in the development of hypertension.

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AMBULATORY BLOOD PRESSURE 59

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60 CHAPl'ER THREE

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AMBULATORY BLOOD PRESSURE 61

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Weber, M. A, Drayer, J. I. M., Nakamura, D. K., & Wyle, F. (1984). The circadian blood pressure pattern in ambulatory normal subjects. American Journal o/Cardiology, 54, 115-119.

Weinberger, M. R., Miller, J. Z., Luft, F. C., Grim, C. E., & Fineberg, N. (1986). Definitions and characteristics of sodium sensitivity and blood pressure resistance. Hypertensian, 8(11), 11127-11134.

White, W. B. (1986). Assessment of patients with office hypertension by 24-hour noninvasive ambulatory blood pressure monitoring. Archives 0/ Internal Medicine, 146, 2196-2199.

CHAPTER FOUR

The Ecological Validity of Laboratory Stress Testing

LORENZ J. P. VAN DOORNEN AND J. RICK TURNER

INTRODUCTION

Hyperreactivity of the cardiovascular system has been implicated as a risk factor for the future development of hypertension and coronary heart disease. At the present time, this assertion has the status of a plausible hypothesis; confirmation, or otherwise, rests with the outcome of longitUdinal studies, such as those discussed in Chapter 15. Since it will be several years before data from some of these studies are available, where should attention be directed in the interim? One strategy is to focus on the relationship between responses seen in the laboratory and those evidenced in real-life situations.

It is of great importance to determine whether reactions to laboratory stressors have predictive validity for reactivity to Stressors in daily life. If cardiovascular reactivity has some role in the etiology of hypertension or cor­onary heart disease, it will have its effects in the periods that persons are exposed to stressful situations in daily life. So the question is, does a "hot reactor" to lab stressors also show exaggerated reactivity to naturally occur­ring stressful situations?

The limits of the predictive validity of lab stress reactivity for the response to real-life stress are set by its reliability over time and by its consistency across

LORENZ J. P. VAN DOORNEN • Division of Psychophysiology, Free University of Amsterdam, Amsterdam, The Netherlands 1081 HV. J. RICK TuRNER • Department of Psychiatry, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599-7175.

63

64 CHAPTER FOUR

lab stressors (see Chapter 1). In the present context, however, there is another very important reliability problem that is often neglected: How reliable is the criterion that we are trying to predict? In other words, is blood pressure reactivity to real-life stress, or blood pressure variability in daily life, a stable personal characteristic? Although we will focus in this chapter on the "state of the art" concerning the lab/real-life connection, it is good to realize that the reliability problem is closely connected to the problem of ecological validity of lab stressors.

A reasonable number of studies has been undertaken in this field. Most of them addressed the simple empirical question of whether reactions to lab tasks are correlated with either blood pressure levels or variability during ambula­tory monitoring in daily life. The basis of their belief that a correspondence should be found is the assumption that reactivity or lability is a characteristic of the cardiovascular system that will express itself in a similar way in response to a broad range of stimuli. The laboratory stressor is supposed to function as a kind of test stimulus that will reveal this characteristic. This reactivity to the test stimulus would reflect the general reactivity of the organism and, there­fore, also be evident in response to naturally occurring events. This is what Manuck and Krantz (1984) have called the ''recurrent activation model": strong responses in the lab are predictive of strong responses to real-life events. This model predicts a correlation between reactivity to lab stressors and variability (as a reflection of repeated strong reactions to natural events) of the parameter in daily life. In addition, several studies have tried to find a relation between lab reactivity and mean level during the ambulatory period. This expectation is based on the idea that continuous exposure to daily events will lead to a generally higher activation level at daytime. This is what Manuck and Krantz (1984) called the "prevailing state model."

Although rarely expressed explicitly, most studies discussed in this chap­ter have taken one of these models as their starting point. We have therefore taken this implicit choice of one of these models as a global criterion of grouping the studies available. Accordingly, then, they may be grouped as follows:

1. Studies looking for a connection between lab reactivity and self-moni­tored casual blood pressure in daily life.

2. Studies exploring the relationship between lab reactivity (or task level) and average ambulatory level. Some of them specify periods of daily activity, either quite global (e.g., sleep, home, or work) or more detailed, by way of subjects' diaries.

3. Studies looking for the relationships between lab reactivity and both average ambulatory levels and variability.

4. Studies specifically directed at measuring blood pressure variability in a detailed way making use of intra-arterial blood pressure measure­ments.

5. Studies that attempted to predict responses to either created or natur-

LABORATORY STRESS TESTING 65

ally occurring, well-defined real-life stressors from the responses in the laboratory.

Because inconsistencies in results may have to do with differences in methodology, information will be presented concerning experimental details (e.g., type of stressors, definitions of reactivity) rather than simply summariz­ing the results. Moreover, this information will enable the reader to compare the success of mental stressors in comparison to physical stressors and to get an impression as to whether reactivity scores and/or task levels are more predictive of real-life parameters than baseline levels.

LAB REACTNITY AND SELF-MONITORED CASUAL BLOOD PRESSURE

One of the earlier studies indicating some correspondence between re­activity to tasks and real-life blood pressure was performed by Manuck, Corse, and Winkelman (1979). The blood pressure response to a frustrating cognitive task bore some relationship to casual blood pressure measurements taken twice daily during working hours across a six-week period in male attorneys. Those men above the median in reactivity to a concept formation task tended to have higher casual peak pressures and significantly larger variability than those men scoring below the median. This applied for systolic pressure but not for diastolic pressure. It is not clear, however, what kind of factors were influencing the casual measurements and thus the variability.

In an experiment reported by Steptoe, Melville, and Ross (1984), three groups of subjects-mild hypertensives, transient hypertensives, and normo­tensives-measured their blood pressure twice on four occasions daily across a period of 12 days. In the lab, they were exposed to two active coping tasks (Stroop test and video game) and a passive coping task (movie). The mean self-monitored systolic blood pressure level was significantly correlated with systolic blood pressure and diastolic blood pressure reactivity to the active coping tasks but not to their reaction to the passive coping task. Because correlations were calculated across groups, and the hypertensive groups had both higher self-monitored levels and stronger reactions to the active coping tasks, these correlations may have a spurious character and may not be com­parable to those obtained within a normal, that is, homogeneous, group.

In a study by Johnson (1989), 24 students monitored their blood pressure daily in the morning and in the evening for a period of four weeks. Their blood pressure and heart rate reactions to two mental challenges in the lab were also assessed. Laboratory baseline systolic pressure accounted for most of the variance in home systolic pressure. Neither systolic blood pressure task levels nor responses (change scores) contributed to the prediction. Heart rate task levels explained about 5% of the variance in home systolic pressure. Diastolic

66 CHAPl'ER FOUR

pressure baseline accounted for most of the variance of diastolic pressure home levels. Some contribution remained for diastolic pressure and heart rate task levels but not for change scores. Considering the number of regression analyses performed on this small subject group, some chance findings are to be expected.

Even neglecting the methodological flaws in the three studies cited, their results do not furnish convincing evidence that it is useful to do lab stress testing for predicting casual self-measured blood pressure. Johnson's (1989) study showed that task levels do contribute to prediction a little but reactivity not at all. Even when a relation between task reactivity and casual measure­ments is present, however, as in Manuck et 01 's (1979) study, this does not show more than the fact that blood pressure level and reactivity are not completely independent phenomena. It would be of interest to show that specifically stress­ful days or stressful periods during a day would be predicted better by re­activity than would relaxed days or relaxed daily periods.

LAB REACTMTY AND AVERAGE AMBULATORY LEVELS

Studies aimed at predicting ambulatory levels from laboratory data implic­itly take the prevaiIing state model as their theoretical basis: reactive subjects in the lab will show higher average levels in daily life. Some of the studies seem to avoid the question as to whether relatively stressful periods would be better predicted by task levels or reactivity than more relaxed periods such as sleep, despite the data having seemingly been available.

Giaconi et 01 (Giaconi, Palombo, Marabotti, Genovesi-Ebert, Volterrani, MezzasaIma, Fommei, & Ghione, 1986) measured ambulatory blood pressure levels for 24 hours. Only data collected during daytime hours were analyzed. Lab tasks consisted of a cold pressor, a mental arithmetic task, an isometric handgrip, an orthostatic test, and bicycle exercise. All tests were repeated after one month. Laboratory blood pressure baselines were significantly correlated with average daytime blood pressure values and were superior to the correla­tions with reactivity scores. The lack of detail in the presentation of the results does not allow a comparison between tasks or a quantitative comparison of the success of the baselines and reactivities.

Morales-Ballejo, Eliot, Boone, and Hughes (1988) measured mean arterial pressure during the work period and at home in a heterogeneous group of subjects, including both normotensives and hypertensives (n = 28). In the lab, a video game, a mental arithmetic task, and the cold pressor were applied. The correlations between lab resting level and video task level with ambulatory working time readings were identical (r = 0.78). The correlation between the maximal mean arterial pressure during the stressors and maximum ambula­tory level was 0.85. This study shows that using stress levels leads to minimal improvement, compared with use of baseline levels, in predicting ambulatory levels. The size of the correlations may be somewhat inflated because they were

LABORATORY STRESS TESTING 67

calculated across nonnotensives and hypertensives. No separate results for the tasks used were presented, and the crucial question as to whether work and home levels were related differentially to lab task levels was not answered

McKinneyet al (McKinney, Miner, Ruddel, McIlvain, Witte, Buell, Eliot, & Grant, 1985) subjected 60 middle-aged subjects to a video game, a reaction time task, and a cold pressor test; subjects also had their blood pressures measured ambulatorily at home and at work. The lab session was repeated after a three-month interval. Systolic blood pressure levels during all tasks in both sessions were significantly correlated with both home and work systolic levels. The correlations for diastolic pressure were lower than for systolic pressure but mostly significant. For both systolic blood pressure and diastolic blood pressure, the correlations with work levels were somewhat higher than with home levels. No clear task specificity with respect to the correspondence was found: the cold pressor did as well as the active coping tasks in this respect. The stress task levels of blood pressure were more strongly related to average work blood pressure than casual office measurements. It is a pity that this study does not give the results for reactivity scores and for laboratory baseline levels.

A later study by Ironson et al (lronson, Gellman, Spitzer, Llabre, de Carlo Pasin, Weidler, & Schneidennan, 1989) did examine this crucial question of the relative value of task levels, reactivity scores, and baselines in predicting ambu­latory values. A large and heterogeneous group of subjects were tested: 119 subjects, including whites and blacks, males and females, and nonnotensives and mild hypertensives. They were exposed to two mental stressors (Type A-B interview and a video game) and two physical stressors (exercise and cold pressor). Blood pressure task levels of the interview and the video game corre­lated well with home and work average ambulatory pressure (coefficients around 0.60 were reported). Correlations of cold pressor levels were, albeit a bit lower, also significant (around 0.50). The levels during exercise correlated least well with ambulatory values (coefficients were between 0.20 and 0.30). Though the correlations with task levels look promising, the highest correlations were found between baseline values and ambulatory levels, thus questioning the purpose of applying stress tests. As stated, this study raised the question of whether reactivity scores would add predictive infonnation. Using multiple regression, minimal supportive evidence was obtained. An exception to these negative results was found when blacks and whites were analyzed separately. In blacks, the diastolic pressure cold pressor level contributed significantly to the prediction of work diastolic pressure. This is an interesting observation because the cold pressor triggers an alpha-adrenergic response, and vascular processes may be relatively more involved in the etiology of hypertension in blacks than in whites. This suggests that the correspondence between lab and real-life blood pressure may depend on whether the physiological mechanism that is triggered by the lab task is the same process underlying blood pressures in real-life situations. The data do not suggest that it is specifically the stress aspect of ambulatory levels that is predicted by laboratory stressors. Although

68 CHAPl'ER FOUR

work blood pressure was higher than home blood pressure, this may have been due to physical activity differences. Moreover, the correlations of task levels with home and work levels did not differ, and baselines predicted work levels as well as home levels.

A parallel kind of experiment was done by Fredrikson et al. (Fredrikson, Blumenthal, Evans, Sherwood, & Light, 1989). Their ambulatory data could be explored in more detail because diaries allowed separation of periods on the basis oflevel of physical activity and amount of perceived stress. Blood pressure was measured ambulatorily in 55 subjects during normal activities at home and at work. Subjects also performed a mental arithmetic task in the lab. They were grouped by median-split on the basis of level or reactivity of blood pressure or heart rate in the lab. The systolic levels during the mental arithmetic task were consistently related to levels during all daily conditions. Interestingly, the largest correlations occurred for periods of physical activity and the smallest for periods of high perceived stress. This poses the question of what the levels during mental stress tasks in the lab actually predict. Laboratory systolic pressure baseline was less consistently related to ambulatory levels; moreover, this relationship was not more pronounced with ambulatory resting conditions than other conditions. Systolic blood pressure reactivity to the task was not related to systolic pressures during any daily life condition. For diastolic pres­sure, a reverse pattern occurred, in the sense that laboratory baselines were more consistently related to ambulatory levels than were task levels. For heart rate, both baseline levels and task levels correlated with ambulatory heart rate at work and during physical activity. Neither diastolic blood pressure nor heart rate reactivity were related to ambulatory levels. This study, as well as the others, shows that reactivity to lab tasks is unrelated to levels during daily life, undermining the ''prevailing state" model. Stress levels are pretty well corre­lated with ambulatory levels but hardly better than baseline levels, again questioning the purpose of stress testing in the prediction of real-life levels of blood pressure. A further differentiation of daily periods of high or low stress or physical activity did not reveal a better prediction on the basis of correspond­ing states in the lab. In other words, stress levels are not specifically related to levels during work periods or periods subjectively assessed as being stressful.

STUDIES PREDICTING BOTH REAL-LIFE VARIABILITY AND/OR AVERAGE LEVELS

Several studies have investigated the prediction of both average level and some parameter of variation of blood pressure or heart rate during the ambu­latory period. Variations are sometimes defined as standard deviations of a series of measurements in certain periods or as differences in level between periods that are supposed to differ in amount of stress or activation: work versus home, awake versus asleep, and so on. Southard et al. (Southard, Coates,

LABORATORY STRESS TESTING 69

Kolodner, Parker, Padgett, & Kennedy, 1986) took a 24-hour measurement of blood pressure and heart rate and had the subjects perform an arithmetic task in the lab. Systolic reactivity to the task was correlated with average systolic pressure level, but the correlation with the waking period was of the same magnitude (0.44) as with systolic level during sleep (0.39). So, the correlation is not "stress specific" but merely a reflection of the general dependency of reactivity on baseline. This may be due to the inclusion of "potential hyper­tensive subjects" who may have both elevated baseline and exaggerated re­activity. The lab baseline of diastolic pressure and heart rate correlated significantly with ambulatory levels, but their reactions did not. The usefulness of stress testing was not demonstrated because lab reactivity was not related to variability of ambulatory blood pressure (SD); moreover, the correlations between laboratory baseline and ambulatory levels were much higher than for reactivity. An interesting observation was that ambulatory blood pressure levels during the day were specifically correlated with a cluster of subjective ratings reflecting ''negative affect": worried, tense, hostile, and depressed.

Harshfield et al. (Harshfield, James, Schlussel, Yee, Blank, & Pickering, 1988) investigated the associations between task levels and reactivity in the lab and levels and several indices of pressure changes over the day. One hundred thirteen (113) hypertensive patients performed an exercise test and 51 of them a set of two active coping tasks (a mental arithmetic task and a video game). The average clinical pressure and pretask baselines correlated around 0.70 with both average work and home pressures. About the same level of correlations emerged for the levels during the active coping tasks. Levels during exercise showed much IQWer correlations with daily levels. Variations in blood pressure during the day were expressed as differences in level between work and home, clinic and home, work and clinic, and as the standard deviation of all pressures during the 24 hours of measurement. The reactivity to the tasks was unrelated to these parameters, so the levels during the active coping task did not perform better than pretask baselines in the prediction, and reactivity scores failed to predict ambulatory variations.

Langewitz, Ruddel, Schachinger, and Schmieder (1989) also studied a large group of hypertensive patients during 24 hours. Daily variation in blood pressure was studied in more detail than in the previous study. The 24-hour period was split up into morning, first and second work periods, evening, late evening, and night. For the full 24 hours, and for each of the separate periods, the following variables were calculated: mean and standard deviation, coefficient of variation, maximum, minimum, and range. In the lab, a mental arithmetic task and a cold pressor test were applied. Lab baseline heart rate correlated around 0.40 with heart rate levels in all periods of measurement. The correlations for levels during mental arithmetic were lower than this value and the levels during the cold pressor higher than this value. The expectation that task levels would specifically correlate with the active working period, and baseline levels with the sleeping period, was not fulfilled. Correlations between

70 CHAPl'ER FOUR

lab levels of blood pressure and ambulatory levels were generally lower than for heart rate. Baseline levels and task levels showed the same size of correlations (between 0.20 and 0.50) with ambulatory levels. Blood pressure during tasks correlated only marginally better with blood pressure at work than with blood pressures during sleep. Correlations between reactivity scores and the mea­sures of variability showed an inconsistent pattern. The systolic pressure and heart rate reactions to mental arithmetic showed moderate correlations (be­tween 0.30 and 0.40) with variability in systolic pressure during the measure­ment period. Again, there was no specific relation between task or resting levels in the lab and corresponding periods, work and sleep, in the field.

It is crucial to discover to what extent these moderate correlations be­tween lab and real life are due to the failure of measuring reliably someone's ''reactivity'' in a single session. McKinney and colleagues (1985) repeated the lab session and found variation in correspondence with ambulatory values between sessions. Van Egeren and Sparrow (1989) extended this approach by repeating both the lab and the ambulatory measurement. In two sessions, separated by about one month, the reactions of heart rate and systolic and diastolic pressure were measured on mental arithmetic, a memory task, and two physical stressors (an isometric handgrip and the cold pressor). Twenty­four-hour ambulatory blood pressure monitoring was performed on two work­days. Subjects kept a diary to score their activities. The test-retest reliabilities of both lab and ambulatory values appeared to be low. Reactivity to real-life situations was defined as variability awake, work minus lab resting level, and mean home minus lab resting level. Seven out of 36 correlations were significant. Systolic and diastolic pressure reactivity to the cold pressor corre­lated positively with ambulatory variability (r = 0.34 and 0.43). The diastolic pressure reaction to the memory test was related to increases in diastolic pressure at home and at work. The reactivity on the first test day was unrelated to ambulatory parameters on the second stress day. This points to the possi­bility that a correspondence between lab and ambulatory parameters only has a chance to occur when both sessions are close in time, a common physiological state of the organism in a certain period being the reason for finding a cor­respondence. Even given this, the portion of ambulatory reactivity accounted for by laboratory reactivity was small. In the best case, the diastolic pressure response to cold pressor explained 19% of diastolic pressure variability in the natural environment. Correcting for the influence of physical activity slightly increased the correlations.

It may be surprising to note here that the cold pressor, being mainly a physical stimulus, was more successful than the mental tasks. This study shows that the problem of reliability, of both lab and ambulatory measurements, may be one of the reasons for the disappointing results of studies done so far. Recent studies have focused on other possible reasons for the moderate results. One improvement may be achieved by better defining the two phenomena that are being compared. Concerning the definition of reactivity to laboratory stressors,

LABORATORY STRESS TESTING 71

two problems prevail: first, the choice of a reference baseline value and, second, the way of defining the response. Two recent studies investigated the influence of these factors on the lab/real-life connection. Concerning the baseline prob­lem, Obrist (1981) pointed out the need of defining a "true baseline." The custom of taking pretask baseline may underestimate the reactivity of hyper­reactive persons because they tend to demonstrate anticipatory increases be­fore the task and thus have higher pretask baselines. A recent study by Pollak (1991) investigated the influence of this factor. Heart rate responses to a video game, a mental arithmetic task, and a reaction time task were defined both in reference to pretask base level and in reference to level during sleep. Ambu­latory heart rate variables were: mean, minimum, and maximum (five lowest and five highest minutes), standard deviation, and ''mean square successive differences" (of all minutes) for the waking period. Activity level was measured by an activity sensor, allowing a separate analysis of active and passive periods. The main result was that task responses defined in the traditional way (task minus pretask level) were not correlated with ambulatory variables, whereas significant correlations were observed when task responses were defined as the difference from (sleeping) baseline. For correlations based on all ambulatory minutes, task responses correlated about 0.40 with mean and minimum ambu­latory heart rate but not with indices of variability. Correlations between task responses and heart rate parameters for the inactive periods were higher (between 0.40 and 0.50) and also significant (but low) with the ''mean square successive difference." The standard deviation never correlated significantly with task responses.

Though this study points to the importance of choosing a correct baseline, it does not show convincingly its relevance. The correlations are spurious in the sense that both task and ambulatory levels are expressed as differences with respect to the same baseline. A task response defined as the difference between task level and sleeping base level includes both the difference between sleeping and pretask level and the net task response. What proportion of the variance in task level is due to these two components is unclear. Maybe the difference between sleep and pretask heart rate (the latter corresponding roughly to casual determinations of average heart rate) correlates as well with ambulatory parameters as task minus sleep differences. In contrast, the data point to the relevance of excluding periods of physical activity from the ambulatory data. This procedure increased the correlations, although only to moderate levels (around 0.40).

A recent study by Johnston, Anastasiades, and Wood (1990) explored in more detail the effect of refining the definitions of both lab and real-life reac­tions. The standard deviation of ambulatory heart rate is a raw representation of the type of variability (a measure similar, but not equivalent, to reactivity) to events that one is trying to predict. It includes both 'acute responses and long-term trends. In this study, an autoregressive technique was applied to allow for the influence of physical activity, as measured by EMG recorded from

72 CHAP1'ER FOUR

the thigh, and for the serial dependency of the heart rate data. The responses to lab tasks were defined both in the traditional way (task minus pretask levels), as simple peak responses (maximum 10-second-period heart rate minus pre­task level), and as a so-called "HR index." The latter represents the ratio of the peak response to the tasks and the peak during bicycle exercise. This resembles the definition of a stress response as an "additional response," that is, that part of the response exceeding the present metabolic requirements (Blix, Stromme, and Ursin, 1974). Subjects performed two active coping tasks (a video game and a mental arithmetic task), the cold pressor test, dynamic exercise, and an isometric handgrip. Ambulatory heart rate responsiveness was expressed in four different ways: the difference between waking and sleeping heart rate; the simple standard deviation; the standard deviation after correction for serial dependency; and the standard deviation after correction for both serial depen­dency effects and activity level. The task responses as defined by average responses or by simple peak responses were not related to any of these mea­sures of heart rate responsiveness in the field. The "HR active coping index," however, correlated with awake-asleep heart rate increases (r = 0.35) and the three indices of ambulatory heart rate variability (r = 0.44, 0.50, and 0.36). None of the heart rate response indices to the cold pressor or to isometric or dynamic exercise was related to heart rate responsiveness in the field.

The same research group also reported the results of another study that took the same approach (Anastasiades, Clark, Salkovskis, Middleton, Hack­man, Gelder, & Johnston, 1990). A group of panic-disorder patients was con­fronted with a series of standard laboratory stressors and some anxiety-pro­voking tasks particularly relevant for this patient population. Peak heart rate responses to active coping and anxiogenic tasks correlated with ambulatory heart rate variability after serial dependency (r = 0.59), and both serial depen­dency and physical activity were taken into account (r = 0.49). In contrast to their first study, neither the correlation with simple heart rate standard devia­tion nor the one with sleep-awake difference was significant. Moreover, it did not matter whether the peak response was defined in a simple way or, as in the previous study, was considered in relation to the peak response to exercise. These studies specifically suggest that peak reactions to active coping tasks are predictive of real-life heart rate variability. It is not clear to what extent this result depends on the way a peak response is defined, either in a simple way or as an "additional response." In the first study, the "additional response" is superior while in the study with panic patients there is no difference. No results are mentioned for the case where the traditional average response is defined in relation to the average heart rate response to exercise (this being the conven­tional definition of an additional response). The precise meaning of the re­activity index as defined is unclear, and the possible influence of aerobic fitness on the response definition (having the heart rate response to exercise as one of the components) cannot be excluded.

LABORATORY STRESS TESTING 73

Concerning the definition of real-life ambulatory variability, the results do not seem to demonstrate a considerable benefit of employing a more complex definition. In the first study, the three definitions of variability correlated about 0.80 with each other, and correlations of lab reactivity with the standard devia­tion of the raw heart rate series were barely lower than for variability as defined with the autoregression techniques. In contrast, in the study with panic patients, the autoregression definitions of variability seem to be superior. Nev­ertheless, this approach is certainly the way to explore the factors influencing the lab/real-life relationship. The main problem, however, is that even after this very sophisticated handling of data, the correlations, although significant, re­mained rather low. Only a small proportion of the variance in ambulatory heart rate is described by the response to lab stress. The question of what aspect of real life actually is predicted is illustrated by the fact that the subjective report of stress and arousal of the subjects was unrelated to heart rate variability measures, and so partialling out this effect did not influence the lab/real-life relationship.

STUDIES MEASURING AMBULATORY BLOOD PRESSURE INVASIVELY ON A BEAT-BY-BEAT BASIS

The recurrent activation model predicts that reactions to lab stressors are related to acute reactions to real-life events. Ambulatory blood pressure is usually measured with intervals between 15 and 30 minutes. It is uncertain whether this approach delivers a good representation of the kind of variation in blood pressure that we try to predict from lab reactivity. An ideal approach is recording beat-by-beat variations in blood pressure during prolonged peri­ods. The invasive measurement of blood pressure can furnish this kind of detailed data. An advantage of using patients is that other physiological param­eters are available that may give insight into some common background of lab and real-life reactivity.

Watson, Stallard, Flinn, and Littler (1980) measured blood pressure intra­arterially for 36 hours in hypertensive patients in an open hospital ward. Patients were exposed to three physical stressors: handgrip, cold pressor, and bicycle exercise. In addition to blood pressure, baroreflex sensitivity, plasma renin, and plasma catecholamines were measured. The blood pressure respon­ses to cycling and handgrip did not correlate with ambulatory arterial pressure or variability. The systolic reaction to the cold pressor correlated significantly with ambulatory systolic variability (r = 0.53). There was also some correlation between the diastolic variables (r = 0.43). The cold pressor response was not related to average pressure levels. Systolic ambulatory variability was inverse­ly related to baroreflex sensitivity (r = 0.65) and positively with supine plasma

74 CHAPI'ER FOUR

renin concentration (r = 0.67). Average systolic and diastolic pressure were also significantly correlated with plasma renin. No correlations were observed with resting or exercise levels of catecholamines. Average diastolic pressure level was correlated with noradrenaline levels at rest and during exercise. Because no correlations were reported between cold pressor reactivity and these param­eters, it remains unclear whether one of these observations can explain the correlation between the blood pressure response to the cold pressor and sys­tolic pressure variability.

This positive result for the cold pressor was not replicated in a study by Parati et aL (Parati, Pomidossi, Casadei, Groppelli, Ravogli, Trazzi, Cesana, & Mancia, 1986). They measured blood pressure intra-arterially for 24 hours in 15 normotensive and hypertensive inpatients. In addition to the cold pressor, subjects completed an isometric handgrip test and two mental stressors (mirror drawing and mental arithmetic). Only the mean arterial pressure response to the mirror-drawing task was related to blood pressure variability. The correla­tions increased when only daytime variability was considered, but due to the small number of subjects, the correlations rarely reached significance. Similar results were obtained for heart rate.

In a much larger sample of 56 hypertensive subjects, Floras, Hassan, Jones, and Sleight (1987) recorded intra-arterial blood pressure during 24 hours. Only the daytime period was analyzed. The variability of mean arterial pressure was observed to correlate significantly with the mean arterial re­sponse to a mental arithmetic task (r = 0.26), to a reaction time task (r = 0.53), to isometric exercise (r = 0.38), and to bicycle exercise (r = 0.35). The heart rate responses to the tasks were unrelated to mean arterial response variability. The authors ascribed their more positive results, as compared to those of Parati and colleagues (1986), to having excluded the sleep period in their analyses. With sleep included, the standard deviation includes both short-term variations and day-night differences. Indeed, Parati and colleagues (1986) mention aug­mented correlations when only daytime variability was taken. The main reason for the difference in significance of the results may be the size of the sample studied; the correlations reported in the two studies are of comparable mag­nitude.

The results of these studies using a very detailed invasive measurement of blood pressure show at most moderate correlations between task reactivity and ambulatory blood pressure variability. Mental and physical tasks are equally (un)successful. This may be due to the fact that periods of physical activity are not separated from periods of rest or mental activity. The use of the standard deviation as a measure of variability is quite rough and includes all short-term and long-term influences on blood pressure. One may hardly expect that this compound index of variability can be predicted by the response to short-lasting physical or mental challenges. In two of the studies, patients were measured in the hospital, which may not yield an accurate reflection of true daily blood pressure variations. The crucial question of whether reactivity or task levels

LABORATORY STRESS TESTING 75

add to the prediction of level or variability above the easily obtainable baseline level was not addressed in these studies.

STUDIES PREDICTING THE RESPONSE TO A WELL-DEFINED REAL-LIFE STRESSOR

As we have seen in the studies reported, a main problem is the vague definition of what aspect of the ambulatory data is expected to be related to the reaction to laboratory stress. Is it level or variability, and should variability include short-term and/or longer term changes? When lab tasks are labeled as "stressors," it is reasonable to expect that they specifically will predict response to stress during daily life. Most of the studies, however, simply try to predict overall level or variability without separating periods with and without physical activity. Only some studies asked students to indicate their experienced stress level during the period of monitoring, and they do not show that these periods specifically are better predicted than others by lab stressors.

The most straightforward approach to test whether the responses to lab stressors are predictive of the reaction to real-life stress is to measure the response to a well-defined stressor under more or less standardized conditions. The studies that have taken this approach used either a public-speaking situa­tion or exams to measure real-life stress. For example, in the study reported by Turner, Girdler, Sherwood, and Light (1990), subjects completed four lab­oratory tasks (two mental arithmetic tasks and two speaking tasks) and also a naturalistic stressor, a public presentation given under simulated seminar con­ditions. In this case, not only was the real-life stressor well defined but it was also very pertinent to the subjects (all of whom were medical, dental, or grad­uate students), who had been specifically chosen from a population for whom public presentation of work and interpersonal interactions are an integral part of professional daily life. Nevertheless, despite the relevance of the real-life task, reactivity to the mental arithmetic and speech laboratory tasks was unrelated to blood pressure and heart rate responses to the naturalistic stres­sor.

Matthews, Manuck,and Saab (1986) measured blood pressure and heart rate prior to public speaking in students. Mter an average period of three weeks, their reactions were measured to a serial subtraction and a mirror­drawing task and to a handgrip test. Individuals were divided into two groups according to the median-split of the reactivity of each of the variables measured per task. Reactions were baseline-corrected by covariance analysis. High sys­tolic and diastolic reactors to the subtraction task showed larger elevations in systolic and diastolic pressure in anticipation of the speech compared to the low reactors. Diastolic hyperreactors to the mirror-drawing task showed higher diastolic pressure to the stress of public speaking. High heart rate reactors to

76 CHAPTER FOUR

the handgrip task tended to show a higher heart rate right before public speaking. There thus seems to be some relation between lab reactivity and the response to real-life stress.

This finding, however, was not replicated in a study by Warwick-Evans, Walker, and Evans (1988). They divided subjects according to median-split with respect to their heart rate response to a mental arithmetic task. Neither the heart rate nor the blood pressure levels of the high reactors exceeded the levels of the low reactors when responses obtained just before an exam were com­pared. The lack of standardization in the approach to this problem hampers the comparison of the results. Warwick-Evans et a1. (1988) divided their subjects on the basis of one criterion: the heart rate reaction to the mental arithmetic task (reactions to a cold pressor being neglected), whereas Matthews et a1. (1986) divided their subjects per task per variable. The latter leads to the drawback that all group comparisons are based on different groupings of subjects.

Part of the inconsistency across studies may also be due to the type of tasks chosen; the rationale for selecting tasks is rarely expressed. This is illustrated by the results of Matthews et al. (1986). The correspondence between lab reactivity and the response to public speaking depended on the type of task and, moreover, varied between physiological parameters.

In a recent study (van Doornen & van Blokland, 1991), we obtained the same puzzling result. We tried to predict the responses of 33 healthy young males to a strong and well-defined real-life stressor: the public defense of their doctoral thesis. The heart rate response to a reaction time task correlated well with the systolic pressure level on the stressful day (r = 0.52) and with the difference between the systolic pressure level on the stressful day and a relaxed control day (the real-life stress response; r = 0.58). The same applied to the heart rate response to a cold pressor test. (Both predictions were significantly better than the prediction on the basis of baseline levels.) The heart rate response to another active coping task, however, a video game, was unrelated to the real-life blood pressure values. Another puzzling effect was that the heart rate response to the reaction time task and the cold pressor did not significantly predict the heart rate response to the real-life stress but it did predict the blood pressure response, whereas the systolic pressure response to the tasks did not predict the systolic pressure response to the real-life stressor.

Even this category of studies that tried to measure real-life stress as purely as possible did not provide convincing evidence that reactivity scores are very useful for the prediction of the reaction to real-life stress. Two studies are completely negative (Turner et a1., 1990; Warwick-Evans et a1., 1988) and two are more or less positive (Matthews et a1., 1986; van Doornen & van Blokland, 1991). In the positive studies, it is unclear why some tasks do better than others and why the physiological parameters as measured in real life do not correlate with the reactions in the same parameters in the lab. A more systematic approach is certainly needed in this young area of research.

LABORATORY STRESS TESTING 77

DISCUSSION

The aim of this chapter so far has been to evaluate whether reactivity to laboratory stressors is related to ambulatory physiological levels and/or their variability. A brief summary of the evidence is appropriate here. The "prevail­ing state" model predicts a relation between laboratory reactivity and ambu­latory levels. No conclusive evidence was found for this model. In some studies, reactivity data seemed not to add to baseline data in the prediction of ambu­latory levels; the same conclusion applies to task levels. In instances where a relationship was observed between either reactivity scores or task levels, there was no indication that the relationship was stress-specific. Relationships were at best only slightly stronger for work periods than for measures taken at home or during sleep, and they were not stronger during periods of subjectively reported stress. Also, the stress-specific connection is further undermined by the observations that responses to mental stressors are not more highly asso­ciated with ambulatory levels than those to the cold pressor and, in fact, are sometimes less so. The picture is less negative for the relationship between lab reactivity and ambulatory variability (the ''recurrent activation" model) and for studies focusing on the prediction of reactions to well-defined naturalistic stres­sors. In both cases, some authors reported negative findings while others found some evidence for a relationship. It should be noted, however, that even where positive results were found, there was again no clear superiority of behavioral tasks over the cold pressor.

It appears, then, that there is only moderate evidence for a connection between lab and ambulatory responses. A crucial question at this point is whether this evidence is the result of only a small degree of "generalized reactivity" for an organism across stimulus situations or whether it is influenced by measurement problems. With regard to the former possibility, the existence of a "generalized reactivity" is questioned by the observation that the correla­tions between reactions to different tasks presented in the same lab session are in the range of about 0.3 to 0.7. This can be thought of as somewhat low, especially in view of the fact that the variety among the types of stressors met in real life is much greater than the variety among different lab stressors. Moreover, test-retest reliability coefficients are in the same range. With regard to the latter possibility (i.e., that the moderate association may be influenced by measurement problems), the methodology employed in this area can perhaps be improved. Such improvements can potentially be made in two directions, a ''psychological'' one and a ''physiological'' one; these will be considered in turn.

From the ''psychological'' point of view, a closer correspondence between the psychological meaning of the lab and the real-life situation should arguably increase the predictive validity of the artificial (Le., laboratory) stressor. Ideal­ly, the laboratory task should mimic the type of psychological process (a certain emotion or mental effort) that is responsible for the physiological reaction to the

78 CHAPTER FOUR

real-life situation. That this approach can be successful was recently demon­strated by Houtman (1990), who examined the relationship between the heart rate reactions to a standardized simulated lecturing situation and to a real lecturing situation. The correlation between the heart rate responses in the two settings was 0.7. The limitation of this approach, however, is that it is hardly feasible to simulate in the lab the entire variety of stressful situations that are encountered in daily life. Also, as Pickering and Gerin (1990) noted, if ''it is only possible to demonstrate correlations between very similar activities in the laboratory and real life, the findings will be of comparatively limited interest." The goal of finding a standardized lab task that elicits a response from an individual that is indicative of hislher propensity to react to any stressful situation would then be undermined.

The ''physiological'' direction of improving methodology employed to in­vestigate the connection between lab and ambulatory responses may be the investigation of a common physiological basis of the reactions to lab and real-life situations. The fact that mental stressors do not appear to be superior in their predictive powers to the cold pressor suggests that it hardly matters what kind of stressor is used as long as it results in at least a certain amount of phys­iological activation in a common physiological mechanism. In the study by van Doomen and van Blokland (1991), for example, the data suggest that noradre­nergic reactivity may be the common denominator of the cold pressor and the response to real-life stress. The heart rate response to the cold pressor corre­lated significantly with both noradrenaline stress-day level and with the dif­ference in noradrenaline between control and stress day. The diastolic blood pressure response to the cold pressor correlated significantly with the nora­drenaline response, and diastolic pressure and noradrenaline levels on the stress day were significantly correlated. These findings suggest that the heart rate and diastolic pressure reactions to the cold pressor derive their predictive power for real-life stress values from the fact that the cold pressor serves as a test of the organism's noradrenergic responsivity to stress.

If common physiological mechanisms are responsible for a correspondence between laboratory and real-life responses, they should be explored more explicitly in both situations. For instance, if sympathetic activity is the common denominator of both laboratory and real-life reactivity, the correspondence should disappear when beta blockers are applied. Johnston et aL (Johnston, Anastasiades, Vogele, Clark, Kitson, & Steptoe, in press) suggested confirmation of this idea. Ironson and associates' (1989) result that the cold pressor was more successful in the prediction of real-life blood pressure for blacks suggests that it is necessary to trigger the relevant mechanisms in order to find any correspondence; blacks have been reported to be relatively stronger alpha-adrenergic vascular responders during stress.

Before leaving the theme of common physiological mechanisms, it is some­what disappointing, from the viewpoint that adrenergic reactivity may be the common mechanism of laboratory and real-life responses, to note the observa-

LABORATORY STRESS TESTING 79

tions of Dimsdale (1984) and of van Doornen and van Blokland (1991) that the catecholamine response to laboratory stressors was not related to the cate­cholamine response to real-life stress. The small number of studies currently reported on this topic, however, may not be sufficient to draw firm conclusions, especially in light of the relative difficulty in obtaining accurate catecholamine data in these contexts.

Having considered possible improvements in lab-field methodology in these "psychological" and ''physiological'' directions, several other sources of potential improvement are worthy of comment. One of these concerns the confounding influence of physical activity, which in itself affects physiological parameters. Removing the influence of physical activity may improve correla­tions between lab and real-life situations (Johnston et aL, 1990; Pollak, 1991; van Egeren & Sparrow, 1989). In the van Doornen and van Blokland (1991) study, the real-life stress was encountered in a seated position (the same position in which the tasks were completed), and blood pressure elevations were correlated to the lab reaction time and cold pressor tasks. Relatedly, Sherwood and Turner have recently examined postural effects on blood pressure and hemodynamic responses during stress (Sherwood & Turner, in press; Turner & Sherwood, 1991; see also Chapter 1). While individuals' blood pressure responses in the seated and the standing positions were not related to each other, their hemodynamic (cardiac output and total peripheral resistance) re­sponses were. The ramifications of the latter finding are potentially very in­teresting for studies of lab/real-life reactivity associations. Given that lab test­ing is usually conducted in the seated position but that many of life's stressors are encountered in the standing position, the advent of ambulatory hemody­namic monitoring may reveal cardiac output and vascular resistance associa­tions even in the absence of blood pressure associations (Sherwood, 1991).

The efforts to improve the lab/real-life connection by employing better definitions of both task responses and ambulatory variability look promising, but to date they have not furnished clear-cut conclusions as to what the most appropriate definitions might be. It is conceptually unclear what Johnston and coworkers' (1990) "active coping index" represents, and the improvement evi­dent in their approach of correcting for serial dependency of heart rate data, while encouraging, needs replication. Pollak's (1991) idea of choosing sleep levels as true baseline values is fruitful. Night-day differences seem adequately to summarize the response of the body to exposure to daily life, and this global response may be a particularly relevant parameter as far as the prediction of disease is concerned.

The ultimate goal of measuring stress reactivity is the prediction of future disease development. At the present, the evidence for the predictive power of reactivity is relatively scarce. Falkner et aL (Falkner, Kushner, Onesti, & Angelakos, 1981) demonstrated some predictive power for the development of hypertension of the reaction to a mental arithmetic task in subjects with a family history of hypertension, and Menkes et aL (Menkes, Matthews, Krantz,

80 CHAPrER FOUR

Lundberg, Mead, Quagish, Lian, Thomas, & Pearson, 1989) showed that the cold pressor may have some predictive value. More recently, Light and col­leagues (see Chapter 15) have demonstrated a relationship between lab reac­tions to a reaction time task and blood pressure status ten to fifteen years later. Much more longitudinal research is needed in this area in order to come to more definitive conclusions regarding the association between lab reactivity and later disease development. As was noted right at the beginning of this chapter, however, it will be quite some time before data from some of these studies are available. In the meantime, the study of lab-life generalization, that is, the lab/real-life connection, seems a potentially informative avenue of investigation. It is appropriate here to consider one of the implicit assumptions behind these studies. There is evidence that ambulatory blood pressure levels, especially during work periods, are better predictors of hypertensive complications and mortality than casual office measurements (Devereux, Pickering, Harshfield, Kleinert, Denby, Clark, Pregibon, Jason, Kleiner, Borer, & Laragh,1983; Perl­off, Sokolov, and Cowan, 1983). Given this relationship between ambulatory levels and end-organ damage, if laboratory reactivity is indeed predictive ofthe same endpoint, it might also be expected to relate to ambulatory levels. Of course, it is not essential for the predictive power of reactivity that this lab-life relationship be found; even if lab reactivity and real-life cardiovascular activity are both related to the same end product (established cardiovascular disease), it is not a logical imperative that they be related to each other. It must be admitted, though, that this is not a particularly satisfying argument; it would be nice to observe a lab-life relationship.

Given that the present evidence for this relationship is less than compel­ling, what suggestions for future investigations can be made? Various sugges­tions for improving methodology have already been discussed. In terms of which ambulatory parameter to focus on, it appears that despite the present lack of encouraging results, our efforts should perhaps be directed at predicting average ambulatory levels, rather than ambulatory variability, from laboratory measurements. As noted, these levels are good predictors of morbidity and mortality. While it was originally supposed that blood pressure variability might be a crucial predictor, current evidence suggests that the average level of blood pressure, particularly during waking hours, is more important than variability (Lavie, Schmieder, and Messerli, 1988). This approach is supported by the observation that ambulatory levels have a higher test-retest relia­bility than measures of variability (James, Pickering, Yee, Harshfield, Riva, & Laragh, 1988).

In further efforts to improve the lab/real-life connection, research should also be directed at the choice of laboratory tasks. Ergometric tests are least successful. Mental tests do not seem to be superior to the cold pressor. A focus on the common physiological basis of reactivity to tasks and real-life levels and variations may prove to be a guideline in our future choice of the most success­ful tasks. The results of Watson and colleagues (1980) with plasma renin,

LABORATORY STRESS TESTING 81

Johnston et aL (in press) with beta-blockade, and van Doomen and van Blok­land (in press) with noradrenaline are promising in this respect.

In summary, then, present evidence of a lab/real-life relationship is weak. Various improvements in the strategies employed to investigate this topic may be feasible, however, and future studies may clarify the nature of this presently elusive association.

REFERENCES

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Blix, A S., Stromme, S. B., & Ursin, H. (1974). Additional heart rate: An indicator of psychological activation. Aerospace Medicine, 45, 1219-1222.

Devereux, R. B., Pickering, T. G., Harshfield, G. A, Kleinert, H. D., Denby, L., Clark, L., Pregibon, D., Jason, M., Kleiner, B., Borer, J. S., & Laragh, J. H. (1983). Left ventricular hypertrophy in patients with hypertension: Importance of blood pressure response to regularly occurring stress. Cireulation, 68, 470-476.

Dimsdale, J. E. (1984). Generalizing from laboratory studies to field studies in human stress physiology. Psychosomatic Medicine, 46, 463-469.

Falkner, B., Kushner, H., Onesti, G., & Angelakos, E. T. (1981). Cardiovascular characteristics in adolescents who develop hypertension. Hypertension, 3, 521-527.

Floras, J. S., Hassan, M. 0., Jones, J. V., & Sleight, P. (1987). Pressor responses to laboratory stresses and daytime blood pressure variability. Journal of Hypertension, 5, 715-719.

Fredrikson, M., Blumenthal, J. A, Evans, D. D., Sherwood, A, & Light, K. C. (1989). Cardiovas­cular responses in the laboratory and in the natural environment: Is blood pressure reactivity to laboratory-induced mental stress related to ambulatory blood pressure during everyday life? Journal of Psychosomatic Research, 33, 753-762.

Giaconi, S., Palombo, C., Marabotti, C., Genovesi-Ebert, A, Volterrani, D., Mezzasalma, L., Fom­mei, E., & Ghione, S. (1986). Casual blood pressure, cardiovascular reactivity tests, and blood pressure monitoring in borderline hypertension. Journal of Hypertension, 4(5), 8331-8333.

Harshfield, G. A, James, G. D., Schlussel, Y., Yee, L. S., Blank, S. G., & Pickering, T. G. (1988). Do laboratory tests of blood pressure reactivity predict blood pressure variability in real life? American Journal of Hypertension, 1, 168-174.

Houtman, I. L. D. (1990). Stress and coping in lecturing: A study of stress responses, individual differences and stress moderators. Dissertation, Vrije Universiteit, Amsterdam.

Ironson, G. H., Gellman, M. D., Spitzer, S. B., Llabre, M. M., de Carlo Pasin, R., Weidler, D. J., & Schneiderman, N. (1989). Predicting home and work blood pressure measurement from resting baselines and laboratory reactivity in black and white Americans. Psychophysiology, 26, 174-184.

James, G. D., Pickering, T. G., Yee, L. S., Harshfield, G. A, Riva, S., & Laragh, J. H. (1988). The reproducibility of average ambulatory, home, and clinical pressures. Hypertension, 11, 545-549.

Johnson, E. H. (1989). Cardiovascular reactivity, emotional factors, and home blood pressures in black males with and without a parental history of hypertension. Psychosomatic Medicine, 51, 390-403.

Johnston, D. W., Anastasiades, P., & Wood, C. (1990). The relationship between cardiovascular responses in the laboratory and in the field. Psychophysiology, 27, 34-44.

Johnston, D. W., Anastasiades, P., Vogele, C., Clark, D. M., Kitson, C., & Steptoe, A (in press). The

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relationship between cardiovascular responses in the laboratory and in the field: The impor­tance of active coping. To appear in T. H. Schmidt, B. T. Engel, & G. Blumchen (Eels.), Tempoml variations of the cardiovascular 81Jstem. Berlin: Springer-Verlag.

Langewitz, W., Rudde!, H., Schachinger, H., & Schmieder, R. (1989). Standardized stress testing in the cardiovascular laboratory: Has it any bearing on ambulatory blood p~ure values? Jqu,'rnm of Hypertensiqn, 7(3),841-848.

Lavie, C. J., Schmieder, R. E., & Messerli, F. H. (1988). Ambulatory blood pressure monitoring: Practical considerations. American Hearl Journal, 116, 1146-1151.

McKinney, M. E., Miner, M. H., Ruddel, H., McIlvain, H. E., Witte, H., Buell, J. C., Eliot, R. S., & Grant, L. B. (1985). The standardized mental stress test protocol: Test-retest reliability and comparison with ambulatory blood pressure monitoring. PBychophysiology, .22, 453-463.

Manuck, S. B., & Krantz, D. S. (1984). Psychophysiologic reactivity in coronary heart disease. Behavioral Medicine Update, 6, 11-15.

Manuck, S. B., Corse, C. D., & Wmkelman, P. A (1979). Behavioral correlates of individual differences in blood pressure reactivity. Joumol of PBycko8O'TTWJ.ic Research, U, 281-288.

Matthews, K. A, Manuck, S. B., & Sasb, P. G. (1986). Cardiovascular responses of adolescents during a naturally occurring stressor and their behavioral and psychophysiological predictors. P81Jchophysiology, U, 198-209.

Menkes, M. S., Matthews, K. A, Krantz, D. S., Lundberg, U., Mead, L. A, Quagish, B., Lian, K. Y., Thomas, C. B., & Pearson, T. A (1989). Cardiovascular reactivity to the cold pressor test as a predictor of hypertension. Hypertensiqn, 14, 524-530.

Morales-Ballejo, H. M., Eliot, R. S., Boone, J. L., & Hughes, J. S. (1988). Psychophysiological stress testing as a predictor of mean daily blood pressure. American Hearl Journal, 116, 673-681.

Obrist, P. A (1981). Cardiovascular psychophysiology: A perspective. New York: Plenum Press. Parati, G., Pomidossi, G., Casadei, R., Groppelli, A, Ravogli, A, Trazzi, S., Cesana, B., & Mancia,

G. (1986). Limitations of lab stress testing in the assessment of subjects' cardiovascular reactions to stress. Joumol of Hypertensiqn, .(6), 851-853.

Perloff, D., Sokolov, M., & Cowan, R. (1983). The prognostic value of ambulatory blood pressures. Joumol of the American Medical Associatio'1l, 2-'9, 2792-2798.

Pickering, T. G., & Gerin, W. (1990). Cardiovascular reactivity in the laboratory and the role of behavioral factors in hypertension: A critical review. Annals of Behavioral Medicine, 12, 3-16.

Pollak, M. H. (1991). Heart rate reactivity to laboratory tasks and ambulatory heart rate in daily life. P81Jcko8O'TTWJ.ic Medicine, 53, 1-12.

Sherwood, A (1991, April 19-21). The use of impedance cardiography in cardiovascular reactivity research. Paper presented at the SUNY/APA Scientific Conference on Cardiovascular Re­activity, Buffalo, New York.

Sherwood, A, & Turner, J. R. (in press). Postural stability of hemodynamic responses during mental challenge. P81Jchopkysiology.

Southard, D. R., Coates, T. J., Kolodner, K., Parker, F. C., Padgett, N., & Kennedy, H. L. (1986). Relationship between mood and blood pressure in the natural environment: An adolescent population. HeaUk PByckology, 5(5),469-480.

Steptoe, A, Melville, D. R., & Ross, A (1984). Behavioral response demands, cardiovascular reactivity, and essential hypertension. P81Jckoscnnatic Medicine, .6, 33-48.

Turner, J. R., & Sherwood, A (1991). Postural effects on blood pressure reactivity: Implications for studies of laboratory-field generalization. Joumol of P81Jckoscnnatic Research, 35, 289-295.

Turner, J. R., Girdler, S. S., Sherwood, A, & Light, K. C. (1990). Cardiovascular responses to behavioral stressors: Laboratory-field generalization and inter-task consistency. Joumol of P81Jckosomatic Research, 34, 581-589.

van Doomen, L. J. P., & van Blokland, A W. (in press). The relationship between cardiovascular and catecholamine reactions to laboratory- and real-life stress. P81Jchophysiology.

LABORATORY STRESS TESTING 83

van Egeren, L. F., & Sparrow, A. W. (1989). Laboratory stress testing to assess real-life cardiova­scular reactivity. Psychosomatic Medicine, 51, 1-9.

Warwick-Evans, L., Walker, J., & Evans, J. (1988). A comparison of psychologically induced cardiovascular reactivity in laboratory and natural environments. J(YUma/, of Psychosomatic Research, 32, 493-505.

Watson, R. D. S., Stallard, T. J., Flinn, R. M., & Littler, W. A. (1980). Factors detennining arterial pressure and its variability in hypertensive man. Hypertension, 2, 233-241.

PART TWO

DETERMINANTS OF INDIVIDUAL DIFFERENCES IN CARDIOVASCULAR RESPONSES

DURING STRESS

CHAPTER FIVE

Genes, Stress, and Cardiovascular Reactivity

RICHARD J. ROSE

INTRODUCTION

People differ in the magnitude and duration of cardiovascular response to stress. Individual reaction to the stressful experience of everyday life and the controlled stressors of laboratory experiments varies substantially. These in­dividual differences are stable over time and across situations (see Chapter 1), and they are associated with one's family history of cardiovascular disease (see Chapter 9). To briefly summarize decades of research, individual differences in cardiovascular stress reactivity aggregate in families and characterize individ­uals. The origin of the differences is due primarily to genetic variation trans­mitted across generations.

When offered some selection among experiences differing in stress, people make different choices. Different people make different decisions at each of life's choice points. The choices people make in their social selection of occupa­tion, education, hobbies, friends, and mates are significantly predicted by their temperamental dispositions. To summarize another research tradition: There are characteristic patterns in a person's social transactions throughout life, and the patterns define a person's lifestyle and personality. As with the variation in stress reactivity, the dispositions that underlie patterns of social transaction are familial and heritable.

RICHARD J. ROSE • Department of Psychology, Indiana University, Bloomington, Indiana 47405.

87

88 CHAPTER FIVE

These vignettes illustrate two processes by which genetic variation con­tributes to stress-disease pathways. Confronted with unifonn stress, people differ in reaction; differential reactivity is a major pathway by which genetic variation modulates effects of stress during the pathogenesis of cardiovascular disease. Conversely, given unifonn life choices, people make different selec­tions, seeking to create environmental opportunities to express their genetic dispositions. Proactive differences in social selection illustrate a transactional pathway by which genetic variation contributes to differences in life-style and stress exposure.

The first pathway I shall call differential reactivity. Its lesson is that no description of a stress-disease relationship is complete without reference to organismic variation in stress response. Different genotypes do not unifonnly react to the same environmental demands, a phenomenon generally described as G x E interaction. People do not unifonnly "react" to stress; some char­acteristically hyperreact, and their exaggerated response alters internal patho­physiology to exacerbate continued hyperresponsiveness. The second pathway I shall call selective transaction. Its lesson is that stressful life-styles do not just "happen" to people: We actively choose most situations to which we are ex­posed, and we alter many situations that we encounter. In so doing, we create opportunities to display the beliefs, attitudes, and behaviors that define our social selves. At a general descriptive level, I refer to the G x E correlation: Genetic differences lead people to seek environmental opportunities in which to express their dispositional tendencies.

In the context of coronary disease, cardiovascular response, and coronary­prone personality, these pathways of gene-disease relationships are largely heuristic. No definitive statements of genetic mechanisms can here be offered, but it is hoped that a consideration of these heuristic pathways may challenge common notions that coronary events "happen" to people, that gene differences are "static," and that coronary-prone personality is a "fixed" temperamental typology. All of our behaviors and each of our characteristic life-styles rep­resent developmental expressions of our unique genetic dispositions. This chapter selectively reviews research findings that illustrate this perspective-a perspective that, for want of a better label, is called developmental behavioral genetics. Several earlier reviews of cardiovascular stress response were written within the framework of behavior genetics (Rose, 1986; Rose & Chesney, 1986); those reviews emphasized familial and heritable contributions to individual variation in stress-response patterns. These contributions are empirically docu­mented and clinically significant, but a narrow focus on stress reactivity invites us to construe all genetic effects as passive in nature. To help correct this limited perspective, I here give equal emphasis to the active (or transactive) effects of heritable variation on individual differences in niche seeking; trans­actional effects are less studied and less well documented but no less important: The stressful life-styles coronary-prone individuals experience may be the creation of their own dispositional tendencies (Rose, 1988, 1990).

GENES, STRESS, AND CARDIOVASCULAR REACTIVITY 89

DIFFERENTIAL REACTIVITY: G x E INTERACTION

AN ILLUSTRATION: GENES AND ALLERGIC REACTIONS

To illustrate the general principle that reactions to standardized stress are conditioned by reactive genetic dispositions, I cite an analysis of twins' reac­tions to stressors relevant to allergic disease. Bronchial reactivity to inhaled methacholine and skin sensitivity to intradermal antigens were studied, and differences in genetic similarity of identical and fraternal cotwins were asso­ciated with differences in similarity of their allergic reactions (Hopp, Bewtra, Watt, Nair, & Townley, 1984). The study serves also as a convenient illustration of the basic logic of the classic twin comparison, widely used in research on cardiovascular stress reactivity. In such research, resemblance of identical cotwins, who are monozygotes (MZ) sharing all their genes (identical by de­scent), is compared with that of fraternal cotwins (dizygotic, or DZ), who like ordinary siblings share, on average, one-half their genes in common. Because MZ twins have a genetic correlation of 1.0 while DZ twins have a genetic correlation of 0.5, the difference in resemblance for representative samples of MZ and DZ twin pairs reflects one-half the genetic contribution to a measured trait. Doubling the difference in MZ and DZ correlations yields, given simplify­ing assumptions, an estimate of the trait's heritability-an estimate of the proportion of observed variation that is attributable to underlying variation in the genes. To assess heritability (h2) of allergic reaction (Hopp et al., 1984), twin pairs were recruited from an outpatient population, public schools, twins clubs, and public appeals; the sample included 61 MZ and 46 DZ twin pairs, ranging in age from 6 to 31, but most were children and adolescents. Cotwins in each of the 107 pairs were tested on the same day (following instructions to tempo­rarily discontinue antihistamine and bronchodilator medication) for their reac­tions to a methacholine inhalation challenge test and intradermal sensitivity to dander of cat and dog, ragweed, mold, and house dust. Bronchial responses to methacholine challenge and diameter of skin reaction to the intradermal anti­gens were measured in each individual. For both variables, average reactions did not differ between MZ and DZ twin individuals but average intrapair differences did. The average difference in intradermal skin test score (lSTS) observed among MZ pairs was 3.58 (±.62); for DZ cotwins, who are half as similar, the corresponding intrapair difference was about double in magnitude: 6.23 (±1.2). The intraclass correlations for ISTS scores were 0.82 for MZs and 0.46 for DZs, suggesting that more than 70% of the individual variation in skin sensitivity is due to underlying genetic variation between the individuals. Bron­chial hyperactivity characterizes asthma, and a predisposition to heightened bronchial responsiveness may be the inherited diathesis for clinical expression of asthmatic disease (analogous to assumptions that heightened cardiovascular responsiveness is a genetic diathesis for coronary heart disease [CHD]). Meth­acholine inhalation challenge provides an index of bronchial responsiveness.

90 CHAPI'ERFIVE

The correlations observed for MZ and DZ twins in this sample (0.67 and 0.34, respectively) match the 2:1 ratio in genetic similarity of MZ and DZ twins; the results are as expected by a simple genetic model, suggesting that bronchial reaction to stress challenge is largely heritable.

CARDIOVASCULAR STRESS REACTMTY: PAST RESEARCH

Observed variation in skin sensitivity or bronchial response to standard­ized challenges is largely due to genetic differences between people, and the same is true for individual differences in susceptibility to most diseases for which known external agents play an etiological role; for example, for measles, leprosy, tuberculosis, scarlet fever, rickets, and many cancers, genetic variance contributes to differential incidence. The literature reveals that different geno­types do not unifonnly react to similar situational demands: G x E interaction. Laboratory studies of genetic contributions to cardiovascular stress reactivity also document G x E interaction (Rose, 1986; Rose & Chesney, 1986; Turner & Hewitt, 1992). Twin family research studies of individual differences in cardiovascular stress reactivity yield evidence of significant genetic contribu­tions to both magnitude and duration of response. Past research is more illus­trative than definitive, for it is characterized by small samples, variations in techniques for recording cardiovascular response, and variation in the protocols for manipulating stress; yet against this background of procedural variation, surprising consistency emerges. In both genders, over a wide age range, and across both physiological and psychological stressors, genetic variance significantly contributes to individual differences in cardiovascular stress re­sponse.

CARDIOVASCULAR STRESS REACTMTY: RECENT AND ONGOING STUDIES

To update this older literature, I selectively review recent studies of rest­ing blood pressure (BP) and heart rate (HR) and of cardiovascular response to laboratory challenge in samples of twin children, adolescents, young adults, and among elderly twin brothers. One strength of these selected studies is their sampling: At baseline testing, the twins ranged in age from the first to eighth decade of life. A second strength of several recent twin investigations is inclu­sion of male-female DZ twin pairs; DZ twins of the opposite sex (OS DZ) permit analyses of gene x gender interactions, which are of great interest given gender differences in the prevalence of coronary disease. A third feature of several recent studies is that they include data not only on BP and HR but also on other CHD risk factors, including temperament and personality; a fourth is that several of these studies are designed as longitudinal in character and include family history data and/or direct assessment of the twins' parents; and a final feature is the use of robust analytic techniques to go beyond mere

GENES, STRESS, AND CARDIOVASCULAR REACTMTY 91

demonstrations of genetic influences, to evaluate modulation of genetic effects by age and gender, and to model genetic mechanisms. To highlight these developments, six twin studies of cardiovascular reactivity, all published sub­sequent to my earlier review of this literature (Rose, 1986; Rose & Chesney, 1986), will be cited.

A Philadelphia Study of Prepubescent Twins

I begin this selective review with a longitudinal study of young twin chil­dren; 71 MZ and 34 DZ pairs, ages 6 to 11 at baseline, were ascertained through schools and Mothers of Twins clubs (Meininger, Hayman, Coates, & Gallagher, 1988). All twin children were white and from middle-income family back­grounds; more than half their parents had received education following high school. As one part of a study of CHD risk factors, three BP measures were taken during a home visit, and during the home visit in which the BP measures were made, blood was drawn to determine the twins' zygosity. Parental con­sents for the venipuncture had been obtained on an initial home visit the preceding day, so the BPs were measured while the twin children were antici­pating the venipuncture to follow-a real-life stress of the kind to which BP reactions are associated with familial history of cardiovascular disease in young children (Warren & Fischbein, 1980). Thus, the BP measures were, effectively, measures of anticipatory stress response. Two BP measures were taken by an automated oscillometric device, the other by a standard auscultatory technique. The average of the three readings was analyzed. Both means and total vari­ances of the average BP readings were equivalent for MZ and DZ twin children, so genetic effects were estimated from the intrapair variance-from Mean Squares within (MSw) pairs. For systolic BP, the MSw for MZ pairs was significantly smaller than that for age-matched DZ pairs (p<.02), and twins' correlations (0.65 for MZs and 0.41 for DZs) estimated h2 = .48; in contrast, the twins' resemblance for diastolic blood pressure (DBP) appeared largely due to effects of their shared environments rather than effects of their shared genes. The Philadelphia twins were reassessed three years later, when 85% of the sample participated (Meininger, Hayman, Gallagher, & Coates, 1991). As pre­viously, data were collected during home visits. Again, systolic blood pressure (SBP) was significantly heritable. Although limited by a small sample, the Philadelphia study is of interest because the twins were very young at baseline, and its multiple measures (including scales of coronary-prone behavior that are cited below) and longitudinal design make the study noteworthy.

The Medical College ofVi-ryinia (MCV) Twin Study

For an ongoing study in Virginia, a twin cohort of 251 white, ll-year-old twins was ascertained from statewide school records, and, as part of a larger

92 CHAPl'ER FIVE

test protocol, three BP measures (using a mercury sphygmomanometer) were made while the twin child was seated (Schieken, Eaves, Hewitt, Mosteller, Bodurtha, Moskowitz, & Nance, 1989a). Strengths of this study are several: (1) baseline testing for all twins was scheduled as close as possible to their eleventh birthday to control for age effects, and the twins have been longitudinally followed to age 14 to permit assessment of gene x age interactions; and (2) inclusion of a representative number of fraternal twins of the opposite sex (OS DZ pairs) permits testing for gene x gender interactions. Such data address the question: Is the expression of genetic (or environmental) effects different in boys and girls and variable across age and development? Correlations for SBP in same-sex DZ twins were, as expected, about one-half those found for MZ twins, but correlations for OS DZ pairs were near zero! Accordingly, subsequent analyses used path modeling, with alternate constraints on model parameters, to evaluate the possibility that different genes contribute to varia­tion in resting SBP among boys and girls. The analyses allow for the magnitude of genetic contributions to vary with gender and for the possibility that differ­ent genes influence SBP in boys and girls. The model fit was significantly better when genetic parameters were allowed to differ in girls and boys, leading to the inference of gender-specific genetic effects for SBP (Schieken, Moskowitz, Bodurtha, Eaves, Hewitt, & Nance, 1989b). Interestingly, although results suggested that genes influencing SBP were different in ll-year-old girls and boys, these different genes accounted for similar proportions of total BP vari­ance (65%) in both genders. For DBP, results were a bit different: Gender­specific genetic effects accounted for 65% of the variance for boys and for 50% of the variance in girls. More recently, follow-up data from this continuing research effort have been reported (Mosteller, Schieken, Eaves, & Hewitt, 1991). The evidence that different sets of genes contribute to SBP levels in prepubertal boys and girls is no longer found at age 14. So, these results from the Virginia twins, consistent with other data, suggest that gene effects on resting BP differ by age and gender. Question: Do gene effects differ also under conditions of relaxation and stress?

A recent report from the MCV study suggests that they may. Genetic and environmental influences on HR response to stress apparently differ from those expressed at baseline (Eaves, Hewitt, Schieken, Mosteller, Moskowitz, Bodurtha, & Nance, 1989). HRs of the MCVtwins, when age 11, were assessed at rest and during dynamic exercise at four increasing load levels. Environ­mental effects on HR were largely measurement-specific, with modest persis­tence from one measure to the next as load increased. The structure of genetic effects was different: Genetic influences monotonically increased with increas­ing load level. The inference drawn is that two sets of genes operate, one on resting HR while the other, expressed during exercise, has effects that persist and accumulate as work load increases. That inference is a provocative one: Are there separate genetic effects on basal BP and stress-induced changes in BP as well?

GENES, STRESS, AND CARDIOVASCULAR REACTIVITY 93

A Dutch Twin Family Study

In Amsterdam, a study of 160 adolescent MZ and DZ twin pairs and their parents studied at rest and during two standardized laboratory tasks has provided evidence of genetic influences on vagal control of HR, assessed with a measure of HR variability as an index of invested mental effort. The measure is operationalized as the difference between the longest interbeat interval during expiration and the shortest interbeat interval during inspiration; the difference is not dependent on gender but declines with age and task involve­ment. Analyses of this measure of respiratory sinus arrhythmia show significant genetic effects as well as a significant contribution from shared experience in both boys and girls (Boomsma, van Baal, & Orlebeke, 1989). The Dutch study uses a twin-parent pedigree design that includes both parents of the adolescent twins in the sampling structure. The design permits robust analyses, for the cross-generational data permit an examination of both vertical and horizonal effects of genes and shared environments. A recent conference report on the Dutch study noted "important contributions from shared en­vironmental factors" to SBP variance, "especially in boys" (Boomsma, Mole­naar & Orlebeke, 1988). Jointly, the ongoing twin studies in Virginia and Holland direct attention to the complexity of these effects. The MCV data suggest that specific environmental effects account for different proportions of total BP variance in boys and girls; the Dutch data suggest that the relative importance of both shared and specific environmental effects differs by gender.

An Adult Twin Study in Montreal

A Canadian study of twin similarity in HR and BP responses to stress features multiple stressors and balanced sampling by gender and twin type (Ditto, 1988). The study is of an adult sample of 20 like-sex twin pairs of each gender and zygosity, including also 20 OS DZ pairs. Repeated measurements of cardiovascular and other psychophysiological variables were made on 200 twin individuals during an hour-long protocol that alternated stress and relaxa­tion periods. Each of four stressors, two active cognitive challenges plus iso­metric handgrip and cold pressor, had significant pressor effects. The stress­induced change scores were corrected for dependence on baseline values after initial standardization for age, gender, and weight. In preliminary analyses, genetic factors were more influential on resting BP levels than on residualized stress-induced changes. A full analysis of these data, based on maximum-like­lihood estimation of the covariance matrices, is in preparation (Ditto, 1991).

A Study of Adult Twin Brothers in Utah

A sample of twin brothers (82 MZ and 88 DZ), aged 21 to 61, was ascer­tained from four decades of birth records in Salt Lake County, Utah; 264

94 CHAPTER FIVE

healthy and medication-free male twin pairs, residing within a 50-mile radius of the University of Utah, were located, and 170 agreed to participate in a re­search protocol (Smith, Turner, Ford, Hunt, Barlow, Stults, & Williams, 1987). An automated device recorded SBP, DBP, and HR at I-minute intervals during baseline and during 4 minutes of self-paced serial subtraction. The task had significant pressor effects: Mean SBP increased about 10 (and DBP about 8) mm Hg over baseline and HR accelerated 7 to 8 bpm. For MZ twins, intraclass correlations for all three cardiovascular variables were significant at baseline and during the cognitive challenge, and, as expected by a simple genetic model, corresponding DZ correlations were about half the value of those observed for MZ twin brothers. Initial levels of the three cardiovascular variables were modestly correlated (sO.2) with change scores. Correlations for simple and residualized change scores for SBP and DBP were significant for MZ pairs, but both measures of reactivity were unrelated for this variable-age sample of DZ twins.

The NHLBI Twin Study

I conclude this selective update with a follow-up report on cardiovascular stress reactivity among elderly twin brothers; the report provides evidence that genetic influences on BP reactivity remain significant in late decades of life (Carmelli, Ward, Reed, Grim, Harshfield, & Fabsitz, 1991). The male twins in this research are participants in ongoing studies sponsored by the National Heart, Lung and Blood Institute (the NHLBI Twin Study). These twin broth­ers, veterans of World War II and/or the Korean conflict, have, since 1970, participated in longitudinal research on risk factors for CHD. Appraisal of their cardiovascular stress reactivity is the latest in the series of continuing research studies. Cardiovascular reactivity was assessed in a subsample of these elderly twin brothers during the second examination at one study center (Carmelli, Chesney, Ward, & Rosenman, 1985); results, albeit interesting, were con­strained by the limited sample, so during the third wave of data collection in 1986-87, the complete NHLBI twin sample was tested. Stress-reactivity data were obtained at four test sites from 101 male twin pairs, 59 to 69 years of age. BP and HR were recorded during an 8-minute baseline and during two chal­lenges, 4 minutes of paced mental arithmetic and a I-minute cold pressor. I illustrate the results with BP and HR reactivity to the cognitive challenge of serial subtraction. SBP, DBP, and HR were recorded at 2-minute intervals during baseline and stress; magnitude of change found during stress was corrected for baseline differences. For all three variables (SBP, DBP, and HR) and for both MZ and DZ twins, cardiovascular levels of cotwins significantly correlated at baseline; heritability estimates (estimated from the doubled dif­ferences of MZ/DZ correlations) were significant for both SBP and DBP. For all three variables, and again for both MZ and DZ twin brothers, cotwin resemblance was greater under stress than at baseline. Significant correlations

GENES, STRESS, AND CARDIOVASCULAR REACTMTY 95

and significant heritabilities were found for both absolute and adjusted change scores. For SBP, MZ/DZ correlations for adjusted change scores were .71 and .31, respectively, yielding an estimated h2 of 0.80; for DBP, those correlations were .56 and .23, respectively, and h2 equaled 0.66. The NHLBI twin data are unusual, given the advanced age and good health of the twins: Pairs were excluded if either cotwin reported any cardiovascular disease, used prescription medications known to affect cardiovascular function, or had elevated blood pressure on examination. Accordingly, the sample is elderly but healthy, and results offer novel evidence that genetic effects on both baseline and stress reactivity of BP and HR remain highly significant into the seventh decade of life. These data provide no suggestion that genetic effects on stress reactivity decline with age.

SELECTIVE TRANSACTION: G x E CORRELATION

If it is a truism of health psychology that people do not uniformly react to similar stress, it is a truism of social psychology that the situations people encounter do not just "happen": People actively seek opportunities to develop and display the dispositional characteristics that define their individuality. Our dispositions selectively lead us to seek reinforcing situations. This is an obvious and everyday observation to social psychologists: "Physicians, clerics, entre­preneurs, and rock stars began by making choices that reflected their personal preferences and capacities" (Ross & Nisbett, 1991); subsequently, the initial choices provided situational contexts that allowed ("even compelled") them to further develop and display their dispositional differences. So it is with genetic dispositions and the social selection of CHD-relevant environments (Rose, 1990). Individual differences in personality and temperament playa significant role in the development of CHD. The personality differences reflect not fixed consequences of hereditary variance but rather interactive processes of life­style selection-choices made by people with different genetic dispositions, choices that lead some to active challenge-engendering life-styles that elevate risk for cardiovascular disease. Early differences in temperamental disposi­tions relevant to CHD (e.g., the tempo and intensity of behavior, developmental differences in approach-avoidance, shyness, and tolerance for repetition and monotony) are strengthened through experience because they provide occa­sions for their own reinforcement; with development, individuals actively create differences in the environments within which they lead their lives. We are also selectively exposed to the environments created by others who, anticipating continuity in our actions, adjust the social settings within which they interact with us. Consider the students of a punctilious professor or the social circle of a pious pastor: Not only does ''The Reverend Fletcher" avoid orgies and opium dens but his social audiences adjust to his presence, so "both the guest list and the evening's entertainment tend to be somewhat more refined" whenever he

96 CHAPI'ERFIVE

is invited (Ross & Nisbett, 1991, p. 155). Thus, people not only make situational choices but also their dispositional tendencies transfonn the situations to which they are exposed. As a result, our social experiences are conditional on, and created by, our genetic dispositions.

One compelling bit of evidence that adults socially select environments within which to live their lives is found in assortative mating for life-styles and risk factors relevant to coronary disease. The most influential of all life choices is mate selection, and data suggest that we select mates who resemble our­selves in risk factors for coronary disease (ten Kate, Boman, Dager, & Mo­tulsky, 1984). Frequencies of myocardial infarction (MI) and coronary artery disease (CAD) were compared in first-degree relative of male MI survivors, their spouses, and male case controls; the frequencies of MI and CAD were as high in relatives of the survivors' spouses as among relatives of the MI survi­vors themselves, and relatives of both spouses and cases had significantly higher rates of MI and CAD than did families of the case controls. The in­ference is that we selectively mate on the basis of resemblance in dietary and exercise patterns, smoking and drinking habits, blood pressure levels (and stress reactivity?), and other CHD risk factors (ten Kate et 01, 1984). In so doing, we create postmarital environments that foster expression of our dis­positions and maintain continuity of our life-styles.

Evidence of assortative mating for health-related behaviors is interesting, but any inference that it reflects genetic influences is indirect. There is, how­ever, more direct evidence of genetic contributions to active niche seeking, and some of it is relevant to cardiovascular disease. The evidence comes from research on the personality disposition of hostility and other components of coronary-prone behavior and from research in which social support and stress­fullife events are conceptualized as dependent variables, whose determinants include dispositional differences. I briefly review selected studies of genetic contributions to (1) social support, (2) stressful life events, and (3) coronary­prone personality dispositions.

SocIAL RELATIONSHIPS, REACTMTY. AND CHD

Buffering Effects of Social Support

There is accumulating evidence that social relationships exert causal ef­fects on health. Prospective studies, including those linking social relationships to rates of coronary disease, consistently show increased risk among those whose social relationships are limited (House, Landis, & Umberson, 1988). Many studies report a buffering effect of social support on stress response, and there is evidence of a specific buffering effect on cardiovascular stress reactivity (Kamarck, Manuck, & Jennings, 1989): In a laboratory setting, the presence of a friend can reduce HR response to transient stress. Curiously, social support is conventionally construed to be an independent variable-as an asset some

GENES, STRESS, AND CARDIOVASCULAR REACTIVITY 97

people luckily possess rather than a dependent consequence of their own ac­tions. House and colleagues (1988) call for an examination of the origins of individual variation in social relationships and decry the fact that little attention has been paid to social support as a dependent variable, although ''biology and personality must and do affect both people's health and the quantity and quality of their social relationships" (House et 01, 1988, p. 544). What are the biopsy­chosocial determinants of a successful marriage and stable employment, of variation in gregariousness, social attraction, and interpersonal social skills: A behavioral-genetic perspective, as advanced here, encourages a search for origins of people's social support in their dispositional differences. Such a search has been made among elderly Swedish twins (Bergeman, Plomin, Ped­ersen, McClearn, & N esselroade, 1990) in a study asking: What are the sources of individual differences in motivation and ability to create and maintain social support during later life? A cohort of MZ and DZ twins, whose average age at time of testing was 65 years, was administered questionnaires containing items to assess availability and perceived adequacy of social support. The sample included twins reared apart (who, on average, were separated at age 2.8 years) as well as twins reared together into late adolescence or early adulthood. With but one exception, all twin correlations for both quantity and quality of social support were significant. Modeling the observed similarities of these elderly MZ and DZ twins suggested that most of the variance in both measures was attributable to unshared experiences, but there was a significant genetic effect on perceived adequacy of the elderly twins' social support networks, an effect that accounts for 30% of the variance.

Adult social support is not a passive acquisition. It is an active creation. Differences in the social support systems of elderly (twin) adults will reflect that fact: The differences will be correlated with individual differences in ability, education, position, and personality. An association of personality dispositions and perceived social support has been found in U.S. college students (Smith & Frohm, 1985); as expected, those who had high scores on a scale of cynical hostility reported fewer and less satisfactory social relationships. If social support is created and maintained by personality characteristics and disposi­tional behaviors, it should surprise no one that differences in adult social support are moderately heritable. A note of caution is in order, however: To suggest that social relationships and life events do not just happen is not to suggest that they are wholly heritable. We need to be very clear about the nature and limits of genetic influences on behavioral and disease outcomes.

Limits of Genetic Effects

With but very rare exceptions (e.g., Huntington's disease, for which a single, dominant gene is the necessary and sufficient etiology), genes· do not mandate outcomes. Genetic differences do not inevitably produce differences in the history and outcome of human lives. For behavioral health variables-

98 CHAPTER FIVE

smoking, alcohol use, personality dispositions, and so forth-our best estimates attribute less than half of the variance to heritable effects, and those effects are indirect. Most of the variance in health behavior lies in individual differences in life experience and in G x E interactions and correlations.

Genes and Obesity: Reaction and Selection

As an instructive example of gene effects on a health variable relevant to CHD, consider obesity. Twin studies have yielded evidence for the role of genetic dispositions in variation in adult weight and obesity (Stunkard, 1988), and there is compelling evidence of G x E interaction in response to controlled dietary manipulation (Bouchard, Tremblay, Despres, & Hadeau, 1990). Popular interpretations of these findings ("Chubby? Blame those genes," Time, 1990, p. SO), though, are simply wrong. The news item in Time reported on laboratory research in which weight gains of MZ cotwins were assessed following chal­lenge with controlled caloric overload (Bouchard et 01, 1989); in parallel re­search, maximal oxygen uptake was assessed among MZ cotwins during long­term endurance training (Bouchard, Perusse, & Leblanc, 1990). Both experiments demonstrate the familiar fact of G x E interaction: There are genetic differences in reactivity to standardized (dietary or exercise) stress. Such results mean that there is a heritable variance in the differential weight gain with which people respond to a uniform diet or in their differential weight loss in response to uniform exercise. The results in no way consign anyone to a lifetime of uncontrollable obesity. Indeed, it. is not certain that G x E inter­action accounts for as much of the observed population variance in weight as does G x E correlation. In real life, people do not choose uniform diets nor do they engage in uniform exercise patterns. People create their own, and G x E correlations are highly relevant to obesity because everyday behavioral choices obese adults make in dietary habits and exercise patterns significantly con­tribute to their weight problems. Obese adults are less active than those of normal weight (Chirico & Stunkard, 1960), and given a department store choice of adjacent stairs or escalator, obese adults more often choose the escalator (Stunkard, 1989). Similarly, obese adults are much more likely to selectively place themselves in environments rich in caloric temptation: They are two to three times more likely to eat at a restaurant on a night when it offers diners an "all-you-can-eat" smorgasbord than on a night when the restaurant's menu is a la carte (Stunkard & Mazer, 1978). Genes do not make people obese nor, given present knowledge, do gene differences consign anyone to coronary outcomes.

Dispositions, Not Destinies

We inherit dispositions, not destinies. Life outcomes are consequences of lifetimes of behavior choices. The choices are directed, in part, by our disposi-

GENES, STRESS, AND CARDIOVASCULAR REACTMTY 99

tional tendencies, and these tendencies are expressed within environmental opportunities that we actively create. Lives, healthy or diseased, are not simple consequences of static or passive genetic consignments.

LIFE EVENTS, REACTIVITY, AND CHD

If the developmental life-styles of individuals are characterized by con­tinual interaction of dispositions and situations, genetic differences must influence exposure to life events. That perspective leads one to conceptualize stressful life events not as slings and arrows that ''happen'' but as dependent variable amenable to behavior-genetic analysis. Recent data from a national U.S. sample of twins ~ age 50 (Hewitt, 1988) suggest that genetic dispositions significantly contribute to the experience of some life events (e.g., perceived personal crises in the twins' families or close friends). These results are con­sistent with the suggestion that some classes of life events are results of active transactions with the environment and, because they are consequences of one's own behavior, they are controllable and heritable. Uncontrollable life events, in which persons are passive observers, do not display heritable variance. Similar data have been reported from research with elderly Swedish twins (Plomin, Lichtenstein, Pedersen, McClearn, & Nesselroade, 1990). The Swedish data yield evidence of significant genetic influences on life events in whose creation people play an active role, events illustrated by improvement/deterioration in financial status, marriage, divorce, deterioration in a married relationship, and changes in relationships with spouse, children, or grandchildren. By contrast, the Swedish twins show little resemblance (and no evidence of heritable influences) for more uncontrollable life events, such as illness or death of a spouse or child or a forced change in residence.

CORONARy-PRONE PERSONALITY

A transactional perspective, in which persons select and maintain environ­ments consistent with their dispositional biases, is useful, perhaps necessary, for conceptualizing coronary-prone personality (Smith & Anderson, 1986; Smith & Rhodewalt, 1986). The personality traits that appear to constitute risk for CHD are not passive reactions; they are active elements of social transaction (Kirmeyer & Biggers, 1988). Individual differences in these mea­sures appear to develop mostly through differences in individual experience, but twin studies of coronary-prone personality measures do find evidence of modest genetic effects (Rose, 1988). That evidence comes from twin children, sharing a home environment, as well as from elderly twins who have lived apart for many decades. The twin children studied in Philadelphia provide some of this evidence (Hayman, Meininger, Stashinko, Gallagher, & Coates, 1988). Coronary-prone behavior was assessed with teacher ratings on the Mat­thews Youth Test for Health (MYTH), with analyses of total scores as well as

100 CHAPTER FIVE

impatience-aggression and competitive achievement striving. Means and vari­ances were equivalent across twin type, and intraclass correlations for MZ twin children were highly significant for all three dimensions of MYTH; on follow-up 3 years later (Meininger et al, 1991), all three dimensions yielded significant heritabilities. Such data suggest an early emergence of heritable influences on personality traits relevant to CHD. Recent data from elderly twin brothers in the NHLBI Twin Study (Cannelli, Rosenman, Chesney, Fabsitz, Lee, & Bor­bani, 1988; Cannelli, Swan, & Rosenman, 1990) suggest that such genetic effects remain present in late adulthood. In the most recent of these reports, the Cook-Medley Hostility scale was administered to 261 pairs of twin brothers during the third wave of NHLBI research, when most of the twins were in their midsixties. Correlations, for both total score and a subscale of cynical hostility, were modest but significant in both MZ and DZ twin brothers; consistent with a genetic model, MZ correlations doubled those observed among DZs. An h2 estimate of 0.28 was obtained for both total and cynical hostility scales. While many uncertainties remain about the relationship of personality to CHD (see Chapter 6 for an appraisal), there is little doubt that genes make some significant, albeit modest, contribution to the personality characteristics impli­cated in coronary risk. That contribution may, of course, be indirect and nonspecific: Behavioral and biological risk factors for CHD (e.g., components of coronary-prone behavior and apolipoproteins), interrelate very early in life, as early as age 6 (Riikkonen, 1990), leading to a suggestion that a behavioral disposition to respond to stress in a coronary-prone manner may be an expres­sion of the same biological factors that underlie dyslipoproteinemia (Riiikkonen, Keltikangas-Jarvinen, & Solakivi, 1990).

SUMMARY

People differ in reaction to stress, and people select life-styles that differ in stress exposure. Genetic differences between people make significant con­tributions to these characteristic differences in reaction and selection. Contin­uing efforts to identify and assess the pathways and mechanisms by which genetic variance influences linkages between behavior, stress, and coronary disease are likely to be richly rewarding.

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Schieken, R. M., Moskawitz, W., Mosteller, M., Bodurtha, J., Eaves, L., Hewitt, J., & Nance, W. (1989b). A genetic analysis of resting blood pressure and heart rate in prepubertal twins (Abstract). Acta Geneticae Medicae et GemeUologiae, 38, 150.

Smith, T. W., & Anderson, N. B. (1986). Models of personality and disease: An interactional approach to Type A behavior and cardiovascular risk. JfYUrna/, af Personality and Social Psychology, 50(6), 1166-1173.

Smith, T. W., & Frohm, K. D. (1985). What's so unhealthy about hostility? Construct validity and psychosocial correlates of the Cook and Medley HO scale. Health Psychology, 4, 503-520.

Smith, T. W., & Rhodewa1t, F. (1986). On states, traits, and processes: A transactional alternative to the individual difference assumptions in Type A behavior and physiological reactivity. JfYUrna/, af Research in Personality, 20, 229-251.

Smith, T. W., Turner, C. W., Ford, M. H., Hunt, S. C., Barlow, G. K., Stults, B. M., & Williams, R. R. (1987). Blood pressure reactivity in adult male twins. Health Psychology, 6, 209-220.

Stunkard, A J. (1988). Some perspectives on human obesity: Its causes. Bulletin New York Academy af Medicine, 64, 902-923.

Stunkard, A J. (1989, April). Family genes, family habits, and human obesity. Presentation at the annual meeting of the Society for Behavioral Medicine, San Francisco.

Stunkard, A J., & Mazer, A (1978). Smorgasbord and obesity. Psychosomatic Medicine, 40, 173-175.

ten Kate, L. P., Boman, H., Dager, S. P., & Motulsky, A G. (1984). Increased frequency of coronary heart disease in relatives of wives of myocardial infarct survivors: Assortative mating for lifestyle and risk factors? American JfYUrna/, afCardiology, 53, 399-403.

Time. (1990, June 4). "Chubby? Blame those genes," p. BO. Turner, J. R., & Hewitt, J. K. (1992). Twin studies of cardiovascular response to psychological

challenge: A review and suggested future directions. Annals af BehaV'imal Medicine, 14, 1~20.

Warren, P., & Fischbein, C. (1980). Identification of labile hypertension in children of hypertensive parents. Connecticut Medicine, 44. 77-79.

CHAPTER SIX

Personality Characteristics, Reactivity, and

Cardiovascular Disease

B. KENT HOUSTON

INTRODUCTION

The objectives of the present chapter are two-fold. One is to survey personality characteristics that have been investigated in relation to cardiovascular disease (CVD) and/or reactivity. The second is to call attention to some of the issues that need to be considered by researchers who investigate possible associations between personality and reactivity. An important overarching consideration for this area of inquiry is that personality characteristics operate within a frame­work of other variables and processes to potentially affect reactivity. In other words, a personality characteristic does not influence reactivity or relate to CVD separately or directly but in the context of other variables and processes. A useful approach for considering the relation between personality character­istics, reactivity, and CVD is in the structure of a model of affective and motivational arousal will be briefly outlined here that underscores a sequence of events and an interplay between variables.

This framework is useful for the purpose of reviewing investigations con­cerning the relation between personality characteristics, reactivity, and CVD, for it helps to organize and interrelate what might otherwise appear to be diverse research findings. It also has heuristic value in that it leads to gener-

B. KENT HOUSTON • Department of Psychology, University of Kansas, Lawrence, Kansas 66045-2160.

103

104 CHAPTER SIX

ating ideas concerning what other personality characteristics might be worth­while to investigate. The model is useful for other reasons as well, which will be mentioned at the outset to emphasize their significance. It helps to highlight important issues that are frequently overlooked in research on reactivity, in particular that research subjects have thoughts, emotions, and motives that influence their cardiovascular responses to the situations that they encounter in the laboratory or in naturalistic settings. An important implication of this point is that investigators interested in reactivity should routinely obtain in­formation about the thoughts, feelings, and motivation(s) of their subjects, without which adequate conclusions about the results cannot be made. Sugges­tions as to how this can be done may be found in Strube (1989) and Tennenbaum and Jacob (1989). An associated issue is that a subject's thoughts, emotions, and motives are influenced by a person by situation interaction, which is implicitly involved in all reactivity research. Thus, consideration needs to be given to what personality characteristics are engaged in every study of reactivity; when the focus of the study is on a particular personality characteristic, consideration needs to be given to: (1) whether the research setting in which subjects find themselves would be expected to engage the personality characteristic under study, and (2) whether there is evidence from an assessment of subjects' thoughts, feelings, and motivations that the situation did in fact engage the personality characteristic.

What are personality characteristics? They are defined here as those thoughts, feelings, motives, and behaviors that serve to identify or distinguish a person. This definition accords well with the model of emotional and motiva­tional arousal presented here. While short-lived personality characteristics (e.g., temporary thoughts, feelings, motives, and behaviors) are necessary for a more complete description and view of individuals, the focus of the present chapter is on enduring personality characteristics. The reason for this is that CVD takes times to develop, and if personality characteristics are to be asso­ciated with this process, they need to be relatively enduring.

The cognitive model of emotional and motivational arousal is depicted in Figure 1. A situation may be perceived or appraised in such a way as to lead to the arousal of positive or negative emotion and/or to the arousal of a motive. (Of course, a situation may be perceived in such a way as to lead to no change in either emotion or motivation.) Both emotional and motivational arousal have physiological arousal components that will merge with the physiological re­quirements of the situation or task (e.g., active versus passive responding, sensory intake versus sensory rejection, response effort, and so on; Krantz, Manuck, & Wing, 1986) to result in the physiological responses that are as­sessed as reactivity. As depicted, personality characteristics may influence how the situation is perceived, that is, the appraisal process, the intensity and kind of emotion aroused, and the intensity and kind of motive aroused.

Anyone situation may be appraised in such a way that results in evoking multiple emotions and/or motives. This is true for what might be regarded as

\

PERSONALITY, REACTMTY, AND CVD

person.IiIY~

SilUriOn

Appraisal

Arousal

1

Motivational

Physiological Arousal

Arousa/ FIGURE 1. A model of emotional, motivational, and physiological arousal.

105

''physical'' stressors as well as ''psychological'' stressors. Take for example, an individual undergoing a cold pressor test with the instructions to basically "do the best you can." Being subjected to a pain-inducing situation may lead to fear or anger, and being exhorted to "do the best you can" may stimulate achieve­ment or mastery strivings. Moreover, appraisal of a stimulus situation is influenced by environmental factors other than the focal situation; for instance, the behavior and appearance of the experimenter, the appearance of the sur­rounding experimental situation, and so forth. The emotions and motives evoked in subjects who are exposed to an experimenter who is unfriendly or who wears a white coat or to a laboratory that is austere or that contains medical accoutrements will probably differ from the emotions and motives evoked in subjects who are exposed to an experimenter who is friendly or who does not wear a lab coat or to a laboratory that is pleasant and that lacks medical trappings. It is likely that some of the inconsistencies in findings from reactivity studies are due to differences in experimenter behavior and/or the physical characteristics of experimenters and laboratories. These possibilities underscore the point made above, which was that it is important to assess subjects' thoughts, feelings, and motivations in every reactivity study in order to properly evaluate the results.

Various personality characteristics will now be considered under five head-

106 CHAPTER SIX

ings that relate to the major components of the model of emotional, motivational arousal. Thus, personality characteristics are discussed: (1) that affect the appraisal process, (2) that affect emotional arousal, (3) that affect motivational arousal, (4) that modulate emotional and motivational arousal, and (5) that are multifaceted constructs in regard to affecting appraisal and evoking emotional and motivational arousal. A personality characteristic is discussed under the heading that seems most appropriate in terms of its original conceptualization; however, it is recognized that anyone personality characteristic could be dis­cussed under another heading depending on how it has or could be recon­ceptualized.

The research reviewed here is intended to be representative of an area rather than comprehensive. Further, the review is confined to studies in which reactivity was investigated in adult humans and was elicited in controlled, identifiable situations, that is, under laboratory conditions. Studies in which children or animals were investigated or in which ambulatory monitoring was employed are not included here.

It should be noted from the outset that not all personality characteristics that are related to reactivity are necessarily related to CVD, for example, Type A as measured by the Jenkins Activity Survey (JAS), trait anxiety, and so on (Matthews, 1988). Therefore, an adequate assessment of the relation between CVD and the personality characteristics that are reviewed here is dependent on further investigation of the pathophysiology of CVD and the results of epidemiological studies that include measures of these personality character­istics.

PERSONALITY CHARACTERISTICS AFFECTING THE APPRAISAL PROCESS

Beliefs or attitudes concerning one's interactions with the physical and/or interpersonal environment would be expected to influence how people think about or appraise situations.

Locus OF CONTROL

The appraisal of a situation is influenced by the extent to which people believe that they can influence the course of physical and/or interpersonal events (Lazarus & Folkman, 1984). Thus, locus of control is a personality characteristic of relevance here. Locus of control (Rotter, 1966) refers to dif­ferences in people's beliefs that the things they want can be obtained as a result of their own behavior (internal control) or are largely a result of luck, fate, chance, or powerful others (external control). Several studies have been con­ducted in which a measure oflocus of control has been related to cardiovascular

PERSONALITY, REACTIVITY, AND CVD 107

reactivity. Generally, it has been found that subjects with an internal locus of control exhibit greater systolic blood pressure (SBP; Manuck, Craft, & Gold, 1978) and heart rate (HR; Houston, 1972) reactivity in various situations, although in one study subjects with an external locus of control were found to exhibit greater diastolic blood pressure (DBP) reactivity when they were given control over an aversive situation (DeGood, 1975).

CYNICAL MISTRUST

The appraisal of interpersonal situations is influenced by the extent to which people believe others to be trustworthy and supportive or untrustworthy and hostile (Lazarus, 1966). Cynical mistrust, therefore, is a personality char­acteristic of relevance here. Cynical mistrust is most commonly measured by the Cook and Medley (1954) hostility (Ho) scale, which was empirically derived from the MMPI (Minnesota Multiphasic Personality Inventory). Several stud­ies have been published that indicate that people who obtain high Ho scale scores are dysphoric, mistrusting, suspicious, resentful, and dissatisfied with relations with others (Blumenthal, Barefoot, Burg, & Williams, 1987; Smith & Pope, 1990). Presently, research findings are inconsistent regarding the nature of the relation between Ho scale scores and CVD (see Smith & Pope, 1990, for a review).

In studies in which interpersonal conflict or harassment has been manip­ulated, relations between Ho scale scores and reactivity have been found in the conflict and harassment conditions but not in the control conditions (Hardy & Smith, 1988; Smith & Allred, 1989; Suarez & Williams, 1989). Moreover, a relation between Ho scale scores and reactivity was found in an investigation in which during the performance of an anagrams task subjects may have become suspicious concerning the nature of the study (Weidner, Friend, Ficar­rotto, & Mendell, 1989). Ho scale scores have not been found to be related to reactivity for laboratory tasks that are not associated with conflict or harass­ment or that arouse suspicion (Kamarck, Manuck, & Jennings, 1990; Sallis, Johnson, Trevorrow, Kaplan, & Hovell, 1987; Smith & Houston, 1987). Collec­tively, the results regarding relations between Ho scale scores and reactivity underscore the issue, mentioned above, that a person by situation interaction needs to be considered in conducting and evaluating reactivity research.

PERSONALITY CHARACTERISTICS INFLUENCING EMOTIONAL AROUSAL

It would be expected that dispositions to experience particular emotional states would influence emotional arousal and thus reactivity. Several emotional dispositions have been investigated in this regard.

108 CHAPTER SIX

ANxIETY

Relations between measures of general anxiety and reactivity have not been found in most studies. Hodges (1968) did not find a relation between general anxiety as measured by the Manifest Anxiety Scale and HR responses during a difficult task following a threat to self-esteem or while subjects were threatened with unavoidable shock. Similarly, Houston (1977) did not find a relation between general anxiety as measured by the trait portion of the State­Trait Anxiety Inventory and HR responses during a memory task in which subjects were threatened with shock for mistakes. Also measuring general anxiety by the trait portion of the State-Trait Anxiety Inventory, no relation was found between cardiovascular responses to videotaped questions under either evaluative threat or no threat in a study by Smith, Houston, and Zu­rawski (1984). In a study by Glass et al (Glass, Lake, Contrada, Kehoe, & Erglanger, 1983), no relation was found between general anxiety as measured by the 16 Personality Factor Questionnaire and cardiovascular responses across a mental arithmetic task and a modified Stroop task. In a study by Warrenburg et al (Warrenburg, Levine, Schwartz, Fontana, Kerns, Delaney, & Mattson, 1989), however, general anxiety as assessed by the anxiety subscale of the SCL-90R was found to be related to SBP responses during a challenging portion of an interview.

Equivocal results also have been found for anxiety that is characteristic of individuals in specific situations. Test anxiety as measured by the Test Anxiety Questionnaire was found to be significantly correlated with SBP, DBP, and HR responses across the tasks employed in the study by Glass et al. (1983) men­tioned above. In a study by Holroyd, Westbrook, Wolf, and Badhorn (1978), though, test anxiety as measured by the Test Anxiety Scale was not found to be related to HR responses during a difficult anagrams task. Knight and Borden (1979) had subjects perform a verbal task that involved social evalua­tion. Social anxiety, as measured by the social anxiety subscale of the Activity Preference Questionnaire, was not found to be related to either HR or finger pulse volume responses during the evaluative task.

In sum, there appears to be little consistent evidence for a direct relation between cardiovascular reactivity and measures of either general or more specific trait anxiety. If defensiveness in reporting anxiety is taken into con­sideration, however, a different conclusion may be warranted. In four studies, defensiveness has been operationalized in terms of scores on the Marlowe­Crowne Social Desirability Scale and general anxiety in terms of a Manifest Anxiety Scale. In three studies (Asendorpf & Scherer, 1983; King, Taylor, Albright, & Haskell, 1990; Weinberger, Schwartz, & Davidson, 1979), scores from the two scales were dichotomized, and on the basis of the combination of their scores on the two scales, subjects were assigned to three or four groups of subjects. One, described as ''repressors,'' was composed of individuals with high defensiveness and low anxiety scores; a second group, described as "low-

PERSONALITY, REACTIVITY, AND CVD 109

anxious," was composed of individuals with low scores on both measures, and so on. In two of the studies, repressors and high-anxious subjects were found to exhibit greater HR reactivity to various tasks than low-anxious subjects (Asendorpf & Scherer, 1983; Weinberger et al, 1979) and in the third study to exhibit greater SBP but not greater HR reactivity (King et al, 1990). The notion behind the procedure of assigning subjects to groups on the basis of a combination of their defensiveness and anxiety scores is that there is an inter­action between these two characteristics. This interaction was directly tested in a fourth study (Warrenburg et al, 1989) and was not found to be significant; rather, main effects for both anxiety (mentioned in the section on anxiety above) and defensiveness were obtained for SBP. (HR data were not reported.) Over­all, these intriguing findings suggest that further research is needed to more thoroughly evaluate whether defensiveness does indeed moderate the relation between anxiety and reactivity. In regard to the ultimate question concerning relations between anxiety, reactivity, and CVD, though, it should be noted that while anxiety may predict chest pain, it has not been found to predict myocar­dial infarction (Medalie, Kahn, Neufeld, Riss, & Goldbourt, 1973), and, based on this and other evidence, Costa and McCrae (1985) assert that anxiety is not predictive of genuine coronary heart disease (CHD).

ANGER

In contrast to the number of studies in which relations between reactivity and anxiety have been investigated, in few studies has the relation between characteristic anger and reactivity been studied. In a study by Holroyd and Gorkin (1983), scores on the Novaco anger scale were related to cardiovascular reactivity during role-played social interactions. It was found that subjects who obtained low scores on the N ovaco scale manifested greater SBP and HR responses than subjects who obtained high scores. These results were inter­preted in terms of subjects manifesting greater reactivity who cope with the experience of anger with suppression or denial. * In addition to studies that have been conducted that reflect on the relation between reactivity and the suppres­sion or denial of the experience of anger, related studies have been conducted on the relation between reactivity and the extent to which individuals cope when angered by suppressing the expression of anger. In a study by Mills, Schneider,

*Investigators who have obtained negative relations between reactivity and negative emotional or motivational characteristics or the expression of such characteristics have typically interpreted such findings as evidence for reactivity being related to denial or suppression of that character­istic. The results of these studies are thus relevant to the later section on coping. Moreover, studies in which reactivity is related to explicit measures of suppression of overtly expressing negative emotions or motives are also relevant to the later section on coping. Such findings, however, are presented in the section dealing with the relevant emotional or motivational char­acteristic to provide a more balanced view of the direction of relations that have been found between measures of the personality characteristic and reactivity.

110 CHAPl'ER SIX

and Dimsdale (1989), HR reactivity to a mental subtraction task was found to be significantly, negatively related to two measures of expressing anger out­wardly when provoked, namely, the anger-out subsca1e of Spielberger's Anger Expression Scale and a component scoring for anger-out from the Structured Interview (SI) originally developed for assessing Type A behavior. These re­sults were interpreted in terms of subjects exhibiting greater reactivity who suppress the expression of anger. Reactivity, however, was not found to be related to an ostensibly more direct measure of suppressing the expression of anger, that is the anger-in portion of Spielberger's Anger Expression Scale. Additionally, in a study by Smith and Houston (1987), reactivity to two ex­perimental tasks was not found to be related to measures of expressing anger outwardly, inhibiting expression of anger, or discussing anger with others that were employed in the Framingham Study (Haynes, Levine, Scotch, Feinleib, & Kannel, 1978). In an interesting analysis of research in this area, Engebretson, Matthews, and Scheier (1989) suggest that measures of suppressing or overtly expressing anger are more likely to be found to be related to reactivity when subjects are provoked. This is an interesting notion that deserves further attention.

Research on reactivity and anger and how individuals cope with experi­encing and expressing it is an important area. Such research has its counterpart in research regarding risk for CVD. In a study by Gentry et al (Gentry, Chesney, Gary, Hall, & Harburg, 1982), a combined measure was obtained of suppression or denial of the experience of anger (assessed in terms of subjects not reporting feelings of anger when provoked) and of suppression of express­ing anger (assessed via subjects reporting that they would not show anger when provoked) and was found to be associated with greater risk of essential hyper­tension. Moreover, focusing on the suppression of expressing angry feelings, Haynes, Feinleib, and Kannel (1980) report that low scores on a measure of expressing anger outwardly were found to predict CHD for white-collar males and low scores on a measure of discussing anger with others predicted chest pain for women.

HOSTILITY

A number of studies have been conducted on the relation between re­activity and a characteristic that is a composite of angerability and antagonistic behavior, which primarily has been referred to as the potential for hostility but also as reactive or expressive hostility (Dembroski & Costa, 1987). The poten­tial for hostility is assessed via the SI in terms of the content and intensity of an interviewee's responses as well as his or her style of interacting with the interviewer (Chesney, Hecker, & Black, 1988; Dembroski, 1978). Presently, the potential for hostility appears to be the most robust personality predictor of CHD, at least in younger middle-aged males. It has been found to predict the incidence of CHD in two prospective studies (Dembroski, MacDougall, Costa,

PERSONALITY, REACTMTY, AND CVD 111

& Grandits, 1989; Hecker, Chesney, Black, & Frautschi, 1988), and no contra­dictory findings have been reported.

The results of the studies concerning a relation between the potential for hostility and reactivity have been mixed, however. In regard to studies of males, the potential for hostility has been found to be positively related to reactivity to various experimental tasks by Dembroski et al (Dembroski, MacDougall, Shields, Petitto, & Lushene, 1978), negatively related to reactivity to two ex­perimental tasks by Glass et al (1983), and unrelated to reactivity to the SI in a study by Chesney et al (Chesney, Ekman, Friesen, Black, & Hecker, 1990) and to a pong game under competition, frustration, or harassment conditions by Diamond et al (Diamond, Schneiderman, Schwartz, Smith, Vorp, & Pasin, 1984). Also relevant to this area of research, a measure of hostility derived from the Videotaped Structure Interview (VSI) was found for males to be related to SBP reactivity to a variety of tasks in a study by Lundberg, Hedman, Medlin, and Frankenhaeuser (1989).

Regarding studies on females, in a set of studies by MacDougall, Dem­broski, and Krantz (1981), the potential for hostility was found to be positively related to reactivity to the SI, both positively and negatively related to a reaction time task, and unrelated to reactivity to the cold pressor task. In another study of females (Anderson, Williams, Lane, Haney, Simpson, & Houseworth, 1986), the potential for hostility was not found to be related to reactivity to either the SI or a mental arithmetic task. In the study by Lundberg and associates (1990) mentioned above, unlike the findings for males, the mea­sure of hostility derived from the VSI was not found for females to be related to reactivity to the variety of tasks.

The reasons for the inconsistencies in the results concerning the potential for hostility and reactivity are unclear. Assessing the potential for hostility from SI audiotapes has been a complex, SUbjective procedure (Dembroski, 1978), which may account for some of the inconsistent findings. The complex, though somewhat more structured procedure for assessing hostility from the SI re­cently developed by Hecker and colleagues (1988) may facilitate reliable, ac­curate scoring of this construct. Ratings of hostility from the VSI are relatively unexplored, though they may be promising by virtue of the availability of both visual as well as auditory cues.

PERSONALITY CHARACTERISTICS INFLUENCING MOTIVATIONAL AROUSAL

It would be expected that motivational dispositions would influence motiva­tional arousal and thus reactivity. One motivational characteristic that has been studied in regard to reactivity is power motivation, which McClelland (1979) describes as the desire to dominate and impress others. There is conflicting evidence concerning a relation between the need for power and reactivity.

112 CHAPrER SIX

Blumenthal, Lane, and Williams (1985) found the need for power to be related to greater SBP responses during the SI and another experimental period. In a study by Fontana, Rosenberg, Marcus, and Kerns (1987), though, the need for power was not found to be related to reactivity during the SI or other ex­perimental tasks. Inhibited power motivation, which McClelland (1979) de­scribes as the controlled expression of power motivation in a socially acceptable manner, is possibly a more important personality disposition in the context of CVD. A measure of inhibited power motivation was found by McClelland (1979) in a prospective study that spanned 20 years to significantly predict signs of hypertensive pathology. In one study, the inhibited need for power was found to be related to SBP reactivity to several experimental arrangements (Fontana et al, 1987), but in two other studies the inhibited need for power was not found to be related to reactivity to some of the same experimental events (Blumenthal et al, 1985; Glass et al, 1983). The inconsistencies in the aforementioned studies may be due in part to the following. Both the need for power and the inhibited need for power are assessed by means of scores derived from re­sponses to Thematic Apperception Test cards, the vagaries of which may affect the accuracy with which these dispositions are measured.

Another motivational disposition of interest, which is similar to the need for power, is dominance. In a study by Rejeski, Gagne, Parker, and Koritnik (1989) in which males were challenged concerning their views by a female experimenter, submissive subjects exhibited significantly more HR reactivity than dominant subjects but dominant subjects exhibited nonsignificantly more SBP and DBP reactivity than submissive subjects. The potential relevance of dominance to CVD has been provided by work conducted by Kaplan and colleagues with cynomolgus monkeys. In one study of males, dominant mon­keys in unstable social environments exhibited more atherosclerosis than sub­missive monkeys in the same environments or dominant monkeys in stable social environments (Kaplan, Manuck, Clarkson, Lusso, & Taub, 1982). In similar studies of female cynomolgus monkeys, however, submissive animals developed greater atherosclerosis than dominant animals (Kaplan, Adams, Clarkson, & Koritnik, 1984). Thus, more work seems warranted concerning the relation between dominance, reactivity, and risk for CVD, at the same time addressing the issue of gender differences.

Competitiveness, in the form of verbal competitiveness assessed during the SI, has been found in univariate analyses to be significantly associated with the incidence of CHD in a reanalysis of data from the Western Collaborative Group Study (WCGS; Chesney et al, 1988). (In multivariate analyses in which other SI-derived components were entered [e.g., hostility], the relation for verbal competitiveness was no longer significant, p = .196; Hecker et al., 1988.) Several studies have been conducted on the relation between verbal competi­tiveness as assessed via the SI and reactivity. In regard to studies on males, positive relations were obtained in a study by Dembroski and coworkers (1978), null relations were found by Diamond et al (1984), and a trend toward a

PERSONALITY, REACTIVITY, AND CVD 113

negative relation was found by Glass et a1. (1983). In regard to studies of females, verbal competitiveness was found to be significantly related to re­activity to one of two tasks in a study by Anderson and colleagues (1986) but unrelated to reactivity for several tasks in two studies conducted by MacDou­gall et al. (1981). Presently, it is equivocal whether in the population there exists a relation between verbal competitiveness and reactivity for either males or females.

While characteristic aggressiveness has been studied in regard to both reactivity and atherosclerosis, again in male cynomolgus monkeys (Manuck, Kaplan, & Clarkson, 1983), a disposition for overt aggressiveness, apart from related concepts such as anger and hostility, has received little attention in human research on reactivity. In a study by Jorgensen and Houston (1988), dispositions for physical and verbal aggression were found to be negatively related to reactivity.

CHARACTERISTICS MODULATING EMOTIONAL AND MOTIVATIONAL AROUSAL

TEMPERAMENT

Variables associated with temperament (e.g., activity level, emotionality, and so on; Buss & Plomin, 1984) seem likely candidates to modulate intensity of affective and motivational responses and hence reactivity. Activity level may influence reactivity because individuals who are more energized or active than others may experience greater emotional and/or motivational arousal and thus greater physiological reactivity to evoking situations. Relevant to this, scores on the activity scale of the Thurstone Temperament Scale were found to be related to greater reactivity in a study by Pittner, Houston, and Spiridigliozzi (1983) and to be related to premature CHD in a study by Brozek, Keys, and Blackburn (1966). Emotionality is another characteristic that would be expected to influence emotional arousal and thus reactivity. Little research, however, has been conducted relating reactivity or CVD to a measure of general emotion­ality, separate from dispositions for particular negative emotions, composite concepts such as neuroticism, and so forth.

COPING

Characteristic ways of coping with the appraisal of potentially stressful situations or with the negative emotions or motives aroused by such situations would be expected to modulate the intensity of emotional and/or motivational arousal and hence reactivity. It is difficult in a practical sense, though, and thus operationally, to separate coping in terms of reappraising a potentially stressful situation from focusing in some fashion on the negative emotions or

114 CHAPI'ER SIX

motives aroused by such situations; therefore, no attempt will be made to do so here.

Denial is one coping characteristic that has been studied in terms of reactivity. Operationally defining denial on the basis of scores on the Little and Fisher Denial Scale, Houston (1973) found that subjects who were high deniers evidenced significantly less HR reactivity across both avoidable and unavoid­able stress conditions than low deniers. Studying male medical patients, War­renburg and colleagues (1989) found that the more individuals denied their illnesses, as defined by the Levine Denial of Illness Scale, the less SBP re­sponsiveness they exhibited to certain interview topics. Cluster analysis was employed in a study by Houston, Smith, and Cates (1989) in an attempt at identifying groups of subjects who differed in reactivity. Exaggerated SBP reactivity to two experimental tasks was found to be exhibited by subjects in a group who appear to have negative feelings toward people but who deny these feelings and suppress aggression so as not to alienate others.

More attention needs to be given to how people cope with stressful situa­tions in terms of cognitive reappraisal and/or cope with the negative emotions and motives that are engendered by such situations. With the possible excep­tions of research on reactivity and coping with anxiety and anger, relatively little research of this kind has been done. Moreover, it would be desirable to employ direct measures of coping, either alone or along with measures of characteristics that would be expected to affect appraisal or emotional and motivational arousal, rather than inferring a coping process from low scores on measures of personality characteristics. There are a number of measures of coping that could be employed in this fashion; for example, Miller's (1987) measures of monitoring and blunting, the Ways of Coping Questionnaire (Folk­man & Lazarus, 1988), the COPE (Carver, Scheier, & Weintraub, 1989), the Multidimensional Coping Inventory (Endler & Parker, 1990), as well as mea­sures by Billings and Moos (1984) and Stone and Neale (1984), to name a few.

MULTIFACETED CONSTRUCTS

Multifaceted constructs encompassing characteristics that may affect ap­praisal processes as well as emotional and motivational arousal have been studied in regard to reactivity. Foremost among such constructs is the Type A behavior pattern. Individuals characterized by Type A are described as exhib­iting impatience, chronic time urgency, enhanced competitiveness, aggressive drive, and an inclination for hostility (Rosenman, 1978). Overall, the evidence suggests that Type A behavior predicts the incidence of CHD in at least younger middle-aged males (Haynes & Matthews, 1988; Matthews, 1988).

A large number of studies has been conducted in which the relation be­tween Type A behavior and reactivity has been investigated. Due to space limitations, some generalizations and only a few studies can be described here.

PERSONALITY, REACTIVITY, AND CVD 115

(Extensive reviews of this literature may be found in Harbin [1989] and Hous­ton [1988].) The most common measures of Type A behavior employed in these studies are the SI (Rosenman, 1978), the JAS (both the adult version [Jenkins, Rosenman, & Zyzanski, 1974] and the student version [Krantz, Glass, & Sny­der, 1974]), and the Framingham Type A Scale (FTAS; Haynes et al., 1978). Because these measures are only weakly intercorrelated, however, it should be kept in mind that they assess somewhat different constellations of character­istics (Matthews, 1982).

Studies in which the SI has been employed to measure Type A behavior suggest the following. For males, there are two classes of situations in which SI-defined Type A behavior is most likely to be related to reactivity.* One is situations in which the subject is annoyed or harassed (Glass, Krakoff, Contra­da, Hilton, Kehoe, Mannucci, Collins, Snow, & Elting, 1980, Study I; Lake, Suarez, Schneiderman, & Tocci, 1985). This finding would be expected con­sidering the defining characteristics of Type A behavior (e.g., an inclination for hostility). Another class of situations in which SI-defined Type A behavior is likely to be found to be related to reactivity involves experimental arrange­ments in which there is moderate incentive to accomplish something that is difficult but not highly difficult. The reason for qualifying the degree of in­centive as moderate incentive is that in experimental arrangements in which there is high incentive to accomplish something, SI -defined Type Bs exhibit as much reactivity as Type As, probably because they become as motivationally aroused, hence as physiologically aroused as Type As. For example, in a study by Blumenthal et al. (Blumenthal, Lane, Williams, McKee, Haney, & White, 1983), subjects performed a concept formation task in conditions involving either monetary incentive or no incentive. Differences between Type As and Bs in SBP and HR reactivity were found in the low-incentive but not in the high-incentive condition. Further, the reason for indicating that SI-defined Type A behavior is likely to be found to be related to reactivity in experimental arrangements that are difficult but not highly difficult is that Type As typically do not exhibit more reactivity than Type Bs in response to experim~ntal ar­rangements that probably are very difficult. For instance, in inferring task difficulty.from subjects' overall cardiovascular responses to a variety of tasks, Ward et al. (Ward, Chesney, Swan, Black, Parker, & Rosenman, 1986) found SI -defined Type A behavior to be related to reactivity for tasks that generated moderately large cardiovascular responses but not for tasks that generated the biggest responses. Because there is evidence that both male and female Type As are characterized by more fear of failure than Type Bs (Gastorf & Teevan,

*It should be noted that some of the generalizations presented here describe the experimental conditions under which Type A behavior is 11WSt likely to be found to be related to reactivity. This qualification is made because Type A behavior is not always found to be related to reactivity under these conditions, and Type A behavior occasionally has been found to be related to reactivity under other conditions.

116 CHAPl'ER SIX

1980; Houston & Kelly, 1987), it Qas been suggested that highly difficult ex­perimental arrangements may be Viewed by Type .As as portending a potential for failure, which they find troublesome and which they avoid by trying less hard than they otherwise might; consequently they do not become more aroused than Type Bs (Houston, 1983).

For females, SI-defined Type A behavior does not seem to be associated with reactivity to most experimental arrangements (Lawler, Schmied, Mitchell, & Rixse, 1984; MacDougall et aL, 1981, Study I and II; Mayes, Sime, & Ganster, 1984). For middle-class white females, SI-defined Type A behavior is probably most likely to be associated with reactivity in verbal exchanges, such as the SI (Kamarck et aL, 1990, Alone Condition; MacDougall et aL, 1981, Study II), but perhaps not for lower-class and/or black females (Smyth, Call, Hansell, Spar­acino, & Strodtheck, 1978).

Reactivity studies in which the JAS has been employed to assess Type A behavior suggest the following. For males, JAS-defined Type A behavior is most likely to be associated with reactivity in experimental arrangements that require speed of response, are difficult but not extremely difficult (Dembroski et aL, 1978; Jorgensen & Houston, 1981), and involve a moderate degree of incentive for performance (Manuck & Garland, 1979). JAS-defined Type A behavior does not seem to be related to reactivity in experimental arrange­ments in which subjects are annoyed or harassed (Holmes & Will, 1985; Zu­rawski & Houston, 1983). This may be the case because of the paucity of anger-related items on the JAS, which may reduce the sensitivity of the JAS for measuring the hostility component of Type A behavior (Matthews, 1982; Zu­rawski & Houston, 1983).

For college-age females, the findings fail to support a relation between JAS-defined Type A behavior and cardiovascular reactivity (Emmons & Weid­ner, 1988; Lawler & Schmied, 1986; MacDougall et aL, 1981, Study I and II). For noncollege-age females, the evidence for a relation between JAS-defined Type A behavior and cardiovascular reactivity is weak (Lawler, Rixse, & Allen, 1983; Mayes et aL, 1984; Morell, 1989).

Relatively few studies have been conducted on the relation between the FTAS and reactivity. In a study of both males and females, FTAS scores were found to be related to SBP reactivity (Smith, Houston, & Zurawski, 1985). In three studies, however, one of males (Gray, Jackson, & Howard, 1990) and two of females (MacDougall et aL, 1981, Study I and II), no relation between the FTAS and cardiovascular reactivity was found. In two other studies, one of males (Dembroski, MacDougall, Herd, & Shields, 1979) and one of females (Schmied & Lawler, 1989), the FTAS was found to be related to reactivity in only one of multiple conditions. Presently, it seems reasonable to infer that the relation between FTAS-defined Type A behavior and reactivity is at best weak.

Overall, the evidence concerning the relation between reactivity and mea­sures of Type A behavior seems to mirror the epidemiological evidence con­cerning the risk of CHD. The evidence concerning a relation between Type A

PERSONALITY, REACTIVITY, AND CVD 117

behavior and the incidence of CHD is strongest when the SI is employed as the assessment procedure and when healthy males are the target population (Haynes & Matthews, 1988; Matthews, 1988).

ISSUES IN CONDUCTING RESEARCH ON PERSONALITY AND REACTIVITY

While several issues were mentioned at the outset concerning research on personality and reactivity, one deserves repeating and two additional ones deserve to be mentioned.

PERSONALITY BY SITUATION INTERACTION

The model of affective and motivational arousal outlined here aids in emphasizing that a person by situation interaction is involved in every study of the relation between personality characteristics and reactivity. The nature of the experimental arrangement determines whether the personality character­istic under study will be engaged and thus contribute to affective or motiva­tional arousal and thus physiological arousal.

The concept of a person by situation interaction is obvious when some aspect of an experimental arrangement is manipulated with the intention of investigating differences in relations between the personality characteristic and reactivity as a function of levels of the manipulated variable. An example of this, mentioned above, were the studies in which interpersonal conflict or harassment were manipulated and relations between Ho scale scores and re­activity were found in the conflict and harassment conditions but not in the control conditions (Hardy & Smith, 1988; Smith & Allred, 1989; Suarez & Williams, 1989).

The issue of a person by situation interaction, however, applies to the choice of experimental arrangements to which to expose subjects, even in the absence of experimental manipulations. While the conceptualization of Type A behavior would lead one to expect that experimental arrangements that in­volved competition, challenge to achieve, anger provocation, and so on would lead to differences in reactivity between Type As and Bs, it would not lead a person to expect experimental arrangements that solely involved physical threat (e.g., eXposure to snakes or painful stimuli) to induce differences in reactivity between Type As and Bs. In fact, this is what is frequently found, at least for SI-defined Type A males (Houston, 1988). Therefore, in the study of personality characteristics and reactivity, care needs to be given to the careful selection of theoretically relevant experimental arrangements rather than rou­tinely administering tasks that frequently have been employed in studies of reactivity (e.g., mental arithmetic or cold pressor).

118 CHAP1'ER SIX

INTERACTION BETWEEN PERSONALITY CHARACTERISTICS

In the preceding discussion, personality characteristics were discussed separately in regard to appraisal and emotional, motivational, and physiological arousal. In everyday life, however, people frequently encounter complex situa­tions that engage multiple personality characteristics, and besides the possi­bility of an additive effect, there is the possibility that an interaction of multiple personality characteristics may affect individuals' reactions to situations. In­teractions between personality characteristics have been studied infrequently in regard to reactivity. An example of an exception to this was a study by Contrada (1989). An interaction between SI -defined Type A behavior and hardiness was obtained for DBP, wherein differences between Type As and Bs in DBP reactivity were found for high-hardy but not low-hardy individuals. Low-hardy Type Bs exhibited almost as much reactivity as did low-hardy Type As.

In research in which interactions between personality characteristics are examined, it is crucial to employ an expanded person by situation approach and to consider whether an experimental arrangement is relevant to all the person­ality characteristics under study. That is, it is important to carefully select or create experimental arrangements that would be expected to engage all the personality characteristics.

A final note is exemplified by the findings of a study by Jorgensen and Houston (1988) in which an interaction was obtained for SBP reactivity between irritability and family history of hypertension, a biological variable. SBP re­activity was positively related to irritability for persons without a family history of hypertension but was negatively related for persons with a family history of hypertension. Thus, a more complete view of the role of personality charac­teristics in reactivity will be obtained not only by considering interactions between personality characteristics but also by considering interactions be­tween individual differences in personality and biological dispositions.

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CHAPTER SEVEN

Toward Understanding Race Difference in Autonomic Reactivity

A Proposed Contextual Model

NORMAN B. ANDERSON, MAYA McNEILLY,

AND HECTOR MYERS

INTRODUCTION

One of the most consistent findings in the cardiovascular epidemiologic lit­erature is the higher resting blood pressure and greater prevalence of essential hypertension among black compared to white adults (Folkow, 1982, 1987). The higher rate of hypertension among blacks has been documented for males between the aged of 25 and 64 years and for females aged 25 through 74 years (Obrist, 1981). Not surprisingly, given the extraordinarily high rate of hyper­tension morbidity among blacks, this group also suffers disproportionately higher rates of hypertension-related mortality from heart disease, cerebral vascular disease, and renal disease (Matthews, Weiss, Detre, Dembroski, Falk­ner, Manuck, & Williams, 1986; Obrist, 1981).

Given the higher rates of hypertension in blacks than in whites, research­ers in the 1980s began to examine racial differences in stress reactivity as one potential contributor to excessive hypertension morbidity in blacks. In this

NORMAN B. ANDERSON • Departments of Psychiatry and Psychology, Social and Health Sci­ences, Duke University, Durham, North Carolina 27710. MAYA McNEILLY • Department of Psychiatry, Duke University Medical Center, Durham, North Carolina 27710. HECTOR MYERS • Department of Psychology, University of California at Los Angeles, and Depart­ment of Psychiatry, Charles R. Drew University of Medicine and Science, Los Angeles, California 90024.

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126 CHAPTER SEVEN

article, we provide a review of studies of racial differences in stress-induced reactivity. This review is based in part on articles on racial differences in autonomic reactivity by Anderson (1989) and Anderson, NcNeilly, and Myers (1991). Following this review, we present a model describing a contextual perspective for understanding the possible biopsychosocial interactions that might underlie the racial differences in reactivity and hypertension prevalence. It is hoped that this model might serve as a guide for future research.

BLACK-WHITE DIFFERENCES IN REACTIVITY

CARDIOVASCULAR RESPONSES

Numerous investigations have been conducted on black-white differences in autonomic reactivity that have included both children and adults and utilized a wide variety of laboratory stressors, experimental designs, physiological measures, and population subgroups. Despite the diversity of approaches used, most studies demonstrate that blacks show higher levels or greater increases in cardiovascular activity in response to laboratory stressors compared to their white counterparts. This is also true for children (Alpert, Dover, Booker, Mar­tin, & Strong, 1981; Arensman, Trieber, Gruber, & Strong, 1989; Berenson, Voors, Webber, Dalferes, & Harsha, 1979; Hohn, Roipel, Keol, Loadholt, Mar­golius, Halushka, Privitera, Webb, Medley, Schuman, Rubin, Pantell, & Braus­tein, 1983; Murphy, Alpert, Moses, & Somes, 1986; Murphy, Alpert, Walker, & Willey, 1988a; Murphy, Alpert, Willey, & Somes, 1988b; Trieber, Musante, Braden, Arensman, Strong, Levy, & Leverett, 1990; Trieber, Musante, Strong, & Levy, 1989; Voors, Webber, & Berenson, 1980) and adults (Anderson, Lane, Monou, Williams, & Houseworth, 1988a; Anderson, Lane, Muranaka, Williams, & Houseworth, 1988b; Anderson, Lane, Taguchi, & Williams, 1989b; Anderson, Lane, Taguchi, Williams, & Houseworth, 1989c; Dimsdale, Graham, Ziegler, Zusman, & Berry, 1987; Durel, Carver, Spitzer, Llabre, Weintraub, Saab, & Schneiderman, 1989; Light & Sherwood, 1989; Light, Obrist, Sherwood, James, & Strogatz, 1987; McAdoo, Weinberger, Miller, Fineberg, & Grim, in press; McNeilly & Zeichner, 1989; Morrell, Myers, Shapiro, Goldstein, & Armstrong, 1989; Myers, Shapiro, McClure, & Daims, 1989; Tischenkel, Saab, Schneider­man, Nelesen, Pasin, Goldstein, Spitzer, Woo-Ming, & Weidler, 1989; Trieber et al., 1990).

Perhaps more important, however, are the findings that the hemodynamic mechanisms producing the stress-induced blood pressure responses may be different in blacks and whites. For example, two patterns of cardiovascular adjustment to stress have been reported: the myocardial and the vascular. The myocardial reactivity pattern is characterized by an increase in blood pressure associated with increases in cardiac output, stroke volume, heart rate, epineph­rine and norepinephrine, and a decrease in total peripheral resistance. In contrast, the vascular pattern produces an increase in blood pressure via the

RACE DIFFERENCE IN REACTIVITY 127

release of norepinephrine and an increase in total peripheral resistance-the hallmark of the alpha-adrenergic pattern.

Research suggests that blood pressure reactivity in blacks is mediated substantially more by vascular peripheral vasoconstriction compared to that in whites. This heightened vasoconstrictive response in blacks has been observed among children (Arensman et al., 1989; Trieber et al., 1989) and normotensive and hypertensive adults (Anderson et al., 1989c; Light et aL, 1987; McAdoo et al., in press; Tischenkel et aL, 1989; Trieber et aL, 1990) and has been most clearly seen in studies using the forehead cold pressor task-a stimulus that produces a profound vascular vasoconstrictive pattern of reactivity (Anderson et aL, 1988b; Anderson et aL, 1989c; Trieber et al., 1990).

In contrast to the augmented vascular reactivity in blacks, most studies have shown that young black adults show either similar or diminished heart rate reactivity relative to their white counterparts (Anderson et al., 1988a; Anderson et al., 1989b; Anderson et aL, 1989c; Durel et al., 1989; Falkner & Kushner, 1989; Fredrikson, 1986; Light & Sherwood, 1989; Light et al., 1987; McAdoo et al., in press; Morrell et aL, 1989; Myers et al., 1989; Strickland, Myers, & Lahey, 1989; Tischenkel et al., 1989). The data on cardiac reactivity among children, however, are less consistent. Some studies have indicated higher levels of exercise-induced heart rate responses among white children relative to black children (Arensman et al., 1989; Berenson et al., 1979; Hohn et al., 1983; Trieber et al., 1989) while others have yielded nonsignificant race differences in cardiac responses in response to exercise, postural tilt, and the forehead cold pressor task (Alpert et aL, 1981; Tell, Prineas, & Gomez-Marin, 1988; Trieber et al., 1990).

On the other hand, studies using psychological challenges, such as video games, have consistently elicited greater heart rate reactivity among black children compared to whites (Murphy et aL, 1986; Murphy et aL, 1988a; Murphy et al., 1988b). In two of these studies, effects of experimenter race on heart rate responses were observed where children, particularly blacks, showed greater heart rate reactivity when paired with a same-race experimenter (Murphy et al., 1986; Murphy et aL, 1988a). There was also a tendency for white children to have higher resting heart rates than black children when paired with a black experimenter. The authors speculated that same-race pairings possibly elicited an increased effort to perform well on the tasks whereas the mixed-race pair­ings resulted in decreased challenge and involvement.

NEUROENDOCRINE RESPONSES

Catecholamines

Few studies have examined the relationship between catecholamines and race. For example, in reviewing the literature, Goldstein (1983) reported that only 8 out of 78 comparative studies identified the racial makeup of the subject population. Of these, five involved only white patients.

128 CHAPTER SEVEN

More recent studies of racial differences in catecholamine responses to laboratory stressors have produced mixed results. For instance, investigators (Berenson et al., 1979; Hohn et al., 1983) have observed that black normo­tensives show lower stress-induced levels of norepinephrine and dopamine beta-hydroxylase compared to white normotensives. Other studies have failed to observe significant differences in catecholamine responses between or within races (Rowlands, De Givanni, McLeay, Watson, Stallard, & Littler, 1982; Tischenkel et al., 1989).

N europeptides

Research indicates that compared to whites, blacks generally show lower levels of plasma renin activity (PRA) and a greater preponderance of low-renin hypertension (i.e., volume-dependent hypertension; Grim, Luft, Miller, Men­eely, Batarbee, Hames, & Dahl, 1980). In studies with black and white children (Berenson et al., 1979; Voors et al., 1980), blood pressure reactivity was nega­tively correlated with PRA among blacks in the highest diastolic blood pressure strata. Nonsignificant effects of race on stress-induced PRA levels were ob­tained, however, by Rowlands et al. (1982) and Tischenkel et al. (1989), who exposed their subjects to a variety of both physical and psychosocial stressors.

Opioid inhibition of sympathetic activity has been shown to be deficient in white individuals at risk for essential hypertension (McCubbin, Surwit, & Willi­ams, 1985, 1988; McCubbin, Surwit, Williams, Nemeroff, & McNeilly, 1989; see Chapter 12 for a review). Race differences in opioid and blood pressure re­sponses to the stress of intravenous catheterization were investigated by McNeilly and Zeichner (1989). In examining beta-endorphin, an opioid that generally exerts depressor effects, they observed that black normotensives showed higher levels of beta-endorphin than black hypertensives. In contrast, white hypertensives showed higher beta-endorphin levels compared to their normotensive counterparts. In addition, lower levels of plasma beta-endorphin were associated with higher blood pressure and heart rate, particularly among black hypertensives.

PREDICTORS OF REACTIVITY AMONG BLACKS

FAMILY HISTORY OF HYPERTENSION

In order to identify predictors of reactivity within the black population, researchers have begun to investigate the effects of factors such as family history of hypertension, blood pressure status, and personality. With few ex­ceptions, the vast majority of studies comparing blacks at differing levels of blood pressure have shown that children and adults with higher blood pressure show greater reactivity to a variety of stressors compared to individuals with

RACE DIFFERENCE IN REACTMTY 129

lower blood pressure (Berenson et al, 1979; Light & Sherwood, 1989; Light et al, 1987; McAdoo et al, in press; McNeilly & Zeichner, 1989; Voors et al, 1980). The one study that did not observe blood pressure status effects on reactivity (Falkner, Kushner, Khalsa, Canessa, & Katz, 1986) observed numerous inter­active effects of race, gender, and task on reactivity that may have over­shadowed any blood pressure status effects. Conversely, although a number of studies have shown that family history of hypertension predicts cardiovascular reactivity among whites (Matthews & Rakaczky, 1986), this effect has been less consistent among blacks. In fact, most studies with black males and females have shown no significant effects of family history on reactivity (Anderson, Williams, Lane, Haney, Simpson, & Houseworth, 1986; Anderson et al, 1989b; Anderson et al, 1989c; Falkner et al, 1986; Morrell et al, 1989). Most studies that have shown effects of family history on cardiovascular responses have examined group differences in absolute levels of blood pressure responses duringstress(Falkneretal,1986;Hohnetal,1983;Johnson,1989)orrecovery (Myers et al, 1989) rather than changes in measures from baseline to stress. In one study that obtained significant effects offamily history on blood pressure as measured by change scores (Anderson et al, 1986; Anderson, Williams, Lane, Houseworth, & Muranaka, 1987), black females with a positive history showed smaller systolic blood pressure and foreann blood flow responses to mental arithmetic compared to white females-a finding that was interpreted to suggest that blacks may show diminished cardiac responsivity and increased vascular responsivity to stressors.

BLOOD PRESSURE STATUS AND PERSONALITY FACTORS

Studies have shown that among blacks, elevated resting blood pressure and hypertension have been associated with suppressed anger and hostility (Gentry, Chesney, Gary, Hall, & Harburg, 1982; Harburg, Erfurt, Hauenstein, Chape, Schull, & Schork, 1973a; Harburg, Blakelock & Roper, 1979; Johnson, Schork, & Spielberger, 1978; Johnson, Spielberger, Worden, & Jacobs, 1987). Similarly, investigations of cardiovascular reactivity and personality among blacks suggest that anger, hostility, and Type A behavior are associated with greater reactivity (Anderson et al, 1986; Armstead, Lawler, Gorden, Cross, & Gibbons, 1989; Clark & Harrell, 1982; Durel et al, 1989; Johnson, 1989). These relationships, however, may depend on gender, family history of hypertension, the personality constructs measured, and the experimental tasks used. For example, Durel et al (1989) found that among black females, trait anger was associated with greater systolic and diastolic blood pressure at rest in the laboratory and at work and with diastolic blood pressure during the cold pressor task. Among black males, though, positive correlations were observed only between cognitive anger and diastolic pressure at rest.

Johnson (1989) observed interactive effects of personality and family his­tory of hypertension on blood pressure where black males with a positive family

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history showed higher levels of trait anger, anger-out, and submissiveness compared to those with a negative family history. Importantly, these males also showed the highest blood pressure levels at rest and during stress. Finally, Armstead et a1. (1989) tested the effects of exposure to racist stimuli on anger and cardiovascular reactivity among blacks. They observed that blood pressure increases were significantly greater to video clips depicting anger-provoking racialistic scenes than those showing nonracist, anger-provoking, and neutral scenes. Additionally, blood pressure responses were positively correlated with trait anger.

SUMMARY OF RESEARCH FINDINGS

As demonstrated by the previous review, there have been a substantial number of studies on black-white differences in autonomic reactivity. These studies have been conducted with both children and adults and have utilized a wide variety of laboratory stressors, experimental designs, physiological mea­sures, and population subgroups. Yet ,despite the diversity of approaches used, a number of studies have demonstrated that blacks show a greater blood pressure reactivity to laboratory stressors compared to their white counter­parts. Perhaps more important, though, is that the mechanisms responsible for producing the stress-induced blood pressure response may be different in blacks than in whites. Blacks have been found to exhibit greater blood pressure reactivity mediated by peripheral vasoconstriction (characteristic of the alpha­adrenergic pattern) while the blood pressure response of whites has shown a greater cardiac involvement (characteristic of the beta-adrenergic pattern). These results, particularly the heightened peripheral vasoconstrictive respons­es in blacks, have been observed among children, adults, normotensives, and borderline hypertensives. It has been most clearly seen in studies using stres­sors, such as the forehead cold pressor test, that are specifically designed to produce a predominantly alpha-adrenergic pattern of reactivity. Fewer studies have been conducted on the variability of responses to laboratory stressors among blacks. The exception is the research on family history of hypertension and reactivity among blacks, where the studies have not consistently uncovered greater reactivity in black adults with a positive family history.

AUGMENTED REACTIVITY IN BLACKS: A CONTEXTUAL MODEL

THE CONTEXT OF AUTONOMIC REACTIVITY

Thus far, research using the reactivity paradigm has been largely con­cerned with describing racial differences in reactivity. It is now apparent that the next logical scientific imperative is to ascertain the factors responsible for

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the greater vascular reactivity among blacks relative to whites and, perhaps more importantly, to identify the variables that are predictive of heightened vascular reactivity within the black population. It is these issues that the proposed contextual model is designed to address. Anderson and McNeilly (1991), in their discussion of a contextual perspective of psychophysiological research, note that physiological and psychophysiological responses obtained in an experimental laboratory are partly a function of the socioecological niche that the individual occupies at that time. With regard to racial differences in reactivity, it is our contention that the degree to which there are black-white differences in vascular reactivity and essential hypertension is due in large part to racial differences in the socioeconomical niches that the two groups occupy in the United States.

Figure 1 illustrates a proposed working contextual model for investiga­tions of stress-induced vascular reactivity in blacks. The principal tenet of the proposed contextual model is that the exaggerated peripheral vascular re­activity observed in many blacks relative to whites is a function of a number of biological, psychological and behavioral, environmental, and sociocultural fac­tors. The model begins with the premise that in reactivity research, race should be viewed as a proxy for the effects of differential exposure to chronic social and environmental stressOr'S rather than as a proxy for the effects of genetic dif­ferences. Black Americans, on average, are exposed to a wider array of chronic stressors than their white counterparts. These chronic stressors interact with biological, behavioral, and psychological risk factors to increase sympathetic nervous system activity, which in turn leads to the release of neuroendocrine substances, including norepinephrine and adrenocorticotrophin hormone (ACTH), augmented sodium retention, and enhanced vasoconstriction. The resulting higher levels of endogenous sodium and ACTH not only increase blood volume but act to potentiate the vasoconstrictive effects of norepineph­rine on the peripheral vasculature. Over time, the repeated stressor-induced episodes of vascular reactivity may lead to structural changes in the vascular wall (e.g., increased wall-to-Iumen ratio), which further augments reactivity. If repeated frequently over a number of years, this process has the potential to lead to the development of sustained hypertension. The remainder of this chapter will be devoted to explicating each component of this model and delin­eating its relevance to research on reactivity in blacks.

CHRONIC STRESSORS

Many writers have voiced the view of race as a sociological designation that indicates exposure to common life experiences. According to the current model, one distinguishing feature of the life experiences between black and white Americans is the greater exposure to chronic life stressors. As Cooper and David (1986, p. 113), noted, "blacks in the United States have a historically determined structural relationship to the social system." This structural rela-

132 CHAPTER SEVEN

INCREASED SYMPATHETIC ACTIVITY

Vascular Hypertrophy

HYPERTENSION

FIGURE 1. A proposed contextual model for investigations of Btress-induced vascular reactivity in blacks.

tionship has involved several hundred years of institutional discrimination and government-sanctioned racism (Katz & Taylor, 1988; Wilson, 1973), which has only recently been remediated through the Civil Rights legislation of the 1960s. As a consequence of this history and the continued race consciousness of our society, blacks currently experience a greater array of chronic stressors rela­tive to whites. These chronic socioecological stressors include, among others, higher unemployment, higher poverty rates and low-income levels, lower status occupations and lower social status, residential crowding, and substandard housing (Blackwell, 1975; Farley, 1984; Farley & AIlen, 1989; Harris, 1982; Jaynes & Williams, 1989; Lawrence, 1981; WIlson, 1989).

RACE DIFFERENCE IN REACTIVITY 133

Many of these chronic social and environmental stressors have been asso­ciated with hypertension among blacks. For example, socioeconomic status (SES) shows a strong inverse relationship with hypertension among blacks (Hypertension Detection and Follow-up Program Cooperative Group, 1977). Additionally, Harburg et al., (1973b) have found that Detroit blacks residing in neighborhoods high in socioecologic stress, characterized by low SES and high social instability (SIS; defined as high crime and divorce rates), exhibited significantly higher blood pressures than blacks living in low SES but more stable neighborhoods. Among whites, socioecologic stress did not influence blood pressure. Similarly, James & Kleinbaum (1976) found that for black males ages 45 to 54, high-stress (low SES, high SIS) counties of North Carolina were associated with significantly higher hypertension-related mortality (e.g., hypertensive heart disease and stroke) than low-stress counties. As in Har­burg's Detroit studies, no stress-mortality relationship was found for white males. Thus, not only are blacks exposed more frequently to chronic stressors but these social and environmental factors may have greater health conse­quences for blacks.

CHRONIC STRESS AND VASCULAR REACTIVITY: PHYSIOLOGIC MEDIATORS

If the differential exposure to chronic stressors is related to acute cardiovascular reactivity, as we have proposed, it should be possible to identify specific physiological mechanisms linking these phenomena in blacks. It is proposed that exposure to chronic stressors enhances sympathetic nervous system activity that results in augmented sodium retention and neuroendocrine release. Augmented sodium retention and neuroendocrine release may, in addi­tion to increasing blood volume, contribute to the greater vascular responses in blacks.

Sympathetic Nervous System (SNS) Effects

Of critical importance is whether exposure to chronic stress is associated with this hypothesized physiological scenario. In support of this, research from animal and human studies has demonstrated that exposure to acute and chronic uncontrollable stress may augment resting SNS tone, enhance sympathetic reactivity to acute, novel stressors, elevate plasma levels of catecholamines, ACTH, and opioid peptides, and augment sodium retention (Baum, Gatchel, & Schaeffer, 1983; Davidson, Fleming, & Baum, 1987; Fleming, 1987b; Guillemin, Vargo, Rossier, Minick, Ling, Rivier, Vale, & Bloom, 1977; Koepke & DiBona, 1985; Koepke, Light, & Obrist, 1983; Light, Koepke, Obrist, & Willis, 1983; McCarthy, Horwatt, & Konarska, 1988; Rossier, French, Rivier, Ling, Guille­min, & Bloom, 1977). For example, in a study of residential crowding, Fleming et al. (l987b) found that individuals living in more crowded neighborhoods had greater blood pressure and heart rate reactivity during a challenging behav-

134 CHAPTER SEVEN

ioral task than those who lived in less crowded neighborhoods. Studies of reactivity indicate that norepinephrine elicits elevations in blood pressure through vasoconstrictive effects on the peripheral vasculature (Goldstein, 1983). ACTH has been shown to potentiate norepinephrine's vasoconstrictive effects, particularly in humans and animals with reduced renal excretory capac­ity (Bassett, Strand, & Cairncross, 1978; Kurland & Freeberg, 1951; Schomig, Luth, Dietz, & Gross, 1976; Strand & Smith, 1980; Whitworth, Coghlan, Den­ton, Hardy, & Scoggins, 1979), and to augment norepinephrine-induced con­tractions of atrial muscle (Bassett et al., 1978; Strand & Smith, 1980). Impor­tantly, ACTH also induces sodium and water retention (Lohmeier & Carroll, 1985).

In a series of studies at the University of North Carolina at Chapel Hill and the University of Iowa, investigators examined the role of stress and sodium retention in dogs and spontaneously hypertensive rats (Gringnolo, Koepke, & Obrist, 1982; Koepke & DiBona, 1985; Koepke et al., 1983; Light, 1987). In these studies, animals who were exposed to chronic stress showed significant reductions in sodium and fluid excretion and an associated rise in blood pres­sure that was mediated by renal sympathetic nerves. In perhaps the first study of stress and sodium retention in humans, Light et al. (1983) discovered that a stressful laboratory (competitive reaction time) task led to decreased urinary sodium excretion in men with risk factors for hypertension (positive parental history of hypertension and/or borderline hypertension) but only if these men showed evidence of high SNS activity as indicated by above-average heart rate increases (see Chapter 13).

Sodium Effects

There are at least four lines of research that implicate sodium as a prin­cipal physiological mediator of heightened vascular reactivity in blacks. First, there is now considerable evidence that heightened sympathetic activity may induce sodium retention (Weinberger, Loft, & Henry, 1982). Second, although the dietary sodium intake of blacks may not be significantly higher than that of whites (Grim et al., 1980), blacks excrete less sodium in urine and exhibit greater pressor responses to sodium loading (Luft, Grim, Fineberg, & Wein­berger, 1979a; Loft, Grim, & Weinberger, 1985). Thus, blacks may be more susceptible to the blood pressure effects of sodium despite a similar dietary intake relative to whites. Third, research suggests that sodium may augment cardiovascular reactivity in subjects at risk for hypertension (Ambrosioni, Cos­ta, Montebugnoli, Borghi, & Margnani, 1981; Ambrosioni, Costa, Borghi, Mon­tebugnoli, Giordani, & Margnani, 1982; Falkner, Onesti, & Angelako~, 1981). Finally, studies in both humans and SHRs (spontaneously hypertensive rats) indicate that sodium may exert its influence on blood pressure via heightened vasoconstriction rather than by increasing cardiac output (Mark et al., 1975; Nilsson, Fly, Friber, Kulstrom, & Folkow, 1985). Therefore, given the influence

RACE DIFFERENCE IN REACTIVITY 135

of the SNS on sodium retention, the greater sodium sensitivity among blacks, and the effects of sodium on both reactivity and vascular resistance, sodium may be the pivotal physiological mechanism responsible for the observed race differences in vascular reactivity.

How might sodium contribute to increased vascular resistance? Ai> shown in Figure 1, sodium may lead to heightened vascular resistance through its effects on plasma norepinephrine release and action. While in normotensive individuals sodium loading has been shown to decrease plasma and urinary norepinephrine levels, the opposite effect has been observed for salt-sensitive and hypertensive individuals. In these individuals, sodium loading increases plasma and urinary norepinephrine levels while sodium deprivation has the inverse effect (Koolen & Van Brummelen, 1984; Luft et 01., 1979b; Takeshita, Imaizumi, Ai>hirara, & Nakamura, 1982). Furthermore, high sodium intake has been shown to potentiate the effects of norepinephrine on the vasculature (Rankin, Luft, Henry, Gibbs, & Weinberger, 1981). High dietary sodium intake has also been associated with increased pressor responses to infused norepi­nephrine in black hypertensives relative to white hypertensives (Dimsdale et 01., 1987). Thus, if blacks exhibit an exaggerated antinatriuresis, this may lead to an increased release or vasoconstrictive action of plasma norepinephrine. This chain of events would increase peripheral vascular resistance in blacks. Moreover, chronic stressors, that in themselves stimulate the release of plasma norepinephrine, would interact with higher prevailing sodium levels to further stimUlate vascular reactivity. It is hypothesized that th~ heightened vascular reactivity observed in blacks may ultimately result in structural changes (i.e., hypertrophy) in the peripheral vasculature, which in turn may further augment vascular hyperreactivity (Folkow, 1982, 1987). A long-term consequence of this process could be sustained hypertension (Folkow, 1982, 1987).

In summary, there is compelling evidence that blacks in American society are systematically exposed to a wider array of chronic social stressors com­pared to their white counterparts. These Stressors involve lower SES, higher rates of poverty, higher unemployment, lower status occupations, exposure to racism, and more crowded and ecologically stressful residential environments. Many of these have been related to elevated blood pressure and increased hypertension prevalence. Research with humans and animals suggests that exposure to chronic stress may increase tonic SNS activity, acute autonomic reactivity, and urinary sodium retention. Future studies may determine wheth­er the types of stressors to which many blacks are confronted on a daily basis are related to these potentially pathologically sequelae.

BEHAVIORAL AND PSYCHOLOGICAL FACTORS

It is conceivable that chronic social stressors may increase neuroendocrine release and sodium retention through specific behavioral or psychological fac­tors. Early research demonstrated an association between anger, Type A be-

136 CHAPTER SEVEN

havior, and higher levels of plasma norepinephrine and blood pressure among whites (Friedman, Byers, Diamond, & Rosenmann, 1975). To date, only one study has examined these relationships in blacks (Durel et 01, 1989). Although this recent study yielded nonsignificant relationships between norepinephrine and anger for both blacks and whites, it did demonstrate positive correlations between anger and cardiovascular reactivity in these individuals.

A number of studies have shown that behavioral and psychological factors are linked to elevated blood pressure and hypertension among blacks (Ander­son, Myers, Pickering, & Jackson, 1989c; James, 1985). For example, sup­pressed anger and hostility have been associated with elevated blood pressure and hypertension in both adolescents and adults (Harburg et 01, 1979; Johnson et 01, 1978; Johnson et 01, 1987). In general, this literature has indicated that blacks who frequently suppress their anger when provoked, or who express their anger without reflection, have higher resting blood pressure levels than those who routinely express their anger or who express it only after some reflection (Gentry et 01, 1982; Johnson et al., 1978). Recently, it has been found that the experience of frequent anger is related to higher ambulatory blood pressures among black women while at work (Durel et 01, 1989). At this time, research has not examined whether inhibited anger expression is related to sodium excretion or neuroendocrine release among blacks.

Another behavioral factor associated with high blood pressure among blacks is the "John Henryism" behavioral pattern of hard work and determina­tion against overwhelming odds. James, Hartnett, and Kalsbeck (1983) spec­ulated that blacks who exhibit this type of determination, but who also have few resources to help them achieve their goals, may be at greatest risk for develop­ing hypertension (James et al., 1983; James, LaCroix, Kleinbaum, & Strogatz, 1984). Furthermore, it has been found that blacks high in John Henryism and low SES have a higher percentage of hypertension than persons who are low John Henryism or have a higher SES (James, Strogatz, Wing, & Ramsey, 1987). Interestingly, no interaction of John Henryism with education or blood pressure has been found for whites, suggesting, as James and colleagues (1983) noted, that this coping style may be particularly relevant to black populations.

As depicted in Figure 1, the behavior of individuals high in John Henryism may actually increase their exposure to stressful social and environmental circumstances. That is, these individuals may continually strive to gain control over their environment in spite of numerous barriers, thereby potentially ex­posing themselves more frequently to frustrating and stressful situations. Whether this exposure to behaviorally mediated chronic stress results in en­hanced SNS and altered sodium regulation remains to be empirically deter­mined. It has been reported, however, that active behavioral coping with acute laboratory stressors enhances sodium retention (Light et al., 1983). It is this active coping with real-life stressors that is the sine qua non of the John Henryism pattern.

RACE DIFFERENCE IN REACTIVITY 137

Chronic social stressors may also have other psychological and emotional effects that could potentially influence sodium retention and neuroendocrine release. For example, low-income blacks have been found to report more psy­chological distress than lower and higher income whites and higher income blacks, perhaps due to the combined burden of poverty and racism (Kessler & Neighbors, 1986). Additionally, the stressful residential environments to which many blacks are exposed (e.g., crowding and crime) are related to stress symptoms, such as anxiety, depression, somatic complaints, lower levels of perceived control, and enhanced sympathetic nervous system activity (Baum et aL, 1983; Davidson et aL, 1987; Fleming et aL, 1987b; Schaeffer & Baum, 1984).

BIOLOGICAL/GENETIC FACTORS

Although genetic variables have been identified as important in determin­ing sodium excretion in both blacks and whites (Grim, Luft, Weinberger, Miller, Rose & Christia, 1984), epidemiologic evidence suggests that the association of parental history and risk for hypertension may not be as strong among blacks relative to whites (Stamler, Stamler, Riedlinger, Algera, & Roberts, 1979). In fact, no published studies have obtained the expected relationship between parental history of hypertension and cardiovascular reactivity among black adults (Anderson et aL, 1986; Anderson et aL, 1989b; Anderson et aL, 1989c; Rowlands et aL, 1982), although this relationship has been found fairly con­sistently among whites (Fredrikson & Matthews, 1990). A possible explanation for these somewhat puzzling findings may be the substantial influence of psy­chosocial factors in the development of hypertension among blacks (Anderson et ai., 1989a). That is, psychosocial factors, such as chronic stress, may over­shadow the influence of parental history such that risk for hypertension and hyperreactivity are augmented even in persons with a negative parental his­tory. This would result in a diminished ability to detect differences between parental history groups among blacks (Anderson, McNeilly, & Myers, 1991).

Second, as we have discussed, although sodium retention has a clear genetic component (Grim et aL, 1984), it may also be stimulated by psychosocial stress. To the degree that blacks, particularly low-income blacks, experience more psychological stress than do whites or upper-income blacks (Kessler & Neighbors, 1986), they may consequently be more susceptible to inhibited sodium excretion.

Finally, the genetic distinction between black and white Americans is, at best, ambiguous. It has been noted that the gene pool of American blacks is comprised of a heterogeneous mixture of genes from genetically diverse pop­ulations in Africa (Hiernaux, 1975; Mourant, 1983) and the U.S. Caucasian population (Glass & Li, 1953; Pollitzer, 1958). In fact, Reed (1969) estimates that up to 50% of the genes of black Americans are derived from Caucasian ancestors, whereas Lewontin and associates (Lewontin, 1973; Lewontin, Rose,

138 CHAPTER SEVEN

& Kamin, 1984) report that genetic differences between individuals within a race have a substantially greater impact on the total species genetic variation than genetic differences between races. Therefore, although genetic factors no doubt playa role in reactivity among blacks, their influence on between-race differences is likely to be considerably less.

COPING RESOURCES

Thus far, we have been discussing the various physiologic, social, and behavioral factors that may contribute to the augmented sodium retention, greater vascular reactivity, and higher hypertension prevalence among blacks compared to whites. It is important to note, however, that there may be factors inherent in the culture and traditions of black Americans that may counteract the sympathetic and hypertensiongenic effects of chronic streSS. A number of authors have advocated the view that black Americans share many character­istics, both social and behavioral, that have their origin in African traditions (Dixon, 1976; Nobles, 1974, 1980a,b; White, 1990). As summarized by Anderson (1989), these African traditions include, among other things: a strong spiritual orientation; a deep sense of kinship and identification with the ''tribe'' and larger group rather than a strictly individualistic orientation; a reverence for the oral tradition and the spoken word; a flexible concept of time, which is marked by events rather than the clock or calendar; an emphasis on the past and present rather than the future; and an unashamed use of emotional ex­pressiveness.

The presence of these African traditions in the black culture is apparent, for example, in the expression of both verbal and nonverbal behaviors (Koch­man, 1981; Smith, 1981); the importance of extended family, which may include, in addition to blood relatives, individuals who are given the same status and responsibilities as blood relatives (Nobles, 1974); the central role of religion and spirituality; the unique style and emotional expressiveness of the black church service, even though the content of the hymns and readings may be Euro­American (White, 1980); and the strong sense of group solidarity, racial iden­tity, or "We-ness" in the black community (Nobles, 1980a,b).

According to our contextual model, certain of these cultural traditions could well decrease the effects of stress and, consequently, the effects of stress on SNS activity, sodium retention, and blood pressure level. It has been found, for instance, that among whites, regular church attendance is associated with lower resting blood pressure levels than less frequent attendance (Graham, Kaplan, Coroni-Huntley, James, Becker, Hames, & Heyden, 1978). It would be of interest to determine whether blacks exposed to chronic life stressors (e.g., low-income blacks) but who also have a high cultural ''buffer'' (e.g., strong religious orientation, social support, or an extended family network) exhibit lower tonic SNS activity, lower sodium retention, and lower cardiovascular reactivity than those individuals less connected with cultural resources.

RACE DIFFERENCE IN REACTMTY 139

TESTING THE CONTEXTUAL MODEL: DIRECTIONS FOR RESEARCH

The contextual model presented herein was designed to provide a stimulus for examining both the basis for racial differences in vascular reactivity as well as for exploring within-race variability in vascular responses among blacks. Toward these ends, the model suggests a number of testable hypotheses and research questions. Various components of the model could be tested using either field or laboratory methodologies. For example, the model would predict that blacks who are exposed to higher levels of chronic stress should have higher resting stress hormone levels (e.g., catecholamines, ACTH) and ex­aggerated responses to novel stimuli, suggesting increased SNS activity com­pared to blacks experiencing lower levels of chronic stress. Second, chronic stress should also be positively associated with increased sodium retention (i.e, slower sodium excretion rates) and greater vascular reactivity in blacks. Third, the combination of chronic stress exposure and behavioral and psychological factors, such as anger-suppression and John Henryism, should be positively associated with both increased SNS activity and greater sodium retention. Furthermore, dietary sodium loading (or saline infusions) should potentiate vascular reactivity in blacks experiencing chronic stress. Finally, the contextual model would predict that blacks with more coping resources (e.g., high social support, strong religious orientation, and racial identity) will show lower SNS activity and decreased sodium retention relative to those with fewer coping resources.

SUMMARY AND CONCLUSIONS

In summary, according to the proposed model, race is viewed as a socio­cultural designation that denotes differential exposure to chronic social stres­sors. It is proposed that blacks are exposed to significantly more chronic social stressors than white Americans. Many of these chronic social stressors have been associated with hypertension prevalence in epidemiological studies. Fur­thermore, chronic stress has been shown to augment cardiovascular reactivity to acute stress in both animals and humans and to increase sodium retention in SHRs. Acute stress has also been demonstrated to increase sodium retention in humans. The essential element of our model is that chronic social stressors that are more represented within the black American population due to his­torical factors are related to an increase in sodium and reactivity retention. This altered sodium metabolism and reactivity may be further augmented by biolog­ical, behavioral, and psychological risk factors for hypertension and modulated by stress coping resources. It is hoped that this model will serve as a stimulus for further research on the biopsychosocial aspects of autonomic reactivity and hypertension in blacks.

140 CHAPTER SEVEN

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CHAPTER EIGHT

The Role of Reproductive Hormones in Cardiovascular and

Neuroendocrine Function during Behavioral Stress

CATHERINE M. STONEY

INTRODUCTION

The role of reproductive hormones-both male and female-in the develop­ment and progression of coronary heart disease has been studied by epide­miologists for many years, yet discrepancies in the epidemiologica1literature are widespread, no doubt due to the complexities of the human reproductive system itself. Despite the discrepancies, there is significant evidence that en­dogenous ovarian hormones-most likely the estrogens-serve a cardioprotec­tive role for women. In some cases, and in small doses, certain exogenous estrogens might also be protective against heart disease. There is little doubt that both endogenous and exogenous reproductive hormones play a compli­cated role in modulating the risk of coronary heart disease.

Exaggerated cardiovascular and neuroendocrine responses to stress are thought to be one mechanism by which behavioral stress impacts on the pro­gression of coronary heart disease and hypertension (Krantz & Manuck, 1984). Evidence for this hypothesis comes from studies of individuals with elevated

CATHERINE M. STONEY • The Miriam Hospital and Brown University School of Medicine, Division of Behavioral Medicine, Providence, Rhode Island 02906. Portions of this chapter were prepared while Dr. Stoney was at the University of Pittsburgh, Pittsburgh, Pennsylvania.

147

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risk of disease, such as offspring of parents with coronary heart disease, demon­strating such exaggerated stress response (Krantz & Manuck, 1984; Stoney & Matthews, 1988). To the extent that the so-called reactivity hypothesis is valid, the investigation of individuals who differ with respect to their reproductive honnone levels might help to explain one mechanism by which reproductive honnones impact on the disease process.

The purpose of this chapter is to review what we currently understand about the impact of endogenous and exogenous reproductive honnones on cardiovascular and neuroendocrine stress responses in males and females. In humans, there are numerous potential populations of study participants, all differing somewhat with regard to their honnonal milieu. My interests, as well as those of others in this field, have been primarily driven by the epidemiolog­ical associations between ovarian honnones (particularly the estrogens) and coronary heart disease. Thus, the few investigators who have addressed this issue have chosen to specifically target subjects who differ with regard to estrogen levels. As in all young fields of study, however, much of the psycho­physiologica1Uterature in this area is sporadic and not optimally systematic in nature. The potential for extensive psychophysiological work in this area is tremendous and should be undertaken with a sophisticated understanding of the social, behavioral, and physiological consequences of changes in reproduc­tive honnone levels, particularly the ovarian honnones. It is through this kind of complex integration that psychologists, especially psychophysiologists, can make significant contributions.

SEX DIFFERENCES IN ADULT STRESS RESPONSES

Coronary heart disease is the major cause of mortality in both males and females of all industrialized nations. Males, though, are more than twice as likely than are females to experience coronary morbidity and mortality (Rice, Hing, Kovar, & Prager, 1984). The sex difference cannot be explained by differences in behavioral risk factors, such as smoking, obesity, and marital status, nor can it be explained by other traditional risk factors, such as age, systolic blood pressure, and total cholesterol (Wingard, 1982; Wingard, Suarez, & Barrett-Connor, 1983). Other manifestations of heart disease, such as angina pectoris and hypertension, do not show the same pattern of sex differences. For example, although males are at greater risk for the development of hyper­tension during early adulthood, after age 55 the relative risk is reversed, with women showing a greater incidence of disease. These observations suggest that the etiology of various forms of heart disease may differ by gender and, more importantly, underscore the necessity to examine those factors that contribute to the disease process in both males and female. To the extent that exaggerated stress responses in the cardiovascular and neuroendocrine systems reflect an increased risk of coronary heart disease, sex differences in reactions to stress

THE ROLE OF REPRODUCTIVE HORMONES 149

may help explain the well-documented but poorly understood sex difference in coronary heart disease (Stoney, Davis, & Matthews, 1987).

Early evidence that reproductive hormones might impact on the mag­nitude and pattern of physiological stress responses came from investigations of sex differences in reactivity. Although few studies have systematically ex­amined the issue of male-female differences in heart rate, blood pressure, and catecholamines, secondary analyses have been performed in several investiga­tions to make such comparisons. My colleagues and I conducted a meta-analysis of the published sex-difference studies in the literature up to 1986 (Stoney et 01, 1987). Meta-analysis is a statistical procedure for combining the results of several disparate studies investigating a similar question. A total of up to 12 studies were included in the analysis, depending on the dependent measure of interest. Overall, there were three major findings from this analysis. First, males had relatively greater systolic blood pressure responses to stress than did females. Second, males had relatively larger urinary epinephrine responses to stress than did females. Third, females had marginally higher heart rate responses to stressors relative to males.

Since that time, several additional studies have further examined, in a more systematic fashion, evidence for possible sex differences in physiological stress responses. For example, a community-based study examined heart rate and blood pressure responses in children and adult males and females during a series of standardized stressors (Matthews & Stoney, 1988). Among the adults, males exhibited larger systolic and diastolic blood pressure stress re­sponses relative to females. In prepubertal children, there were no sex differ­ences. Thus, this large-scale study demonstrated considerable evidence for sex differences in blood pressure stress responses in male and female adults, who differ dramatically in reproductive hormones, but not in children. .

Several laboratory-based studies have continued this line of research. For instance, a study designed to examine more extensive indices of physiological functioning reported that males had larger blood pressure and lipoprotein stress responses to a variety of behavioral tasks (Stoney, Matthews, McDonald & Johnson, 1988). In another investigation, greater blood pressure reactivity to an unsolvable anagrams task was demonstrated among men while women had larger heart rate responses to the same task (Weidner, Friend, Ficarrotto, & Mendell, 1989). Transthoracic impedance measures have also been used to noninvasively compare men and women in their cardiac output and total per­ipheral resistance responses to structured stressors (Girdler, Turner, Sher­wood, & Light, 1990). This recent study demonstrated that males had greater increases in total peripheral resistance to speech and mathematics tasks rel­ative to females while females exhibited larger stress-associated increases in cardiac output relative to males. Unlike most previous studies in this area, there were no sex differences noted in blood pressure.

In addition to the laboratory studies cited above, there has also been some exploration of sex differences in response to real-life stressors. These studies

150 CHAPl'ER EIGHT

have by and large also demonstrated some evidence for sex differences in stress responses. For example, van Doomen (1986) reported that male students had larger urinary epinephrine changes during an examination day compared to female students. In contrast to many of the above investigations, however, there were no significant male-female differences in the cardiovascular param­eters examined.

Taken together, the results of the literature exploring male and female differences in cardiovascular and neuroendocrine stress responses strongly suggest that males exhibit exaggerated pressor and urinary catecholamine responses to behavioral stress relative to females. There is some indication that this effect can be modulated in part by race (Dimsdale, Pierce, Schoenfeld, Brown, Zusman, & Graham, 1986), age (Matthews & Stoney, 1988), menstrual cycle phase (Hastrup & Light, 1984), and behavioral characteristics, such as the Type A behavior pattern (see Saab, 1989, for a review). Nonetheless, the rather consistent finding that males show exaggerated cardiovascular and urinary epinephrine adjustments to stress suggests that female ovarian hormones (pro­gesterone and/or the estrogens) can modulate physiologic stress responses, and this may ultimately serve as a protective effect against coronary heart disease. The next section reviews the human literature that has directly examined the impact of female reproductive hormones on reactivity.

INVESTIGATIONS OF INDIVIDUALS THROUGH THEIR REPRODUCTIVE LIVES

One strategy for examining the impact of endogenous reproductive hor­mones on stress responses is to investigate individuals throughout various phases of their reproductive lives. This section will review the psychophysiolog­ical studies in this area, as well as highlight some relevant aspects of the physiology of ovarian function. The purpose of this review is to illustrate some of the complexities involved in studying boys and girls throughout puberty and women through the menstrual cycle, pregnancy, and menopause rather than to provide a complete description of the relevant physiological mechanisms in­volved.

PuBERTY

There is a paucity of data specifically examining stress responses of girls and boys during puberty. One particular drawback with this type of study is that accurate assessment of pubertal status in potential study participants is difficult. Although the use of Tanner staging of secondary sexual characteristics is most accurate for the assessment of pubertal status (Tanner, 1962), invasive procedures such as this are usually not appropriate for psychophysiological studies. Other equally obtrusive methods include X-ray identification of bone

THE ROLE OF REPRODUCTIVE HORMONES 151

age and skull size, measurement of serum gonadotropin levels, and neurologic examinations. Thus, investigations of this nature have relied on chronological age as the best indicator of pubertal stage.

In a previous study, my colleague and I (Matthews & Stoney, 1988) ex­amined the influence of age in a group of boys and girls in the peripubertal stage of development. Children in grades 2 through 8 were compared to those in grade 9 through 12 during rest and during three laboratory tasks: serial sub­traction, mirror-image tracing, and isometric exercise. Heart rate and blood pressure were measured throughout the rest and task periods. Interestingly, the postpubertal adolescents (grades 9 through 12) displayed sex differences in cardiovascular stress responses that were similar to those found in adult sam­ples, whereas, the prepubertal children did not show significant sex differences in any response system. For example, during the isometric handgrip task, adolescent boys demonstrated significantly larger systolic blood pressure re­sponses relative to adolescent girls, while the responses to this task in the younger boys and girls were the same. Age also influenced heart rate stress responses, such that the older adolescents has smaller heart rate responses to the tasks relative to the younger children. Therefore, to the extent that age is an adequate index of pubertal status, this study demonstrates that postpubertal cardiovascular stress responses are similar to adult stress responses and can be reliably differentiated from those of prepubertal children. Perhaps more im­portantly, this study provides additional evidence that reproductive hormones serve, either directly or indirectly, to modulate the magnitude of cardiovascular stress responses. Whether stress responses are attenuated with the female ovarian hormones or are augmented with the male testicular hormones is a question for additional research in this area.

MENSTRUAL CYCLE

The normal female menstrual cycle consists of predictable, monthly fluctuations in luteinizing hormone (LH), follicle-stimulating hormone (FSH), estrogens, and progesterone that prepare the endometrial lining of the uterus for possible conception of a mature ovum. The cycle begins with menses, during which time actual bleeding occurs. This phase is initiated by increased FSH levels and is characterized by relatively low levels of circulating estradiol, progesterone, and LH. The follicular phase follows menses and corresponds to the development of the follicle in preparation for ovulation. Through a complex system, a dominant follicle is selected, and estradiol levels begin to rise. As estradiol rises during the midfollicular phase, it exerts both positive and neg­ative feedback to suppress the further release of FSH and increase the release of LH. During the late follicular phase, progesterone production is initiated, and LH and FSH begin to peak. Approximately 10 to 12 hours after LH peaks, ovulation occurs (pauerstein, Eddy, Croxatto, Hess, Siler-Khodr, & Croxatto,

152 CHAPTER EIGHT

1978) and estradiol levels markedly decrease. Ovulation is the release of the mature ovum from the follicle. The luteal phase follows ovulation and rupture of the follicle. This phase corresponds to the time at which the corpus luteum develops and, in the absence of conception, regresses. It is characterized by a surge in progesterone, which peaks about 8 days after the LH surge, to sup­press the development of another follicle. Estradiol also demonstrates a second peak during the luteal phase while the gonadotropins remain at low levels. The cycle then begins again.

There are now at least 12 published studies examining women's cardio­vascular and neuroendocrine responses to stress throughout the normal men­strual cycle. These studies can be broadly categorized into those that compare separate groups of women at different menstrual cycle phases and those that examine the same women throughout one or more menstrual cycles. This distinction becomes important when trying to reconcile disparate results.

Studies with a between-subjects design have frequently but not always found that the menstrual cycle phase does influence some measures of cardio­vascular and neuroendocrine function during stress but in an inconsistent manner. For example, several investigators (Hastrup & Light, 1984) have reported that women tested in the luteal phase of the menstrual cycle exhibit greater cardiovascular reactivity relative to women tested in the follicular phase of the cycle. Using a similar design, however, Polefrone and Manuck (1988) found that women in the follicular phase of the cycle had enhanced blood pressure reactivity relative to women tested in the luteal phase. Other studies of this type have failed, by and large, to find an effect for the menstrual cycle phase (Cuche, Kuchel, Barbeau, & Genest, 1975; Plante & Denney, 1984).

Investigations utilizing a within-subjects design have generally found that the menstrual cycle phase does not influence cardiovascular and neuroendo­crine stress responses. Several studies tested women during their follicular and luteal phases of the cycle and found that their stress responses were not altered in any significant way as a function of the menstrual cycle phase (Carroll, Turner, Lee, & Stephenson, 1984; Kaplan, Whitsett, & Robinson, 1990; Stoney, Langer, & Gelling, 1986; Stoney, Owens, Matthews, Davis, & Caggiula, 1990). One possible exception is a study of Swedish women tested during two con­secutive menstrual cycles, which reported that urinary catecholamine excretion was higher at the luteal phase but only during one of the two menstrual cycles tested (Collins, Eneroth, & Landgren, 1985). It is important to note that in this particular study, there was not a significant increase in catecholamines during stress, casting some doubt on the conceptual importance of the catecholamine difference among the phases studied. Finally, when phases in addition to, or in place of, the follicular and luteal phases are also investigated, results are inconsistent. For example, greater heart rate reactivity was found during the luteal relative to the premenstrual phase in one study (Ladisich, 1977) while cortisol responses were higher premenstrually relative to midcycle in another study (Marinari, Leshner, & Doyle, 1976). Most studies of other phases reveal

THE ROLE OF REPRODUCTIVE HORMONES 153

no differences in cardiovascular responses between the menstrual, follicular, and luteal phases (Stoney et aL, 1990) or between the follicular, ovulatory, and luteal phases (Collins et aL, 1985; Little & Zahn, 1974).

Several possible methodological explanations might clarify the discrep­ancies noted above. One obvious way to reconcile the differences found in the studies of menstrual-cycle effects is to speculate that the choice of a between­or within-subjects design impacts significantly on findings. To date, studies incorporating between-subjects designs have more frequently indicated car­diovascular differences across the menstrual cycle than have studies involving within-subjects comparisons. It can be speculated that the habituation that may occur in a test-retest design has a more powerful impact on cardiovascular responses than the menstrual cycle effects themselves, leading to these re­ported differences related to design.

Most studies reviewed above relied on participant reports of menstrual cycle phase to determine the time of testing, based on calendar records. This is an inaccurate method of determining the menstrual cycle phase, however, and ideally should be supplemented with biochemical measures. The impor­tance of verifying hormonal status and cycle phase can be underscored by understanding the enormous frequency of menstrual cycle irregularities in the healthy population (Bean, Leeper, Wallace, Sherman, & Treloar, 1979; Treloar, 1976). Obviously, vigorous screening prior to testing of women with overt hormonal or menstrual cycle irregularities is necessary. It is not sufficient, though, because it will not eliminate women with hormonal or menstrual cycle irregularities that are not known to those women. For example, many women have large variations in cycle length but consider themselves to cycle normally. For these women, the accurate prediction of the menstrual cycle phase based only on calendar records or basal body temperature is not feasible. There­fore, the measurement of estradiol, progesterone, LH, and FSH is minimally necessary.

Even within the normally cycling, healthy population with no hormonal irregularities, the failure to employ biochemical indices of the menstrual cycle phase for identification purposes will lead to inaccuracies for several reasons. First, reproductive hormones change rapidly and dramatically over the course of the normal cycle. Trying to target, for instance, the 36-hour ovulatory phase without any hormone measures is largely a matter of guesswork, even in women with exceptionally regular cycles. Second, the days of the cycle gener­ally associated with specific phases can only be considered approximate ones and only are appropriate for a 28-day cycle. Adjustments must be made for cycles that are longer or shorter than 28 days. For example, the follicular phase is commonly referred to as occurring between days 5 to 13. For a women with a 26-day cycle, however, the follicular phase will usually be shorter. Interest­ingly, variations in menstrual cycle length that do occur, both within and between individuals, occur most commonly in the follicular phase (Speroff, Glass, & Kase, 1989). If only the onset of menses is used to identify the

154 CHAPI'ER EIGHT

menstrual cycle phase, the timing of the phases must be relative to the initiation of menses, not the cessation (compare with Plante & Denney, 1984).

One word of caution about blood measures of the ovarian and pituitary honnones is in order. The gonadotropins, LH and FSH, are released from the pituitary in a pulsatile fashion. In addition, during the luteal phase, progest­erone release is episodic (Veldhuis, Christiansen, Evans, Kolp, Rogol, & John­son, 1988). A single blood draw taken at an isolated point in time may simply reflect the episodic nature of progesterone and the gonadotropins and not the true honnonal milieu of the individual. Therefore, one blood draw, in the ab­sence of other infonnation or a second draw, may be inadequate for identifying cycle phase and honnonal abnonnalities.

The choice of phase to study has conceptual importance. The menstrual cycle is most easily divided into the follicular, ovulatory, and luteal phases. The honnonal variations that occur during the follicular phase are large, however. For example, while estradiol and gonadotropin levels are low in the early follicular phase, during the midfollicular phase, estradiol levels begin to rise; by the late follicular phase, LH and FSH begin to peak.

Reconciling the studies described above is obviously difficult given the different choices made about phases to study. Ideally, the choice of which menstrual cycle phases to study should be biologically based and would depend on the particular honnones that are of interest. For instance, if estradiol is the gonadal honnone ofpriroary interest, responses during the midfollicular, mid­luteal, and menstrual phases might be compared. This would allow one to test during a time when estradiol levels are high, when both estradiol and pro­gesterone levels are high, and when both estradiol and progesterone levels are low, respectively (Stoney et 01, 1990).

It is clear from reviewing the above studies that the few effects of the menstrual cycle phase that have been reported are small and inconsistent in direction. It is likely that in nonnally cycling females tested during discrete phases of the menstrual cycle, the relatively small fluctuations in reproductive honnones that occur are not large enough to significantly influence stress responses. This is not to say, though, that reproductive honnones cannot mod­ulate cardiovascular and neuroendocrine responses to stress in women with abnonnal or irregular menstrual cycles or that larger magnitude honnonal changes than those that occur with the menstrual cycle cannot modulate stress responses.

Finally, it is important to note that most of the studies described above measured a limited number of cardiovascular (heart rate and blood pressure) and/or catecholamine (epinephrine and norepinephrine) stress responses, and so this discussion is confined to only those measures. Adjustments in other physiological parameters, such as respiratory (tidal volume, oxygen consump­tion), cardiovascular function (cardiac output, peripheral resistance), and lipid (cholesterol, lipoproteins) indices, have not been adequately investigated, and conclusions regarding any possible effects of the menstrual cycle phase on these measures cannot be established at this time.

THE ROLE OF REPRODUCTIVE HORMONES 155

PREGNANCY

The study of pregnant individuals within a reactivity context is valuable from at least two perspectives. First, nulliparity (never having borne a child) is associated with an increased risk of coronary heart disease in both human and nonhuman primates. For example, in humans, nulliparity is positively asso­ciated with the incidence of sudden cardiac death (Talbott, Kuller, Detre, Matthews, Norman, Kelsey, & Belle, 1989). In female cynomolgus macaques, those who experienced one or more pregnancies had less extensive athero­sclerosis than nulliparous macaques (Adams, Kaplan, Koritnik, & Clarkson, 1987). Second, pregnancy represents an ideal and unique model to further explore the effects of reproductive hormones on stress-induced physiological adjustments. During pregnancy, estrogens and progesterone are dramatically increased to levels far exceeding those during the normal female menstrual cycle.

At rest, heart rate and cardiac output are consistently shown to increase during pregnancy while blood pressure generally is increased or remains the same (Cole & Sutton, 1989; Speroff et al, 1989). During physical challenges that mayor may not have a psychological component, pregnant women experienced significantly lower catecholamine and heart rate responses than nonpregnant women (Barron, Mujais, Zinamen, Bravo, & Lindheimer, 1986; Nisell, Hjem­dahl, Linde, & Lunnell, 1985). Regarding the effects of pregnancy on more standard psychological stressors, only one published study has examined wom­en prior to and during the second trimester of pregnancy (Matthews & Rodin, 1992). Subjects participated in a serial subtraction task, a mirror-image tracing task, and an isometric handgrip task prior to and during pregnancy, while heart rate and blood pressure were periodically monitored. The results of the study included the finding that blood pressure responses to each of the tasks were somewhat reduced during pregnancy relative to the prepregnancy levels. A control group of nonpregnant women tested at two similar time intervals did not demonstrate a similar decline in blood pressure.

These findings suggest that the dramatic changes in reproductive hor­mones (both progesterone and the estrogens) that occur during pregnancy may affect cardiovascular stress responses to a modest degree. Further studies with larger group sizes and more varied physiological parameters are clearly neces­sary to further elucidate the magnitude of the effect of reproductive hormones on physiological stress responses.

MENOPAUSE

Regular menstruation commences at the onset of puberty in females and ends at menopause. In the United States, menopause occurs at an average age of about 50 years (Krailo & Pike, 1983) and corresponds to the complete cessation of ovarian function. This cessation is a gradual process, however, with the frequency of ovulation slowly diminishing, beginning at about age 40 years.

156 CHAP1'ER EIGHT

During this perimenopausal period, important hormonal changes occur. FSH may rise but LH usually remains at premenopausal levels. Estradiol begins to decline, and the cycles often become irregular due primarily to a shortening of the follicular phase. Vaginal bleeding and ovulation may occur irregularly during the perimenopausal period. After complete ovarian failure, FSH and LH are elevated dramatically, and estradiolleve1s decline considerably. One to three years after the onset of menopause, FSH and LH levels begin to grad­ually decline.

Studies of women in the postmenopausal period may help to elucidate the role that reproductive hormones play in psychophysiologic reactivity. In addi­tion to providing a model for studying the effects of hormones, however, it is a critically important population to study in and of itself. Today, women have a life expectancy of greater than 80 years and so can expect to spend nearly one-third of their lives in a postmenopausal state. In this decade, the United States can look forward to a population of more than 50 million women over the age of 50. Thus, the study of psychological as well as physiological aspects of menopause is clearly warranted.

Unfortunately, few psychophysiologic studies of premenopausal and post­menopausal women have been performed to date. Three exceptions can be noted. The earliest of these was specifically designed to explore the extent to which reproductive hormones in females affect blood pressure, heart rate, and respiratory rate at rest and during the stress of a mental arithmetic task (von Eiff, Plotz, Beck, & Czernik, 1971). Postmenopausal women had higher systolic blood pressure levels at rest relative to regularly cycling premenopausal wom­en at an unspecified point in their menstrual cycles. There were no apparent group differences during the stressful task, however.

Two additional studies expanded the design of this early study. Hastrup and colleagues (Hastrup, Kraemer, & Phillips, 1986) compared age-matched premenopausal women to women who had undergone a surgical menopause (hysterectomy with bilateral oophorectomy). Measures of heart rate and blood pressure were determined during a series of laboratory stressors. While the two groups did not differ in their cardiovascular stress responses, there was a significant interaction with family history of hypertension. Thus, the surgical group with a positive family history experienced significantly larger blood pressure stress responses relative to the other three groups.

Finally, a recent study by my colleagues and me compared similarly aged premenopausal and postmenopausal women in several indices of cardiovascular and neuroendocrine function during a series of standardized laboratory stres­sors (Saab, Matthews, Stoney, & McDonald, 1989). In this study, 31 women performed a serial subtraction task, a mirror-image tracing task, a speech task, and a postural tilt task. Blood pressure, heart rate, and plasma blood samples for the analysis of epinephrine and norepinephrine were measured at rest and during the tasks. Blood samples for the measurement of FSH were used to verify the hormonal status of postmenopausal women only. While premeno-

THE ROLE OF REPRODUCTIVE HORMONES 157

pausal women were only tested during the follicular phase of the menstrual cycle (based on calendar records), no hormonal verification was made in these women. After adjustments were made for body weight and age, postmen­opausal women still exhibited larger heart rate responses to all of the stressors and greater systolic blood pressure and epinephrine responses to the speech task relative to premenopausal women. These results suggest that large-mag­nitude differences in reproductive hormones, such as those that occur between premenopausal and postmenopausal women, interact with task characteris­tics to influence certain measures of cardiovascular and neuroendocrine functioning.

Despite the limitations noted in each of these studies of postmenopausal women, each provides limited evidence that reproductive ovarian hormones affect cardiovascular and catecholamine function at rest and/or during stress. More importantly, perhaps, each of the models described in this chapter, with the exception of the studies of the menstrual cycle, suggests that endogenous female reproductive hormones may attenuate cardiovascular and catechol­amine responses to stress, albeit modestly. The relatively small fluctuations in hormones during the normal female menstrual cycle further suggest that it may be necessary for hormone levels to be substantial prior to exerting an effect on stress responses of the cardiovascular system. Thus, the role of endogenous ovarian hormones in modulating cardiovascular and neuroendo­crine stress responses may likely be a modest but significant one. The next section explores the extent to which exogenous female reproductive hormones influence stress responses.

INVESTIGATIONS OF INDIVIDUALS RECEIVING EXOGENOUS HORMONES

Another strategy for understanding the impact of reproductive hormones on reactivity is one that takes advantage of those populations of individuals who are receiving exogenous hormones for medical or contraceptive reasons. Such groups would primarily include women taking oral contraceptive preparations and postmenopausal women receiving estrogen replacement therapy but would obviously not be limited to these two groups. While both preparations serve to increase circulating levels of estrogens, progesterone, or both, estrogen re­placement therapy generally does so at lower hormone doses than do most oral contraceptives (Bush & Barrett-Connor, 1985).

From an epidemiological point of view, women receiving estrogen replace­ment therapy and women taking oral contraceptives may differ with respect to their risk for coronary heart disease. For example, use of estrogen replacement therapy among postmenopausal women has been most consistently associated with declines or no changes in risk of disease (Stamfer, Willett, Colditz, Rosner, Speizer, & Hennekens, 1985), while oral contraceptive users are at the same or

158 CHAPI'ER EIGHT

greater risk for development of cardiac complications, such as stroke, myocar­dial infarction, and hypertension, than are nonusers (Jick, Dinan, & Rothman, 1978; Stern, Brown, Haskell, Farquhar, Wehrle, & Wood, 1976). Further com­plicating the picture is the fact that male patients who were administered conjugated estrogens prophylactically in an effort to reduce their risk of cor­onary mortality in fact experienced an increased mortality rate due to cardiac and thromboembolic complications (Coronary Drug Project Research Group, 1973). Therefore, the cardiovascular risks associated with the use of exogenous hormones are probably determined by the interaction of the particular hor­monal compound used (natural conjugated estrogens or synthetic estrogens alone or in combination with progestins) and age, smoking status, and gender. Nonetheless, it is clear that exogenous hormones exert some effect on the risk of cardiovascular disease and are therefore interesting to study from a re­activity perspective.

ORAL CONTRACEPTIVES

Oral contraceptive use among premenopausal women today is a prevalent form of birth control. Prescriptions for oral contraceptives in the United States and other industrialized nations still rank among the most common; as many as 8 million women in this country take oral contraceptives for the prevention of pregnancy. Thus, the psychophysiological effects of these preparations have both methodological and conceptual implications.

Among the published investigations comparing oral contraceptive users and nonusers, there is little agreement regarding whether stress responses are the same, greater, or smaller in users than in nonusers. Garrett and Elder (1984) examined four oral contraceptive users and compared them to an equal number of normally cycling women at several points in the menstrual cycle. Heart rate and blood pressure during reaction time and mental arithmetic tasks did not discriminate the groups, suggesting that oral contraceptive use did not impact on physiological stress responses. Other studies of oral contra­ceptive users, however, have found that oral contraceptive use is associated with enhanced physiologic stress responses. For example, two published stud­ies examined women taking any form of oral contraceptives and compared their physiological responses to nonusers during a variety of laboratory stressors. Women taking oral contraceptives had significantly larger blood pressure and triglyceride responses to stress than did nonusers (Davis & Matthews, 1990), effects that may be in part modulated by smoking status (Emmons & Weidner, 1988). Finally, oral contraceptive users have also been reported to have dimin­ished systolic blood pressure (Neus & von Eiff, 1985) and cortisol (Marinari et aL, 1976) responses to stress relative to nonusers.

In contrast to the usual emphasis on exploring the effects of estrogens, Ladisich (1977) examined the effects of progestagen treatment in healthy, normally menstruating women. Pulse rate and pulse variability were measured

THE ROLE OF REPRODUCTIVE HORMONES 159

during a memory task while electric shocks were randomly administered to the subjects' hand. Findings indicated that the pharmacologic group had greater heart rate stress responses relative to the nonpharmacologic group.

The combined results of these investigations again suggest that while there is some disagreement among the studies, there is some minimal evidence for a modest effect of oral contraceptive preparations on cardiovascular func­tioning during stress. The discrepancies noted may be due to wide variations in the actual preparations used, very small sample sizes, and diverse subject and stressor characteristics. Clearly, however, when designing studies with young women, it is important to screen participants for current oral contraceptive use.

ESTROGEN REPLACEMENT THERAPY

The use of estrogen replacement therapy in perimenopausal and post­menopausal women today is extensive. These drugs, whether given as con­jugated estrogens in the natural form (Premarin®) or as synthetic hormones, have well-established effects on reducing the discomforts of physiologic symp­toms of menopause. The effects of such replacement therapy have only been briefly examined in the psychophysiology literature.

Collins and colleagues (Collins, Hanson, Eneroth, Hagenfeldt, Lundberg, & Frankenhaeuser, 1982) examined 17 middle-aged women who were admin­istered a combined estrogen/progestin compound for the treatment of symp­toms associated with menopause. Prior to participating, all women were amen­orrheic for at least 6 months and had increased FSH levels, indicating that they were in the perimenopausal period. Women participated in three experimental sessions consisting of a mental arithmetic task, a cognitive-conflict task, and a visual search task. Blood pressure and heart rate were monitored and urine samples for the assessment of urinary catecholamines were collected during the experimental sessions, and some women were tested during both treatment and nontreatment times. The findings suggested that estrogen replacement therapy did not significantly influence cardiovascular or catecholamine stress responses, although the absolute levels of epinephrine in the urine were some­what higher than the authors generally find in younger women. Thus, there is little evidence from this study that the particular estrogen/progestin compound used exerted a significant impact on reactivity.

The other investigation of estrogen replacement therapy in middle-aged women is from von Eiff and associates (von Eiff et aL, 1971). Three groups of women with a surgical menopause participated in this phase of the study. One group of 8 women was treated with a long-acting synthetic estrogen; one group of 8 women was treated with a long-acting estrogen and progesterone com­bined; the third group of 12 women served as a placebo control. All participants were tested before and during hormone treatment in a mental arithmetic paradigm while heart rate, blood pressure, muscle tone, and respiratory rate were monitored. Both hormone replacement groups had significantly smaller

160 CHAPl'ER EIGHT

systolic blood pressure responses to the mental arithmetic task relative to the placebo control group and somewhat smaller diastolic blood pressure stress responses. These data, in contrast to the previous study, suggest that honnone replacement therapy does in1luence blood pressure stress responses in men­opausal women.

Unfortunately, reconciling the results of these two studies is difficult be­cause both investigations included different honnona! preparations, different groups of participants (natural versus surgical menopause), and small numbers of subjects. Further investigations are warranted, especially considering the large numbers of postmenopausal women in the United States and elsewhere. Additionally, because the natural conjugated estrogens are typically used to.­day, wide-scale psychophysiological investigations of women taking these prep­arations are necessary to our further understanding of the psychophysiological consequences of honnone replacement therapy.

CONCLUSIONS

This chapter has reviewed most of the available psychophysiological lit­erature investigating the relationship between ovarian reproductive honnones and cardiovascular and neuroendocrine responses to behavioral stress. The limited number of studies, small numbers of subjects in most studies, and the tremendous diversity of honnona! characteristics among study participants preclude firm conclusions being made regarding the relationship between stress responses and reproductive honnones. There is little doubt, however, that some forms of ovarian honnones act to modulate the magnitude and pattern of physiological stress responses in certain populations of women. The importance of further elucidating these relationships can be underscored by the fact that ovarian honnones (both endogenous and exogenous) playa significant role in determining the psychological and physical well-being of millions of women worldwide.

ACKNOWLEDGMENT

I wish to thank Tilmer O. Engebretson for his very helpful comments on an earlier version of this manuscript.

REFERENCES

Adams, M. R., Kaplan, J. R., Koritnik, D. R., & Clarkson, T. B. (1987). Pregnancy-associated inhibition of coronary artery atherosclerosis in monkeys. Evidence of a relationship with endogenous estrogen. Arteriosclerosis, 7, 378-384.

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THE ROLE OF REPRODUCTIVE HORMONES 161

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THE ROLE OF REPRODUCTIVE HORMONES 163

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CHAPI'ER NINE

The Role of Cardiovascular Reactivity

in Hypertension Risk

WILLIAM R. LOVALLO AND MICHAEL F. WILSON

INTRODUCTION

The purpose of this chapter is to describe the occurrence of cardiovascular hyperactivity in the prehypertensive state. In doing so, we will focus on studies of persons having a parental history of hypertension or who are borderline hypertensive. This discussion will examine interactions between behavioral challenges, cardiovascular reactivity, and hypertension risk. We also will pre­sent a model of hypertension in Chapter 14 that emphasizes cardiovascular hyperreactivity along with genetic risk of hypertension as factors leading to development of the disorder. Chapter 7 addressed racial differences in cardio­vascular reactivity. Our goal is to evaluate the possibility that behavioral factors may influence the development of hypertension.

BACKGROUND ISSUES

Hypertension is a significant cardiovascular disorder affecting 60 million persons in the United States (Kannel & Thorn, 1986). Its prevalence is greater

WILLIAM R. LOVALLO • Department of Psychiatry and Behavioral Sciences, University of Oklahoma Health Sciences Center, and Veterans Affairs Medical Center, Oklahoma City, Okla­homa 73190. MICHAEL F. WILSON • Department of Medicine, University of Oklahoma Health Sciences Center, and Veterans Affairs Medical Center, Oklahoma City, Oklahoma 73190.

165

166 CHAPl'ER NINE

in older age groups, and its principal endpoint is an increased risk of major target organ damage, including renal insufficiency, stroke, and cardiac failure. It is also a major risk factor for atherosclerosis and obstructive coronary artery disease. These conditions are debilitating, costly to manage, and have adverse long-tenn consequences for the patient.

Essential hypertension is characterized by a gradual rise in blood pressure that surpasses the nonnal range for a given age group, eventually achieving values exceeding the 95th percentile. The lack of a known organ pathology suggests that the disorder is the result of an "essential" or ''primary'' long-tenn dysregulation of blood pressure control (Folkow, 1982). Although the etiology of this dysregulation is not known, both genetic and environmental factors are clearly implicated (Hunt, Williams, & Barlow, 1986; Munger, Prineas, & G0-mez-Marin, 1988). Along with environmental factors, personality and behav­ioral dispositions have long been suspected to contribute to hypertension (Ale­xander, 1939).

A pervasive and early consequence of hypertension is that the rise in blood pressure is accompanied by a remodeling of the heart and blood vessels, alter­ing how the cardiovascular system reacts to various demands and resulting in a structurally induced hyperreactivity (Folkow, 1982). For this reason, the study of persons who are already hypertensive (having a systolic pressure ~ 160 mm Hg and/or diastolic ~ 95 mm Hg) has yielded inconclusive evidence of the role of behavioral contributions in the development of the disorder. In response, researchers have studied nonnotensive persons who are at increased risk due to a positive parental history of hypertension (PH +) or who are borderline hypertensive (BH; 140 :s: SBP < 160 and/or 90 :s: DBP < 95 mm Hg).

Behavioral and emotional influences on the cardiovascular system are integrated by the central nervous system and mediated by the sympathetic and parasympathetic branches of the autonomic nervous system (Cohen & Mac­Donald, 1974). For this reason, the search for linkages between behavior, cardiovascular hyperreactivity, and hypertension has examined tonic activation in persons at rest as well as changes between baseline conditions and activity during a variety of challenges.

TASKS AND RESPONSE TYPES IN STUDIES OF REACTMTY

If behavioral influences act via the nervous and neuroendocrine systems to produce cardiovascular hyperreactivity, which in turn may exaggerate the hypertensive process, then it should be possible to identify hyperreactive per­sons and to identify tasks most effective in evoking this hyperresponse ten­dency. This is one version of the reactivity hypothesis. The issues raised in this section are discussed in detail in Chapter 1.

Reactivity is never directly observed. It is inferred by observing responses to various tasks and stimuli. In inferring that a person is relatively hyper-

CV REACTMTY AND HYPERTENSION 167

reactive or hyporeactive, the investigator must make comparisons of the in­dividual subject's responses and compare these with responses observed in some reference group.

Identifying hyperreactive persons may be done in at least three ways. First, a group of volunteers may be exposed to a challenging task and those producing the largest responses (change from a given baseline state) classified as hyperreactive. This has the disadvantage of measuring responses at a single time to a single challenge. The reactivity classification is confounded with stimulus-response specificity effects, making it risky to conclude that the hy­perreactive subgroup would be so under other circumstances (Lovallo, Pin­comb, & Wilson, 1986a). Second, these volunteers may be retested later using the same challenge. This is a good test of the reliability of response to the stressor (Manuck & Garland, 1980), and persons who are hyperreactive both times may be labeled with more confidence. This approach, however, does not identify with certainty the persons likely to be hyperresponsive to a range of circumstances. In the third case, a group of volunteers may be exposed to qualitatively different challenges. Persons showing a relative hyperreactivity to these dissimilar stressors (e.g., exercise and mental arithmetic) may be con­sidered to be hyperreactors without the limitations imposed by the first two cases (Allen & Crowell, 1989; Lovallo, Pincomb, & Wilson, 1986b; Manuck & Garland, 1980). Such evidence provides the strongest basis for inferring that an individual or a group is consistently hyperreactive.

These are all instances in which persons are categorized by exaggerated changes from baseline, which may indicate greater risk of cardiovascular dis­ease (the ''recurrent activation hypothesis"; Manuck & Krantz, 1984). Another approach is to classify persons according to characteristic levels of activity. Persons with high-normal resting levels (of blood pressure, for example) who show relatively normal change to a task will thus end up with elevated levels during the task. These persistently high levels of blood pressure may also contribute to increased risk of disease although they do not index hyper­reactivity (the ''prevailing state hypothesis"; Manuck & Krantz, 1984). Either of these patterns of activity may indicate increased risk of hypertension, and each may well reflect chronically exaggerated sympathetic nervous system activation. Most studies in the area have focused on responses viewed as change from baseline, although the potential importance of persistently elevated ac­tivity should not be overlooked.

The term cardiovascular reactivity has come into current usage for two reasons. It is presumed that since resting blood pressure is an imprecise predictor of future hypertension, some method for estimating the system's response to challenge may point to underlying sympathetic nervous system activation not seen at rest, and also, knowledge of an exaggerated response tendency may provide a better basis for prediction. It is useful to restate Folkow's (1982) suggestion, that in a predisposed individual, the occurrence of exaggerated stress on the walls of the blood vessels-either by high steady-

168 CHAPTER NINE

state pressures or by frequent high pressure peaks-is the primary stimulus to vessel wall hypertrophy leading to fixed hypertension. This is depicted in the positive feedback loop in the model of hypertension we offer in Chapter 14, Figure 1. The occurrence of a normal response upon a high-normal baseline will yield elevated pressures during challenge but produce a normal reactivity score. In this case, the individual will show persistently high steady-state pressures that may be as detrimental as high-peak pressures superimposed on a lower baseline. These considerations should lead investigators to be aware of the importance of high-normal steady-state blood pressures while also looking for evidence of exaggerated reactivity.

Cardiovascular reactivity is most easily tested in the laboratory, and so investigators have been concerned with responses characteristically produced by different types of tasks. Systems of task classification have been proposed based on tasks' overt or covert behavioral demands, employing distinctions such as mental versus physical, sensory intake versus rejection, and active versus passive coping (Obrist, 1981). Given the relatively limited range of data on the integrated cardiovascular adjustments occurring during behavioral tasks, however, it may be premature to assign tasks to such global categories. For example, the difference in responses to the cold pressor task (vasocon­striction, variable cardiac activation) and a demanding reaction time task (mild vasodilation, much cardiac activation) has been attributed to their respective passive and active behavioral requirements (Obrist, 1981). More recent evi­dence has shown that coping either passively or actively with an aversive stressor may lead to enhanced cardiac activity and sustained reduction in vascular resistance (Lovallo, Wilson, Pincomb, Edwards, Tompkins, & Brack­ett, 1985). To use another example, two tasks considered active in their behav­ioral requirements (mental arithmetic and reaction time) have been shown to evoke dissimilar patterns of response (Allen, Obrist, Sherwood, & Crowell, 1987b). Finally, it has been argued that active coping tasks evoke beta-adre­nergically mediated responses that are likely to be most prognostic of hyper­tension. A recent meta-analysis, though, concluded that blood pressure re­activity to the cold pressor, largely alpha-adrenergic in origin, can be predictive of the disorder (Fredrikson & Matthews, 1990).

Broad groupings of tasks classified by behavioral criteria may not provide the best basis for selecting tasks in reactivity studies. Psychophysiological research has begun to provide detailed information about cardiovascular ad­justments to challenging tasks through the use of safe, relatively nonobtrusive techniques, such as impedance cardiography (Sherwood, Allen, Fahrenberg, Kelsey, Lovallo, & van Doornen, 1990; Wilson, Lovallo, & Pincomb, 1989). Matching tasks to the requirements of given studies based on knowledge of their patterns of circulatory activation will provide the most useful basis for choosing future tests of cardiovascular reactivity. Of equal importance is selec­tion of tasks based on their capacity to discriminate between persons with different response pattern tendencies.

CV REACTMTY AND HYPERTENSION 169

RATIONALE FOR BEHAVIORAL STUDIES OF REACTIVITY IN HIGH-RISK NORMOTENSIVES

As blood pressure chronically increases beyond the nonnotensive range, the heart and blood vessels undergo structural changes to adapt to the pressure overload (Folkow, 1990). Cardiovascular function in established hypertension may then reflect these dimensional alterations in the heart and blood vessels, and function may be further altered by target organ damage. Hypertrophy of blood vessel walls may result in an enhanced increase in vascular resistance and blood pressure following a given sympathetic nervous system response, again illustrating a structurally determined hyperresponsiveness. In addition to vas­cular adaptations, adolescents and young adults with borderline hypertension may show early signs of cardiac hypertrophy (Fujita, Noda, Ito, Isaka, Sato, & Ogata, 1989; Zahka, Neill, Kidd, Cutilletta, & Cutilletta, 1981). These structural adaptations may result in exaggerated cardiac and vascular responses to be­havioral tasks, again in the absence of alterations in sympathetic activation.

In order to study autonomic and neuroendocrine precursors of hyper­tension, it is therefore necessary to study persons free of such confounding structural influences. A strategy for avoiding this structural confounding is to study persons at high risk of becoming hypertensive but prior to the develop­ment of significant structural modifications. If reactivity influences the course of hypertension, those at risk should display the greatest degree of cardiovas­cular reactivity across tasks and should illustrate the clearest relationship between task demands, cardiovascular responses, and the pathophysiology of hypertension. This is essentially a restatement of the reactivity hypothesis. Persons best meeting these requirements are PH + and BH.

This chapter will briefly review studies of cardiovascular responses to stress in PH + and BH persons.

PARENTAL HISTORY OF HYPERTENSION

Persons whose parents are hypertensive are at double the risk of develop­ing the disorder relative to those whose parents are nonnotensive (PH -; Stamler, Stamler, Riedlinger, Algera, & Roberts, 1971). Among children 8 to 16 years of age, the mother's systolic blood pressure was more closely associated with the child's systolic pressure (r = .32) than was the father's (r = .22), which may reflect a combination of genetically and environmentally transmitted influences, with the mother having a greater environmental effect than the father (Munger et 01, 1988). The blood pressure distribution across a popula­tion of children aged 2 to 14 years was seen closely to model the distribution across their parents (Zinner, Levy, & Kass, 1971), again reflecting a probable mix of genetic and environmental factors.

170 CHAPI'ER NINE

Excellent discussions of the issues surrounding selection of subjects in studies of family history of hypertension are available (Hunt et al, 1986; Watt, 1986). A key issue is verification of the parents' pressor status, ranging in methodological rigor from report of offspring to report by parents to their physicians to actual measurement of the parents' blood pressures. Checks of physician and parent reports against reports by offspring of parental blood pressure status typically agree 90% or more in college-age samples (Allen, Lawler, Mitchell, Matthews, Rakaczky, & Jamison, 1987a; Ditto, 1986; Sausen, Lovallo, & Wilson, 1991).

CARDIOVASCULAR FUNCTION IN PH+ AND PH- PERSONS

RESTING DIFFERENCES

Comparisons of resting hemodynamic activity in PH + and PH - groups have yielded mixed results.

Hearl Rate Comparisons.

While some studies have found PH + to have higher resting heart rates than PH- persons (Hastrup, Light, & Obrist, 1982; Lawler & Allen, 1981; Manuck & Proietti, 1982), others have found PH + persons to have heart rates that are lower than in PH - persons (Schachter, Kuller, & Perfetti, 1984) or equivalent to them (Anderson, Mahoney, Lauer, & Clarke, 1987; Ginter, Holl­andsworth, & Intrieri, 1986; Jorgensen & Houston, 1981; Manuck, Proietti, Rader, & Polefrone, 1985; Obrist, Light, James, & Strogatz, 1987; Sausen et al, 1991; Weipert, Shapiro, & Suter, 1987).

Systolic Blood Pressure

Comparisons of PH + and PH - groups for resting blood pressure levels have produced a similarly mixed pattern. In some cases, PH + groups have been found to have higher resting pressures (Ayman, 1934; Hastrup et al, 1982; Obrist et al, 1987; Ohlsson & Henningsen, 1982; Stamler et al, 1971; Warren & Fischbein, 1980). In other studies, PH + groups have had systolic pressures that are lower (Ewart, Harris, Zeger, & Russell, 1986) or similar to pressures seen in PH - (Anderson et al, 1987; Ditto, 1986; Ginter et al, 1986; Jorgensen & Houston, 1981; Lawler & Allen, 1981; Manuck & Proietti, 1982; Manuck et al, 1985; Montanari, Vallisa, Ragni, Guerra, Colla, Novarini, & Coruzzi, 1988; Munger et al, 1988; Sausen et al, 1991; Schachter et al, 1984; Schulte & von Eiff, 1985; Weipert et al, 1987).

CV REACTIVITY AND HYPERTENSION 171

Diastolic Blood Pressure

A mixed pattern of results has emerged as well from comparisons of PH + with PH - persons on resting diastolic blood pressure. Several studies have reported PH + persons to have higher diastolic pressures than PH - persons (Ayman, 1934; Ewart et 01, 1986; Jorgensen & Houston, 1981; Stamler et 01, 1971; Warren & Fischbein, 1980). On the other hand, a greater number of studies have found no difference (Anderson et 01, 1987; Ditto, 1986; Ginter et 01, 1986; Hastrup et 01, 1982; Lawler & Allen, 1981; Manuck & Proietti, 1982; Manuck et 01, 1985; Montanari et 01, 1988; Munger et 01, 1988; Obrist et 01, 1987; Ohlsson & Henningsen, 1982; Sausen et 01, 1991; Schachter et 01, 1984; Schulte & von Eiff, 1985; Weipert et 01, 1987).

These comparisons of PH + with PH - persons at rest provide some sup­port for the idea that PH + persons have greater unstimulated levels of hem­odynamic activity than do PH - persons. Studies with the largest samples, however, have found PH + persons to have higher resting pressures (Ayman, 1934; Munger et 01, 1988; Stamler et 01, 1971; Warren & Fischbein, 1980), and a dose-response effect has been reported in which persons with two hyper­tensive parents have the highest resting pressures (Ayman, 1934; Warren & Fischbein, 1980). Studies conducted with small samples appear to yield the most mixed results, suggesting substantial variability of blood pressures and heart rates within PH subgroups.

In addition to heart rate and blood pressure differences, PH + persons compared to PH - persons have a higher peripheral vascular resistance in early adulthood (Lovallo, Pincomb, Sung, Everson, Passey, & Wilson, 1991; Ohlsson & Henningsen, 1982). Neither of the last two studies observed a higher resting cardiac output among PH + persons. Catecholamine studies have shown PH + persons to have higher plasma norepinephrine concentrations than PH - per­sons, suggesting elevated sympathetic nervous system function, but have not found higher concentrations of epinephrine (Horikoshi, Tajima, Igarashi, Inui, Kasahara, & Noguchi, 1985).

Significant considerations in conducting such work in the future concern conditions of measurement and determining the influence of cardiac output and vascular resistance on the blood pressures. Since PH + persons may be more reactive than PH - persons, resting comparisons should ensure adequate time to adapt to the lab or clinic setting, and extraneous influences should be min­imized. When resting measures are used to provide a baseline for subsequent tests of reactivity, estimates of cardiac output and vascular resistance at rest can provide a useful basis for interpreting the causes of blood pressure re­sponse differences between PH subgroups (Lovallo et 01, 1991).

The evidence above suggests that PH + persons may have an elevated sympathetic drive that increases blood pressure at rest by elevating peripheral resistance rather than cardiac output. Considerable variability, however, is observed between different PH + and PH - sample populations.

172 CHAPTER NINE

PHARMACOLOGIC STUDIES

Doyle and Fraser (1961) reported that PH + males compared to PH­controls exhibited a larger decrease in forearm blood flow during norepineph­rine infusion. In their review, Weidmann and Beretta-Piccoli (1988) concluded that persons with a family history of hypertension have a disproportionate vascular reactivity to infused norepinephrine. They attributed this to enhanced sodium uptake by vascular smooth muscle cells leading to dysregulation of calcium channel mechanisms, with the result that vascular responses are po­tentiated for a given amount of sympathetic activation. In line with these results, PH + men compared to PH - men had larger decreases in forearm vascular resistance to administration of an alpha-receptor blocker (Miller & Ditto, 1989).

EXERCISE STUDIES

PH + and PH - young adults have been compared in their responses to static and dynamic exercise. Ditto (1986) measured blood pressure response to isometric handgrip over two days and found a larger systolic blood pressure response in PH + compared to PH - men on Day 2, indicating a lack of response adaptation over days in the PH + men. Ohlsson and Henningsen (1982) showed that among PH + men only, stroke volume and peripheral resistance were negatively correlated during isometric and dynamic exercise. This would be consistent with a predominance of enhanced sympathetic vascular influences over cardiac influences.

Norepinephrine increases to bicycle exercise are greater among PH + than PH - men (Nielsen, Gram, & Pedersen, 1989). Systolic pressure at peak dynamic exercise was observed to be higher in adolescent PH + normotensives than PH - controls (Alli, Avanzini, DiTullio, Mariotti, Salmoirago, Taioli, & Radice, 1990). Wilson and coworkers observed an exaggerated blood pressure response to bicycle exercise (~ 230 mm Hg systolic and/or 100 mm Hg diastolic) in 35% of PH + men but in none of the PH - men they tested (Wilson, Sung, Pincomb, & Lovallo, 1990). These PH + exaggerated responders also produced the highest blood pressures during treadmill exercise on another day. Com­parison of cardiac outputs and vascular resistances during the bicycle exercise indicated that the reactive PH + subgroup had a normal cardiac output rise across exercise stages, with a consistent elevation in vascular resistance, result­ing in blood pressure changes that were greater than normal.

The results of Wilson and colleagues (1990) and Ohlsson and Henningsen (1982) suggest that PH + men, as a group, have an elevation in vascular re­sistance at rest and a deficient decrease in resistance during exercise. This is consistent with an exaggerated sympathetic tonus in PH + persons, resulting in larger-than-expected blood pressure changes to equivalent increases in car­diac output.

CV REACTIVITY AND HYPERTENSION 173

A similar vascular influence during exercise has been observed in border­line hypertensives, as noted below.

COLD PRESSOR STUDIES

Differences between PH + and PH - groups in cardiovascular responses to the cold pressor test have been extensively reviewed by Fredrikson and Mat­thews (1990) using meta-analysis techniques. Among five such studies pub­lished through 1985, two had found PH + groups to have greater systolic blood pressure rises than PH - groups to cold pressor stimulation. In light of the three negative findings, the collective PH + versus PH - difference was judged to be not significant. Of three studies since 1985, one reported PH + persons to have modestly higher diastolic pressures during cold pressor than PH - per­sons (Allen et al., 1987a) while two other studies found no differences (Everson, Lovallo, Sausen, & Wilson, 1992; Sausen et al., 1991).

The cold pressor test elevates blood pressure by increasing vascular re­sistance, sometimes in combination with elevated cardiac output (Allen et al., 1987b). This mixed pattern of response may cause results to vary across studies depending on the balance of cardiac and vascular factors shown by a given subject sample. On the other hand, the difference between PH + and PH­groups in response to exercise is due to differences in tonic vascular activity, with cardiac output change being similar for both groups. Therefore, the blood pressure change to cold pressor depends on a greater number of active re­sponse elements and may thus be more variable across persons and studies.

MENTAL AND PSYCHOMOTOR CHALLENGES

Work on mentally demanding tasks has frequently been found to produce larger cardiovascular responses in PH + compared to PH - men. The most frequently used challenge has been some type of mental calculation requiring work on a series of discrete arithmetic problems or involving serial calculations. Effortful engagement in this task produces increased heart rate along with rises in systolic and diastolic blood pressures, which are larger for PH + than PH - persons (Allen et al., 1987a; Anderson et al., 1987; Ditto, 1986; Falkner, Onesti, Angelakos, Fernandes, & Langman, 1979; Ginter et al., 1986; Horikoshi et al., 1985; Jorgensen & Houston, 1981; Manuck & Proietti, 1982; Manuck et al., 1985; Riiddel, Neus, Langewitz, von Eiff, & McKinney, 1985; Sausen et al., 1991; Schulte & von Eiff, 1985). Similar results have been reported for other mentally challenging tasks, such as work on concept identification problems (Manuck, Giordani, McQuaid, & Garrity, 1981; Manuck & Proietti, 1982), the Stroop color-word interference task (Ditto, 1986; Jorgensen & Houston, 1981), and backward recall of digits (Jorgensen & Houston, 1981, 1986; Sausen et al.,

174 CHAPTER NINE

1991). In studies of renal function, PH + persons have been found to have abnonnally low renal blood flow during work on Raven's progressive matrices (Hollenberg, Williams, & Adams, 1981). PH + persons have also shown a de­crease in sodium excretion during prolonged work on a variety of mental and psychomotor tasks, but only if the PH + persons were highly heart rate reactive (Light, Koepke, Obrist, & Willis, 1983).

PH + persons undergoing psychomotor challenges have also shown larger cardiovascular responses than PH - persons. During work on a video game, PH + persons showed higher heart rates, greater increases in forearm blood flow, and increased forearm vascular resistance (Miller & Ditto, 1989). Heart rate and systolic blood pressure rises during a reaction time task were greater among PH + persons (Hastrup et aL, 1982), as were diastolic pressure rises (Lawler & Allen, 1981), although one study reported no differences in response between PH + and PH - persons (Ohlsson & Henningsen, 1982). When PH + men with mildly elevated blood pressures (134/78 mm Hg) were compared with PH - men who had low-nonnal pressures (119/67 mm Hg), the groups showed equivalent cardiac output increases and vascular resistance decreases during a reaction time task. The PH + group, however, had a relative elevation in vas­cular resistance, sustained across baseline and the task, which in combination with their cardiac output increase led to a relatively exaggerated diastolic blood pressure response (Lovallo, Pincomb, Sausen, Everson, Silverstein, Sung, & Wilson, 1987).

These studies employing mental and psychomotor stressors indicate a consistent pattern of greater blood pressure responses among PH + relative to PH - persons. In contrast to studies using pharmacologic challenge and ex­ercise-all of which suggested that PH + persons show enhanced vascular reactivity-the mental and psychomotor challenges have yielded a mixed pat­tern of greater cardiac and vascular responses among PH + subjects. Mental and psychomotor stressors appear to have stimulus properties that are distinct from those of exercise and pharmacologic challenge. Cardiac output and vas­cular resistance changes should be studied more frequently in response to mental stressors in order to evaluate their relative contributions to the blood pressure responses of high- and low-risk groups. Additional infonnation on familial aspects of cardiovascular reactivity to stress may be found in Matthews and Rakaczky (1986).

BORDERLINE HYPERTENSION

Borderline hypertensives (140/90 s BP s 159/94 mm Hg) are at three to four times the risk of nonnotensives of developing hypertension (Levy, White, Stroud, & Hillman, 1945), with 20% progressing to fixed hypertension over long-tenn follow-up (Julius, 1986). Borderline hypertensives constitute an espe-

CV REACTIVITY AND HYPERTENSION 175

cia11y interesting group in which to study the etiology of hypertension. First, borderline hypertension may represent a transitional phase from a normoten­sive state. Second, borderline hypertensives may possess an optimal balance (from the researcher's point of view) between predisposing factors and a mini­mum of secondary cardiovascular and renal structural changes.

HYPERKINETIC CIRCULATORY STATE IN BORDERLINE HYPERTENSION

Borderline hypertensives are frequently characterized as having a resting hyperkinetic circulatory state consisting of an elevated cardiac output and a normal peripheral resistance. This contention is supported by strong evidence from studies of prehypertensive spontaneously hypertensive rats (SHR) show­ing an elevated cardiac output and normal systemic vascular resistance at rest (Folkow, 1982).

Lund-Johansen (1983) demonstrated that young (17 to 29 years) border­line hypertensives had elevated resting cardiac output and normal vascular resistance. On a 10-year follow-up, cardiac output was normal but vascular resistance was elevated, supporting the concept of a transition from normoten­sion through elevated cardiac output to elevated vascular resistance in the etiology of hypertension. Similar findings have been reported by others (An­dersson, Beckman-Suurkiila, Sannerstedt, Magnusson, & Sivertsson, 1989; Weiss, Safar, London, Simon, Levenson, & Milliez, 1978). In studying 186 borderlines and 286 hypertensives, Julius and coworkers found that 24% of the borderlines and 5% of the normotensives had a hyperkinetic state at rest (defined as cardiac output> 2.0 SD above the sample mean; Julius, Schork, & Schork, 1988). Complete cardiac blockade with atropine and propranolol, how­ever, unmasked an elevated vascular resistance in the borderlines, suggesting that their apparently normal vascular resistance prior to blockade was actUally a failure to vasodilate sufficiently for their level of cardiac output. These re­searchers also demonstrated that the normokinetic variant of borderline hyper­tension possesses a depressed myocardial performance and an elevated vas­cular resistance at rest (Julius, Randall, Esler, Kashima, Ellis, & Bennett, 1975).

The borderline hypertensive group may therefore be more accurately characterized as possessing two variants, one with an elevated cardiac output and one with a normal output, the former having a masked and the latter having an unmasked elevation of vascular resistance. The common factor may be an enhanced sympathetic output with differing relative levels of cardiac activation. The occurrence of a subgroup of borderlines with elevated cardiac output contrasts with the studies cited above, which did not find such a subgroup among PH + persons. The PH + groups were consistently characterized by elevated vascular resistance along with normal-to-blunted cardiac output.

176

CARDIOVASCULAR RESPONSES IN BORDERLINE HYPERTENSION­

PHARMACOLOGIC CHALLENGE

CHAPrER NINE

In addition to the above studies of centrally mediated cardiovascular acti­vation at rest, some studies have examined peripherally mediated responses of borderline hypertensives to administration of norepinephrine or sympathetic blocking agents. Borderline hypertensives who showed elevated resting vas­cular resistance showed a larger-than-normal resistance decrease in response to the alpha-receptor blocker phentolamine, demonstrating that their blood pressure was elevated due to an exaggerated sympathetic outflow to the blood vessels (Esler, Julius, Randall, Ellis, & Kashima, 1975). Weidmann (1989) has reviewed a series of studies showing that borderlines have larger blood pres­sure rises than normals to norepinephrine infusion, although it should be noted that negative findings have also been published (Kawano, Fukiyama, Takeya, Abe, & Omae, 1982). Enhanced responsiveness to norepinephrine is consistent with the likelihood that borderline hypertensives may have an early thickening of the medial layer of the walls of their blood vessels or stronger and more prolonged contraction of vascular smooth muscle cells to a given stimulus. Either case would result in an exaggerated vascular response to a given con­centration of norepinephrine (Folkow, 1990).

EXERCISE STUDIES

In studies of dynamic exercise, borderline hypertensives have shown ele­vated resting pressures and exercise pressures that rose in parallel with those of the control groups Miller, Ruddy, Zusman, Okada, Strauss, Kanarek, Chris­tensen, Federman, & Boucher, 1987; Sannerstedt, 1969). In a related study, PH + normotensives showed higher resting pressures than PH - normoten­sives, parallel rises during exercise, and significantly higher exercise pressures after correction for baseline pressures (Molineux & Steptoe, 1988). In agree­ment with studies on borderlines, Wilson and coworkers (1990) found high-risk normotensives (PH + and high-normal pressures) to have greater systolic pres­sure rises to exercise compared to low-risk persons. These exaggerated rises were accompanied by blunted cardiac output changes along with persistent elevations in vascular resistance. This suggests that subgroups of persons at risk may show exaggerated blood pressure rises to exercise that are masked in grouped data.

Studies of cardiovascular responses to exercise in high-risk normotensives, borderlines, and established hypertensives therefore show substantial agree­ment that exercise blood pressures are excessive relative to those of low-risk or unselected normotensive groups. The underlying hemodynamics appear to be subnormal vasodilation and normal-to-blunted cardiac output changes to the demands of the exercise. These results suggest a predominance of vascular factors accompanying exercise response in those at greatest risk for future hypertension.

CV REACTMTY AND HYPERTENSION 177

PHYSICAL STRESSORS

Borderline hypertensives, when compared to normotensives, have been shown to produce exaggerated cardiovascular reactions to a variety of other physical challenges. Borderlines have shown enhanced diastolic pressure rises to orthostatic tilt (Drummond, 1985; Eliasson, Hjemdahl, & Kahan, 1983; Hull, Wolthuis, Cortese, Longo, & Triebwasser, 1977). Using orthostatic challenge, McCrory, Klein, and Rosenthal (1982) found borderline hypertensive adoles­cents to have higher blood pressures than normotensive controls when supine but to produce smaller blood pressure and norepinephrine increases to stand­ing. The authors argued that the borderlines had inappropriately elevated sympathetic activation when supine. Cuddy et al. (Cuddy, Smulyan, Keighley, Markason, & Eich, 1966) showed that borderline hypertensives had larger blood pressure rises to the cold pressor test than normotensives when cardiac vagal reflexes had been blocked by atropine (data reanalyzed by Drummond, 1983).

The foregoing results argue that borderline hypertensives may manifest exaggerated sympathetic drive to the heart and blood vessels when exposed to physical stressors but that such activation occasionally may be masked by vagal reflexes acting upon the heart.

MENTAL STRESSORS

Borderline hypertensives have also been found to produce larger blood pressure responses than normotensive controls to work on demanding informa­tion processing and problem-solving tasks. These differences have been seen during mental arithmetic (Drummond, 1983, 1985; Eliasson et al., 1983; N estel, 1969), the Stroop task (Steptoe, Melville, & Ross, 1984), and Raven's pro­gressive matrices (Nestel, 1969). This last study also showed a larger increase in catecholamine excretion during mental stress in the borderlines.

These studies complement those using physical stressors in showing that mental activation can also produce rises in sympathetic drive that are larger than normal in borderline hypertensives.

LONGITUDINAL STUDIES OF BORDERLINE HYPERTENSIVES AND OTHER HIGH-RISK GROUPS

The prognosis of borderline hypertensives for development of hyperten­sion has been explored in a variety of studies of blood pressure at rest and in response to various challenges.

RESTING BLOOD PRESSURE

Epidemiological studies have demonstrated that borderline hypertensive pressures at rest are prognostic of hypertension upon long-term follow-up

178 CHAPTER NINE

(Joint National Committee, 1988; Kannel & Thorn, 1986). A related study of young PH + men found that parental history was a significant predictor of hypertension but only when elevated systolic pressure (~ 125 mm Hg) was also present (Thomas & Duszynski, 1982). These studies indicate the importance of elevated resting pressure as a predictor of risk with an additional contribution by a family history of hypertension.

RESPONSES TO EXERCISE

Exaggerated blood pressure responses to static and dynamic exercise may be useful predictors of future hypertension. Dynamic exercise is characterized by elevated cardiac output balanced by muscular vasodilation with a resulting rise in systolic pressure and a very moderate rise in diastolic pressure (usually ~ 5 mm Hg). Hypertensives show exaggerated systolic and diastolic blood pressures during exercise (Leibel, Kobrin, & Ben-Isbay, 1982). A number of studies reviewed below suggest that exaggerated exercise blood pressures may presage development of hypertension as well as the left-ventricular hyper­trophy usually accompanying the disorder.

Exercise responses in normotensives

Resting systolic blood pressure in 274 children, 6 to 15 years old, was predicted at 3.4-year follow-up by systolic response to bicycle exercise at entry (Mahoney, Schieken, Clarke, & Lauer, 1988). Consistent with these suggestive findings in children, future hypertension in adults was predicted by exagge­rated blood pressures during exercise over follow-up periods of32 months to 14 years (Dlin, Hanne, Silverberg, & Bar-Or, 1983; Jackson, Squires, Grimes, & Beard, 1983; WIlson & Meyer, 1981). Diastolic blood pressure during dynamic exercise in conjunction with elevated resting diastolic pressure predicted hy­pertension on 14-year follow-up (Chaney & Eyman, 1988). These results sug­gest again the importance of examining subgroups with exaggerated responses to exercise, targeting them for follow-up.

RelaJ,ionships to left-ventricular mass

Blood pressures during exercise are also predictive of present and future left-ventricular mass enlargement, an important accompaniment of hyperten­sion. Diastolic blood pressure during bicycle exercise was a significant predictor of left-ventricular mass in children over a 3.4-year follow-up period (Mahoney et al, 1988). Systolic pressure during maximal and submaximal exercise was found to be a significant correlate of left-ventricular mass and was superior to resting pressure as an indicator of mass (Gosse, Campello, Aouizerate, Rou­daut, Broustet, & Dallocchio, 1986; Nathwani, Reeves, Marquez-Julio, & Leenen, 1987).

CV REACTMTY AND HYPERTENSION 179

The findings cited above suggest that compared to resting pressures, blood pressures measured during exercise are more sensitive as indicators of future hypertension and as indicators of hypertensive target organ changes. Anal­ogous studies using the cold pressor provide some hints at why the exercise response is senitive to hypertension risk.

RESPONSES TO COLD PRESSOR

The cold pressor test-immersion of a hand or foot in ice water accom­panied by blood pressure measurements-has perhaps the longest and most controversial history of any test proposed as being sensitive to future hyper­tension risk. This area has been recently reviewed in detail (Fredrikson & Matthews, 1990; Manuck, Kasprowicz, & Muldoon, 1990). These authors con­cluded that blood pressure responses to the cold pressor task can be useful predictors of future hypertension and that such responses provide additional risk prediction beyond resting blood pressure alone. They further conclude that despite some positive findings, the cold pressor test may not be the best challenge for such purposes.

Some mechanistic considerations may help elucidate the source of the inconsistency across outcome studies using cold pressor. As shown by Drum­mond's (1983) reanalysis of the cold pressor data of Cuddy et al (1966), during the first minute of cold immersion the cardiac response is suppressed by a vagal reflex. The borderlines showed consistent exaggerations in blood pressure response to the cold pressor only after this vagal reflex had been blocked using atropine. Left-ventricular function is also known to be depressed in normals during the first minute of cold pressor and to return to normal only during the second minute (Dymond, 1984). Since 1 minute has been the most commonly used duration of cold immersion in prospective studies, the cardiac response would be masked to varying degrees across persons, severely reducing the reliability of the test. This observation is amplified by contrasting cold pressor results with those of the above exercise studies. In these we have seen that the predictive value of exercise derives from its ability to increase cardiac output in the face of the high-risk person's elevated vascular resistance. The most useful predictors of risk probably allow both components of the blood pressure response to operate fully.

RESPONSES TO LIFE STRESS

There are no prospective, randomized studies of life stress as a cause of hypertension. Three studies are of interest, however, in suggesting that person­environment interactions may have etiologic significance. Cobb and Rose (1973) found hypertension to be more prevalent, to have a higher annual incidence, and to occur at an earlier age among those air traffic controllers working at control centers having higher air traffic densities-and presumably creating

180 CHAPI'ER NINE

more job stress. Timio et al. (Timio, Verdecchia, Venanzi, Gentili, Ronconi, Francucci, Montanari, & Bichisao, 1988) studied a group of Italian nuns belong­ing to a secluded order and found that when compared over 20 years to matched laywomen living in a nearby community, the nuns did not show the expected age-related rises in blood pressure. Finally, hypertension prevalence has been observed to vary widely across workplaces and appears higher in occupational groups, such as typesetters, that have the greatest work pressure (Schlussel, Schnall, Zimbler, Warren, & Pickering, 1990).

These studies may be criticized on at least two counts. First, the subjects in all three selected their occupations, and a self-selection bias may underlie the observed risk differentials. The finding of risk differences between groups of air traffic controllers, however, mitigates this concern to a degree. Second, in the Italian study, numerous life-style differences may have contributed to blood pressure differences between the nuns and community women. While these studies suggest that life stress contributes to elevated blood pressure in hu­mans, they do not provide conclusive evidence.

RESPONSES TO MENTAL STRESS

We are aware of only one study prospectively showing that magnitude of blood pressure change to mental stress is a useful predictor of hypertension (Falkner, Kushner, Onesti, & Angelakos, 1981). In this study, 50 borderline hypertensive adolescents (90th percentile :s BP < 95th percentile for 14 to 15-year-olds) were compared to 14 normotensive controls on heart rate and blood pressure response to a 10-minute mental arithmetic task. Among the borderlines, after 5 to 41 months: 28 became hypertensive (BP ~ 95th percentile for age group), 12 remained borderline, 6 were normotensive, and 4 were lost to follow-up. Those who became hypertensive had initially shown the largest heart rate and blood pressure rises to the stressor. These findings are the clearest to date that large blood pressure responses to mental stress predict clinical hypertension. Light, Dolan, Davis, and Sherwood (1990) have recently shown that the diastolic blood pressure response to a reaction time task can significantly enhance prediction of diastolic pressure among normotensives 10 to 15 years later (see Chapter 15).

In contrast to the cold pressor test's variable cardiac activation, the mental arithmetic task consistently provokes cardiac activation-seen in elevated heart rate and cardiac output-and may therefore more readily demonstrate pressor influences affecting those at greatest risk.

SUMMARY

Studies of resting blood pressures in PH + persons and borderline hyper­tensives, along with evidence of greater blood pressure responses to mental and

CV REACTIVITY AND HYPERTENSION 181

physical stressors, suggest that a tendency toward future hypertension is accompanied by an exaggeration of cardiovascular reactivity. Nearly all re­activity studies have been conducted under controlled conditions in the lab­oratory, and technical and study design problems have made it extremely difficult to obtain adequate response data in nonlaboratory settings (Pickering & Gerin, 1990). While acknowledging these difficulties, other reviewers have emphasized the robustness of the presumed reactivity-hypertension relation­ship in view of the methodologic difficulties in obtaining adequate data even in the laboratory (Fredrikson & Matthews, 1990; Manuck et 01., 1990). The evi­dence that cardiovascular responses are exaggerated in those at greatest risk of essential hypertension is certainly suggestive that this exaggerated re­activity tendency has etiologic significance. Chapter 14 will be devoted to a discussion of the possible form that such a relationship may take.

ACKNOWLEDGMENTS

Preparation of this chapter was supported by funds from the Medical Research Service of the Department of Veterans Affairs and by a grant from the National Heart Lung and Blood Institute (HL32050).

We thank Cynthia Sabouri and Jack Shepard for their careful work in the preparation of this chapter. We further thank Sue Everson, who generously commented on earlier versions.

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CHAPl'ER TEN

Stress Reactivity in Childhood and Adolescence

BRUCE S. ALPERT AND DAWN K. WILSON

INTRODUCTION

Numerous investigators have sought to measure cardiovascular reactivity (i.e., response to acute stress) in healthy individuals before manifestations of car­diovascular disease are apparent. In this light, cardiovascular reactivity could serve as either a marker or a mechanism for the development of essential hypertension or coronary disease. As a marker, hyperreactivity is concept­ualized as a consequence of preexisting cardiovascular damage or of heightened sympathetic tone that results in vasoconstriction and/or excessive myocardial work (cardiac output). As a mechanism, hyperreactive peaks are thought to damage the intimal layer of arteries, resulting in arteriosclerosis and/or sub­sequent hypertension. An alternative hypothesis suggests that hyperreactive peaks cause greater release of mitogens, which result in hypertrophy of smooth muscles. Whether hyperreactivity is found to be a mechanism of essential hypertension evolution or a marker for future essential hypertension, further research is warranted. This association would allow detection of individuals at the highest risk, and, possibly, lead to primary prevention of cardiovascular disease. The study of children and adolescents is extremely valuable because in these populations, cardiovascular disease is minimally present and potentially reversible.

The hypothesized interactions of known or suspected risk factors of car-

BRUCE S. ALPERT AND DAWN K. WILSON • Department of Pediatrics, University of Tennessee, Memphis, Tennessee 38103.

187

188 CHAPl'ER TEN

diovascular reactivity are shown in Figure 1. These factors will be discussed individually in sections that follow. The probes, or stressors, used to elicit cardiovascular reactivity have varied from primarily physical tasks, such as exercise (dynamic or isometric) or the cold pressor test, to psychologic chal­lenges, such as mental arithmetic, video games, the Type A interview, or puzzles. Extensive reviews of the various paradigms tested have been pub­lished (Krantz & Manuck, 1984; Sallis, Dimsdale, & Caine, 1988). Laboratory stressors such as classroom speeches and reading aloud have also been utilized to simulate responses that occur in the natural environment (Matthews, Man­uck, & Saab, 1986a; Thomas, Lynch, Friedmann, Subinohara, Hall, & Peterson, 1984). For a stressor to be useful in a cardiovascular reactivity paradigm, it

Hyperreactivity as a Mechanism GENETIC Race Gender Body Size Puberty BPControl

" OIANGES ENVIRONMENT Diet Physical Rtness stress

~ vasCUlar I Hyperreactivity Heart Kidney Brain

Social Support

PERSONALIT¥ Type A Behavior Coping Styles Hostility Anxiety

GENETIC Race Gender Body Size Puberty BPControl

ENVIRONMENT Diet Physical Fitness Stress SodalSupport

PERSONALITY Type A Behavior Coping Styles 1----' Hostility Anxiety

, \

Hyperreactivity as a Marker

Hypertension h L.--tor----' ~

Hyperreactivity I MORBIDITY Brain Heart Kidney

FIGURE 1. Correlates of hyperreactivity as a mechanism versus a marker of essential hyper­tension and morbidity.

STRESS REACTMTY IN CHILDHOOD 189

must elicit sufficient change in the target variables to allow separation of individuals or subgroups of individuals for meaningful comparisons.

Measures that are monitored in studies of cardiovascular reactivity usually include heart rate (HR), systolic blood pressure (SBP), and diastolic blood pressure (DBP). Baseline values may be taken prior to the administration of the stressor, either on the same or previous day or in the recovery period after the stressor has been given. Individual protocols vary, making comparison between studies difficult. In addition to the standard measures already mentioned, more complex measures, such as cardiac output or systemic vascular resistance, may be measured. These parameters allow a more physiologic determination of the mechanisms that may underlie differences in cardiovascular reactivity. With the addition of blood and urine measurements, investigators have also begun to probe the physiologic mechanisms that may lead to understanding differences in cardiovascular responsivity in individuals or subgroups of individuals.

INDIVIDUAL DIFFERENCES IN GENETIC BACKGROUND

DEMOGRAPHIC CHARACTERISTICS

Research on stress reactivity in children and adolescents has primarily focused on the genetic contribution of demographic characteristics, such as family history of hypertension, gender, body surface area, sexual maturation, and race. The most extensively studied correlate of reactivity has been family history of hypertension. To our knowledge, 11 studies have evaluated the role of family history of hypertension on cardiovascular reactivity in young subjects (Table 1). Of the studies reviewed, 73% (8/11) demonstrated a positive relation­ship between family history and either SBP or DBP reactivity. Only 30% (3/10), however, showed greater HR reactivity in subjects with a positive family his­tory. Two studies (Coates, Parker, & Kolodner, 1982; Matthews et aL, 1986a) failed to show a significant relationship between family history and reactivity; both of these studies employed relatively small sample sizes.

Blood pressure status has also been found to interact with family history in identifying adolescents who are hyperreactive. For example, Falkner, One­sti, Angelakos, Fernandes, and Langman (1979) demonstrated that adolescents who were hypertensive (DBP > 95th percentile) and had a positive family history of hypertension (FH +) had greater SBP, DBP, and HR responses to mental arithmetic than normotensive adolescents who had no family history of hypertension (FH -). In another study, Falkner, Kushner, Onesti, and Ange­lakos (1981a) reported that adolescents with borderline hypertension and a genetic predisposition for hypertension showed similar cardiovascular response patterns to labile hypertensives.

Other factors that have interacted with family history include Type A behavior pattern and race. McCann and Matthews (1988) found that Type A

190 CHAPTER TEN

TABLE 1. Family History of Hypertension and Cardiovascular Reactivity in Children

Study Sample BP status Age Stressor SBP DBP HR

Coates et al. (1982) 42 Hyperten 41-17 Video game Null Null Ewart et al. (1986) 77 Borderline M = 15 Video game Negative Positive Null Falkner et al. (1979) 75 17 Hyperten 10-17 Mental math Positive Positive Positive

58 Normal Falkner et al. (1981) 74 28 Hyperten M = 16 Mental math Positive Positive Positive

18 Border 28 Normal

Hastrup et al. (1986) 51 Normotensive 8-10 Reaction time Null Null Positive

Hohn et al. (1983) 143 Normotensive 10-17 Treadmill Positive Positive Null Lawler & Allen

(1981) 39 Normotensive 11-13 Reaction time Positive Null Null Matthews et aL

(l986a) 25 Normotensive M = 15 Class speech Null Null Null McCann &

Matthews (1988) 171 Normotensive M = 14 Mental math, Null Positive Null star tracing, handgrip

Remington et al. (1960) 131 Normotensive 8-18 Orthostatic, Positive Null Negative

cold pressor Warren & Fischbein

(1980) 166 Normotensive 5-6 Tetanus shot Positive Positive

adolescents who were FH + had the greatest increases in SBP reactivity to stress (e.g., handgrip). Hohn Riopel, Keil, Loadholt, Margolius, Halushka, Privitera, Webb, Medley, Schuman, Rubin, Pantell, and Braunstein (1983) found that FH + blacks had greater DBP reactivity to exercise than FH­blacks; no effect of family history was found among whites. Overall, these data lend strong support for a genetic detennination of blood pressure reactivity in children but less support for HR reactivity.

Researchers have become increasingly interested in studying gender dif­ferences in cardiovascular reactivity (see Chapter 8). In regard to children, evidence is accumulating that suggests that boys have greater blood pressure reactivity than girls (McCann & Matthews, 1988; Matthews & Stoney, 1988; Murphy, Alpert, Moes, & Somes 1986; Murphy, Alpert, Walker, & Willey, 1988a; Strong, Miller, Striplin, & Salehbhai, 1978; Voors, Webber, & Berenson, 1980). Several investigators have also found that girls show higher HR re­activity than boys (Falkner et al, 1981a; Godfrey, Wozniak, & Barnes, 1971; Murphy et al, 1986). In contrast, some researchers have not found a significant relationship between gender and reactivity in young children aged 4 to 10 (Thomas et al., 1984; Treiber, Musante, Strong, & Levy, 1989).

Several interesting gender interaction effects have been reported in the

STRESS REACTMTY IN CHILDHOOD 191

reactivity literature. Research on gender by race interactions has demon­strated that black boys, in particular, show the greatest cardiovascular re­sponse to both psychological (Murphy, Alpert, Willey, & Somes, 1988b) and physiological stressors (Alpert, Dover, Booker, Martin, & Strong, 1981; Ber­enson, Voors, Webber, Dalferes, & Harsha, 1979; Voors et al., 1980). In terms of personality factors, Lawler, Allen, Critcher, and Standard (1981) found that Type A behavior was more strongly correlated with hyperreactivity in girls than boys. Lundberg (1983), however, found that Type A boys showed greater increases in cardiovascular reactivity than Type B boys while no effect was found for girls.

Cardiovascular responses to stress may also be affected by individual differences in body surface area or quetelet index. Adjusting for body surface area is critical if the age range in a study spans more than several years. This is especially important because adolescent growth spurts may occur in in­dividual children at varying ages. Some investigators have reported results based on analyses adjusted for body surface area (Alpert et al., 1981; Hohn et al., 1983; Thomas et al., 1984). Alpert and colleagues (1981) reported that racial differences in reactivity were significant for boys regardless of body surface area. For girls, though, SBP and DBP reactivity to exercise was significantly higher in blacks than whites in the 1st, 2nd, and 3rd quartiles of body surface area but not the 4th quartile (i.e., the largest children). Matthews and Stoney (1988) found that when body mass index was controlled for, high school stu­dents had smaller HR responses during three different stressors (mental arith­metic, mirror tracing, and isometric handgrip) than did younger students.

Although researchers have recognized that sexual maturation (puberty) can affect reactivity responses, little research has addressed the significance of this factor. Previous research has indicated that hormonal fluctuations, such as menstrual cycle and oral contraceptives, may significantly affect reactivity and/or peak level responsivity (Watkins & Eaker, 1986). Furthermore, several investigators have demonstrated that age is correlated with stress reactivity in children (James, 1980; Matthews & Stoney, 1988; Strong et al., 1978). Research from our laboratory (Wilson, Alpert, Harshfield, Willey, & Somes, 1990a) has examined the effect of sexual maturation on reactivity with respect to Tanner stages. The Tanner stage of sexual maturation was the most significant factor (of those tested) in predicting blood pressure reactivity in response to the Type A structured interview. Other factors included in these analyses were race, gender, quetelet index, and Type A behavior. These preliminary findings sug­gest a need for more extensive research on the effects of puberty on individual variability in blood pressure responses to stress.

The rruijority of research on racial differences in children. has demon­strated that blacks show greater blood pressure reactivity to physiological and psychological stressors than whites (Table 2). Table 2 also illustrates that racial differences are stronger for SBP (80% of the studies) than DBP (60% of the studies) reactivity. Blacks also had greater HR reactivity than whites primarily

192 CHAPTER TEN

TABLE 2. Studies Showing Greater Cardiovascular Reactivity in Black Children Than in White Children

Study Sample/Race Age Stressor SBP DBP HR

Alpert et oJ.. (1981) 221 W/184 B 6-15 Ergometry Positive Null Berenson et oJ.. (1979) 143 W/99 B 5-14 Cold pressor, Positive Null Null

orthostatic Hohn et oJ.. (1983) 79W/62B 10-17 Treadmill Positive Positive Null Murphy et oJ.. (1986) 104 W/109 B 6-18 VIdeo game Positive Positive Positive Murphy et oJ.. (1988a) 411 W/68 B 6-18 Video game Positive Positive Positive Murphyet oJ.. (l988b) 175 W/135 B 6-18 Video game Null Positive Positive Thomas et oJ.. (1984) 31 Wr.n B M= 10 Reading aloud Null Null Null TreIber et oJ.. (1989) 51 W/24 B 4-6 Treadmill Positive Null Null Treiber et oJ.. (1990) 2OW/20B 10-14 Cold face Positive Positive Null

stimulus Voors et oJ.. (1980) 134 W/138 B 5-14 Orthostatic, Positive Positive Negative

cold pressor, handgrip

in response to psychological stressors. Only one study in Table 2 demonstrated no effect for race on blood pressure reactivity (Thomas et al, 1984). There was a significant three-way interaction, however, between test period, race, and gender that was not discussed in this study. Thus, it is unclear whether a racial effect at some level did actually occur. Further, there is some question as to the accuracy of the blood pressure assessment method. The authors note that blood pressure readings during rest and reactivity were quite high as compared with other studies on similar-aged children. While cardiovascular reactivity respons­es appear greater in blacks than whites at younger ages, this difference is less clear as children reach young adulthood (see Chapter 7). As yet, it is unclear why these age-related differences exist.

HORMONAL MECHANISMS

Two hormonal regulatory systems have been examined in relation to stress reactivity: catecholamines (epinephrine and norepinephrine) and the renin­angiotensin-aldosterone system (RAAS). The vast majority of this research has been conducted among adults (see Chapter 2).

The few studies conducted among children and adolescents have demon­strated findings consistent with the adult literature. Falkner et al (1979) showed that labile hypertensive adolescents and normotensive adolescents who were FH + had higher epinephrine and norepinephrine levels after performing mental arithmetic than normotensive adolescents who were FH -. Similarly, McCrory, Klein, and Rosenthal (1982) found that epinephrine and norepineph­rine levels in response to orthostatic stress were higher among children with

STRESS REACTIVITY IN CHILDHOOD 193

established and borderline hypertension than normotensive children. Hohn et al. (1983), however, did not find a significant difference in norepinephrine levels in response to exercise in a biracial sample of children who varied in their genetic predisposition for hypertension.

It is well known that the sympathetic nervous system directly stimulates the RAAS (Ganong, Rudolph, & Zimmerman, 1980). In addition, acute in­creases in plasma renin activity have been demonstrated in response to a variety of psychological stressors among adult populations (Matthews, Weiss, et aL, 1986b; see also Chapter 3).

Only a few studies have examined cardiovascular reactivity and the RAAS in children. One study demonstrated that FH + black children tended to have higher plasma renin levels in response to exercise than FH - blacks (Hohn et al., 1983). Additionally, Berenson and colleagues have reported that black boys in the highest resting (casual) blood pressure strata, who had significant in­creases in reactivity, had the lowest baseline levels of plasma renin activity relative to other race-sex groups (Berenson et al., 1979; Voors et al., 1980). Further research is needed to better our understanding of the RAAS as a mechanism of reactivity in children.

ENVIRONMENTAL FACTORS AND REACTIVITY

DIETARY FACTORS

Dietary factors that are relevant to stress reactivity in children include intake of electrolytes (sodium, potassium, ratio of sodium/potassium), minerals (calcium, magnesium), and fat. One of the most controversial dietary issues has concerned the effect of sodium intake on blood pressure regulation. Some investigators have argued that dietary changes in salt do not result in cor­responding blood pressure changes. Miller, Weinberger, Daugherty, Fineberg, Christian, and Grim, (1988) examined sodium sensitivity in white children aged 3 to 20 years. Sodium sensitivity has been defined as a change of 5 mm Hg in mean blood pressure or greater in response to sodium depletion or sodium loading. Children and family members were restricted to a 60 mEq/24hr so­dium diet for 12 weeks. After adjusting for age, sex, height, and weight, there was a significant decrease in DBP and mean blood pressure for both boys and girls. Miller et aL (1988) argued that the magnitude of change was insignificant ( - 2 rom Hg) and that blood pressure is too variable across individuals to draw any valid conclusions. Other investigators have also not found a significant decrease in casual blood pressure in white children who were sodium restricted from 4 weeks to 1 year (Gillum, Elmer, Prineas, & Surbey, 1981; Watt, Foy, Hart, Bingham, Edwards, Hart, Thomas, & Walton, (1985).

More recently, researchers have demonstrated that certain subgroups of individuals are more likely to show sodium sensitive blood pressure responses.

194 CHAPTER TEN

For example, Rocchini, Key, Bondie, Chico, Moorehead, Katch, & Martin (1989) found that obese adolescents had significantly greater decreases in mean blood pressure when they went from a high-salt to a low-salt diet than nonobese adolescents. Furthermore, Becker et al., (Becker, Murphy, Alpert, Stapleton, Harshfield, & Thomas, 1989) studied sodium sensitivity in black versus white high school children who were placed on a one-week sodium restricted diet (50 mEq/24hr). Consistent with adult studies, a higher percentage of black children (21 %) showed sensitivity to sodium restriction than white children (9%). Over­all, black children also showed a significantly greater drop in mean blood pressure than did white children following the low-sodium diet.

Only two studies have examined the effects of sodium intake on cardio­vascular response to stress in children. Falkner, Onesti, and Angelakos (1981b) demonstrated that female adolescents who were FH + showed greater DBP reactivity after salt loading than FH - females. No effect, however, was found for SBP reactivity. Work done in our laboratory examined the effects of a low-sodium/high-potassium diet on cardiovascular reactivity in 19 black chil­dren aged 11 to 16 years (W'llson, Moody, Harshfield, Pulliam, & Alpert, 1990b). Subjects were randomly assigned to either a 6-week low-sodium/high-potas­sium dietary intervention (sodium = 40, potassium = 80 mEq/24hr) or a stan­dard diet control group. Based on urinary sodium excretion, 66% (6/9) of the children complied with the diet (49.8 versus 27.7 mEq/night, p<O.Ol). Potas­sium excretion also decreased in response to the diet (6.8 versus 5.3 mEq/night, p<O.05). Casual SBP decreased in the treatment group from baseline (109 mm Hg) to post treatment (104 mm Hg, p<O.05). Contrary to expectations, though, SBP reactivity increased in the treatment group (SBP change = 10.6 versus 13.1 mm Hg, p<O.05); absolute levels of SBP reactivity, however, did not significantly change. Differences in blood pressure were not significant in the control group. These results suggest that different physiological mechanisms may underlie changes in casual versus stress-induced blood pressure responses during low-sodium intake.

Studies on young adults have generally not found a significant increase in blood pressure reactivity in response to salt loading. Falkner, Katz, Canessa, and Kushner (1986) found that sodium sensitive individuals had greater DBP throughout a mental stress test but showed no change in reactivity. In another study, blood pressure during mental stress was unchanged in salt-loaded con­ditions; however, greater SBP in response to postural tilt was shown in the sodium-sensitive group as compared to the sodium-insensitive group (Falkner & Kushner, 1989).

Research examining the effects of potassium intake on stress reactivity has been scarce. The few studies that have been conducted have been correla­tional in nature or have shown positive results in only a subgroup of individuals. Berenson et al. (1979) reported that black boys in the highest blood pressure strata, who showed significant increases in blood pressure reactivity to the handgrip, also had lower urinary potassium excretion than whites. Wilson,

STRESS REACTIVITY IN CHILDHOOD 195

Alpert, Willey, and Somes (1992) examined the relationship between HR re­activity and sodium and potassium excretion in a biracial sample of 153 children (aged 9 to 18 years). Subjects were divided using a median split into hyporeac­tors (range HR change = -15.5 to +6.4 bpm) and hyperreactors (range HR change = +6.5 to +31.9 bpm). Differences in sodium excretion, potassium excretion, and sodium/potassium ratios were compared across HR classifications. The hyperreactive group had higher sodium/potassium ratios (4.2 versus 3.6, p<0.05) and lower potassium excretion (36.2 versus 41.7 mEq/24hr, p<0.05) than the hyporeactive group. The same group comparisons were made with race included in the model. Blacks demonstrated greater sodium/potassium excretion (4.4 versus 3.5, p<O.OI) and lower potassium ex­cretion (36.6 versus 41.6 mEq/24hr, p = 0.05) than whites. These results sug­gest that potassium may playa stronger role than sodium in decreasing hyper­reactivity, especially in black children. Furthermore, in a study by Falkner, Kushner, and Graeber (1990), potassium supplementation significantly de­creased blood pressure reactivity in obese black young adults.

Recently, more investigators have grown interested in evaluating the role of mineral and dietary fat intake on blood pressure regulation. To the best of our knowledge, however, no research to date has examined the impact of these factors in relation to stress reactivity.

STRESS AND COPING

An increasing number of studies have evaluated the relationship between laboratory stressors and stressors that occur in everyday life. Matthews et a1. (1986a) compared blood pressure responses to three different laboratory stres­sors (mental arithmetic, star tracing, and handgrip) with blood pressure re­sponses during a naturally occurring stressor (public speaking). Adolescents who exhibited exaggerated increases during laboratory task performance also showed elevated levels of blood pressure and HR reactivity during the natur­ally occurring stressor. Southard et a1. (Southard, Coates, Kolodner, Parker, Padgett, & Kennedy (1986) also demonstrated significant correlations between laboratory SBP reactivity (to video games) and average SBP in the home environment (awake r = 0.44, asleep r = 0.33).

More recently, work by Boyce and Chesterman (1990) examined the role of stressful life events, sense of permanence, and social support on cardiovas­cular reactivity in adolescent boys. Opposite to their hypotheses, adolescents who reported a low number of previous stressful life events had the highest level of blood pressure and HR reactivity. Adolescents who had a high sense of permanence also tended to show greater levels of blood pressure reactivity. Social support was unrelated to blood pressure reactivity. The validity of the social support measure used in this study may have been questionable because no external criterion was compared to the scale developed for their study. These findings are interpreted as suggestive of an ''inoculation effect," in which

196 CHAPl'ER TEN

previous stressful life events facilitate the development of effective coping strategies. Coping strategies, in turn, may decrease reactivity to stressful laboratory tasks.

PERSONALITY FACTORS AND REACTIVITY

A number of personality factors have been studied in relation to cardio­vascular reactivity among children. The majority of work has been done on Type A behavior, but an increasing number of studies have also evaluated individual differences in hostility, anxiety, and mood states.

Previous research has established Type A behavior as an independent risk factor in the development of coronary heart disease (Matthews & Haynes, 1986). It remains unclear whether Type A behavior is an independent risk factor for hypertension. Type A behavior pattern has generally been charac­terized as an extreme sense of time urgency, competitiveness, impatience, aggressiveness, tenseness, and explosive speech stylistics (Matthews & Haynes, 1986). Type B behavior has generally been defined as the absence of Type A behavior.

A summary of research on Type A behavior and reactivity in children is presented in Table 3. To date, 12 studies have evaluated the hypothesis that Type A children show greater blood pressure reactivity than Type B children. The majority of studies have confirmed this hypothesis for SBP reactivity (67%). Type A behavior was significantly related to DBP reactivity in four studies and HR reactivity in only three studies. Three studies reported no significant relationship between blood pressure or HR reactivity and Type A behavior (Hastrup, Kraemer, Hotchkiss, & Johnson, 1986; Matthews et al., 1986a; Murray, Blake, Prineas, & Gillum, 1985).

There are several possible explanations for the discrepancies in findings. One possibility is that Type A behavior is not consistently correlated with cardiovascular reactivity because the relationship is not a strong one. Another explanation could be related to differences in protocols, Type A measures, and experimental designs across studies. Hastrup et al. (1986) were one of the few groups of investigators who used a median split as opposed to an upper and lower proportion of subjects (tertiles) for categorizing Type As Versus Type Bs. Other investigators have suggested that subjects in the middle range represent a "mixed" typology that is different from the extreme groups. Murray et al. (1985) were the only group that used a manual blood pressure reading as opposed to an automated one. Matthews et al. (1986a) employed a relatively small sample size, making the statistical power of detecting Type A versus B differences limited. Nonetheless, further research that utilizes a standardized procedure relative to past work is needed to understand these inconsistencies in findings.

An increasing number of investigators have found specific affective states,

STRESS REACTIVITY IN CHILDHOOD 197

TABLE 3. Type A Behavior and Cardiovascular Reactivity in Children

Type A Study Sample Age Measure Stressor SBP DBP HR

Brown & Tanner (1988) 144 4-7 MYTH ° Memory game Positive Null Null

Coates et aL (1982) 42 14-17 Bortnerb Video Game Positive Null Hastrup et aL

(1986) 51 8-10 MYTH; Reaction time Null Null Null PATCH"

Lawler et aL (1981) 41 11-12 MYTH; Reaction time Positive Positive Bortner

Lundberg (1983) 26 3-6 MYTH Brief exercise Positive Null Null Matthews &

Jennings (1984) Study I 34 M = 10 ASId;MYTH Video game Positive Positive Positive Study II 30 M= 10 ASI;MYTH Star tracing, Positive Null Positive

mental math Matthews et aL

(1986a) 25 M = 15 MYTH Class speech Null Null Null McCann &

Matthews (1988) 171 M= 15 ASI Mental math, Null Positive Null star tracing, handgrip

Murray et aL (1985) 87 M = 12 MYTH Mental math Null Null Null

Southard et aL (1988) 28 13-18 JAS"; Bortner Video game Positive Positive/ Negative

Negative Spiga (1986) 48 10-12 MYTH Video game Positive Positive Null

°MYTH = Matthews Young Test for Health. bBortner = Bortner Adjective Rating Scale. "PATCH = Parents' Assessment of Their Children for Health. dABI = Adolescent Structured Interview. "JAB = Jenkins Activity Survey.

such as hostility, anxiety, depression, and tenseness, to be related to hyper­reactivity in children. Matthews et al. (1986a) found that anxious adolescents achieved the greatest levels of SBP and HR reactivity in response to public speaking whereas angry adolescents achieved the greatest levels of DBP re­activity. McCann and Matthews (1988) also demonstrated that adolescents who were rated high on potential for hostility had elevated SBP and DBP responses during isometric exercise. These studies are the first to suggest that individual differences in specific affective states may be a diagnostic characteristic of hyperresponsive children.

Southard et al. (1986) investigated the relation between psychological mood states and blood pressure reactivity during daily activities over a 24-hour

198 CHAPTER TEN

period. Adolescent boys completed mood ratings on 11 affective states and five items regarding mood perceptions of the environment. Ambulatory SBP was positively associated with worried, hostile, depressed, and tense mood ratings and perceptions of the environment as hostile, demanding, and noisy. Ambu­latory DBP was correlated with hostile, depressed, and upset mood ratings and hostile and demanding perceptions of the environment. In general, these findings suggest that an interaction of personality and environmental mood states are important factors in understanding blood pressure reactivity in the natural environment.

CONCLUSIONS

Insufficient longitudinal studies have linked cardiovascular reactivity to adult disease morbidity and mortality (see Chapter 15); thus, we cannot use HR, SBP, DRP, or other responses to laboratory or natural environment stress as criteria for intervention studies. This link is critically needed so that mecha­nisms of hypertension on the cellular and molecular level can be characterized and primary prevention trials designed and implemented. Cardiovascular dis­ease remains the leading cause of morbidity and mortality in the United States; therefore, more funding for longitudinal studies and limited intervention trials utilizing cardiovascular reactivity is warranted. The prevention of morbidity and mortality should be the goal of the twenty-first century to relegate car­diovascular disease from the leading cause of death and disability in Americans.

ACKNOWLEDGMENTS

This project was supported by a grant funded by the National Institutes of Health (HL35788). The authors wish to thank Gregory A Harshfield for his helpful suggestions on earlier drafts of this chapter and Karen Williams for her technical assistance.

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Becker, J. A, Murphy, J. K., Alpert, B. S., Stapleton, F. B., Harshfield, G. A, & Thomas, T. D. (1989, November). Biracial sodium sensitivity in youth. Presented at the American Heart Association Conference, New Orleans, Louisiana.

Berenson, G. S., Voors, A W., Webber, L. S., Dalferes, E. R., Jr., & Harsha, D. W. (1979). Racial differences of parameters associated with blood pressure levels in children-the Bogalusa Heart Study. Metabolism, 28(12), 1218-1228.

Boyce, W. T., & Chesterman, E. (1990). Life events, social support, and cardiovascular reactivity in adolescence. Journal of Develn[mtental Behavimal Pediatrics, 11, 105-111.

STRESS REACTMTY IN CHILDHOOD 199

Brown, M. S., & Tanner, C. (1988). Type A behavior and cardiovascular responsMty in pre­schoolers. Nursing Research, 87, 152-155.

Coates, T. J., Parker, F. C., & Kolodner, K. (1982). Stress and heart disease: Does blood pressure reactivity offer a link? In T. J. Coates, C. Peterson, & C. Perry (Eds.), Promoting adolescent health: A dialog on 1'fJ8earch and practice (pp. 305-321). New York: Academic Press.

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Falkner, B., & Kushner, H. (1989). Race differences in stress-induced reactivity in young adults. Health Psychology, 8(5),613-627.

Falkner, B., Onesti, G., Angelakos, E. T., Fernandes, M., & Langman, C. (1979). Cardiovascular response to mental stress in normal adolescents with hypertensive parents: Hemodynamics and mental stress in Adolescents. Hypertension, 1, 23-30.

Falkner, B., Kushner, H., Onesti, G., & Angelakos, E. T. (1981a). Cardiovascular characteristics in adolescents who develop essential hypertension. Hypertension, 8, 521-527.

Falkner, B., Onesti, G., & Angelakos, E. T. (1981b). Effect of salt loading on the cardiovascular response to stress in adolescents. Hypertension, 8(11): 11195-11199.

Falkner, B., Katz, S., Canessa, M., & Kushner, H. (1986). The response to long-term oral sodium loading in young blacks. Hypertension, 8(1): 165-168.

Falkner, B., Kushner, H., & Graeber, C. (1990). Obesity as a determinant of blood pressure sensitivity to sodium and potassium. American Jou1'1tOl of Hypertension, 8, 28A.

Ganong, W. F., Rudolph, C. D., & Zimmerman, H. (1980). Neuroendocrine components in the regulation of blood pressure and renin secretion. Hypertension, 1, 207-218.

Gillum, R. F., Elmer, P. J., Prineas, R. J., & Surbey, D. (1981). Changing sodium intake in children: The Minneapolis children's blood pressure study. Hypertension, 8, 698-703.

Godfrey, S., Wozniak, D. E., & Barnes, C. A. (1971). Cardiorespiratory response to exercise in normal children. Clinical Science, 40, 419-431.

Hastrup, J. L., Kraemer, D. L., Hotchkiss, A. P., & Johnson, C. A. (1986). Cardiovascular respon­sivity to stress: Family patterns and the effects of instructions. Jou1'1tOl of Psychos01/U1J,ic Research, 80, 233-241.

Hohn, A. R., Riopel, D. A. Keil, J. E., Loadholt, C. B., Margolius, H. S., Halushka, P. V., Privitera, P. J., Webb, J. G., Medley, E. S., Schuman, S. H., Rubin, M. I., Pantell, R. H., & Braunstein, M. L. (1983). Childhood familial and racial differences in physiologic and biochemical factors related to hypertension. Hypertension, 5, 56-70.

James, F. W., Kaplan, S., Glueck, C. J., Tsay, J., Knight, M. S., & Sarwar, C. J. (1980). Responses of normal children and young adults to controlled bicycle exercise. Circulation, 61, 902-912.

Krantz, D. S., & Manuck, S. B. (1984). Acute psychophysiological reactivity and risk of cardiovas­cular disease: A review and methodologic critique. Psychological Bulletin, 96, 435-464.

Lawler, K. A., & Allen, M. T. (1981). Risk factors for hypertension in children: Their relationship to psychophysiological responses. Jou1'1tOl of Psychos01/U1J,ic Research, 28, 199-204.

Lawler, K. A., Allen, M. T., Critcher, E. C., & Standard, B. A. (1981). The relationship of physi­ological responses to the coronsry-prone behavior pattern in children. Jou1'1tOl of BehavioTal Medicine, 4, 203-216.

Lundberg, u. (1983). Note on Type A behavior and cardiovascular responses to challenge in 3-6-yr old children. Jou1'1tOl of Psychos01lU1J,ic Research, 27, 39-42.

McCann, B. S., & Matthews, K. A. (1988). Influences of potential for hostility, Type A behavior, and parental history of hypertension on adolescents' cardiovascular responses during stress. Psychophysiology, 25, 503-611.

McCrory, W. W., Klein, A. A., & Rosenthal, R. A. (1982). Blood pressure, heart rate, and plasma catecholamines in normal and hypertensive children and their siblings at rest and after standing. Hypertension, 4, 507-613.

Matthews, K. A., & Haynes, S. G. (1986). Type A behavior pattern and coronsry disease risk: Update and critical evaluation. American Jou1'1tOl of Epidemiology, 128, 923-960.

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Matthews, K. A., & Jennings, J. R. (1984). Cardiovascular responses of boys exhibiting the Type A behavior pattern. Psychosumatic Medicine, .. 6, 484-497.

Matthews, K. A., & Stoney, C. M. (1988). Influences of sex and age on cardiovascular responses during stress. Psychosomatic Medicine, 50, 46-56.

Matthews, K. A., Manuck, S. B., & Saab, P. G. (1986a). Cardiovascular responses of adolescents during a naturally 0CCUITing stressor and their behavioral and psychophysiological predictors. Psychophysiology, 23, 198-209.

Matthews, K. A., Weiss, S. M., Detre, T., Dembroski, T. M., Falkner, B., Manuck, S. F., & Williams, R. B. (Eds.). (1986b). Handbook of stress, reactivity, and cardiovascular disease. New York: Wiley.

Miller, J. Z., Weinberger, M. H., Daugherty, S. A., Fineberg, N. S., Christian, J. C., & Grim, C. E. (1988). Blood pressure response to dietary sodium restriction in healthy normotensive children. American JCYUrnal of Clinical Nutrition, .. 7, 113-119.

Murphy, J. K., Alpert, B. S., Moes, D. M., & Somes, G. W. (1986). Race and cardiovascular reactivity: A neglected relationship. Hypertens1nn, 8, 1075-1083.

Murphy, J. K., Alpert, B. S., Walker, S. S., & Willey, E. S. (1988a). Race and cardiovascular reactivity: A replication. Hypertension, 11, 308-311.

Murphy, J. K., Alpert, B. S., Willey, E. S., & Somes, G. W. (1988b). Cardiovascular reactivity to psychological stress in healthy children. Psychophysiology, 25, 144-152.

Murray, D. M., Blake, S. M., Prineas, R., & Gillum, R. F. (1985). Cardiovascular responses in Type A children during a cognitive challenge. JCYUrnal of Behavioral Medicine, 8, 377-395.

Remington, R. D., Lambarth, B., Moser, N., & Hoobler, S. W. (1960). Circulatory reactions of normotensive and hypertensive subjects and of the children of normal and hypertensive parents. American Heart Jcyurrw1, 59, 58-70.

Rocchini, A. P., Key, J., Bondie, D., Chico, R., Moorehead, C., Katch, V., & Martin, M. (1989). The effect of weight loss on the sensitivity of blood pressure to sodium in obese adolescents. New England JCYUrnal of Medicine, 321, 580-585.

Sallis, J. F., Dimsdale, J. E., & Caine, C. (1988). Blood pressure reactivity in children. JCYUrnal of Psychosomatic Research, 32, 1-12.

Southard, D. R., Coates, T. J., Kolodner, K., Parker, F. C., Padgett, N. E. & Kennedy, H. L. (1986). Relationship between mood and blood pressure in the natural environment: An adolescent population. Health Psychology, 5(5) 469-480.

Spiga, R. (1986). Social interaction and cardiovascular response of boys exhibiting the coronary­prone behavior pattern. JCYUrnal of Pediatric Psychology, 11, 59-69.

Strong, W. B., Miller, M. D., Striplin, M., & Salenhbhai, M. (1978). Blood pressure response to isometric and dynamic exercise in healthy black children. American JCYUrnal of Diseases in Children, 132, 587-591.

Thomas, S. A., Lynch, J. J., Friedmann, E., Subinohara, M., Hall, P. S., & Peterson, C. (1984). Blood pressure and heart rate changes in children when they read aloud in school. Public Health Reports, 99, 77-84.

Treiber, F. A., Musante, L., Strong, W. B., & Levy, M. (1989). Racial differences in young children's blood pressure. American JCYUrnal of Diseases of Children, 1J,3, 720-723.

Treiber, F. A., Musante, L., Braden, D., Arensman, F., Strong, W. B., Levy, M., & Leverett, S. (1990). Racial differences in hemodynamic responses to the cold face stimulus in children and adults. Psychosomatic Medicine, 52, 286-296.

Voors, A. W., Webber, L. S., & Berenson, G. S. (1980). Racial contrasts in cardiovascular response tests for children from a total community. Hypertens1nn, 2, 686-694.

Warren, P., & Fischbein, C. (1980). Identification oflabile hypertension in children of hypertensive parents. Connecticut Medicine, 44. 77-79.

Watkins, L. 0., & Eaker, E. (1986). Population and demographic influences on reactivity. In K. A. Matthews, S. M. Weiss, T. Detre, T. M. Dembroski, B. Falkner, S. B. Manuck, & R. B. Williams (Eds.), Handbook of stress, reactivity, and cardiovascular disease (pp. 231-257). New York: Wiley.

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Watt, G. C. M., Foy, C. J. W., Hart, J. T., Bingham, G., Edwards, C., Hart, M., Thomas, E., & Walton, P. (1985). Dietary sodium and arterial blood pressure: Evidence against genetic susceptibility. British Medical Journal, 291, 1525-1528.

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Wilson, D. K., Moody, K. E., Harshfield, G. A., Pulliam, D. A., & Alpert, B. S. (l990b). Influence oflow sodium-high potassium diets on cardiovascular reactivity in black children. Unpublished manuscript, available upon request from D. K. Wilson.

Wilson, D. K., Alpert, B. S., Willey, E. S., & Somes, G. W. (1992). Race, electrolyte excretion, and cardiovascular reactivity in children and adolescents. Journal of Human Hypertension. (Sub­mitted)

CHAPTER ELEVEN

Does Aerobic Exercise Reduce Stress Responses?

ROGER B. FILLINGIM AND JAMES A. BLUMENTHAL

INTRODUCTION AND OBJECTIVES

Physical exercise has become increasingly popular as a leisure-time activity, in part due to its potential health benefits. In particular, physical activity has been shown to decrease the risk of cardiovascular disease (Leon, Connett, Jacobs, & Rauramma, 1987; Paffenbarger, Hyde, Irving, & Steinmetz, 1984). The cardio­protective effects of exercise may be due to a reduction in cardiac risk factors, such as obesity, hyperlipidemia, and hypertension (Dufaux, Assmann, & Holl­mann, 1982; Martin, Dubbert, & Cushman, 1990; Paulev, Jordal, Kristenen, & Ladefoged, 1984; Vu Tran & Weltman, 1985). In addition, exercise may reduce cardiovascular risk by attenuating cardiovascular and neuroendocrine respons­es to psychosocial stressors. It has been shown that improved aerobic fitness is associated with altered cardiovascular and sympathoadrenal functioning. Specifically, decreased heart rate at rest and during exercise, as well as de­creased plasma concentrations of epinephrine and norepinephrine during ex­ercise, result from aerobic training (Blomqvist & Saltin, 1983). It is believed that these cardiovascular and hormonal changes are related to decreased sym­pathetic activity and increased vagal tone following aerobic training (Astrand & Rodahl, 1986). In addition to altering physiologic activity at rest and during

ROGER B. FILLINGIM • Department of Psychiatry, Duke University Medical Center, Durham, North Carolina 27710. JAMES A. BLUMENTHAL • Departments of Psychiatry and Psychol­ogy, Duke University Medical Center, Durham, North Carolina 27710.

203

204 CHAPI'ER ELEVEN

physical work (i.e., exercise), it is hypothesized that exercise also may modulate cardiovascular responses to psychological stress.

The primary purpose of this chapter is to examine the relationship of both chronic and acute physical exercise to cardiovascular stress responses. First, a number of methodological issues that are relevant for research in this area will be discussed. Next, the relationship of aerobic fitness and psychophysiologic reactivity will be reviewed along with research concerning the potentially stress-modulating effects of acute and chronic exercise. Last, a summary of this area with an emphasis on directions for future research will be discussed.

METHODOLOGICAL ISSUES

Because research in this area spans several disciplines (e.g., exercise physiology, cardiovascular psychophysiology, and psychological stress re­search), methodological issues demand particular attention. These include, but are not limited to, the experimental design, the nature of control conditions, individual difference variables, the assessment and manipulation of aerobic fitness, the psychologic stressor(s) employed, the dependent measures used to assess psychophysiologic reactivity, and the statistical analysis of the phys­iological data.

Two basic experimental designs, correlational and interventional, have been used. Correlational designs typically assess aerobic fitness and cardio­vascular reactivity concurrently and examine the relationship of the two. The cross-sectional study typically identifies groups of fit and unfit subjects and compares the cardiovascular stress responses of the two groups. These designs are efficient and economical, and they are a reasonable choice for gathering initial data and performing exploratory research; however, they do not permit causal interpretation and are susceptible to selection bias. In contrast, inter­ventional designs in this area usually involve assigning subjects to a treatment condition in which fitness levels are manipulated over time. For example, in a simple prepost design, the fitness level and stress reactivity of a group of subject are compared before and after a physical exercise program. If exercise is practiced over an extended period (e.g., 8 to 12 weeks), changes in fitness level and stress reactivity can be examined. In the absence of a control group, however, investigators are unable to attribute changes specifically to exercise, as nonspecific factors also may influence outcome measures. The inclusion of a control group can overcome many of these interpretive problems, and the selection of appropriate control conditions will be discussed below. Several longitudinal studies have used subjects who volunteer for an exercise program as the treatment group but employ nonrandom comparison groups (e.g., sub­jects who have elected not to exercise or who have chosen to perform some other activity). Therefore, selection bias remains a potential confound. Ideal longitudinal designs involve the random assignment of subjects to exercise or

AEROBIC EXERCISE 205

control conditions and comparison of the groups' psychophysiological responses before and after the training period. Although this design is highly desirable, it may not always be practical.

Aerobic exercise training requires a significant commitment of time, and dropout rates are typically high (Dishman, 1982). Because there is often con­siderable contact with experimental personnel throughout the training pro­gram, interpretation of changes is not always straightforward. Nonspecific factors, such as subject expectations, presence of social support, and demand characteristics, also may affect outcome measures; thus, it is important that a control condition be matched fairly closely to the experimental condition on these nonspecific variables. If no control group is employed then artifacts such as regression to the mean and habituation may explain changes in the depen­dent measures across the treatment period. Group differences in experiments that rely only on a no-treatment control condition may be biased by other nonspecific effects, such as subject expectations and experimenter attention. In general, a relaxation group (Roth & Holmes, 1987) or a nonaerobic exercise program (Blumenthal, Emery, Walsh, Cox, Kuhn, Williams, & Williams, 1988; Blumenthal, Fredrikson, Kuhn, Ulmer, Walsh-Riddle, & Appelbaum, 1990a; Blumenthal, Fredrikson, Matthews, German, Steege, Walsh-Riddle, Kuhn, Ri­fai, & Rodin, 1990b) more closely matches the aerobic exercise condition on these nonspecific factors than a no-treatment control group.

A number of variables, such as age (Steptoe, Moses, & Edwards, 1990), race (Anderson, 1989), gender (Stoney, Davis, & Matthews, 1987), family his­tory of cardiovascular disease (Falkner, Onesti, Angelakos, Fernandes, & Langman, 1979), blood pressure status (Fredrikson & Matthews, 1990), and Type A behavior and other psychological attributes (Houston, 1986; Manuck & Krantz, 1986), can contribute to individual differences in psychophysiologic reactivity to psychological and behavioral stressors. These subject character­istics may interact with exercise in altering reactivity; therefore, they must be taken into account when conducting research in this area. Random subject assignment and adequate sample sizes are necessary and may be sufficient; however, in some settings, it may be preferable to assess these individual differences and either match the groups or include them as independent vari­ables (Lake, Suarez, Schneiderman, & Tocci, 1985; Sherwood, Light, & Blu­menthal, 1989).

FITNESS AsSESSMENT

Accurate assessment of aerobic fitness is an important methodological issue because fitness is used as an independent variable in correlational designs and assessment of aerobic capacity is critical for evaluating the effect of ex­ercise training in longitudinal studies. A number of methods to measure aerobic fitness are available, and no one method is optimal for all purposes. Ques­tionnaires that inquire as to subjects' physical activity patterns have been used

206 CHAPI'ER ELEVEN

as gross measures of physical fitness (Fillingim, Roth, & Haley, 1989; Light, Obrist, James, & Strogatz, 1987). Even if subjects accurately report their exercise habits, though, these self-report measures are based on the assump­tion that compared to inactive people more active people are more physically fit, which is not necessarily true. For example, genetic factors may be an important determinant of physical fitness (Bouchard & Malina, 19&'l). Therefore, paper and pencil instruments ideally should be used only for mass screening. Exercise testing is necessary to accurately measure aerobic fitness.

There are a variety of exercise testing protocols. Submaximal exercise tests involve having the subject exercise to a specified submaximal endpoint (e.g., 70% of age-predicted maximum heart rate, maximum distance run in 12 minutes, and so on). Then, maximal oxygen uptake is estimated based on a previously derived fonnula. These methods are often used with healthy persons when practical limitations prevent the use of maximal tests. There are several submaximal cycle ergometer tests that use a standard nomogram to predict aerobic fitness that are relatively easy to perfonn (see Astrand & Rodahl, 1986, for a discussion). Submaximal tests, however, are less accurate at estimating maximal oxygen uptake than maximal tests. Ideally, a multistage maximal exercise test on a treadmill or cycle ergometer with direct measurements of oxygen consumption (VOJ is perfonned to provide the most accurate measure of aerobic fitness. This must be perfonned under adequate professional super­vision, and the American College of Sports Medicine (ACSM) guidelines for exercise testing should be followed (ACSM, 1986). Several protocols for maxi­mal exercise testing are available. For exm:nple, the Bruce treadmill protocol (Bruce, 1971) increases the speed and slope every third minute while the Balke protocol (1954) keeps treadmill speed constant and increases the slope by 2.5% every, or every other, minute. Many different treadmill testing protocols prov­ide similar assessments of maximal aerobic power (Pollock, Wilmore, & Fox, 1978).

EXERCISE TRAINING

After assessment of aerobic fitness, the manipulation of fitness level by exercise training is an important part of research in this area. Exercise pro­grams can vary along a number of dimensions, including the type, intensity, duration, and frequency of the exercise regimen. In designing an exercise program, ACSM guidelines for exercise prescription should be observed (ACSM, 1986). Briefly summarized, these guidelines recommend the use of an exercise involving large muscle groups that is relatively continuous in nature (e.g., running, cycling, or swimming). Exercise intensity should be 70% of VOz max or maximum heart rate reserve, that is, (HR max - HR rest) .7 + HR rest). Exercise should be perfonned three to five times per week for 20 to 60 minutes per day. The magnitude of the conditioning effect depends, in part, on the length of the exercise program as well as the frequency, duration, and

AEROBIC EXERCISE 207

intensity of each exercise session. Studies in the fitness-stress reactivity area have generally used training programs from 10 to 16 weeks in length, which is adequate to produce a significant training stimulus.

STRESS REACTMTY TESTING

The selection of stressors is another important methodological issue that can affect results in this area. First, the stressor must elicit a robust psycho­physiologic response pattern that is measurable and large enough to be modifiable. Also, the stressor should require minimal physical exertion, as this can alter the cardiovascular response. The most common stressors in this area of research have been mental arithmetic (Blumenthal et al, 1988, 1990a), various cognitive tasks, such as the Stroop test (Holmes & Roth, 1987; Hull, Young, & Ziegler, 1984; Sinyor, Golden, Steinert, & Seraganian, 1986) and public speaking (Blumenthal et al, 1990b), and cold pressor (Blumenthal et al, 1990b). Optimally, a battery of behavioral stressors, perhaps varying along important dimensions, such as intensity or active/passive coping, may be useful to evaluate the generality of changes in cardiovascular reactivity and to help identify the most effective and valid laboratory stressors (Hull et al, 1984; Light et al, 1987; Peronnet, Massicotte, Paquee, Brisson, & de Champlain, 1989; Roskies, Seraganian, Oseasohn, Hanley, Collu, Martin, & Smilga, 1986).

PSYCHOPHYSIOLOGICAL MEASURES

Another important methodological issue concerns the psychophysiological measure under consideration. Studies in this area have used primarily heart rate and systolic and diastolic blood pressure and, less frequently, peripheral pulse volume and T -wave amplitude. It is difficult to make general recommen­dations as to the optimal measure(s) of reactivity as no one variable reflects overall physiologic function. Work by Sherwood et al (1989) is particularly noteworthy. Because blood pressure is affected by a variety of factors (e.g., total peripheral resistance, stroke volume, and cardiac output), examination of cardiovascular function by impedance cardiography is extremely useful.

Choice of dependent measures should be based on both practical and conceptual considerations. The nature of the stressor is important because different stressful tasks elicit different cardiovascular response patterns (Allen, Obrist, Sherwood, & Crowell, 1987; Sherwood, Allen, Obrist, & Langer, 1986). Due to their ease of measurement, heart rate and blood pressure are the most commonly employed dependent variables. In some studies, these measures have been found to be sensitive to fitness-related differences in reactivity; however, they offer relatively little information regarding the mechanisms underlying such differences. Thus, if a study aims to clarify mechanisms for decreased cardiovascular reactivity, then more specific hemohynamic mea­sures, measures of circulating catecholamines, and other factors may need to be

208 CHAPrER ELEVEN

considered (de Geus, van Doomen, De Visser, & Orlebeke, 1990; van Doomen & de Geus, 1989).

STATISTICAL APPROACH

An additional experimental issue concerns the statistical analysis of the physiological data. In longitudinal studies, repeated measures analysis of vari­ance, with baseline, stress, and recovery periods as the levels of the repeated measure, is used most often. This method may be appropriate, but it requires a degree of freedom correction to protect against false positives (see Vasey & Thayer, 1987, for a discussion). Analysis of change scores, calculated by sub­tracting the baseline value from the stress period, is mathematically similar to the use of repeated measures ANOVA Both of these methods fail to account for the law of initial values, however, which holds that the magnitude of the physiological response is inversely related to the pre stimulus level (Wilder, 1967). Analysis of covariance using the baseline measure as the covariate is an option; when comparing fit versus unfit groups, however, there are often base­line differences on cardiovascular measures, which makes the application of ANCOVA questionable (Keppel, 1982). Another option is to compare the abso­lute level of response (rather than change from rest to task) of the experimental and control groups during stress and recovery. This approach can reveal whether fit individuals show lower cardiovascular levels than unfit persons during stress, but it will not provide information as to the magnitude of the increase in cardiovascular activity relative to baseline values. None of these procedures takes into account the possible effects of differences in baseline levels, which may be especially important in longitudinal studies. To account for these baseline differences in prepost designs, an analysis of covariance should be performed in which the level of physiologic activity during the postexercise stressful task is the dependent variable, group membership is the independent variable, and both the postexercise baseline period (i.e., immediately prior to onset of the stressor) and the level of physiologic activity during stress before the exercise manipulation serve as covariates. This procedure takes into ac­count both preexercise stress response levels as well as the postexercise base­line differences. Statistical analysis of these data is not clear-cut, and even with careful experimental design and execution, the data may be difficult to analyze. A priori predictions based on theory or previous research will be quite helpful in guiding statistical analysis in this complicated area.

CROSS-SECTIONAL STUDIES OF PHYSICAL FITNESS AND CARDIOVASCULAR REACTIVITY

Several studies have examined differences in psychophysiologic stress reactivity among subjects who differ in physical fitness. Holmes and Roth

AEROBIC EXERCISE 209

(1985) assessed the aerobic fitness of 72 females using a submaximal cycle ergometer test and compared the heart rate responses to a memory test of the 10 least and 10 most fit subjects. It was found that the highly fit subjects showed a smaller increase in heart rate during the memory task than the low-fit subjects. Other studies have reported similar results. One study found that diastolic blood pressure responses to a cognitive task were smaller for fit subjects over 40 years of age compared to their same-age unfit counterparts (Hull et al., 1984). Light et al. (1987) categorized subjects based on self-re­ported exercise habits and found that cardiovascular reactivity (preejection period, heart rate, and systolic blood pressure) to a reaction time task was greater in subjects reporting lower levels of exercise. Relatedly, van Doornen and de Geus (1989) reported that highly fit subjects (based on a maximal exercise test) showed smaller increases in heart rate, diastolic blood pressure, and total peripheral resistance than low-fit subjects during a reaction time task. It has also been found that aerobically fit borderline hypertensives tend to show smaller increases in systolic and diastolic blood pressure than their unfit coun­terparts (Perkins, Dubbert, Martin, Faulstich, & Harris, 1986). In another study (Shulhan, Scher, & Furedy, 1986), low-fit subjects showed greater T­wave amplitude attenuation than highly fit subjects during mental arithmetic, but no differences in heart rate response emerged. A recent study found decreased diastolic blood pressure reactivity to stress in highly fit subjects, and the authors attributed some of the decreased reactivity to differences in anger between the two groups (Czajkowski, Hindelang, Dembroski, Mayerson, Parks, & Holland, 1990). These cross-sectional findings suggest that aerobic fitness is inversely related to cardiovascular stress responses. Only one study assessed fitness with a maximal exercise test (van Doornen & de Geus, 1989), however, and the physiologic measures used varied quite widely; therefore, it is difficult to compare findings across studies. Additionally, no causal conclusion is warranted based on these cross-sectional studies.

Other cross-sectional research has only partially supported these results. For example, some investigators have reported that while aerobic fitness was not related to decreased cardiovascular reactivity during stress, highly fit subjects showed more rapid physiological recovery from stress than did low-fit subjects (Cox, Evans, & Jamieson, 1979; Holmes & Cappo, 1987; Sinyor, Schwartz, Peronnet, Brisson, & Seraganian, 1983). Further, Plante and Karpo­witz (1987) reported that while subjects who reported more exercise showed less cardiovascular reactivity (i.e., lower heart rate and pulse volume) than low-exercise subjects, there were no differences during stress or recovery when baseline differences were controlled. One study actually reported that aerobic fitness was associated with greater blood pressure reactivity during a compet­itive game; however, these subjects were Type A college athletes compared to regular college students, and their high level of competitiveness, rather than fitness level, may have affected the results (Lake et al., 1985).

210 CHAPTER ELEVEN

LONGITUDINAL STUDIES OF PHYSICAL FITNESS AND CARDIOVASCULAR REACTIVITY

Although much of the early research in this area was correlational, recent studies have employed longitudinal designs with random assignment of ex­ercise training programs to manipulate levels of aerobic fitness. Table 1 sum­marizes the IIlBjor methodological aspects and the results of these studies. Three well-controlled studies have demonstrated that aerobic exercise affects stress responses. In an initial study, Blumenthal and colleagues (1988) com­pared 12 weeks of aerobic training to nonaerobic strength training in a sample of 36 healthy Type A men. Subjects' cardiovascular reactivity to a mental arithmetic test was assessed before and after the exercise training period. Results indicated that the aerobic group showed more rapid recovery of heart rate, systolic and diastolic blood pressure, and myocardial oxygen consumption following the mental arithmetic task, and there also was an attenuation of heart rate, systolic blood pressure, and myocardial oxygen consumption reactivity to the task. Using a similar experimental design in which cardiovascular and neuroendocrine responses were assessed in a new sample of 37 healthy Type A men, they reported that compared to strength-trained subjects, aerobically trained Type A men showed reduced heart rate, diastolic blood pressure, and myocardial oxygen consumption. Epinephrine levels during recovery also tended to be lower for the aerobic group (Blumenthal et al., 1990a). There was no clear-cut reduction in reactivity to the mental arithmetic task as a function of exercise condition, however, and Blumenthal et al. concluded that aerobic exercise training did not reduce cardiovascular and neuroendocrine reactivity but that aerobic training reduced absolute levels of blood pressure and heart rate. In a third study based upon a subgroup of subjects from the initial cohort, Sherwood et al. (1989) showed that diastolic blood pressure responses during a competitive reaction time task were attenuated in a subgroup of Type A borderline hypertensive subjects who were aerobically conditioned.

Other studies have reported more equivocal results. For example, Holmes and McGilley (1987) found that compared to a no-treatment control group, aerobic training decreased heart rate reactivity during a memory task for subjects who initially had low aerobic fitness but not for subjects who were highly fit, even though fitness increased significantly in both groups. Subjects were not randomly assigned to treatment groups, however, Holmes and Roth (1987) found lower absolute heart rates during a memory task in subjects who were aerobically trained versus strength-trained; however, the groups did not differ when reactivity (i.e., changes in heart rate from baseline to stress) was compared.

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212 CHAPrER ELEVEN

aerobic training among a group of healthy Type A men. The results of their 10-week program indicated that despite behavioral changes, there were no differential effects on cardiovascular reactivity to a series of mental stressors (Roskies et 01., 1986). Blumenthal et 01. (1990b) compared the effects of aerobic exercise training with nonaerobic strength training in a group of 46 healthy pre-menopausal and postmenopausal women. Although results were complex, in general the data indicated that the reductions in cardiovascular or neu­roendocrine responses to a public speaking task and to a cold pressor challenge procedure were not consistently greater for the participants in the aerobic exercise group than for the strength-training group. Another recent study combined cross-sectional and longitudinal methodology and found that lower cardiovascular stress responses were related to higher initial fitness levels, but a seven-week aerobic exercise program did not reduce psychophysiologic re­sponses to stress (de Geus et 01., 1990).

Taken together, there is some, but not universal, support for the efficacy of aerobic exercise in reducing cardiovascular reactivity. Cross-sectional stud­ies generally support the notion that subjects who are more highly aerobically fit show smaller cardiovascular responses to acute stressors than do less fit subjects. Findings from the longitudinal research are inconsistent.

EFFECTS OF ACUTE AEROBIC EXERCISE ON CARDIOVASCULAR REACTIVITY

It has been suggested that many of the psychosocial benefits of chronic exercise may be attributable to the cumulative benefits of individual bouts of exercise (Haskell, 1987). Research in both humans (Raglin and Morgan, 1987) and nonhumans (Overton, Joyner, & Tipton, 1988) suggests that acute exercise reduces resting blood pressure. In this regard, a few studies have examined the effects of single sessions of aerobic exercise on subsequent cardiovascular reactivity to stress. Several studies found that psychophysiological responses to mental tasks were not altered by single bouts of exercise (McGowan, Rob­ertson, & Epstein, 1985; Russell, Epstein, & Erickson, 1983). These studies, however, were plagued by methodological problems. For example, Russell et al (1983) allowed only a five-minute postexercise recovery period before assessing reactivity, and subjects' residual exercise-induced arousal likely obscured any potential reactivity changes. Also, McGowan and colleagues (1985) presented the same stressor to subjects multiple times, providing an opportunity for habituation, and the stressor apparently was innocuous as subjects showed very little heart rate reactivity (i.e., <5 bpm) regardless of treatment condition. In a recent well-designed study, Roth (1989) found no effect of 20 minutes of cycle ergometry on heart rate or blood pressure reactivity to a memory task. Conversely, Fillingim, Roth, and Cook (1992) reported smaller peripheral pulse volume responses to aversive emotional imagery following cycle ergometry

AEROBIC EXERCISE 213

relative to quiet rest. Additionally, Peronnet and coworkers (1989) found de­creased adrenergic responses to physical and mental tasks following two hours of cycle ergometry. The discrepancies in these studies of physiologic reactivity could result from differences in the timing of postexercise tasks since the last two experiments assessed cardiovascular reactivity while subjects remained cardiovascularly aroused from exercise; on the other hand, Roth allowed a substantial recovery period. In addition, different cardiovascular indices were used in these studies. Roth measured heart rate and blood pressure while Fillingim et al. and Peronnet et al., found differences in peripheral pulse volume and epinephrine, respectively. In fact, Peronnet also assessed heart rate and blood pressure responses to the stressor, but no exercise-induced changes emerged. Thus, certain physiological variables may be more sensitive as indices of stress reactivity than others.

CONCLUDING COMMENTS AND FUTURE DIRECTIONS

Despite mixed results at present, there is a growing trend that suggests that physical exercise may reduce psychophysiologic stress responses. Cross­sectional studies have shown that fit individuals generally show a lower car­diovascular response to psychological stress compared to their unfit counter­parts (Crews & Landers, 1987; de Geus et al., 1990; Holmes & Roth, 1985; Hull et al., 1984; Light et al., 1987; Perkins et al., 1986; Shulhan et al., 1986; van Doornen & de Geus, 1989); however, results have not been entirely consistent (Cox et al., 1979; Holmes & Cappo, 1987; Plante & Karpowitz, 1987; Sinyor et al., 1983). Longitudinal investigations in which exercise training has increased fitness levels have also shown that exercise may attenuate stress responses (Blumenthal et al., 1988, 1990a; Sherwood et al., 1989). Once again, though, results have not always been consistent (Blumenthal et al., 1990b; de Geus et al., 1990; Holmes & Roth, 1987; Roskies et al., 1986; Sinyor et al., 1986; Soth­man et al., 1987). Differences in subject characteristics, experimental design, and exercise training regimens appear to be responsible for some of the vari­able results.

Future research in the area will address several important issues. It will be important to investigate individual difference factors that may be critical for understanding the relationship of fitness and stress reactivity. For example, such factors as Type A behavior, initial fitness level, health status (e.g., hyper­tension), age, and gender may all be relevant.

Second, it will be important to identify mechanisms by which exercise may attenuate stress responses. Modification of stress responses has been attrib­uted to several processes, including reduced sympathetic activity, increased vagal tone, and reduced adrenoreceptor sensitivity (Friedman, Ordway, & Williams, 1987), among others. Systematic investigations in this area are clearly needed.

214 CHAPI'ER ELEVEN

Finally, the clinical significance of reduced stress reactivity needs to be addressed. It is widely believed that exaggerated psychophysiologic stress responses are associated with increased risk for coronary heart disease (Krantz & Manuck, 1984). There is evidence that reducing responses by surgery (Beere, Glagov, & Zarsins, 1984) or by pharmacologic action (e.g., beta blockade) may slow the progression of atherosclerosis in animals. Moreover, human data suggest that aerobic exercise training may reduce the risk for reinfarction among cardiac patients (Oldridge, Guyatt, Fischer, & Rimm, 1988). The mecha­nism for the beneficial effects of exercise may be the reduction of traditional risk factors, such as elevated blood pressure and lipids, but also may involve reduced stress responses. Thus, future research needs to assess the long-term consequences of reduced stress reactivity on health outcomes.

ACKNOWLEDGMENTS

This chapter was supported in part by grants from the National Heart, Lung and Blood Institute (IROIHL30675 and lROIHL43028).

The authors also wish to thank Janet Ivey for her secretarial assistance.

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Roth, D. I., & Holmes, D. S. (1985). Inftuence of physical fitness in determining the impact of stressful life events on physical and psychologic health. Psychosomatic Medicine, 47, 164-173.

Roth, D. L., & Holmes, D. S. (1987). Influence of aerobic exercise training and relaxation training on physical and psychologic health following stressful life events. Psychosomatic Medicine, 49, 355-365.

Roth, D. L., Bachtler, S. D., & Fillingim,R. B. (in press). Acute emotional and cardiovascular effects of stressful mental work during aerobic exercise. Psychaphysiology.

Russell, P.O., Epstein, L. H., & Erickson, K. T. (1983). Effects of acute exercise and cigarette

AEROBIC EXERCISE 217

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PART THREE

CARDIOVASCULAR STRESS RESPONSES AND

CARDIOVASCULAR DISEASE

CHAPTER TWELVE

Endogenous Opioids and Stress Reactivity in the Development of

Essential Hypertension

JAMES A MCCUBBIN, ROBYN CHEUNG,

THOMAS B. MONTGOMERY, RONALD BULBULIAN, AND JOHN F. WILSON

INTRODUCTION

The mechanistic bases of individual differences in cardiovascular stress re­activity are not fully understood. Variations in blood pressure and heart rate reactivity are believed to cOITespond to autonomic nervous system activity, but the precise neuroendocrine origins of these response differences have not been characterized. Equally deficient is an appreciation of the clinical significance of these individual differences in reactivity. This chapter will highlight a series of experiments designed to investigate the neuroendocrine origin and possible clinical significance of individual differences in cardiovascular reactivity during behavioral stress.

JAMES A. MCCUBBIN, ROBYN CHEUNG, AND JOHN F. WILSON • Department of Behavioral Science, University of. Kentucky College of Medicine, Lexington, Kentucky 40536-0086. THOMAS B. MONTGOMERY • Department of Medicine, University of Kentucky College of Med­icine, Lexington, Kentucky 40536-0086. RONALD BULBULIAN • Department of Health, Physical Education, and Recreation, University of Kentucky College of Education, Lexington, Kentucky 40536-0219.

221

222 CHAPI'ER TWELVE

STRESS REACTIVITY AND THE DEVELOPMENTAL ETIOLOGY OF ESSENTIAL HYPERTENSION

The relationship of stress reactivity to the etiology of essential hyper­tension is complex and poorly understood by researchers and clinicians alike. A major obstacle to understanding the etiology of essential hypertension is the limited conceptual grasp of the disease. Essential hypertension, by definition, is prolonged high blood pressure of unknown origin. This means that this diagnostic category is defined by exclusion of known causes, such as renova­scular disease and catecholamine-secreting pheochromocytoma. The result is that the set of all patients diagnosed with essential hypertension is probably comprised of several subcategories. Although essential hypertension may en­compass several distinct disorders, much of the apparent heterogeneity may relate, in part, to the possible developmental nature of essential hypertension. In other words, the primary physiological deficit in the early stages of hyper­tension may become obscured over time by various compensatory physiological adjustments (Folkow, 1982; Guyton, Coleman, Bower, & Granger, 1970; Lang­er, Obrist, & McCubbin, 1979; Lund-Johansen, 1980). This means that the initiating event in the hypertensive process may be quite different from the maintaining mechanism in later stages of the disease. This may partly explain the variable effectiveness of antihypertensive medications both within and between individuals. Additionally, this notion implies that pathophysiological changes in the early stages of the disease directly contribute to the more intractable conditions that are characteristic of hypertension of long-standing duration. Therefore, it becomes increasingly important to focus on the early stages of the disease, at a time before the primary hypertensive stimulus is obscured by compensatory adjustments.

This developmental view of hypertension is important for two major rea­sons. First, this view provides a conceptual framework to guide investigation of the etiologic mechanisms. This framework tells us how to categorize patient populations by age, duration of disease, and physiological profile to maximize the conceptual precision required to interpret existing literature. Second, this view emphasizes that individual differences in blood pressure reactivity, once viewed as benign, may have a direct etiologic link to the more traditional pathophysiological changes associated with well-established hypertension. Thus, it becomes easier to justify early treatment of patients with borderline or mild hypertension in order to short-circuit the developmental process. It is during the early stages of the disease that reactivity to behavioral stress may be important, and it is during this stage that behavioral therapeutics may be efficacious in reversing the cascade of pathophysiology that ultimately results in the treatment-resistant fixed essential hypertension.

Despite the circumstantial evidence linking stress reactivity to cardiovas­cular pathophysiology, the causal pathway has not been adequately demon­strated (Manuck, Kasprowicz, & Muldoon, 1990; Pickering & Gerin, 1990). The

ENDOGENOUS OPIOIDS 223

most problematic obstacle to empirical demonstration of this reactivity/disease link is the necessity to repeatedly monitor cardiovascular integrity of particular individuals over an extended period of time. Unfortunately, the period of time necessary to produce adequate longitudinal data usually surpasses the life span of most conventional research investigations. Therefore, most researchers ac­tive in the field rely on the suggestive nature of cross-sectional methodologies. Given these limitations, there are numerous reports of response differences between groups of young adults with different levels of risk for development of cardiovascular disease. For example, exaggerated cardiovascular responses during stress have been observed in patients with borderline hypertension (Nestel, 1969), offspring of hypertensive patients (Falkner, Onesti, Angelakos, Fernandes, & Langman, 1979; Hastrup, Light, & Obrist, 1982), persons ex­hibiting the Type A coronary-prone behavior pattern (Glass, Krakoff, Contra­da, Hilton, Kehoe, Mannucci, Collins, Snow, & Elting, 1980), and young adults with mildly elevated blood pressure (McCubbin, Surwit, & Williams, 1985). How these risk-group differences in reactivity develop and how they evolve are not adequately understood.

There are a number of hemodynamic and neuroendocrine similarities be­tween young persons with exaggerated blood pressure reactions during and young hypertensive patients. Both groups demonstrate exaggerated reactivity during behavioral stress (Falkner et a1., 1979; Nestel, 1969), both groups dem­onstrate sensitivity of blood pressure responses to adrenergic receptor block­ing agents (Julius, 1976; Obrist, 1976), and both groups show neuroendocrine signs of excessive sympathetic nervous system tone (McCubbin et aL, 1985; Nestel, 1969). Individual and/or risk-group differences in cardiovascular re­activity are believed to correspond to variations in autonomic nervous system activity. The neurogenic basis of some hypertensive disease is supported by a number of studies. Several investigators have noted that pretreatment with adrenergic blocking drugs will diminish or eliminate many of these in­dividual differences (Langer, McCubbin, Stoney, Hutcheson, Charlton, & Obrist, 1985; Obrist, 1976). Moreover, the individual differences in cardiovas­cular response to stress are often accompanied by similar differences in cir­culating levels and excretion of the sympathoadrenomedullary catecholamines, epinephrine and norepinephrine (McCubbin, Richardson, Langer, Kizer, & Obrist, 1983).

Although the abnormalities of catecholaminergic function and the efficacy of sympatholytic pharmacotherapy are intriguing, it may be premature to conclude that the early stages of essential hypertension are characterized by a primary dysfunction of the sympathetic nervous system. In fact, Julius (1976) has suggested that both sympathetic and parasympathetic branches of the autonomic nervous system are deranged in young patients with hypertension. Administration of the nonselective beta-adrenergic blocking agent propranolol to young hypertensive patients and normotensive controls decreased but did not eliminate heart rate differences between the groups. Only after treatment

224 CHAPl'ER TWELVE

with both propranolol and the parasympathetic antagonist atropine were the group differences eliminated. These data suggest that the alterations of auto­nomic tone in young hypertensive patients may result from an abnormality in central nervous system (CNS) integration of autonomic outflow. Likely candi­dates for this regulatory mechanism are the endogenous opioid peptides, in­cluding the endorphins and the enkephalins. These peptides function as stress hormones and inhibitory neurotransmitters; they are released during intense stimulation and moderate responses during stress via several distinct mecha­nisms.

STRESS REACTIVITY AND THE ENDOGENOUS OPIOID NEUROPEPTIDES

The opioid neuroendocrine system is not a single pathway but is a complex set of neurons, neurosecretory cells, and multiple receptor subtypes. Opioids are released during heat stress, cold stress, and painful stimulation and are important in various aversively motivated behaviors. Opioid receptor binding inhibits behavioral, neuroendocrine, and circulatory reactivity. The anatomical intimacy of opioid and autonomic control nuclei is compelling (Lang, Gaida, Ganten, Hermann, Kraft, & Unger, 1983). For example, opioid peptides and/or receptors have been found in adrenal medullae and peripheral sympathetic ganglia (Konishi, Tsuno, & Otsuka, 1979; Vardnell, Tapia, De Mey, Rush, Bloom & Polak, 1982), nucleus tractus solitarius (Hassen & Feuerstein, 1987), and hypothalamic para ventricular nuclei (Kiritsy-Roy, Appel, Bobbitt, & Van Loon, 1986).

The functional interaction between opioid and circulatory control mecha­nisms is equally compelling. Faden, Holaday, and associates (Faden & Holaday, 1979; Faden, Jacobs, & Holaday, 1980; Holaday, 1983; Holaday, D'Amato, Ruvio, & Faden, 1983) have provided an elegant series of studies that demon­strates quite convincingly the important hypotensive action of opioids during systemic shock, including hemorrhagic, spinal, and endotoxic syndromes. The opioids are also important in baroreflex control of blood pressure (Mastrianni, Palkovits, & Kunos, 1989). For example, baroreflexes are altered by systemic and central administration of enkephalin and by the opioid antagonist naloxone in spontaneously hypertensive rats (Schaz, Stock, Simon, Schlor, Unger, Rock­hold, & Ganten, 1980). Moreover, the antihypertensive effect of clonidine ap­pears to operate via opioid mechanisms (Farsang, Ramirez-Gonzales, & Kunos, 1980; Farsang, Kaposci, Varga, Malisak, Fekete, & Kunos, 1984). Finally, previous studies have suggested that alterations in opioid function may coincide with the multiple neurocirculatory irregularities in the development of essential hypertension (Kraft, Theobald, Kolloch, & Stumpe, 1987; McCubbin et al, 1985; McCubbin, Surwit, & Williams, 1988; McCubbin, Surwit, Williams, Nemeroff, & McNeilly, 1989).

ENDOGENOUS OPIOIDS 225

These various findings suggest that opioid neuropeptides are capable of inhibiting stress reactions, including responses of the sympathetic nervous system. If a deficiency occurs in these postulated sympathoinhibitory opioid circuits, then the sympathetic nervous system may exhibit a disinhibition char­acterized by exaggerated fluctuations in catecholaminergic neurotransmission, resulting in circulatory dysregulation. Therefore, individual differences in cir­culatory and sympathoadrenomedullary reactivity may reflect variations in inhibitory opioid function. If this reasoning is correct, then certain functional disorders of the sympathetic nervous system may result directly from a defect in opioid activity.

EXPERIMENTAL STUDIES OF INDIVIDUAL DIFFERENCES IN INHIBITORY OPIOID TONE

BLOOD PRESSURE RESPONSES DURING A PSYCHOLOGICAL STRESSOR

If opioid activity during stress has blood pressure lowering effects, then pretreatment with the opioid antagonist naloxone should increase blood pres­sure responses during stress. Furthermore, there should be a semiquantitative relationship between the pressor effect of opioid antagonism and the degree of opioid inhibition of blood pressure. Thus, if there are individual differences in the efficacy of opioidergic blood pressure inhibition, the pressor effects of naloxone should show corresponding differences. If the individual differences in blood pressure reactivity are relevant to the development of essential hyper­tension, and if they are mediated by variation in the efficacy of opioidergic sympathoinhibition, then opioid antagonists should have a differential pressor effect during stress in groups with different levels of risk for development of hypertension.

These hypotheses have been the impetus for a series of investigations designed to determine the role of endogenous opioids in the development of hypertension (McCubbin et 01, 1985, 1988, 1989). The basic experimental procedure requires identification of young adults who are presently normoten­sive but who are at enhanced risk for hypertension development. In order to investigate the etiological process, it is methodologically important to study groups of young adults prior to the development of clinical hypertension. This is because prolonged elevation in arterial pressure could itself produce compen­satory alterations in opioidergic function. Therefore, variations in opioid func­tion in patients with well-established hypertension could as easily be inter­preted as resulting from the high blood pressure. In order to establish observed changes in blood pressure control mechanisms as a possible etiologic mecha­nism, it is necessary to study prehypertensive populations.

Measurement or, more realistically, estimation of opioid inhibitory tone in humans is a difficult methodological problem, especially in the initial stages of

226 CHAPrER TWELVE

this research. Several approaches could be taken. For example, one could measure the response to an exogenously administered opioid agonist. This is a severely limited approach for preliminary studies because there is no guarantee that the appropriate ligand system and/or site of action would be invoked by systemic administration. One could measure circulating levels of endogenous opioids, and this approach could be useful if the opioid alterations are wide­spread or involve systemically released opioids, such as pituitary beta-en­dorphin; however, this approach is limited by the fact that levels in the blood may not necessarily be sensitive to altered opioid neurotransmission in discrete nuclei. Measurement of the effect of naloxone was viewed as an acceptable approach in the initial studies because this is a relatively wide-spectrum opioid antagonist that is reasonably nonselective for opioid receptor subtypes at high­er doses. The logic is that if anyone of several opioid systems were responsible for the expression of individual differences, then pretreatment with opioid antagonists should affect the responsible circuits and thereby reduce or elim­inate blood pressure reactivity differences.

Subject Recruitment

The level of pressure in young, college-age adults predicts both the level of pressure and the incidence of hypertension later in life (Paffenbarger, Thorne, & Wing, 1968; Rabkin, Mathewson, & Tate, 1982). Therefore, young adults with mildly elevated pressure are at enhanced risk for hypertension development. Prior to recruitment into laboratory studies, blood pressure screenings of potential subjects were performed on campus. A recruitment table was set up in the Student Activity Center, and interested students were given informed consent and were asked to complete a personal and family medical history questionnaire. Recruits were then sent to a quiet, semidark­ened room, where they rested for five minutes prior to blood pressure measure­ment, then four successive blood pressure (BP) determinations were made at one-minute intervals using an automated oscillometric technique (Dinamap Adult/Pediatric Vital Signs Monitor TM, Critikon, Tampa, Florida). This auto­mated technique eliminates error due to observer bias and minimizes contact between screener and subject. Results were analyzed after screening 100 par­ticipants. The most consistent finding was that despite the five-minute rest period and the automated nature of the measurement process, there was a drop in pressures across successive determinations. This presumably reflects both the psychosocial stress of the measurement process and habituation to the effects of cuff inflation on resting pressures. The reduction in pressures from the first to the second reading and from the second to the third reading was highly significant p< .(05), but the reduction from the third to the fourth reading was not statistically reliable. This suggests that pressures had stabil­ized by the third successive reading. Thus, the third and fourth readings were averaged to derive an index of stable mean arterial pressures. Subjects in the

ENDOGENOUS OPIOIDS 227

screening were then rank ordered by their stable pressures, and subjects in the upper, middle, and lower quintiles of the distribution were selected for recruit­ment into laboratory studies. Subjects in the upper quintile (High BP) were operationally defined as at enhanced risk for hypertension development while persons in the middle (Mid BP) and lower (Low BP) quintiles were defined as at low risk for hypertension development.

Procedures

Recruited volunteers were then brought into the laboratory for placebo­controlled stress tests using naloxone. Two laboratory studies were scheduled about a week apart. During each study, subjects were asked to perform a series of difficult arithmetic problems. On one visit, subjects were pretreated with an 8-mg naloxone intravenous infusion (N arcan@, DuPont) while on the other visit subjects were given a placebo saline infusion. The order of administration of drug and placebo was counterbalanced within each risk group in order to minimize problems resulting from repeated stress testing. On each visit, sub­jects were instrumented with a cannula in a superficial arm vein for drug infusion and blood sampling. After insertion of the cannula, subjects were given 45 minutes to allow for recovery from the venipuncture procedure, then sub­jects were given sequential 10-minute periods for the following: preinfusion rest, infusion of drug or placebo, postinfusion rest, the arithmetic task, and a poststress recovery period while blood pressures were automatically deter­mined at one-minute intervals. The arithmetic task in the first two studies required serial additions of three digit numbers. In subsequent studies, a variation of Turner's graded arithmetic task (Turner, Hewitt, Morgan, Sims, Carroll, & Kelly, 1986) was used. This task uses a computer to vary the difficulty of the arithmetic problems based on operator performance and elicits similar mean changes in cardiovascular parameters. This type of task minim­izes response rate differences between subjects with different mathematical abilities.

Blood Pressure

The results from the first laboratory experiment are shown in Figure 1. As expected, there were differences in the magnitude of mean arterial blood pressure in the three groups during the saline control experiment, with the largest blood pressure responses observed in the High BP group. Pretreatment with naloxone produced a significant increase in blood pressure reactivity in the Low BP group only. This suggests that naloxone-sensitive opioids have a blood pressure lowering effect during stress in certain low-risk subjects. There were no observable effects of naloxone on resting pressures, suggesting that opioid­ergic inhibition of blood pressure was primarily confined to stressful periods in the present experiment. The BP Group x Drug interaction on change in mean

228 CHAPl'ER TWELVE

Change in MAP (mmHg) 14r-~----------~-----------------'

12

10

8

6

4

2L-----~----~------~-----L----~

SALINE NALOXONE

--e-- Low BP ~ Mid BP -a- High BP

FIGURE 1. Effects of opioid antagonism with naloxone on mean arterial blood pressure response to behavioral stress in young adults with different levels of casual arterial pressure. Data are expressed as response magnitude on drug and placebo days. Naloxone pretreatment significantly increased mean arterial pressure reactivity in the low blood pressure quintile (Low BP) only (p<.05). ANOVA = analysis of variance, F(257) = 9.06. (From McCubbin et al., 1985. Reprinted by pennission from the American Heart Association.)

arterial pressure was significant (F[2, 7] = 9.06, p<.05). The absence of a pressor effect of naloxone during stress in the High BP group suggests that these individuals have a minimal opioidergic blood pressure lowering mecha­nism. Since pretreatment with naloxone decreased BP group differences in blood pressure response to stress, it is reasonable to conclude that the group differences under saline conditions are mediated, at least in part, via naloxone­sensitive opioid receptors. Absence of a pressor response to naloxone and stress in the High BP group suggests that these individuals may exhibit a preexisting functional deficit in opioidergic inhibition of blood pressure reactivity. This could result from a defect in opioid biosynthesis, a deficiency in number or sensitivity of opioid receptors, or an overproduction of an endogenous opioid antagonist.

The results in the Mid BP group are somewhat intriguing. In the present experiment, these subjects responded with a moderate response to stress during saline experiments, with the response magnitude falling between High and Low BP groups. If only the High BP group is at enhanced risk for hyper-

ENDOGENOUS OPIOIDS 229

tension, then the efficacy of opioidergic inhibition of blood pressure does not coincide precisely with enhanced risk. Several explanations are possible. First, opioid inhibition of blood pressure reactivity may not be an exclusive marker of enhanced risk. This means that development of an efficacious opioid depressor mechanism may only be characteristic of certain very low risk individuals. For example, maybe opioid inhibition of blood pressure develops as a protective mechanism in a well-defined set of low-risk individuals, such as well-trained athletes. This is plausible considering the opioid-releasing effects of exercise. Alternatively, it may require a combination of risk factors to summate into significant cardiovascular risk. For instance, it may require not only a poorly developed opioid response to stress but also another risk factor as well, such as a genetic predisposition. This may be further clarified by measurement of opioid tone in groups with a different family history of hypertension. Although additional studies are necessary to identify the precise mechanism, these findings suggest a protective effect of opioidergic modulation of cardiovascular responses during psychological stress in persons with the lowest risk for hyper­tension development.

This first experiment established several important conclusions. First, classification of subjects by level of casual pressure allows identification of groups of young adults who differ not only in presumed risk for hypertension development but also who differ in the magnitude of their blood pressure response during behavioral stress. This further supports the notion that varia­tion in blood pressure reactivity may coincide with clinical risk. This could indicate that stress reactivity is a part of the etiopathophysiology of essential hypertension. Alternatively, exaggerated stress reactivity could be an epiphen­omenon, correlating with but not directly involved in the etiologic process. Although the latter situation would view stress reactivity as an important marker of some other process, it would minimize the direct role of stress reactions in production of clinical hypertension (see Chapter 10). The second conclusion is that the pressor effects of naloxone are observable in some low­risk groups, and these pressor effects are absent or diminished in some high­risk groups. This indicates a blood pressure control mechanism that varies in efficacy across groups with differing levels of stress reactivity. The precise neuroendocrine integration of these individual differences in opioidergic control of blood pressure, however, remains to be elucidated.

BLOOD PRESSURE RESPONSES DURING AN ORTHOSTATIC STRESSOR

The first experiment suggested that an opioid-mediated depressor mecha­nism has variable efficacy in groups with differing levels of casual arterial pressure and, presumably, different degrees of risk for later development of essential hypertension. These data did not, however, elucidate the precise level of integration of opioid/autonomic interaction. The opioid depressor mechanism in the Low BP group could affect blood pressure control at the baroreflex level

230 CHAPl'ER TWELVE

or at higher levels of central autonomic outflow. A second experiment was therefore designed to examine the role of baroreflex function·in the differential pressor effect of naloxone (McCubbin et al., 1988). If the opioid anomaly is in series with baroreflex circuits, then the effects of naloxone on an orthostatic baroreflex challenge should mimic its pressor effects on the cognitive challenge. If, however, the peptide anomaly resides in the adrenal medullae or at levels of central autonomic control that are parallel with or rostral to baroreflex circuits, then there should be no abnormal pressor effect of naloxone during an ortho­static challenge in persons at risk for hypertension. This second experiment was similar to the first with the addition of a simple orthostatic baroflex chal­lenge, that is, postural change from sitting to standing upright. Although baroreflexes typically have been studied by examination of heart rate changes following infusion of a pressor agent, the gravitational stress of orthostasis was seen as a sympathoexcitatory challenge and thus more appropriate for the study of opioidergic sympathoinhibition.

Comparison of responses during arithmetic versus orthostatic stress was facilitated by calculation of an index of drug effect on response magnitude, that is, the difference in response magnitude between the saline test and the nalo­xone test for each task. These response differences were then averaged by risk group and task. Results indicated that there was a significant Task x Group interaction (F[2, 62] = 3.44, p<.05) for systolic blood pressure reactivity. Dur­ing minutes 1 to 3 and minutes 6 to 8 of the arithmetic stressor (MATH 1 and MATH2, respectively), there were positive pressor drug effects in the Low BP group and either no change or depressor drug effects in the High BP group. This pattern was reversed during the standing orthostatic challenge (Figure 2). These data suggest that abnormal systolic responses to the arithmetic stressor in the High BP group cannot be explained by altered opioidergic control of baroreflexes. This is not surprising because there were no observable risk­group differences in blood pressure response during the orthostatic stressor. Reported abnormalities in baroreflex responsiveness in hypertensive patients may result from a compensation to the prolonged high pressures rather than a part of the etiologic sequel1ce. These results are consistent with the notion that the alteration in opioidergic control of blood pressure response to stress is not reflecting a simple disruption of opioidergic control of baroreflex responsi­veness. These data suggest that the differential opioid influence on stress reactivity operates at sites that are possibly rostral to or parallel with baroreflex circuitry.

QpIOIDERGIC INHIBITION OF SYMPATHOADRENOMEDULLARY AND

HYPOTHALAMo-PITUITARy-AnRENOCORTICAL AXEs

The next experiment was designed to determine the effects of opioid antagonism with naloxone on sympathoadrenomedullary and hypothalamo­pituitary-adrenocortical (HPA) function (McCubbin et al., 1989). With proce-

ENDOGENOUS OPIOIDS 231

SBP Response Difference (mmHg)

4

2

o +---~

-2

-4

-6 ~-,---.---,----.---.--~

MATHl MATH2 STAND

_ Low BP ~ High BP

FIGURE 2. Systolic blood pressure (SBP) response differences (response magnitude during placebo test subtracted from response magnitude during naloxone test) for the average of minutes 1 to 3 (MATH1) and 6 to 8 (MATH2) of mental arithmetic stress and minutes 1 to 3 of orthostatic stress (STAND) in young adults with high (High BP) and low (Low BP) casual arterial pressure, F(2, 26) = 3.44. (From McCubbin et al., 1988. Reprinted with permission from the American Heart Association.)

dures similar to the first experiment, this study examined the effects of nalo­xone on neuroendocrine responses to the arithmetic stressor in young adults with high and low casual arterial blood pressures. Blood was sampled through­out the experiment for later determination of plasma concentration of adreno­corticotropic hormone (ACTH), cortisol, and beta-endorphin, as well as the sympathoadrenomedullary catecholamines epinephrine and norepinephrine.

An intravenous cannula was inserted into a superficial arm vein. Subjects were allowed 45 minutes to recover from the venipuncture procedure. Blood samples were obtained through the indwelling cannula at the end of each rest period and twice during the arithmetic stressor. Whole blood was drawn into sample tubes containing Ethylenediaminetetraacetic acid for ACTH and beta­endorphin assay and separate tubes containing reduced glutathione for cate­cholamine assay. All samples were immediately centrifuged and the plasma supernate frozen at -90°C until assay. ACTH was determined by the method of Gutkowska, Julesz, St. Louis, and Genest (1982); cortisol was assayed by the method of Murphy (1967); and beta-endorphin was measured by the method of Wardlaw and Franz (1979). Catecholamines were determined by high perform-

232 CHAPTER TWELVE

ance liquid chromatography methods of Kilts, Gooch, and Knopes (1984) using electrochemical detection.

SympaJ,hoadrenomedullary Catecholamines

The effect of naloxone on plasma epinephrine responses during the arith­metic stressor in High and Low BP groups is shown in Figure 3. Preinfusion resting epinephrine levels were comparable in High and Low BP groups, but after saline infusion, the High BP group had significantly higher levels than those obtained from Low BP subjects (F(I,15) = 7.835, p<.025). Naloxone infusion significantly increased plasma epinephrine concentrations during stress in the Low BP group only. The effect of naloxone on plasma epinephrine levels was significantly correlated with the effect of naloxone on mean arterial pressure in the Low BP group only. There were no consistent effects of nalo­xone on plasma norepinephrine responses.

The results of this experiment suggest that the pressor effect of naloxone may relate to opioid inhibition, either direct or indirect, of sympathoadrenom­edullary responses to stress. Individuals with low casual arterial pressures have moderate sympathoadrenomedullary and circulatory responses during psychological stress. Naloxone-sensitive opioid receptors apparently inhibit responses in these individuals because opioid blockade significantly potentiates both blood pressure and epinephrine reactivity. The High BP group was char­acterized by exaggerated epinephrine and blood pressure responses, and these responses were relatively unaffected by opioid antagonism. These findings suggest that the relative efficacy of opioidergic inhibition of the sympatho­adrenomedullary axis during psychological stress is diminished in the High BP group.

Anterior Pituitary Hormones

Figure 4 shows the effect of naloxone and stress on plasma ACTH levels. Naloxone had no apparent effect on basal plasma ACTH levels in the High BP group (t<I), but it marginally increased resting ACTH concentrations in the Low BP group (t[9] = 2.167, p = .058). Multivariate analysis of variance utilizing drug-effect scores revealed a significant Group x Period interaction for the ACTH-stimulating effect of naloxone (F[4, 15] = 3.24, p<.05). Pretreat­ment with naloxone significantly increased plasma ACTH concentrations dur­ing both stress periods as well as during recovery in the Low BP group. In contrast to Low BP group results, naloxone was a relatively poor stimulus for ACTH release in the High BP group. Plasma levels of cortisol were comparable with the findings for ACTH levels, suggesting that the effects of naloxone on ACTH concentration had observable effects at the adrenal cortex.

Beta-endorphin and ACTH are costored and released concomitantly from the anterior pituitary. Therefore, beta-endorphin levels in plasma provide an

PLASMA EPINEPHRINE (pg/ml) 100.---------------~--~--------__ ~

A *

80

* 60

40

20+----.----.----.-----.----r---~ REST INFUSION MATH1 MATH2 RECOVERY

--B- SALINE -&- NALOXONE

PLASMA EPINEPHRINE (pg/ml) 100~--------------~~--------------~

B

80

60

40

20+-----.-----r---~r_--_,----_.-----J

REST INFUSION MATH1 MATH2 RECOVERY

--B- SALINE -&- NALOXONE

FIGURE 3. Effects of opioid antagonism with 0.1 = mglkg naloxone on plasma epinephrine (pgIml) in young adults with low (SA) and high (3B) levels of casual arterial pressure. ·p<.05 compared with saline. (From McCubbin, 1991. Reprinted with pennission from Academic Press, Orlando, Florida.)

PLASMA ACTH (fmol/mJ) 6r---------------------------------, A

5

4 **

3

2

OL---~----~----~-----L-----L----~

REST INFUSION MATH1 MATH2 RECOVERY

-e- SALINE -e- NALOXONE

PLASMA ACTH (fmollmJ) 6r-----------------------------------. B

5

4

.3

2

OL---~~--~----~----~-----L----~

REST INFUSION MATH1 MATH2 RECOVERY

-e- SALINE -e- NALOXONE

FIGURE 4. Effects of opioid antagonism with naloxone on plasma ACTH-Iike immunoreactivity (fmol/ml) in young adults with low (4A) and high (4B) levels of casual arterial pressure .• p<.06, ··p<.01 compared with saline. (From McCubbin et 01., 1989. Reprinted with pennission from the American Heart Association.)

ENDOGENOUS OPIOIDS 235

additional index of anterior pituitary activity. The results with plasma beta­endorphin-like immunoreactivity are comparable to the ACTH data. Infusion of naloxone significantly increased plasma beta-endorphin-like immunoreactivity in the Low BP group only (p<.OO5), with no effect in the High BP group. The group difference in the endorphin-releasing effect of naloxone was maintained across postinfusion samples (F[1, 8] = 5.718, p<.05). There were no consistent effects of stress or blood pressure grouping on the ratio of ACTH to beta­endorphin in plasma, suggesting that opioid blockade did not alter the origin of beta-endorphin in blood. Whether or not beta-endorphin is involved in the circulatory effects of naloxone remains to be determined.

These results provide several clues regarding the integration of endog­enous opioid function and circulatory reactivity. First, the pressor effect of naloxone corresponds to a naloxone-induced potentiation of plasma epinephrine responses during stress in the Low BP group. This suggests that the apparent opioidergic inhibition of circulatory reactivity may be mediated, at least in part, via opioidergic inhibition of sympathoadrenomedullary epinephrine release. Furthermore, the correlation between drug effects on the HPA and the sym­pathoadrenomedullary axes suggests that the group differences in reactivity may relate to group differences in opioidergic inhibition of hypothalamic mechanisms controlling both effector pathways. In the High BP group, absence of a drug effect on either circulatory or neuroendocrine responses suggests a deficient opioidergic inhibitory mechanism. At present, it is difficult to deter­mine whether or not an efficacious opioidergic inhibitory mechanism is a char­acteristic of the general low-risk population or whether it is a protective mecha­nism found in only certain individuals. In a related question, is an efficacious opioidergic inhibitory mechanism genetically programmed, or can this system be stimulated by experiential factors? For example, will a vigorous aerobic exercise program stimulate opioidergic inhibition of stress reactivity? Acute exercise releases beta-endorphin, and it is feasible that repeated exercise­induced stimulation of this system could facilitate opioid reactivity to other stressors, including psychological stimuli. An additional experiment was de­signed to determine the effects of fitness on opioidergic inhibition of stress reactivity.

AEROBIC EXERCISE CONDITIONING AND OPIOIDERGIC INHIBITION OF STRESS

REACTMTY

Epidemiological studies have suggested that chronic vigorous physical exercise can reduce the risk for cardiovascular disease (Leon, Connett, Jacobs, & Rauramma, 1987; Paffenbarger, Hyde, Irving, & Steinmetz, 1984). The risk-reducing aspects of exercise conditioning are unclear, however. Exercise conditioning may reduce neuroendocrine (Oleshansky, Zoltick, Herman, Mougey, & Meyerhoff, 1990) and cardiovascular (Saltin, 1990) responses during physical exertion. It is possible that at least part of the salubrious effects of

236 CHAP1'ER TWELVE

exercise on cardiovascular health may be mediated via reduction of circulatory and neuroendocrine responses during psychological stress as well. Several psychophysiological studies have sought to detennine if chronic aerobic fitness conditioning will reduce cardiovascular reactions during psychological stress. Reviews (Blumenthal & McCubbin, 1987; see also Chapter 11) have found some evidence for effects of chronic exercise conditioning on cardiovascular reactivity during psychological stress. Since vigorous exercise releases the proopiomel­anocortin-derived peptides, beta-endorphin, beta-lipotropin, and ACTH (Ole­shansky et 01, 1990), it is possible that regular exercise-induced stimulation of opioids could facilitate opioidergic responses during psychological stress. Therefore, an experiment was designed to examine blood pressure reactivity during stress in persons with high versus low levels of aerobic fitness and to detennine the role of inhibitory opioids in fitness-associated decrements in psychological stress reactivity (McCubbin, Cheung, Montgomery, Bulbulian, & Wilson, 1992).

Subject Selection

Two hundred forty (240) young adult college students between the ages of 18 to 35 with no medical abnormalities were given a brief activity questionnaire to determine their current exercise habits. Activity questionnaires were scored on a four-point scale based on the frequency and duration of self-reported aerobic activities. Persons with the highest and lowest current activity patterns (n = 14 per group) were recruited for a maximal oxygen consumption (V02 max) treadmill test to verify their maximal aerobic capacity. Subjects were then scheduled for two in-laboratory psychological stress tests using the standard computer-controlled arithmetic task. Because of an interest in ambulatory pressures, the opioid blocking drug used in these placebo-controlled lab tests was naltrexone (Trexan TM, Dupont), the long-lasting, oral opioid antagonist. High- and low-fit subjects entered the laboratory and were given either a placebo tablet or 50 mg Trexan TM. Subjects then rested for one hour while resting blood pressures and heart rate were determined by a Dinamap Vital Signs MonitorTM. Participants then performed for 10 minutes on the graded arithmetic task, followed by a poststress recovery period. Pre-drug and post­drug resting and task-induced blood pressures and heart rate were determined for subjects in both fitness conditions. Appropriate control experiments were scheduled about a week later.

Evaluation of the V02 max test results indicated that ratings from the activity diaries and the treadmill performance were highly correlated (r[26] = 0.668, p<.01). For example, there was one V02 max outlier in each activity group. The person judged to have a low level of recent activity was a former long-distance runner who had not trained in the past six months. Apparently, this period of time was insufficient for deconditioning. The other outlier was judged to have a high level of recent activity, but the V02 max data suggested

ENDOGENOUS OPIOIDS 237

that he was physiologically similar to the low activity group. All subsequent analyses used the V02 max data as the final criterion, yielding two groups with no overlap in maximal oxygen consumption.

Heart Rate

Results during placebo control conditions suggested that high-fitness sub­jects had significantly lower resting heart rates than low-fitness subjects. Re­peated measures multivariate analysis of variance (MANOVA) indicated that highly fit subjects had lower heart rates across all experimental conditions (p<.05). Not only did the high-fitness group show decreased resting heart rates but their heart rate responses during the arithmetic task were also significantly less than responses in the low-fitness group. Figure 5 shows the effects of fitness and opiate blockade on heart rate responses. The effect of fitness level on heart rate response was significant during both five-minute blocks of arith­metic performance and during the last five minutes of a 10-minute recovery period (ps<.05). These data suggest that chronic exercise conditioning is asso­ciated with decreased heart rate reactivity during the arithmetic stressor. Fitness group response differences are not likely to have resulted from differ-

Heart Rate Response (bpm) 8~-----------------------------,

-2~----~------~------~------~

Math1

~ Athlete-Intact

....... Nonathlete-Intact

Math2 Rec1 Rec2

-+- Athlete-Blocked

--e- Nonathlete-Blocked

FIGURE 5. Effects of opioid antagonism with naltrexone on heart rate response to stress in young adults with low and high levels of aerobic fitness. ·p<.05 compared with nonathletes. (From McCubbin et aJ. 1992. Copyright 1992 the Society for Psychophysiological Research. Reprinted by permission of the publisher and from McCubbin et al.)

238 CHAPrER TWELVE

ences in baseline values. Although there were group differences in resting heart rate, there was no correlation between resting heart rate level and heart rate reactivity. Furthermore, the law of initial values would predict, contrary to the present findings, a larger response in the group with the lowest resting level.

There were no statistically reliable effects of opioid blockade on resting heart rates in either group. In contrast to the placebo condition, however, pretreatment with naltrexone eliminated heart rate response differences be­tween groups (Figure 5). This was a result of a naltrexone-induced increase in heart rate reactivity in the high-fitness group coupled with no significant effect in the low-fitness group. The stimulatory effect of naltrexone on heart rate responses in the athletes was significant during the arithmetic task and during the last block of the recovery period (ps<.05). These data suggest that aerobic exercise conditioning decreases heart rate reactivity during psychological stress via stimulation of an opioid inhibitory mechanism.

Blood Pressure

There were no clearly apparent inhibitory effects of fitness on blood pres­sure reactions during the arithmetic stressor. Interestingly, there were effects of fitness on mean arterial blood pressure immediately before and after psycho­logical stress. The high-fitness group showed lower mean arterial pressures in the rest period immediately preceding arithmetic performance and during both poststress recovery periods (ps<.05). These group differences were eliminated by pretreatment with naltrexone. In the high-fitness group, naltrexone in­creased blood pressure levels immediately before stress and during the re­covery period, suggesting an opioidergic inhibition of blood pressure in antici­pation of stress as well as during recovery from psychological stress in aerobically fit individuals.

These results suggest that chronic aerobic exercise conditioning can re­duce cardiovascular stress reactivity via stimulation of an opioidergic inhibitory response. Because of the between-subjects design, it is possible that these fitness group differences are not necessarily a result of conditioning per se. For example, preexisting differences between athletes and nonathletes could me­diate both cardiovascular and opioidergic group differences. Nevertheless, these results are consistent with the notion that fitness-induced decrements in cardiovascular stress reactivity may be mediated, at least in part, via condition­ing-induced facilitation of opioidergic neuroendocrine mechanisms.

DISCUSSION

The collective results of these experiments suggest that endogenous opioid peptidergic neuroendocrine systems are an important mechanism in the ex­pression of individual differences in cardiovascular responsivity. This variation

ENDOGENOUS OPIOIDS 239

in opioid inhibition of cardiovascular responsivity corresponds with risk status and may be important in the development of cardiovascular disease. Young adults with mildly elevated casual blood pressure are at risk for development of essential hypertension later in life. Despite their higher resting blood pres­sure levels, these individuals also show exaggerated responses during psycho­logical stress relative to low blood pressure controls. Pretreatment with opiate receptor blocking agents reduces the risk-group differences in blood pressure reactivity primarily by potentiation of the otherwise modest responses in the Low BP group. Since opioid blockade decreases risk-group response differ­ences, it can be concluded that opioid mechanisms may participate in the mediation of these group differences in reactivity.

Several findings suggest that this opioidergic inhibitory mechanism in­teracts with circulatory control at levels of the neuraxis that are either parallel with or rostral to the baroreflex circuitry. Although opioids are probably in­volved in baroreflex control, opioid effects on baroreflex control of systolic pressure cannot explain the risk-group response differences during psycholog­ical stress. Furthermore, the differential effect of naloxone on epinephrine responses during psychological stress suggests that the expression of risk­group differences in cardiovascular response may be associated with secretion of the sympathoadrenomedullary catecholamine, epinephrine. Changes in plas­ma norepinephrine were not reliably associated with risk group or drug effects. At present, it is difficult to determine if these results indicate that the opioid mechanism primarily affects the adrenomedullary branch of the sympathetic nervous system. It is possible that measurement of norepinephrine in plasma is insufficiently sensitive to subtle variations in catecholamine release from the peripheral sympathetic nerves. In humans, epinephrine is primarily a hormone released directly into the circulation for a distant site of action, whereas nore­pinephrine is primarily a neurotransmitter released locally into synaptic clefts. Additionally, since norepinephrine is subject to reuptake, the amount appear­ing in plasma is a small subfraction of total norepinephrine released into the synaptic clefts. In contrast, epinephrine is released from the adrenal medulla directly into systemic circulation, and the concentrations in blood more accur­ately reflect the quantitative levels available for receptor binding.

The differential effects of naloxone on plasma levels of the anterior pitu­itary hormones ACTH and beta-endorphin suggest that opioid inhibitory mechanisms apparently affect both the HPA as well as the sympathoadreno­medullary axes of the classic defense reaction pathway. This suggests that CNS opioids inhibit stress reactivity in a highly integrated fashion, and this integra­tion is altered in persons at risk for hypertension development. Although neither ACTH nor cortisol reactivity was exaggerated in the High BP group, naloxone failed to stimulate release of these hormones in this group. An efficient cortisol-mediated feedback inhibition of ACTH release may have produced the apparently normal degree of HPA responsivity in high BP subjects. The significantly greater effect of naloxone on HPA activity in Low BP subjects,

240 CHAPl'ER TWELVE

however, suggests that opioids do have inhibitory effects on the anterior pitu­itary, and the efficacy of this inhibitory tone is diminished in High BP subjects.

One potential site of integration of HPA and sympathoadrenomedullary reactivity is the hypothalamic para ventricular nuclei (Swanson & Sawchenko, 1980). Corticotropin releasing factor (CRF) neurons in this brain region control release of ACTH at the pituitary. Para ventricular CRF neurons also project to spinal sympathetic fibers, suggesting both neurochemical and anatomical prox­imity of central sympathetic outflow and HPA regulation. The effects of nalo­xone on pituitary function and blood pressure responses may be mediated via direct or indirect opioidergic input to hypothalamic CRF neurons. Although paraventricular CFR control of central sympathetic outflow and ACTH/en­dorpbin secretion may reflect two distinct populations of neurons, these two CRF systems may have a common opioidergic input, possibly via limbic, brain stem, or intrinsic afferents.

Taken together, these results suggest that endogenous opioids inhibit reactivity of both the HPA and the sympathoadrenomedullary axes. This inhibi­tion apparently results in moderation of cardiovascular stress reactivity. Young adults with mildly elevated casual blood pressure, enhanced risk for hyper­tension development, and exaggerated reactivity during psychological stress have an apparent deficiency in the efficacy of this inhibitory opioid system. This deficiency is suggested by the relative lack of responsivity to opioid receptor antagonism. If the efficacy of this opioidergic inhibitory mechanism influences stress reactivity as well as subsequent cardiovascular risk, then it provides one specific target for preventative measures. If behavioral techniques can improve the responsivity of this inhibitory mechanism, then it may be possible to nonnal­ize opioidergic responses and thereby moderate blood pressure fluctuations during stress in persons at risk for cardiovascular disease.

Aerobic exercise conditioning is one behavioral technique that is believed to reduce cardiovascular reactivity and also to decrease risk for cardiovascular disease. Evidence has been presented that suggests that the effects of aerobic conditioning on heart rate reactivity and blood pressure are mediated via opioid mechanisms. It may be possible to stimulate these inhibitory opioid systems via aerobic exercise conditioning. Understanding of the precise mechanisms that detennine individual differences in stress reactivity will allow more strategic design of intervention programs to delay or prevent the development of chronic degenerative cardiovascular sequelae in persons at enhanced risk for hyper­tension.

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ENDOGENOUS OPIOIDS 241

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Kiritsy-Roy, J. A, Appel, N. M., Bobbitt, F. G., & Van Loon, G. R. (1986). Effects of mu-opioid receptor stimulation in the hypothalamic para ventricular nucleus on basal and stress-induced catecholamine secretion and cardiovascular responses. Journal of Pharmacology and Ex­perimental Therapeutics, 239, 8142nd822.

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Langer, A W., Obrist, P. A, & McCubbin, J. A (1979). Hemodynamic and metabolic adjustments during exercise and shock avoidance in dogs. American Journal of Physiology, 236, H225-H230.

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(1985). Cardiopulmonary adjustments during exercise and an aversive reaction time task: Effects of beta-adrenoceptor blockade. Psychophysiology, .u, 59-68.

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CHAPTER THIRTEEN

Differential Responses to Salt Intake-Stress Interactions

Relevance to Hypertension

KATHLEEN C. LIGHT

INTRODUCTION

There is a well-established literature in the field of hypertension documenting an association between higher dietary salt intake and elevated blood pressure. & long ago as 1904, Ambard and Beajard published a report showing that some hypertensive patients demonstrate a substantial reduction in blood pressure when they restrict their salt intake (cited in Tobian & Hanlon, 1990). Since then, numerous additional clinical investigations have documented beneficial lower­ing of elevated pressure in many hypertensive patients. Additionally, cross­cultural comparisons have highlighted the fact that societies where the average daily salt intake is less than half of that consumed in the United States demon­strate a parallel reduction in the incidence of hypertension while societies consuming more salt show an even higher incidence. Furthermore, "salt-sen­sitive" and "salt-resistant" animal models have been developed and studied in which the direct causal role of high salt intake in the pathogenesis of hyper­tension and related cardiovascular morbidity and mortality has been verified. (For reviews, see MacGregor, 1983; Meneely & Battarbee, 1976; Meneely & Dahl, 1961).

A parallel literature with a similarly long history focuses on the association

KATHLEEN C. LIGHT • Department of Psychiatry, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599-7175.

245

246 CHAPrER THIRTEEN

between behavioral stress exposure and elevated blood pressure levels. As cited by Julius (1987), Gaisbock reported in 1905 that he had observed frequent "hypertonica" in men with heavy responsibility and psychic overwork. It has even been observed from the cross-cultural comparisons of blood pressure differences that societies showing a higher level of life stressors associated with urbanization and industrialization typically show increased salt intake as well, so that the influences of these two environmental factors on blood pressure cannot be easily separated (for reviews, see Cottier, Perini, & Rauchfleish, 1987; Denton, 1976; Gutmann & Benson, 1971; Henry & Cassel, 1969; Julius, 1987). Nonetheless, until comparatively recently, there was only a limited number of research pUblications addressing the influence of stress exposure and salt intake or salt retention on blood pressure simultaneously. The intent of this chapter is to review this new and growing literature and, where possible, to address the patterns and pitfalls revealed by these studies in the hope of guiding future research on salt and stress interactions.

THE INFLUENCE OF SODIUM EXCRETION AND RETENTION ON BLOOD PRESSURE

The physiological mechanisms whereby an increase in salt intake leads to elevated blood pressure are still hotly debated, yet many authorities agree that if the high salt intake still remains within the normal physiological range, a primary defect in the kidney's ability to eliminate sodium must be involved (MacGregor, 1983). The major spokesman for this dominant role of the kidneys in blood pressure control is Dr. Arthur Guyton, who recently described the role of the kidneys in this way:

The body requires fluid to maintain blood volume, and it requires blood volume to maintain arterial pressure. Therefore, if ever the pressure rises too high, removal of sufficient fluid should eventually reduce the pressure back to normal. Fortunately, the body has an automatic mechanism for doing just this ..•. The mechanism is a simple one that operates in the following way. Elevated arterial pressure has a direct effect on the kidneys themselves to increase urinary output of both fluid volume and also of sodium. The increased volume output is called ''pressure diuresis," and the increased sodium output is called ''pressure natriuresis." ... In effect, each person is continually eating salt and drinking water, thus continually building up his body fluid volume. The pressure diuresis-natriuresis mechanism simultaneously counters this, functioning as a relief valve for letting off excess volume when pressure rises too high. Conversely, when the pressure falls too low, excretion falls below normal, allowing even the normal intake of volume to accumulate and bring the pressure back up to normal. (Guyton, 1989, p. 575)

Thus, in healthy normal kidneys, an increase ip. salt intake and subsequent expansion of blood volume would raise blood pressure only briefly, when pres­sure natriuresis would return it back to its original equilibrium pressure. Of course, if this were true in every case, no one would ever be shown to be

SALT INTAKE-STRESS INTERACTIONS 247

"salt-sensitive," defined as someone whose blood pressure increases and de­creases as salt intake increases and decreases. Clearly, the fact that salt­sensitive individuals do exist indicates that in some vulnerable subset of human beings, this process has been compromised. There are a number of ways in which compromises in the pressure natriuresis relationship may occur. It is important to state that in addition to the process of pressure natriuresis itself, a variety of neural and hormonal factors influence filtration and reabsorption of sodium and water, the net effect of which is the quantity excreted. Among the best understood of these other factors are renal efferent sympathetic nerve activity and the renin-angiotensin-aldosterone system. Usually, these neural and hormonal factors operate to make elimination of excess sodium even more rapid, efficient, and precisely tuned to bodily homeostasis, but under certain circumstances, they can operate to induce retention of sodium and fluid despite increases in blood pressure. Other factors altering natriuresis may be struc­tural, relating to the arteries supplying the kidneys, and to the working tissues of the kidneys, which perform the constant and complex tasks of filtration and reabsorption.

It is important here to draw a distinction between sodium sensitivity and sodium retention. Kimura et al. (Kimura, Ashida, Abe, Kawano, Yoshini, Sahai, Imanishi, Yoshida, Kawamura, Kojima, Kuramochi, & Omar, 1990) have dem­onstrated using a water tank model that these are two independent constructs. Sodium-sensitive individuals can show a rise in blood pressure associated with an increase in fluid volume and cardiac output that does involve sodium and fluid retention; however, they also can show a rise in blood pressure associated with increased total peripheral resistance, in which sodium and fluid retention occur only transiently and then the excretion rates return rapidly to previous levels. Studies in primarily white, borderline hypertensive samples have indicated that the more common pattern among salt-sensitive groups is the one involving increased cardiac output (Hollenberg & Williams, 1989; Sullivan, 1986). Still, different patterns may occur in older and black samples because these have been less well characterized to date. Equally importantly, the Kimura et al. model indicates that elevations in blood pressure resulting from sodium and fluid retention can occur even in individuals who are not salt-sensitive. Such sodium-retaining, salt-insensitive subjects were modeled as showing elevated blood pressure associated with increased cardiac output similar to the sodium­retaining, salt-sensitive group, yet when salt intake was increased in the model, the salt-insensitive subjects showed normal pressure natriuresis (although at their elevated equilibrium pressure) while salt-sensitive subjects showed fur­ther increases in mean arterial pressure and cardiac output, a distortion of the normal pressure--excretion rate relationship. These model-generated out­comes confirm the importance of independently verifying whether an individual is salt-sensitive and/or salt-retaining and also the importance of examining the underlying hemodynamic parameters, cardiac output, and total peripheral re­sistance to verify these patterns.

248 CHAPTER THIRTEEN

Guyton (1989, p. 575) asserts that " ... chronic hypertension probably never occurs without abnormal function of the kidney system for excreting fluid volume." This description would be true for both the salt-sensitive and the salt-retaining individuals modeled by the work of Kimura et al. (1990). The difference is that, however, in the salt-sensitive case, the slope of the renal function that defines the relationship between blood pressure and natriuresis is altered while in the case of the sodium-retaining, salt-insensitive individual, the slope of this relationship is completely normal but the entire curve is shifted so that it functions at a higher than normal equilibrium pressure.

STRESS EXPOSURE ALTERS SODIUM EXCRETION IN ANIMAL MODELS

Evidence from numerous studies involving animal models has indicated that stress exposure may result in slowed excretion of a salt load when the animal under study has an inherited or acquired susceptibility. In a series of investigations using mongrel dogs, where such predispositions varied from animal to animal, exposure to a shock-avoidance task led to slower sodium excretion in some but not all dogs tested; however, when an individual dog did show this slow natriuresis response to stress, the response was reliably repro­duced over many testing sessions (Grignolo, Koepke, & Obrist, 1982; Koepke, Light, & Obrist 1983b). In contrast to shock-avoidance, treadmill exercise led to faster excretion of sodium, even though similar levels of myocardial activa­tion were evoked (Grignolo et al., 1982).

In studies comparing two genetic strains of rats, the spontaneously hyper­tensive rat and the Wistar-Kyoto normotensive rat, exposure to air jet stress has been shown to induce slowing of sodium excretion in the hypertensive strain but not in the normotensive strain (Koepke & DiBona, 1985a,b; Koepke, Jones, & DiBona, 1987). In the spontaneously hypertensive rats, this slowed sodium excretion during stress was greater in animals fed a high-salt versus a low-salt diet (Koepke & DiBona, 1985a). On the low-salt diet, the sodium retention was due to greater reabsorption. On the high-salt diet, stress also increased reab­sorption but in addition was found to decrease blood flow to the kidneys due to greater vasoconstriction and thereby to reduce the rate at which fluid, sodium, and other solutes were filtered by the kidneys (the glomerular filtration rate). The combination of less sodium being filtered and more sodium being reab­sorbed led to greater total slowing of sodium excretion on the high-salt diet. Borderline hypertensive rats (offspring of one hypertensive and one normo­tensive parent from these two strains) showed decreased sodium excretion during air jet or unavoidable shock stressors but only when fed a high-salt diet (DiBona & Jones, 1991; Sanders, Cox, & Lawler, 1988). Similarly, in two other rat strains, the salt-sensitive and the salt-resistant Dahl strains, air jet stress elicited slower sodium excretion in animals fed a high-salt but not a low-salt diet

SALT INTAKE-STRESS INTERACTIONS 249

(Koepke, Jones, & DiBona, 1988). The reduced sodium excretion during stress was greater in the salt-sensitive rats but was also evident to a lesser extent in the salt-resistant animals fed a high-salt diet. Thus, stress-induced sodium retention may not be restricted to individuals who are salt-sensitive, an ob­servation consistent with Kimura et aL (1990) and other recent theoretical and empirical reports. In these strains, glomerular filtration rate was not de­creased, and greater reabsorption of sodium was the source of the slower elimination.

These investigations in animal models have provided the most direct ev­idence to date on the central and peripheral mechanisms mediating these stress-related decreases in sodium excretion. Studies in the dog (Koepke et aL, 1983b), the spontaneous hypertensive rat strain (Koepke & DiBona, 1985b), and the salt-loaded borderline hypertensive and Dahl rat strains (DiBona & Jones, 1991; Koepke et aL, 1988) are all consistent in demonstrating that the stressors evoked an increase in renal nerve activity that appears to be the final link in the primary pathway since destruction of the renal nerves prevents stress-induced sodium retention. At the level of the central nervous system, the presently available data are limited to observations from the spontaneously hypertensive rat. These studies demonstrated that slow stress natriuresis is prevented by injection of beta-adrenergic receptor antagonists or alpha­adrenergic receptor agonists directly into the cerebral ventricles or into the central amygdaloid nucleus (Koepke & DiBona, 1985a, 1986; Koepke et aL, 1987). Administration of beta-antagonists into the systemic circulation pre­vented slow stress natriuresis in the dog, but only if the dose was high and if the antagonist was one that readily crossed the blood-brain barrier (Koepke, Grignolo, Light, & Obrist, 1983a). These latter findings likewise confirmed that blockade of peripheral beta-receptors does not prevent stress-induced slowing of sodium excretion.

The link between these observations of short-term decreases in sodium excretion induced by stress exposure and the development of hypertension is still unverified. Indirect support for a relationship to hypertension is provided by the demonstrations that this response is more common among animal strains that develop hypertension. The problem is that most of these animal models do not require exposure to behavioral stress to become hypertensive. Thus, the stress-related sodium retention may be simply a correlate, not a contributory or independently causal factor. Nevertheless, stress exposure has been shown to playa causal role in the development of hypertension in one of these animal models, the borderline hypertensive rat. Lawler and colleagues initially re­ported that these rats developed a progressive and irreversible hypertension with associated myocardial pathology when exposed daily to 22 weeks of a shock-shock conflict task while similar rats not exposed to this stressor showed no such pathogenic changes (Lawler, Barker, Hubbard, & Schaub, 1981). Bor­derline hypertensive rats did not demonstrate stress-related slowing of sodium excretion, however, except when fed a high-salt diet, and continued exposure to

250 CHAPTER THIRTEEN

a high-salt diet has been shown to be a sufficient environmental cause without stress exposure to result in sustained hypertension in these animals (DiBona & Jones, 1991; Sanders et al., 1988). Further research is needed to test the possibility that stress-related decreases in sodium excretion may playa critical role if dietary salt intake is held to a moderate level somewhere between the extremes studied to date.

The strongest evidence currently available showing that stress exposure and consequent sodium retention can playa causal role in the development of hypertension is the work of Anderson and associates with the saline-infused dog. In a series of investigations, these researchers demonstrated that when exposed daily for two weeks to the combination of high sodium intake (via infusion of normal saline) and two to three 30-minute bouts ofa shock-avoidance task, dogs developed a progressive hypertension that was associated with 24-hour retention of sodium but not water (Anderson, Kearns, & Better, 1983a; Anderson, Dietz, & Murphy, 1987). When exposed to the saline infusion alone or to the stressful task schedule alone, no sodium retention and no increase in blood pressure occurred. These studies provided clear evidence that stress exposure plays an essential and causal role, as did the increased sodium intake, in the development of this hypertension. The physiological mechanisms con­tributing to this hypertension, however, do not appear to be the same ones that mediate the short-term decreases in sodium excretion seen during the periods of stress exposure. The development of hypertension in this dog model was prevented by increasing potassium intake but not by sustained infusion of alpha-adrenergic antagonists or by destruction of the renal nerves (Anderson, 1986; Anderson, Kearns, & Worden, 1983b). A number of aspects of this model are strongly suggestive that the salt-retaining hormone aldosterone may be involved, particularly the observations that sodium retention occurred while fluid retention did not and the prevention of this hypertension by increasing the intake of potassium, which is one of the primary negative feedback controls on release of aldosterone. Anderson, Gomez-Sanchez, and Dietz (1986) have eval­uated this possibility but reported that the saline infusion, with or without stress exposure, results in a decrease in plasma aldosterone levels via suppres­sion of renin release. Nonetheless, these researchers feel that since they have ruled out many other mechanisms and since the evidence pointing toward adrenocorticoid hormone involvement is so strong, these effects may be due to aldosterone (which, in fact, showed less suppression than the low renin levels should have induced) acting together with other unspecified hormones having analogous or complementary actions on sodium reabsorption in the kidney.

STRESS EXPOSURE ALTERS SODIUM EXCRETION IN MAN

Relatively few studies have evaluated the effect of stress on sodium ex­cretion in man. Parfrey, Wright, and Ledingham (1981a,b) assessed sodium and

SALT INTAKE-STRESS INTERACTIONS 251

fluid excretion rates before, during and after isometric exercise and found no slowing of excretion in controls, in young adults with a positive family history of hypertension, or in hypertensive patients. These negative findings, however, have a rough parallel in the animal literature; as mentioned previously, Grig­nolo et al. (1982) observed that while shock-avoidance induced slower natriur­esis in dogs, exercise induced more rapid sodium excretion. More recently, Lawton, Sinkey, Fitz, and Mark (1988) evaluated renal excretion responses to the postural change occurring with arising in the morning while on a high­versus a low-sodium diet. They reported that water excretion was slowed to a greater extent in borderline hypertensives compared with normotensive sub­jects on both diets and that on the high-sodium diet, the borderline hyper­tensive group showed greater decreases in renal blood flow and glomerular filtration rate after standing. Since their protocol required that subjects be tested after an overnight fast with water loading but no acute sodium loading involved, group differences in sodium excretion did not yield robust evidence of greater slowing of natriuresis in the borderline hypertensive group, although there was a consistent trend in this predicted direction.

In contrast, Light, Koepke, Obrist, and Willis (1983) did observe greater slowing of both sodium and water excretion during a one-hour exposure to competitive mental tasks in healthy young men with borderline hypertension and/or hypertensive parents if these men also demonstrated high sympathetic nervous system activation as indexed by heart rate increases. In the other subjects tested, stress exposure induced the opposite pattern-more rapid elimination of sodium and water. This latter pattern is consistent with the responses that would be anticipated by the model of pressure natriuresis and pressure diuresis in the isolated kidney while the slower excretion pattern shown by high-risk subjects who were high reactors ran counter to this model since their blood pressure increases were the greatest of all. This protocol involved an acute salt load ingested in the form of a standard high-sodium meal together with water loading; this was done to create a loaded state similar to those in the previous· animal studies, which achieved both salt and water loading by saline infusion. Subsequently, Light, Wagner, and Willis (unpublished manuscript) have utilized a test-retest design that provided evidence that both slow-stress natriuresis and fast-stress natriuresis patterns are generally con­sistent and reproducible responses. In neither study demonstrating slow-stress natriuresis, however, did Light and associates employ a controlled dietary regimen prior to testing, leaving open the possibility that prior differences in dietary intake of sodium may have contributed to their results.

The importance of prior diet was highlighted by another recent investiga­tion by Harshfield, Pulliam, and Alpert (1991). In this study, young normoten­sive men were asked to fast overnight and then were given only an oral water load with no salt load, but unlike the subjects of Lawton et al. (1988), they had not been placed on a controlled diet prior to testing. Subjects were divided into those who showed faster versus slower sodium excretion during one hour of

252 CHAPI'ER THIRTEEN

competitive video games than they had during an initial two-hour baseline. Although within-group comparisons confirmed that both the stress-related increase and the decrease in sodium excretion rate were significant, the two groups did not differ significantly from each other in sodium excretion during or after stress. In fact, the only time at which the two groups differed significantly was at baseline, when the subjects showing slower sodium excre­tion during stress actually excreted sodium faster than the other subjects. This observation suggests the possibility that differences that existed prior to the stress exposure (such as previous dietary intake of sodium and potassium) may have contributed to the results. Plasma aldosterone levels showed a nonsignificant tendency to be higher overall among subjects showing slow natriuresis during stress, although only the fast natriuresis group showed a significant rise in aldosterone during stress. Both groups had similar baseline levels and stress-related increases in plasma renin activity. Slow-stress natri­uresis subjects also showed slower diuresis and a drop in glomerular filtration rate (indexed by creatinine clearance) during stress.

Subsequently, a new investigation by Light and Turner (1992) assessed stress-induced excretion patterns in 14 black and 14 white men who had been placed on a controlled, moderately high salt diet for three days prior to testing. AB in the previous work from this laboratory, subjects were sodium loaded via a standard high-salt meal as well as water loaded prior to testing, and their responses to competitive mental arithmetic and reaction time tasks were as­sessed. After dividing subjects into those showing slower versus faster sodium excretion during stress, their results confirmed Harshfield and associates' (1991) observation that the glomerular filtration rate fell among the slow nat­riuresis group; however, slower sodium excretion persisted for 30 minutes after the end of the stressors while filtration rate differences were not sustained (Figure 1). Replicating findings by Light et al (1983), the slow-stress natriur­esis subjects were typically those men with higher baseline blood pressures who also were high heart rate and cardiac output reactors to stress. In a new preliminary finding, stress-induced slowing of sodium excretion was found to occur more often in the black men versus the white men tested (42% versus 14%). Black subjects as a group tended to excrete the sodium load more slowly even at baseline and showed lesser increases in sodium excretion during stress than white subjects. Previously, Luft, Grim, Fineberg, and Weinberger (1979) had reported that blacks excreted a large salt load induced by saline infusion more slowly than whites. This combination of slower baseline elimination of sodium plus an apparently blunted capacity to increase natriuresis during stress-induced pressor responses resulted in these black subjects showing reduced sodium excretion, which was sustained over the 90 minutes during and just after the stressful tasks (Figure 2). This observation is also consistent with recent observations by Harshfield and associates that blacks with a high intake of salt (indexed by 24-hour urine collections) showed higher ambulatory blood

SALT INTAKE-STRESS INTERACTIONS

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254

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CHAPTER THIRTEEN

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pressure than whites with high salt intake, presumably because their excretion of this excess salt occurred more slowly (see Chapter 13).

Findings from Harshfield et al. (1991) regarding aldosterone and renin represented a first effort to examine possible hormonal mediation of the stress­related sodium retention in man. Light, Wagner, and Willis (unpublished manu­script) have completed a similar initial effort to examine the possible role of sympathetic nervous system activity in mediating this renal response. This study evaluated the effects of intravenous administration of the beta-antagonist propranolol versus placebo on renal excretion responses to stress in a within­subject, counterbalanced design. It also included infusion to para-aminohip­purate and inulin to permit estimation of changes in renal blood flow and glomerular filtration rate. Even though propranolol was effective in minimizing heart rate and systolic blood pressure increases, diastolic pressure increases were potentiated. Furthermore, during the stress-induced increases in mean arterial pressure seen after both placebo and propranolol, renal sodium and water excretion patterns were not altered; every subject showing decreased natriuresis after placebo likewise showed the same direction and magnitude of decrease after propranolol, and all but one of the subjects showing faster natriuresis during stress after placebo showed the same pattern after pro­pranolol. Across all subjects, renal blood flow decreased during stress while glomerular filtration rate showed only a nonsignificant decline. Like the study by Light and Turner (1992), this investigation tested equal numbers of blacks and whites but failed to yield any association between race and slow-stress natriuresis. Since both studies employed relatively small samples, this incon-

SALT INTAKE-STRESS INTERACTIONS 255

sistency reinforces the need for further research into possible racial differences using larger sample sizes.

Altogether, the animal and human literature represent a convincing doc­umentation that exposure to stressors up to one hour in duration can produce two different patterns of renal sodium: (1) a more rapid natriuresis (which is consistent with the pressure-natriuresis response of healthy kidneys), or (2) the opposite response, a slowing of natriuresis. In most species, including man, when slowed natriuresis occurs, it is accompanied by slowed diuresis as well. There is a clear need to further expand the animal studies in order to document more clearly whether such short-term decreases in sodium excretion are im­portant in the pathogenesis of hypertension. This might be accomplished using the saline-infused dog model of Anderson and Associates (1987) or the salt­loaded borderline hypertensive rat (Sanders et 01, 1988) by first characterizing each individual animal according to its response to acute stress exposure (faster versus slower excretion). Then, while researchers continue to monitor the excretion rates of these animals during the stressor and on a 24-hour basis during daily salt loading plus stress exposure, the eventual development of hypertension in fast versus slow-stress natriuresis groups can be directly com­pared. Studies of the effects of augmenting potassium intake on natriuretic responses to short-term stressors in various animal models might also yield an important bridge to the long-term stress exposure model.

In humans, much additional work needs to be done to seek to replicate the prior racial group differences in excretion patterns during stress and to assess the possibility of gender and age-related differences. Furthermore, additional efforts focusing on possible physiological mechanisms are needed to determine whether central and peripheral pathways are similar to or different from those that have been shown to mediate responses in animal models. Attention needs to be paid to renal alpha-adrenergic receptors (contacted by renal nerves) and to various unstudied hormonal factors, including atrial natriuretic peptide and dopamine. Just as importantly, future studies in humans need to control and standardize important procedures, including prior dietary intake of sodium and potassium and the use of salt loading and water loading as part of the stress testing protocol.

CARDIOVASCULAR RESPONSES ON HIGH- VERSUS LOW-SALT DIETS

It has long been suspected that increasing dietary intake of salt may influence cardiovascular reactivity as well as resting blood pressure and un­derlying hemodynamics. High-salt intake has been shown to have multiple effects, all of which may influence reactivity; these include expansion of blood volume and cardiac output, increases in the density and/or sensitivity of per­ipheral adrenergic receptors, alterations in centrally mediated sympathetic

256 CHAPl'ER THIRTEEN

tone, and alterations in sodium transport at the cell membrane and related cellular function changes that can affect the performance of myocardial and vascular smooth muscle cells (Dimsdale, Ziegler, Mills, & Berry, 1990b; Fujita, Ando, & Ogata, 1990). Nonetheless, relatively few studies in the literature have directly compared cardiovascular responses to standard stressors while vary­ing the intake of salt.

The work of Dimsdale and colleagues is a notable exception. These in­vestigators began by examining the effects of dietary salt intake on pressor responses to intravenous infusion of norepinephrine in black and white normo­tensive and hypertensive men (Dimsdale, Graham, Ziegler, Zusman, & Berry, 1987). Their observations indicated that the majority of black subjects showed greater pressor responses to this sympathetic agonist after four days on the high-salt versus the low-salt diet while white subjects were roughly evenly divided among those who showed greater and those who showed lesser re­sponses to the higher salt intake. Blacks who were hypertensive consistently showed this salt-related increase in pressor responses while whites who were hypertensive typically showed either no change or a decreased pressor re­sponse. Since normal free intake of salt is much closer to the high-salt than the low-salt diet, these racial group differences have been interpreted as evidence of "augmented alpha receptor sensitivity among blacks" with hypertension (Falkner, 1990, p. 683). Although this interpretation can be challenged, the evidence does strongly suggest that more black than white individuals may show increases in alpha-adrenergic receptor density or sensitivity when their salt intake is increased.

Dimsdale and colleagues have published two subsequent reports contrast­ing cardiovascular responses on a high-versus a low-salt diet. The first of these focused on sodium sensitivity as defined by salt-induced increases in resting blood pressure (Dimsdale et 01., 1990b). In a very carefully executed study involving a total of 75 subjects, these researchers reported this perplexing result: In blacks and whites, normotensive and hypertensive patients alike, resting diastolic pressure was lower, not higher, on average on the high-salt diet. Resting systolic pressure also was lower on average on the high-salt diet in all subgroups except hypertensive black men, who showed higher systolic levels after high-salt intake. Among their large sample, the minority of in­dividuals who showed higher blood pressure levels on the high-salt diet (salt­sensitive group) were characterized by lesser decreases in plasma renin and norepinephrine during salt loading. Dimsdale and colleagues (1990b) reviewed the prior studies on controlled salt intake and salt sensitivity of blood pressure, acknowledging that their reverse findings, while not unique, were discrepant from the general trend; however, the greater frequency of salt sensitivity in black hypertensives was consistent with most prior reports (Grim, Luft;, Miller, Meneely, Battarbee, Hames, & Dahl, 1980; Luft et 01., 1979; Zenel, Zenel, Beck, Walsh, & Zawada, 1988; Sullivan, 1986). In their second recent report, blood pressure and heart rate increases during a serial subtraction task and a foot-

SALT INTAKE-STRESS INTERACTIONS 257

immersion cold pressor test were evaluated (Dimsdale, Ziegler, Mills, Dele­hanty, & Berry, 1990a). They observed that both systolic and diastolic pressure reactivity to the cold pressor test were decreased on the high-salt diet among the black hypertensive subjects, in contrast to the white hypertensive subjects whose pressor reactivity was slightly increased. These findings seem to run counter to their prior observation of enhanced alpha-receptor sensitivity in black but not white hypertensive men on a high-salt diet since the cold pressor test has been shown to influence blood pressure primarily via alpha-receptors (Bolli, Amann, Hulthen, Kiowski, & Buhler, 1981). Reactivity to the mental arithmetic task was much less than to the cold pressor and was unaffected by diet. Dimsdale and colleagues (l990a) concluded that despite prior evidence that high-salt intake enhances response to infused agonists, these results sug­gest that it does not generally alter blood pressure reactivity.

Falkner and colleagues have also performed a series of investigations of the effects of increasing dietary salt intake on blood pressure reactivity. In one study, fifteen normotensive adolescent girls (seven with and eight without a positive family history of hypertension) were tested at rest and during mental arithmetic before and after adding 10 grams of salt to their normal dietary intake for a two-week period (Falkner, Onesti, & Angelakos, 1981). The girls with a positive family history of hypertension showed an increase in resting baseline blood pressure while the other girls did not. Peak levels of blood pressure during the mental stressor were likewise increased only in the girls with a positive family history, but changes from baseline during stress were of similar magnitude before and after salt loading. In a much larger subsequent study, 121 young adults (38 whites and 83 blacks) were tested using the same dietary intervention and behavioral paradigm (Falkner & Kushner, 1990). S0-dium-sensitive and sodium-insensitive subjects were identified as those who did versus did not show increases in mean arterial blood pressure of at least 5% while salt loaded. Sodium sensitivity occurred more frequently in blacks versus whites (37% versus 18%). Although salt loading increased both baseline and peak stress levels of blood pressure in the sodium-sensitive group, blood pres­sure reactivity defined by changes from baseline was not affected. Interest­ingly, both this study and the study by Dimsdale et al (1990) reported that independent of diet, blood pressure reactivity to a mental arithmetic stressor was greater in the white subjects than the black subjects tested (See Chapter 7 for a review of additional literature on cardiovascular reactivity in blacks versus whites.)

The only evidence of clearly enhanced blood pressure reactivity displayed by subjects on a high-salt diet to date is that reported by Ambrosioni and associates. This investigation differed from the work of Dimsdale and col­leagues because only young adults with borderline hypertension were tested and their intervention was much longer in duration, that is, six weeks versus four days (Ambrosioni, Costa, Borghi, Montebugnoli, Giordani, & Magnani, 1982). It differed from the approach employed by Falkner and colleagues in

258 CHAPl'ER THIRTEEN

that their intervention was to decrease rather than to increase salt intake from the usual intake levels. The intervention was accomplished by providing menus and dietary counseling, with the goal of decreasing daily salt intake by 50% (from 6 to 10 grams daily on the free diet to 3 to 5 grams on the low-salt diet). Compliance was verified by six consecutive 24-hour urine collections; 26 par­ticipants maintained good compliance. Their results indicated that lowering salt intake for six weeks did not significantly reduce casual or baseline blood pres­sure, but it did reduce both systolic and diastolic blood pressure responses during mental arithmetic, bicycle and handgrip exercise, as well as lowering blood pressure during the first five minutes of recovery after the stressors. These same scientists subsequently tested additional borderline hypertensive subjects, increasing their sample size to 44, and then in a five-year follow-up study, they identified which individuals had developed established hypertension over that interval (Borghi, Costa, Boschi, Mussi, & Ambrosioni, 1986). Their results indicated that both diastolic pressure reactivity to the mental stressor and high intracellular sodium content on the free diet were predictors of early development of hypertension. All of the subjects who developed hypertension during that interval had shown a diastolic increase to mental arithmetic greater than 25% of baseline and a diastolic level after five minutes of recovery that was at least 6% above baseline, as well as a high content of sodium in their lym­phocytes. Failure to reduce intralymphocytic sodium on the low-salt diet, whether due to less conscientious compliance or other factors, was the most specific predictor of hypertension at follow-up; it was shown by only two sub­jects who did not become hypertensive. These studies have exceptional significance, both because their initial dietary intervention is more typical of the sustained life-style modifications that are used clinically and because of the documented relationships to subsequent morbidity provided by their five-year follow-up study.

Our research group recently compared the effects of a high- versus low­salt diet on the hemodynamic factors (cardiac output and total peripheral resistance) underlying blood pressure responses during baseline and a series of stressors (Light, Turner, & Sherwood, unpublished observations). Of 18 nonno­tensive young men tested after one week on each diet, 6 showed increases in resting mean arterial pressure on the high-salt diet and we~ identified as salt-sensitive while the remaining 12 were labeled salt-resistant. These groups did not differ in systolic, diastolic, or mean arterial blood pressure overall, but on the high-salt diet, the salt-sensitive subjects had higher mean arterial blood pressure both at rest and during stress while on the low-salt diet the salt­resistant subjects had higher blood pressures (Figure 3). Total peripheral resistance decreased in the salt-sensitive subjects and increased in the salt­resistant subjects on the high-salt diet, both at rest and during stress; these effects were most pronounced during the cold pressor. Cardiac output was generally higher across both subgroups on the high-salt diet, but this dietary difference was most pronounced in the salt-sensitive subjects during stressors

SALT INTAKE-STRESS INTERACTIONS

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that evoke large increases in cardiac output, namely, a competitive reaction time task and giving a simulated public speech (Figure 4).

SUMMARY

Altogether, these investigations reviewed in this chapter have not led to a clear consensus on the effects of altering dietary salt intake on cardiovascular stress reactivity. The bulk of evidence indicates that short-term variation (4 to 14 days) in salt intake from very low to high or from moderately high to very high levels does not consistently alter blood pressure reactivity, although it may alter underlying hemodynamic factors. Nonetheless, the evidence also very much emphasizes that there are dramatic individual differences in response to

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CHAPTER THIRTEEN

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salt loading, which may mean that reactivity will be altered in certain subgroups of subjects. Furthermore, based on the findings of Ambrosioni et al (1982) and Borghi et al (1986), it appears that longer term (six weeks) dietary interven­tions may more powerfully alter reactivity and possibly also influence sub­sequent development of hypertension.

It is important that the failure of the short-term dietary manipulations not deter researchers from continuing to study salt intake and reactivity. After all, the eventual clinical intervention would be a permanent change in dietary habits in identified high-risk individuals. Further study of the effects of long­term dietary decreases in salt intake are definitely warranted, particularly in subjects who have been characterized as salt-sensitive. Benefits for other sub­jects may not be ruled out either. Recent work by Tobian and Hanlon (1990) in Dahl salt-resistant rats showed that among animals made borderline hyper­tensive by pretreatment with deoxycorticosterone acetate and high-salt intake, those that were later returned to a low-salt intake versus those maintained on a high-salt intake did not differ in blood pressure at any time; however, after 15 weeks, all the animals on the high-salt diet had died due to apparent vascular damage and strokes that occurred despite the absence of hypertension.

Future research also needs to examine the effect of increasing potassium intake as a potential buffer against the effects of moderate or high-salt intake. Potassium depletion has been shown to increase blood pressure in association with slower sodium excretion (Krishna, Miller, & Kapoor, 1989). The ratio of sodium to potassium intake has been shown to be a better predictor of blood pressure than salt intake alone in a number of investigations (Meneely & Battarbee, 1976), and low dietary potassium itself is a strong predictor of

SALT INTAKE-STRESS INTERACTIONS 261

stroke-associated mortality (Khaw & Barrett-Connor, 1987). In addition, p0-

tassium has been shown to reduce mortality and hemorrhagic stroke in Dahl rats even when no blood pressure reduction occurred (Tobian, Lange, Ulm, Wold, & Iwai, 1985). Also, recall that increasing potassium intake prevents stress-induced hypertension in the saline-infused dog (Anderson et al., 1983b). Given these dramatic observations, it is clear that future research on the interactive effects of salt intake and stress in man must expand the dietary focus to include potassium intake as well.

ACKNOWLEDGMENTS

Portions of this chapter describe research supported by NIH grants 31533 and RR00046.

REFERENCES

Ambrosioni, E., Costa, F. V., Borghi, C., Montebugnoli, L., Giordani, M. F., & Magnani, B. (1982). Effects of moderate salt restriction on intralymphocytic sodium and pressor response to stress in borderline hypertension. Hypertension, 4, 789-794.

Anderson, D. E. (1986). Operant conditioning, sodium loading, and experimental hypertension. Journal of Cardiovascular Pharmacology, 8(5), S23-830.

Anderson, D. E., Kearns, W. D., & Better, W. E. (1983a). Progressive hypertension in dogs by avoidance conditioning and saline infusion. Hypertension, 5, 286-291.

Anderson, D. E., Kearns, W. D., & Worden, T. J. (1983b). Potassium infusion attenuates avoidance­saline hypertension in dogs. Hypertension, 5, 415-420.

Anderson, D. E., Gomez-Sanchez, C., & Dietz, J. R. (1986). Suppression of plasma renin and aldosterone in stress-salt hypertension in dogs. American Journal of Physiology, 251, R181-RI86.

Anderson, D. E., Dietz, J. R., & Murphy, P. (1987). Behavioral hypertension in sodium-loaded dogs is accompanied by sustained sodium retention. Journal of Hypertension, 5, 99-105.

Bolli, P., Amann, F. W., Hulthen, L., Kiowski, W., & Buhler, F. R. (1981). Elevated plasma adrenaline reflects sympathetic overactivity and enhanced alpha-adrenoceptor-mediated vaso­constriction in essential hypertension. Clinical Science, 61, 161s-164s.

Borghi, C., Costa, F. V., Boschi, S., Mussi, A, & Ambrosioni, E. (1986). Predictors of stable hypertension in young borderline subjects: A five-year follow-up study. Journal ofCardiova­scular Pharmacology, 8(5), SI38-S14l.

Cottier, C., Perini, Ch., & Rauchfleish, U. (1987). Personality traits and hypertension: An overview. In S. Julius & D. R. Bassett (Eds.), Handbook of hypertension, Vol. 9: Behavioralfactors in hypertension (pp. 123-140). New York: Elsevier.

Denton, D. (1976). Hypertension: A malady of civilization? In M. P. Sambhi (Ed.), Systemic effects of antihypertensive drugs (pp. 559-583). New York: Stratton Intercontinental.

DiBona, G. F., & Jones, S. Y. (1991). Renal manifestations of NaCI sensitivity in borderline hypertensive rats. Hypertension, 17, 44-53.

Dimsdale, J. E., Graham, R., Ziegler, M. G., Zusman, R., & Berry, C. C. (1987). Age, race, diagnosis, and sodium effects on the pressor response to infused norepinephrine. Hyper­tension, 10, 564-569.

262 CHAPTER THIRTEEN

Dimsdale, J. E., Ziegler, M. G., Mills, P., Delehanty, S. G., & Berry, C. C. (199Oa). Effects of salt, race, and hypertension on reactivity to stressors. Hypertension, 16, 573-580.

Dimsdale, J. E., Ziegler, M. G., Mills, P., & Berry, C. C. (l990b). Prediction of salt sensitivity. American Juumal of Hypertension, 3, 429-435.

Fallmer, B. (1990). Differences in blacks and whites with essential hypertension: Biochemistry and endocrine. Hypertension, 15, 681-686.

Fallmer, B., & Kushner, H. (1990). Effect of chronic sodium loading on cardiovascular response in young blacks and whites. Hypertension, 15, 36-43.

Fallmer, B., Onesti, G., & Angelakos, E. T. (1981). Effect of salt loading on the cardiovascular response to stress in adolescents. Hypertension, 3(11), 11195-11199.

Fujita, J., Ando, K., & Ogata, E. (1990). Systemic and regional hemodynamics in patients with salt-sensitive hypertension. Hypertension, 16, 235-244.

Grignolo, A., Koepke, J. P., & Obrist, P. A. (1982). Renal function, heart rate, and blood pressure during exercise and avoidance in dogs. American Juumal of Physiolngy, $42. R482-R490.

Grim, C. E., Luft, F. C., Miller, J. Z., Meneely, G. R., Battarbee, H. D., Hames, C. G., & Dahl, L. K. (1980). Racial differences in blood pressure in Evans County, Georgia: Relationship to sodium and potassium intake and plasma renin activity. Juumal of Chronic Diseases, 33, 87-94.

Gutmann, M. C., & Benson, H. (1971). Interaction of environmental factors and systemic arterial blood pressure: A review. Medicine, 50, 543-553.

GuYton, A. C. (1989). Dominant role of the kidneys and accessory role of whole-body autoregulation in the pathogenesis of hypertension. American Juumal of Hypertension, 2, 575-585.

Harshfield, G. A., Pulliam, D. A., & Alpert, B. S. (in press). Patterns of sodium excretion during sympathetic nervous system arousal. Hypertension, 17.

Henry, J. P., & Cassel, J. C. (1969). Psychosocial factors in essential hypertension. Recent epide­miological and animal experimental evidence. American Juumal of Epidmniolngy, 90, 171-200.

Hollenberg, N. K., & Williams, G. H. (1989). Sodium-sensitive hypertension: Implications of pathogenesis for therapy. American Juumal of Hypertension, 2, 809-815.

Julius, S. (1987). Hemodynamic, pharmacologic and epidemiologic evidence for behavioral factors in human hypertension. In S. Julius & D. R. Bassett (Eds.), Handbook of hypertension, VoL 9: Behauinralfactors in hypertension (pp. 59-74). New York: Elsevier.

Khaw, K. T., & Barrett-Connor, E. (1987). Dietary potassium and stroke-associated mortality. New England Juumal of Medicine, 316, 235-240.

Kimura, G., Ashida, T., Abe, H., Kawano, Y., Yoshimi, H., Sanai, T., Imanishi, M., Yoshida, K., Kawamura, M., Kojima, S., Kuramochi, M., & Omae, T. (1990). Sodium sensitive and sodium retaining hypertension. American Juumal of Hypertension, 3, 854-858.

Koepke, J. P., & DiBona, G. F. (1985&). Central beta-adrenergic receptors mediate renal nerve activity during stress in conscious spontaneously hypertensive rats. Hypertension, 7, 350-356.

Koepke, J. P., & DiBona, G. F. (1985b). High sodium intake enhances renal nerve and antina­triuretic responses to stress in spontaneously hypertensive rats. HypertensimI. 7, 357-363.

Koepke, J. P., & DiBona, G. F. (1986). Central adrenergic receptor control of renal function in conscious hypertensive rats. HypertensimI. 8, 133-141.

Koepke, J. P., Grignolo, A., Light, K. C., & Obrist, P. A. (198m). Central beta-adrenoceptor mediation of the antinatriuretic response to behavioral stress in conscious dogs. Juumal of Pharmacological and E:r;perimental Therapeutics, ~7, 73-77.

Koepke, J. P., Light, K. C., & Obrist, P. A. (1985). Neural control of renal excretory function during behavioral stress in conscious dogs. American Juumal of PhysioWgy, 245, R251-R258.

Koepke, J. P., Jones, S. Y., & DiBona, G. F. (1987). Alpha-2 adrenoceptors in amygdala control renal sympathetic nerve activity and renal function in conscious spontaneously hypertensive rats. Brain Research, 40,," 80-88.

SALT INTAKE-STRESS INTERACTIONS 263

Koepke, J. P., Jones, S. Y., & DiBona, G. F. (1988). Sodium responsiveness of central alpha­adrenergic receptors in spontaneously hypertensive rats. Hypertension, 11, 326-333.

Krishna, C. G., Miller, E., & Kapoor, D. (1989). Increased blood pressure during potassium depletion in normotensive men. New England Journal of Medicine, 320, 1177-1182.

Lawler, J. E., Barker, G. F., Hubbard, J. W., & Schaub, R. G. (1981). Effect of stress on blood pressure and cardiac pathology in rats with borderline hypertension. Hypertension, 3, 496-505.

Lawton, W. J., Sinkey, C. A, Fitz, A E., & Mark, A L. (1988). Dietary salt produces abnormal renal vasoconstrictor responses to upright posture in borderline hypertensive subjects. Hy­pertension, 11, 529-536.

Light, K. C., & Turner, J. R. (in press). Stress-induced changes in the rate of sodium excretion in healthy black and white men. Journal of Psychoscrmatic Research.

Light, K. C., Koepke, J. P., Obrist, P. A, & Willis, P. W., N (1983). Psychological stress induces sodium and fluid retention in men at risk for hypertension. Science, 220, 429-43l.

Light, K. C., Turner, J. R., & Sherwood, A (unpublished observations). Available upon request from K. C. Light.

Light, K. C., Wagner, P. G., & Willis, P. W., N (unpublished manuscript). Effects of propranolol on renal excretion of sodium and fluid during rest and stress. Available upon request from K. C. Light.

Luft, F. C., Grim, C. E., Fineberg, N., & Weinberger, M. H. (1979). Effects of volume expansion and contraction in normotensive whites, blacks, and subjects of different ages. Circulation, 59, 643-650.

MacGregor, G. A (1983). Sodium and potassium intake and blood pressure. Hypertension, 5,(111), II179-II184.

Meneely, G. R., & Battarbee, H. D. (1976). High sodium-low potassium environment and hyper­tension. American Journal of Cardiology, 38, 768-785.

Meneely, G. R., & Dahl, L. K. (19610. Electrolytes in hypertension: The effects of sodium chloride. Medical Clinics of North America, 45, 271-283.

Parfrey, P. S., Wright, P., & Ledingham, J. M. (1981a). Prolonged isometric exercise. Part 1: Effect on circulation and on renal excretion of sodium and potassium in mild essential hypertension. Hypertension, 3, 182-187.

Parfrey, P. S., Wright, P., & Ledingham, J. M. (1981b). Prolonged isometric exercise. Part 2: Effect on circulation and on renal excretion of sodium and potassium in young males genetically predisposed to hypertension. Hypertension, 3, 188-199.

Sanders, B. J., Cox, R. H., & Lawler, J. E. (1988). Cardiovascular and renal responses to stress in borderline hypertensive rat. American Journal of Physiology, 255, R431-R438.

Sowers, J. R., Zemel, M. B., Zemel, P., Beck, F. W. J., Walsh, M. F., & Zawada, E. T. (1988). Salt sensitivity in blacks: Salt intake and natriuretic substances. Hypertension, 12, 485-490.

Sullivan, J. M. (1986). Borderline hypertension and salt sensitivity. Journal of Cardiovascular Pharmacology, 8(5), 831-835.

Tobian, L., & Hanlon, S. (1990). High sodium chloride diets injure arteries and raise mortality without changing blood pressure. Hypertension, 25, 900-903.

Tobian, L., Lange, J., Ulm, K., Wold, L., & Iwai, J. (1985). Potassium reduces cerebral hemorrhage and death rate in hypertensive rats, even when blood pressure is not lowered. Hypertension, 7(1), IllO-Ill4.

CHAPTER FOURTEEN

A Biobehavioral Model of Hypertension Development

WILLIAM R. LOVALLO AND MICHAEL F. WILSON

A MODEL OF HYPERTENSION DEVELOPMENT

In order to address the role played by exaggerated cardiovascular reactivity in the development of hypertension, we first present a model of the disorder, next describe evidence for the major components of the model, derived primarily from animal models of hypertension, and then relate these animal studies to those conducted with humans. Finally, we will attempt to integrate this evi­dence with possible models of the reactivity-hypertension relationship.

An appropriate model for our purpose should postulate a primary cause for hypertension and demonstrate how such a causal mechanism may interact with exaggerated cardiovascular reactivity. These together should be consistent with the central fact of hypertension development, which is the progressive, relentless structural alteration of the heart and the blood vessels. This struc­tural adaptation may be both a response to elevated pressure and a contributor to its maintenance. Figure 1 is a diagram of the model that contains three major components. The primary cause is argued to be renal. Second, the central and autonomic nervous systems control direct neurohormonal inputs to the cardio-

WILLIAM R. LOVALLO • Department of Psychiatry and Behavioral Sciences, University of Oklahoma Health Sciences Center, and Veterans Affairs Medical Center, Oklahoma City, Okla­homa 73190. MICHAEL F. WILSON • Department of Medicine, University of Oklahoma Health Sciences Center, and Veterans Affairs Medical Center, Oklahoma City, Oklahoma 73190.

265

266

CNS

HEMODYNAMIC ACTIVATION

LV & RESISTANCE VESSEL WALL STRESS

MEDIAL THICKENING & GREATER LV MASS

BLOOD PRESSURE: ELEVATED AT REST;

RESPONSE IS ENHANCED

CHAPTER FOURTEEN

--- _ .... -............ --.... -....... _-_ ......... -. CONTRIBUTORY

CONSTITUTIONAL : TENDENCY FOR : CV ACTIVATION :

... __ .............. ______ .... _________ .1

-_ .. -...... -......... -_ ........... _ ..... ---_ ...... -• CAUSAL FACTOR

UNIDENTIFIED CIRCULATING

AGENT OF RENAL ORIGIN

TENDENCY FOR STRUCTURAL ADAPTATION

..... ------_......... _ ... __ ._-------. : CONTRIBUTORY .

PERMISSIVE • HORMONAL

FACTORS · . ~ __ .. _______ .. __ .... ____ .... _____ .. ,J

FIGURE 1. This model of hypertension development contains three nuijor elements. A primary, causal factor for hypertension is assumed to lie in a renal defect that directly influences the blood vessels to promote thickening of the vessel wall. Other hormonal factors may play a contributory role by altering renal function or by acting directly on the vascular wall to render it susceptable to possible renal agents. A secondary, contributory factor is assumed to be a tendency for ex­aggerated cardiovascular reactivity. This is assumed to originate in a tendency for the central and autonomic nervous systems to produce high levels of tonic and phasic sympathetic activation. The third element is the vascular tree. It is assumed that in a person predisposed to hypertension, the primary renal factor and its resulting tendency toward vascular wall hypertrophy interact with descending activation to actually induce the process of structural adaptation in the blood vessels. This contnbutes to a positive feedback loop in which structural factors drive blood pressures higher and these pressures in turn initiate further structural modification. The ultimate result is per­manently elevated pressure.

vascular system and control indirect ones via the renal system. Third, the heart and blood vessels are seen to be at the center of a positive feedback loop in which structural alterations and higher pressures each drive the other. The outcome of the interaction between these three elements is a long-term struc­tural alteration of the heart and blood vessels supporting a sustained elevation in pressure.

The model is based on the following assumptions. First, there is an

HYPERTENSION MODEL 267

unidentified circulating agent that the kidneys of hypertension-prone persons either produce or fail to remove from the circulation. This renal defect is most likely inborn. Second, the central nervous system integrates the cardiovascular system with the external environment and controls the reactive tendencies of the cardiovascular system through a combination of cognitive, learned, and constitutionally based influences. These tendencies are of paramount impor­tance during the early development of the disorder when structural elements are within normal physical limits. Third, there is an abnormal tendency toward structural adaptation to pressure overload that is not present in the normo­tensive system. This results in a shift from an early, functionally determined hyperreactivity of blood pressure to a later, structurally determined hyper­reactivity.

EVIDENCE FOR THE MODEL

We will review evidence pertinent to this model, acknowledging in advance that the presentation is both brief and highly selective. Evidence will be drawn from studies of the Okamoto strain of spontaneously hypertensive rats (SHRs). The SHR and its normotensive progenitor strain, the Wistar-Kyoto rat (WKY), have provided an invaluable model of hypertension with many pathophysiolog­ical features that parallel the human disorder. Trippodo and Frohlich (1981) previously have examined the validity of the SHR as a model of human hyper­tension.

Activation of Central and Autonomic Nervous Systems

Evidence reviewed in Chapter 9 suggests that hypertension risk in hu­mans is accompanied by enhanced activation of central nervous system car­diovascular control centers. Evidence from studies in SHRs supports this parallelism between hypertension risk and nervous system excitability. SHRs appear to be deficient in brain stem norepinephrine during their prehyperten­sive period and thus are low in alpha-2 receptor-mediated inhibition of the cardiovascular control centers in this area (yao, Matsumoto, Hirano, Kuroki, Tsutsumi, Uchimera, Nakamura, Nakahara, Masatoshi, 1989). Lesions ofselec­tive excitatory areas in the medulla of young SHRs reduce, but do not abolish, the later development of hypertension (Mangiapane, Skoog, Rittenhouse, Blair, & Sladek, 1989).

Exaggerated excitability of control centers in the medulla of SHRs is accompanied by enhanced neurogenic drive to the heart and blood vessels. Compared to WKY s, SHRs have a greater neural contribution to their heart rate and diastolic blood pressure reactivity, and this neural component is ele­vated well in advance of their hypertension (Smith, Poston, & Mills, 1984). This contribution by the nervous system to cardiovascular activity of SHRs is ac­companied by enhanced smooth muscle cell reactivity in the blood vessel wall.

268 CHAPTER FOURTEEN

Carotid artery strips from stroke-prone SHRs show faster and larger respons­es to vasoconstrictive agonists compared to WKY strips. These hyperresponses are attenuated by the application of calcium channel blockers (Thompson, Bruner, Lamb, King, & Webb, 1987).

These studies argue that in SHRs, the prehypertensive state is associated \\ith exaggerated nervous system reactivity that is related to enhanced activa­tion of the heart and blood vessels. This heightened reactivity potentially is associated with alterations in sodium, potassium-adenosine triphosphatase (Na,K-ATPase) dynamics-associated with calcium channel activation of smooth muscle cells and with excitability of nerve cells.

Of relevance to our understanding of human hypertension development are data from studies of chronic stress in SHRs and the borderline hyper­tensive rat (BHR), which is an SHR-WKY hybrid (first-generation offspring of SHR and WKY). The progress of hypertension in the SHR can be accelerated by exposing the animals to chronic stress (yamori, Matsumoto, Yamabe, & Okamoto, 1969). Similarly, the progress of their hypertension may be retarded by exposure to an understimulating home cage environment (Hallback, 1975). Chronic exposure of BHRs to prolonged daily shock avoidance produces sus­tained hypertension, but it does not do so in WKY controls (Lawler, Barker, Hubbard, & Allen, 1980; Lawler & Cox, 1985).

These latter studies provide reasonable evidence that the organism­environment interaction, coupled with exaggerated nervous system and car­diovascular reactivity, may be a contributor to the development of hyper­tension.

Structural Adaptation

Folkow (1990) has argued persuasively that regardless of the ultimate cause, the structural development of the blood vessels and heart plays an essential proximal role in the progression and maintenance of hypertension. Cardiac hypertrophy (increased left-ventricular mass, thickened posterior wall and septum) and thickened artery walls were long viewed as consequences of hypertension. More recent studies, however, have shown that these structural changes accompany and, in Folkow's view, may even take precedence in the development of hypertension. Greater vascular wall thickness and greater wall thickness to luminal diameter ratios have been observed in neonatal and pre­natal SHRs in comparison to WKYs (Eccleston-Joyner & Gray, 1988). Thus, SHRs may begin life with a tendency toward vascular hypertrophy. These hypertrophic tendencies should be especially responsive to episodes of elevated pressure resulting in rapid cellular proliferation (see Folkow, 1990, for a de­tailed discussion).

Normotensive strains of rats will show vascular wall thickening to repeat­edly induced episodes of high blood pressure (Owens & Reidy, 1985; Plunkett & Overbeck, 1988). These changes are reversible, however, and do not produce

HYPERTENSION MODEL 269

sustained hypertension. Similar manipulation of blood pressure in normoten­sive dogs produces cardiac hypertrophy but not sustained hypertension (Julius, Li, Brant, Krause, & Buda, 1989). In SHRs, however, stressor-induced pressor episodes permanently alter the course of their hypertension (Hallbiick, 1975). There thus appears to be a factor at work in the SHRs by which pressor episodes result in vascular wall alterations that have a self-sustaining, positive feedback effect, as depicted in the model in Figure 1.

Structural factors also appear to play an early role in hypertension devel­opment in humans. Among 12-year-old children in the upper 20% of the blood pressure distribution for their age, either cardiac output or vascular resistance was found to be elevated at rest, and left-ventricular mass was found to be high (Schieken, Clarke, & Lauer, 1981). Among normotensive adolescents, those with one or two hypertensive parents (PH +) have been shown echocardio­graphically to have significant cardiac hypertrophy in comparison to adole­scents with normotensive parents (PH -; Alli, Avanzini, DiTullio, Mariotti, Salmoirago, Taioli, & Radice, 1990).

Kishi and Inoue (1990) have advanced a hypothetical model relating func­tional, and ultimately structural, alterations in resistance vessels of SHRs to an initial alteration in calcium channel regulation that is of genetic origin. This is in keeping with Folkow's (1982) argument that an unknown agent causes greater energy exchange in sodium pumps of SHRs, thus implicating the N a,K-ATPase system and resulting in prolonged activation of calcium channels.

The resting state of vascular smooth muscle and other excitable tissues is brought about by membrane pumps along with the ion channels of the semi­permeable cell membrane. The membrane pumps therefore actively achieve and maintain the electrochemical gradient known as the resting potential. In order to maintain the resting state of vascular smooth muscle, sodium is pumped out and potassium enters into the cell. In addition, transport of calcium across cellular and intracellular membranes is also essential to terminate con­tractions and to maintain muscle relaxation. Energy to fuel these membrane pumps is provided by ATP. The enzyme ATPase splits ATP, which -is then converted to adenosine diphosphate (ADP), and energy is liberated. While vascular smooth muscle undergoes spontaneous, rhythmic contraction and re­laxation, sympathetic nerve impulses will also initiate contraction. When a nerve impulse arrives, excitation of the cell membrane results in a reduced potassium permeability, but a highly increased sodium permeability, through selective opening of sodium ion channels. Sodium ions flow rapidly into the cell, resulting in an increased membrane permeability to calcium ions. Calcium entry into the cell is thus coupled to this rapid sodium influx.

The increased intracellular calcium concentration during smooth muscle excitation activates intracellular contractile protein mechanisms, causing the muscle cell to contract. The extent and duration of contractions resulting from this excitation-contraction coupling between sodium and calcium may be modified by neurohormonal and other influences. In turn, relaxation occurs

270 CHAPTER FOURTEEN

when the membrane's resting state permeabilities are reestablished, and the intracellular calcium concentration is correspondingly reduced by the mem­brane pumps. Therefore, relaxation and maintenance of the resting state of the smooth muscle cell is an active, energy-consuming process that is fueled by ATP.

It is possible for regulation of the calcium and sodium channels to be altered so that more energy than normal is needed to end a contraction or maintain a state of rest. In this case, the smooth muscle cell may be rendered hyperexcitable. As a result, the cell will contract to a smaller excitatory stim­ulus and also maintain a longer, more vigorous contraction. Similar alterations may occur in the excitability of neuronal systems activated by sodium-potas­sium gradients. The consequences for the organism would be enhanced ex­citability of nervous system centers, hyperreactivity of the heart and blood vessels, a resulting blood vessel wall thickening, and cardiac alterations sec­ondary to pressure overload. The reader is referred to Folkow (1982) for an extended discussion of these issues.

It is therefore possible that in the SHRs, alteration of sodium and/or calcium channel mechanisms may produce hyperexcitability of the nervous system, resulting in functional hyperresponsiveness of the cardiovascular sys­tem, along with direct alterations in the activity of the vascular smooth muscle. Both of these influences may result in hypertrophy of the heart and resistance vessels. The SHR recently has been shown to have enhanced sodium channel activation in vascular smooth muscle cells accounting for increased vascular reactivity in this strain of rats (Davies, Ng, Ameen, Syrne, & Aronson, 1991). In a later section, we will present evidence concerning the joint occurrence of cardiovascular hyperreactivity and hypertension risk.

In the present model of hypertension, episodes of pressure elevation in hypertension-prone organisms are capable of producing structural alterations in the cardiovascular system, thus aggravating the course of hypertension in SHRs. Evidence of early structural alterations in young PH + subjects argues for a parallel set of processes in humans. The inability of researchers to produce sustained hypertension following induced pressor episodes in normotensive animal strains argues that a genetic background for hypertension is needed to activate the positive feedback loop between structure and function that is characteristic of the SHR.

Renal and Endocrine Factors

Studies reviewed above suggest that an inborn factor seems necessary to allow cardiovascular responses to lead to the permanent structural and func­tional alterations needed to maintain hypertension. We briefly will review studies that point strongly, if not conclusively, to the causal role of the kidney. These renal influences appear to be mediated via the Na,K-ATPase system and the related calcium channel mechanism.

HYPERTENSION MODEL 271

It is possible without the use of immunosuppressive drugs to transplant kidneys between WKYs or SHRs and BHRs but not between WKY-SHR pairs. Rettig and colleagues (Rettig, Folberth, Strauss, Kopf, Waldherr, & Unger, 1990b) transplanted kidneys to BHRs from adult WKYs and SHRs, both of which were treated with antihypertensive medication. The BHR hybrids thus received kidneys from groups of adult rats that both had normal blood pres­sures but differing genetic backgrounds for hypertension. Recipients of SHR kidneys became permanently hypertensive. Recipients of WKY kidneys did not. BHR animals also acted as donors to the other groups; in this case, SHR recipients of BHR kidneys did not become hypertensive, and, as expected, neither did the WKY recipients. The area of renal transplantation and hyper­tension has been extensively reviewed (Rettig, Folberth, Kopf, Strauss, & Unger, 1990a), and several lines of evidence converge on the conclusion that hypertension may be transmitted to recipients of hypertensive kidneys, and normotension may be transmitted to otherwise-hypertensive recipients of nor­motensive kidneys. A variety of controls has been instituted to rule out known sources of confounding and artifact.

In an analogous study in humans, six hypertensives had their kidneys removed because of nephrosclerosis caused by hypertension. All patients showed cardiac hypertrophy prior to receipt of a kidney from a normotensive donor. Following transplantation, all six became normotensive and showed complete or nearly complete reversal of their cardiac hypertrophy (Curtis, Luke, Dustan, Kashgarian, Welchel, Jones, & Diethelm, 1983).

The renal transplantation studies are consistent with two alternatives: Either (1) the kidneys of hypertensive rats and humans secrete a pressor substance or (2) they fail to remove a circulating pressor substance produced elsewhere. This research shows that the kidney of the SHR is not only neces­sary to initiate hypertension but also to maintain the state once it has occurred. We note that there is another family of models of hypertension development that also gives a primary role to the kidney. These assume an inborn defect of sodium and/or water excretion in the kidney of hypertensives. This defect is argued to be the cause of a persistent volume expansion that results in hyper­tension. A recent example is a model proposed by deWardener (1991). These models are distinguished from the model proposed here primarily in their assumed defect in sodium excretion. Whether the renal alteration is an excre­tion defect or the production of an endogenous pressor substance, however, either type of renal alteration would be consistent with the other elements in the model we present here. The sodium-excretion defect model, however, lacks a compelling candidate for an exaggerated reactivity tendency and the neces­sary proneness toward vascular hypertrophy. Future research will have to resolve this issue.

Research with parathyroid tissue indicates that organs other than the kidney are also candidates for the source of a pressor substance involved in hypertension. Pang and colleagues have shown that parathyroid glands of

272 CHAPl'ER FOURTEEN

SHRs possess a previously unidentified cell type that is absent in tissue from the WKY. Removal of the parathyroid decreases blood pressure in SHRs, and the transplanted parathyroid of the SHR increases blood pressure in nonno­tensive rats (pang, Kaneko, & Lewanczuk, 1990).

This complex area is reviewed only briefly here, however, the renal trans­plantation studies and the work on parathyroid tissue are both complemented by other research that shows that extracts from the plasma of human hyper­tensives, but not nonnotensives, may increase tension in isolated aortic strips from nonnotensive rats (Pillai & Sutter, 1989; Zidek, Bachmann, Schluter, Witzel, Storkebaum, & Sachinidis, 1990). An extract of human hypertensive plasma was also found to produce transient increases of 23.6 mm iIg in mean arterial pressure of intact Sprague-Dawley rats (Lewanczuk, Resnick, Blu­menfeld, Laragh, & Pang, 1990). The substances involved in each case do not appear to be any previously identified pressor agent.

Therefore, recent research has produced at least two candidate organs that may produce circulating substances capable of altering calcium dynamics at the smooth muscle cell membrane. Either or both may be responsible for the responsivity and structural alterations associated with hypertension develop­ment.

INTERACTIONS WITH SMOOTH MUSCLE

The apparent existence of a circulating agent that contributes to hyper­tension is consistent with the hypothesis that a biochemically active substance may enhance activity of smooth muscle cells, perhaps prolonging contractions and contributing to vascular hypertrophy. Recent work has shown that me­tabolites of arachidonic acid produced in the kidney of SHRs may produce hypertension, and prevention of these metabolites prevents the hypertension (Sacerdoti, Escalante, Abraham, McGiff, Levere, & Schwartzman, 1989). One renal metabolite of arachidonic acid inhIbits Na,K-ATPase (Rettig et al., 1990a) and thus may contribute to prolongation of smooth muscle cell contractions. There are also indications that a circulating substance may be structurally related to ouabain that has digitalislike actions, including inhIbition of sodium pumps in vascular smooth muscle cells. An endogenous ouabainlike compound has been isolated from the plasma of hypertensive humans and has been shown to increase the force of contraction of isolated guinea pig atrial strips and aortic segments-during stimulation but not at rest (Bova, Blaustein, Ludens, Har­ris, Duchanne, & Hamlyn, 1991). Such a substance or substances would have the effect of enhancing the magnitude and duration of the vascular response to a given amount of afferent autonomic stimulation. Supporting studies in hu­mans have shown that PH + and PH - persons differ in response to calcium channel blockade as indexed by larger changes in renal plasma flow and in­creased sodium excretion rate in the fonner group (Montanari, Vallisa, Ragni, Guerra, Colla, Novarini, & Coruzzi, 1988). Although reasonable candidates now

HYPERTENSION MODEL 273

exist, our hypothetical substance acting as the mediating link between the kidneys and the hyperactive vascular smooth muscle cell is speculation until a substance is definitively characterized in those with hypertension and clearly has the necessary actions.

CARDIOVASCULAR REACTIVITY AND HYPERTENSION RISK IN SHRs

The existence of both an increased risk for hypertension and enhanced cardiovascular activity in SHRs raises the question of the relationship between the risk and the reactivity. On the one hand, they may be unrelated charac­teristics that are both present in SHRs as well as in some humans at risk for hypertension. On the other, the presumed causal agent may itself produce the reactivity. For example, an agent capable of acting on Na,K-ATPase and calc­ium channel mechanisIDS may well enhance activity in medullary cardiovascular control centers. Recent work with SHR-WKY hybrids favors the first alter­native. Inbreeding of SHR-WKY hybrids has produced two new rat strains. The first, known as WK.-HA, shows behavioral hyperactivity and cardiovascular lability, both important characteristics of SHRs but that are absent in WKYs. The second, known as WK.-HT, lacks behavioral or cardiovascular hyperreac­tivity but does become hypertensive (Hendley, Wessel, & VanHouten, 1986). The WK.-HAs have elevated plasma norepinephrine concentrations, and during foot shock stress, they show large catecholamine responses, similar to those shown by SHRs and larger than responses shown by WKYs or WK.-HTs (Hendley, Cierpal, & McCarty, 1988). When all four of the above strains were exposed to air-jet stress, the WK.-HAs and SHRs showed large cardiovascular responses while the WKYs and WK.-HTs did not (Knardahl & Hendley, 1990).

These studies show that the tendencies for hypertension and cardiovas­cular hyperreactivity seen in SHRs are genetically separable and that cardio­vascular hyperreactivity does not of necessity precede the hypertension. On the other hand, the postulated Na,K-ATPase actions of a circulating causative agent suggest that a coexisting cardiovascular hyperreactivity would enhance the development of vascular structural adaptation, as occurs in SHRs. Such a combination would contribute to the positive feedback relationship called for by the model in Figure 1. The foregoing argument is consistent with the fact that decreasing stimulation in SHRs (Hallback, 1975) merely retards hypertension but does not prevent it. The view that emerges from these considerations is that cardiovascular hyperreactivity contributes to hypertension development-but does not cause it.

CRmCAL PERIODS

Another consideration in our speculation about the causes of hypertension has to do with the possibility that a critical period exists for the development of the disorder. Unger and Rettig (1990) have discussed this interesting possi-

274 CHAP1'ER FOURTEEN

bility. There are at least three converging sets of evidence. First, treatment of SHRs from weeks 6 to 10 with an angiotensin-converting enzyme inhibitor caused a pennanent alteration in the course of their blood pressures (Harrap, Van der Merwe, Griffin, MacPherson, & Lever, 1990). Second, prevention of renal metabolites of arachidonic acid was similarly effective in 7-week-old but not in 20-week-old SHRs (Sacerdoti et 01, 1989). Third, studies cited in Chapter 9 show that human borderline hypertensives often, but not always, pass through a stage of elevated cardiac output that later diminishes.

Should there prove to be a critical period in the development of hyper­tension, studies of cardiovascular reactivity would most productively focus on adolescent humans.

HERITABILITY OF RESTING BLOOD PRESSURE AND CARDIOVASCULAR REACTMTY IN HUMANS

A review of twin studies of cardiovascular function is provided in Chapter 5. Some brief comments are provided here because of their relationship to studies of BHR offspring of SHR-WKY matings.

Resting blood pressure has a very large genetically determined component relative to environmental effects, as shown in studies of twins reared apart (Bouchard, Lykken, McGue, Segal, & Tellegen, 1990). Another twin study of resting blood pressure and cold pressor responses suggests a significant, gen­etically transmitted reactivity tendency. McIlhaney, Shaffer, and Hines (1975) reported larger intraclass correlation coefficients and smaller intrapair vari­ances in blood pressure response to cold pressor in monozygotic twins com­pared to dizygotic twins. Similarly, in a test of cardiovascular responses to mental arithmetic challenge and work on a video game, monozygotic twins have been shown to have greater concordance than dizygotic twins in heart rate response (Turner, Carroll, Sims, Hewitt, & Kelly, 1986). These studies showing heritability of cardiovascular function measured at rest and in response to a variety of challenges complement those reviewed above showing familial trends in resting blood pressure. They are of particular interest in light of strong genetically transmitted tendencies toward hypertension and exaggerated car­diovascular reactivity in SHRs.

FAMILIAL BLOOD PRESSURE TRENDS IN HUMANS

As we noted in Chapter 9, PH + persons are at roughly twice the risk of future hypertension as PH - persons (Hunt, Williams, & Barlow, 1986), indi­cating a significant familial trend in resting blood pressure and hypertension. Given the possibility that the risk of hypertension and exaggerated cardiovas­cular reactivity may be separable traits in SHRs, we ask in this section and the next how closely these are associated in humans.

HYPERTENSION MODEL 275

We also mention potentially interesting evidence concerning parental fac­tors. Again, findings from the SHR model may provide some useful guides. When BHRs were examined for cardiovascular responses to handling stress, those having SHR dams showed more rapid and sustained cardiovascular responses than offspring of SHR sires (Woodworth, Knardahl, Sanders, Kirby, & Johnson, 1990). Related evidence in humans suggests that family blood pressure trends are stronger for maternal blood pressure than paternal blood pressure. Munger, Prineas, and Gomez-Marin (1988) noted that childrens' blood pressures were more strongly correlated with their mothers' than with the fathers' pressures. Pearson r correlations of systolic/diastolic pressures for parent-child pairs were mother-daughter (.32/.17), mother-son (.22/.17), father­daughter (.19/.15), and father-son (.15/.13). The systolic pressure correlation for mother-daughter pairs was significantly greater than for father-daughter pairs (p<.05). When comparing biological parent-child pairs with adoptive pairs, these authors found that systolic pressures of biological mother-daughter pairs were more strongly correlated than were pressures of adoptive mother-daugh­ter pairs (p<.05), again suggesting a maternally transmitted influence. The authors concluded that the larger correlations between mother-child pairs were evidence of greater rearing and nurturing effects of mothers on their children. Data cited above from the twin studies, however, argue that the inherited component of blood pressure is considerably greater than that due to the family environment. The relative correlations between biological versus nonbiological mother-daughter pairs in the Munger and coworkers' study may be viewed in a similar light.

The SHR data suggest that reactivity is transmitted more strongly by the dam than by the sire. Data published by Munger et al (1988) suggest that resting blood pressure is transmitted more strongly by the mother than the father. An implication of these far-from-conclusive data is that studies of re­activity in PH + and PH - persons may benefit from separating PH + subject groups into subgroups based on the gender of the hypertensive parent.

RELATIONSHIP BETWEEN CARDIOVASCULAR REACTIVITY AND HYPERTENSION RISK

A straightforward application to humans of research using SHRs would lead to the prediction that borderline hypertensives are destined to become hypertensive (BP :2: 160/95 mm Hg) and that such persons will show a hyper­kinetic circulatory state with exaggerated blood pressure rises to various chal­lenges. Relevant studies on humans do not support such blanket assumptions, however. Among borderlines followed for 12 to 15 years, 89% were nonnoten­sive at follow-up (Froom, Bar-David, Ribak, VanDyk, Kallner, & Benbassat, 1983). In a Japanese sample followed for 10 years, 19% became hypertensive,

276 CHAPTER FOURTEEN

53% of whom were PH + persons (Sasakawa, Fujii, Hogi, Shinera, Tsumira, Seld, Wada, & Kobata, 1983). As noted in Chapter 9, in a sample of 286 borderlines and 186 nonnotensives, 24% of the borderlines showed a hyper­kinetic resting state (Julius, Schork, & Schork, 1988). Among the hyperkinetics, 77% were borderline hypertensives and 23% were nonnotensives. The nonno­kinetic borderlines showed depressed cardiac responses to sympathetic ner­vous system stimulation and increased venous return (a depressed Frank­Starling response; Julius, Randall, Esler, Kashima, Ellis, & Bennett, 1975). These studies suggest that human borderline hypertension represents a range of true hypertension risk and a wide variation in cardiovascular response to stimulation.

The precise coincidence of elevated resting pressure, cardiovascular hy­perreactivity, and ultimate risk is not yet known. Evidence, however, suggests that cardiovascular hyperreactivity and potential risk are only modestly related in samples of young nonnotensives. In a study of predictors of cardiovascular responses to mental arithmetic challenge, we indeed found that PH + young men had larger blood pressure rises from baseline than did PH - young men (Sausen, Lovallo, & WIlson, 1991). Heart rate hyperreactors, detennined by heart rate change to a subsequent cold pressor, were also hyperreactive in heart rate change to the mental arithmetic. The PH + and PH - subgroups, however, were equivalent in heart rate responses to both cold pressor and mental arithmetic. In a similar study, high-risk young men (PH + and systolic pressure :t 125 mm Hg at rest) were greater than low-risk men in blood pressure change to mental arithmetic (Everson, Lovallo, Sausen, & WIlson, 1992), but their heart rate responses to cold pressor did not enhance prediction of their responses to mental arithmetic. It should be noted that these studies may merely point to weaknesses in the cold pressor as a reactivity challenge. They also suggest that in persons exposed to mental stressors, those presumed to be at high risk may have changes in blood pressure that are exaggerated but changes in heart rate that are normal. The overlap between blood pres­sure response distrIbutions of high- and low-risk groups makes it difficult to predict the degree of reactivity for an individual high-risk person. Finally, heart rate response tendencies were not different between PH + and PH­groups in either study, and so some response parameters appeared to be related to risk and some not. These comments apply to studies done on predominantly white populations. In Chapter 7, the authors noted that PH + and PH - groups of blacks have not been found to differ in cardiovascular re activity.

Longitudinal studies with large groups will be needed before more is known about the extent to which cardiovascular hyperreactivity increases risk prediction in young nonnotensives. The separability of hypertension risk from the tendency for cardiovascular hyperreactivity in SHRs and the wide range of cardiac responsiveness in human borderline hypertensives suggest caution in approaching this question.

HYPERTENSION MODEL 277

IMPLICATIONS

MODELS OF CARDIOVASCULAR REACTMTY AND HYPERTENSION RISK

Manuck, Kasprowicz, and Muldoon (1990) outlined four models relating cardiovascular hyperreactivity to risk of hypertension. In the first model, hy­perreactivity may be a marker for increased risk but acts neither as a cause nor as an enhancer of risk. In the second, the reactivity tendency may be directly causal. In the third, reactivity acts as a cause only when evoked by frequent behavioral challenges. In the fourth, cardiovascular hyperreactivity modifies the risk of future hypertension but is not a direct cause. The model outlined in Figure 1 is consistent with the fourth alternative. The preponderance of renal transplantation data suggests that this is so.

We note in passing that the term essential hypertension is used here as if the disorder were a unitary entity. The extent to which the broad range of persons currently identified as having essential hypertension possesses a single disorder is unknown. The possible identification of one or more circulating factors may be a key to a better description of disease SUbtypes.

WHO Is AT HIGHEST RISK?

It is too early for finn conclusions, but selected evidence reviewed above indicates that knowledge that a person shows cardiovascular hyperreactivity may improve prediction of risk. The follow-up studies of young persons and adults showing large blood pressure rises to cold pressor, mental arithmetic, and dynamic exercise are the best evidence to date. Long-term prospective studies of reactivity as a suspected risk factor, such as those discussed in Chapter 15, are clearly called for if we are to improve upon existing risk prediction based on the standard risk factors.

A final consideration is that in any sample population, the subgroup identified as showing cardiovascular hyperreactivity may include a large per­centage of individuals who are not truly at risk for hypertension. This suggests that the ultimate risk prediction model should include ways of eliminating this group of false positives if it is sufficiently large.

AcKNOWLEDGMENTS

Preparation of this chapter was supported by funds from the Medical Research Service of the Department of Veterans Affairs and by a grant from the National Heart, Lung and Blood Institute (HL32050).

We thank Cynthia Sabouri and Jack Shepard for their careful work in preparation of this chapter. We further thank Sue Everson, who generously commented on earlier versions.

278 CHAPTER FOURTEEN

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CHAPTER FIFTEEN

High Cardiovascular Reactivity to Stress

A Predictor of Later Hypertension Development

KATHLEEN C. LIGHT, ANDREW SHERWOOD, AND J. RICK TURNER

INTRODUCTION

Recently, considerable debate has been sparked concerning the strength of published evidence supporting what has been called ''the Reactivity Hypoth­esis." This hypothesis, as most broadly defined, is that greater cardiovascular reactivity to behavioral stressors may play some role in the development of sustained arterial hypertension. Thus, when focusing on the wide individual differences in blood pressure, heart rate, cardiac output, or any other cardio­vascular responses that are evoked by a stressor, it is postulated that the high reactors will have an increased risk of becoming hypertensive over time. Some re~ers (Pickering & Gerin, 1990) do not find the current evidence support­ing this hypothesis to be compelling, citing, among other things, the lack of many prospective investigations showing that high reactivity is a significant independent risk factor. Other authorities (Manuck, Kasprowicz, & Muldoon, 1990) prefer to see the gla&s half full rather than half empty, and they find the combination of a great deal of consistently supportive indirect evidence and positive results from the relatively few prospective studies to encourage fur­ther, better-designed tests of the Reactivity Hypothesis.

KATHLEEN C. LIGHT, ANDREW SHERWOOD, AND J. RICK TuRNER • Deparbnent of Psychiatry, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599-7175.

281

282 CHAPTER FIFTEEN

The objectives of the present chapter are to summarize the few prospec­tive studies of stress reactivity in man completed to date. Longitudinal studies of one animal model, the borderline hypertensive rat, which develops hyper­tension when exposed to chronic stressors, will also be described as a contrast­ing approach to help highlight what we can and cannot hope to learn from our less controlled but ultimately most definitive human research.

HIGH PRESSOR RESPONSE TO THE COLD PRESSOR TEST ENHANCES RISK OF HYPERTENSION

High reactivity to the cold pressor test has been evaluated as a potential risk factor for hypertension since the 1930s, when Hines and Brown first standardized the procedure and promoted its use as a clinical predictor equival­ent to borderline hypertension and a positive family history of hypertension (see Hines & Brown, 1936). Hines (1940) reported the results of the first long-term study on reactivity, a six-year follow-up of 66 initially normotensive individuals; development of hypertension had occurred in one-third of the high reactors versus none of the low reactors. There followed a number of other similar follow-up studies focusing on the relationship of cold pressor reactivity to subsequent hypertension development, but several (including some with larger sample sizes) failed to replicate the original finding (Armstrong & Raff­erty, 1950; Eich & Jacobsen, 1967; Harlan, Osborne, & Graybiel, 1964).

In recent years, however, two larger scale studies incorporating a more extended follow-up interval have brought renewed attention to cold pressor reactivity as a potential predictor of hypertension. The first of these investiga­tions (Wood, Sheps, Elveback, & Schirger, 1984) reported the findings of a 45-year follow-up study of 142 subjects originally tested as children aged 7 to 17 years by Hines and Brown in 1934 and then retested in 1961 as adults aged 34 to 44 years. The cold pressor procedure involved obtaining basal supine blood pressure (after a minimum of a 30-minute rest) then immersing one hand and wrist in ice and water for one minute. "HypelTeactors" were defined as subjects who showed systolic increases of 25 mm Hg or more or diastolic increases of 20 mm Hg or more at either the 1934 or the 1961 testing or both while all subjects showing lesser increases at both test times were classified as "normoreactors." In 1979, 68% of subjects who had been hypelTeactors as children, and 61% of subjects who had been hyperreactors at either test time, were hypertensive, in contrast to only 19% of subjects who had remained normoreactors. The results also indicated that classification as a hypelTeactor in 1934 was the single strongest predictor of blood pressure level in 1979, followed by peak level during the cold pressor in 1961 (not reactivity), casual systolic and diastolic levels in 1961, and family history of hypertension.

This study, although clearly yielding results supportive of the Reactivity Hypothesis, was found to be less than totally definitive, for these principal reasons (Horwitz, 1984). First, the initial cohort tested in 1934 included 300

HIGH CARDIOVASCULAR REACTMTY 283

subjects; Wood et ol (1984) failed to obtain outcome data in 1979 from fully half of them because they had not been retested in 1961, an omission that may have biased the final follow-up sample. Second, the decision to classify as hyper­reactors those who showed larger pressor responses either as children or as adults does not fulfill the criterion set for such prospective research, namely, that classification of reactivity is to be made at a single uniform time in the course of their development. Third, their statistical analysis did not make it clear whether hyperreactivity added significant additional predictive power to the standard clinical predictors, family history of hypertension, and casual blood pressure level.

The second recent investigation on cold pressor reactivity and hyper­tension development settled many of these remaining doubts (Menkes, Mat­thews, Krantz, Lundberg, Mead, Qaqish, Liang, Thomas, & Pearson, 1989). In this prospective study, 910 white males (95% of eligible students attending Johns Hopkins Medical School from 1948 to 1964) were tested just as described previously. The way in which hypertension status was determined during fol­low-up, however, was quite different. Self-reported follow-up information on blood pressure and family history of hypertension was obtained not once but annually by mail surveys for the 20- to 36-year follow-up period. The response rate was excellent for any given five-year period (87 to 94%), and since these participants were physicians, it was felt that their responses to the surveys were highly accurate. Their results were analyzed in several ways to address specific issues. First, to determine the impact of age on the relationship of reactivity to hypertension, a survival curve analysis was used with age to hypertension as the outcome measure. This revealed that subjects who showed a systolic pressure increase placing them in the top quartile for reactivity had a greater incidence of hypertension from age 40 onward compared to other less reactive subjects and that the difference in hypertension incidence was greater for subjects who reported hypertension onset before versus after age 45 (Fig­ure 1). In addition, analyses employing Cox proportional hazards models confirmed that the risk associated with high systolic reactivity remained significant after partialing out the effects of other standard risk factors, in­cluding age, weight/height index, casual systolic pressure, family history of hypertension, and cigarette smoking. Heart rate and diastolic reactivity to the cold pressor were not significant predictors. These findings provide very robust evidence of the independent predictive relationship between high systolic re­activity to the cold pressor and hypertension development.

HIGH DIASTOLIC PRESSURE REACTMTY TO MENTAL ARITHMETIC PREDICTS EARLY HYPERTENSION

Although these recent findings by Wood et ol (1984) and Menkes et ol (1989) provide strong support for high systolic pressure reactivity as a predic­tor of later hypertension, they do not provide a clear test of a second expanded

284 CHAPl'ER FIFTEEN

c ~~ r 10.25 .-_J ~ r~ &. 0.20 r.J ~O.IS r---J r····J•• ••

-d 0.10 jI .. 'u rI .50.05 r.r-...r---.r'-····

. 1"~~~~~~~~~,~r~J~:;~~~~~~~~~~ ~ O.OOio 25 30 3S ••.• ~... 4S so SS 60

Age (years) t"IGURE 1. Cumulative incidence of hypertension of 15 to 30 years of follow-up according to level of systolic blood preIl811l'e change during cold pressor test at baseline. Based on change in blood pressure from baseline to the stressor, the three groups are: (1) lowest quartile (dots); (2) middle two quartiles (solid line); and (3) highest quartile (dashed line). Incidence of hypertension in the highest quartile is significantly different from the other two groups. (From Menkes et aL, 1989. Reprinted with permission from the American Heart Association.)

variation of the Reactivity Hypothesis. In this variation of the hypothesis, high reactivity itself plays a causal role in hypertension development in those cases where exposure to life stressors of sufficient chronicity and intensity occur, either independently or in conjunction with other genetic or environmental factors (e.g., high-salt diet or poor stress management and coping skills). This is in contrast to the less ambitious variation of the hypothesis, which leaves open the possibility that high reactivity may be a marker of hypertension risk simply because it is correlated with some other factor that is directly pathogenic. The data obtained using the cold pressor may be interpreted in either way; however, because the cold pressor is so unlike the stressors of daily life to which humans are chronically exposed, the argument that similarly high reactivity to life stressors is occurring chronically and thereby contributing to the eventual hypertension is not totally convincing.

Other investigations, however, have documented that reactivity to an ef­fortful mental task-mental arithmetic-is also predictive of later hyperten­sion. Such mental effort is a very common element of daily life stressors; thus, it is more convincing to argue that the individual who shows high reactivity to an arithmetic task may demonstrate the same exaggerated response repeat­edly over weeks, months, and years of his or her normal activities, thereby contributing to hypertension development. These two studies are somewhat less compelling than the work by Menkes et 01 (1989) because their sample sizes are considerably smaller and their follow-up period much shorter, but they represent important first efforts using reactivity to mental stress as predictors of hypertension. The first investigation examining reactivity to men-

HIGH CARDIOVASCULAR REACTIVITY 285

tal arithmetic as a predictor of hypertension (Falkner, Kushner, Onesti, & Angelakos, 1981) involved a 5- to 41-month follow-up (median 17 months) of 50 borderline hypertensive and 28 normotensive adolescents. Despite the rela­tively brief follow-up interval, 28 of the 46 borderline hypertensive children retrieved at follow-up (61%) had developed hypertension in contrast to none of the normotensive children. Hypertension was defined as maintenance of pres­sure levels above the 95th percentile for their age groups for at least three months. The results of this study point to an association between high reactivity to mental arithmetic and hypertension development, but they do not establish high reactivity as an independent predictor. The reported findings show that the borderline hypertensive group was more reactive to the arithmetic task at initial testing than the normotensive group and maintained peak reactivity longer during the task. These two groups, however, also differed in the in­cidence of positive family history of hypertension and obesity, as well as in baseline blood pressure, all of which may have contributed to the higher in­cidence of subsequent hypertension. Furthermore, those 18 borderline hyper­tensive children who did not demonstrate sustained hypertension at follow-up were not reported to be less reactive than those who did.

The second investigation provided stronger support for high reactivity to mental arithmetic as an independent predictor of later hypertension (Borghi, Costa, Boschi, Mussi, & Ambrosioni, 1986). This investigation involved a follow­up interval of five years in a study sample of 44 nonobese young adults, all of whom initially had borderline hypertension. At follow-up, 9 subjects (20%) had developed established hypertension while 35 had not. All of the hypertensive individuals had initially demonstrated hyperreactivity to a mental arithmetic task; 100% had shown high diastolic reactivity (increases greater than 25% of baseline) during the five minutes of stress exposure and failure of diastolic pressure to recover to baseline five minutes after the end of the task, in contrast to only 21 % of subjects who had not yet developed hypertension. Additionally, the subjects who had versus had not developed fixed hypertension did not differ in their resting systolic and diastolic levels at initial testing. These results indicate that high diastolic reactivity to mental arithmetic is a predictor of later hypertension development in young adults, independent of baseline blood pres­sure or obesity. Nonetheless, the authors underscored two points that have implications for future investigations. First, the sensitivity of reactivity during stress as a predictor was high, but without simultaneous consideration of failure to recover, its specificity was poor; many subjects who did not become hyper­tensive also showed high reactivity, but few of them maintained elevated blood pressure during recovery. Thus, future studies need to focus on responses during recovery as well as peak initial levels as predictors. Second, high dia­stolic reactivity was correlated with another predictor, high sodium concentra­tion within blood lymphocytes. This observation indicates that it still cannot be ascertained whether high stress reactivity itself plays a causal role or whether it is simply a marker for later hypertension.

286 CHAPl'ER FIFTEEN

HIGH HEART RATE AND BLOOD PRESSURE REACTIVITY AS PREDICTORS OF RESTING AND AMBULATORY BLOOD

PRESSURE ON FOLLOW-UP

Our own laboratory has recently completed a follow-up study in which baseline blood pressure levels versus reactivity measures to a reaction time task involving threat of shock as a performance incentive were compared as predictors (Light, Dolan, Davis, & Sherwood, 1992). In this investigation, all subjects were initially tested at age 18 to 22 years while college students. At the time of follow-up 10 to 15 years later, they were still all under age 37 and none of them had yet developed sustained hypertension. Therefore, this investigation was designed to focus on reactivity as a predictor of later differences in blood pressure levels rather than as a predictor of the development of sustained hypertension. Furthermore, since it was important to characterize follow-up blood pressure levels as fully as possible, in addition to clinical stethoscopic determinations, the 51 subjects who completed the follow-up testing also un­derwent ambulatory blood pressure monitoring during all of the waking activ­ities of a normal working day.

High absolute levels of systolic pressure during the active coping task were associated with higher stethoscopic and ambulatory systolic pressure 10 to 15 years later while high absolute levels of diastolic pressure were likewise asso­ciated with higher diastolic pressure at follow-up. More importantly, measures of reactivity (defined as task levels minus baseline levels) were found to be valuable predictors of subsequent blood pressure levels. Systolic blood pres­sure at follow-up was significantly predicted by a model incorporating three standard clinical measures: resting systolic pressure, resting diastolic pressure, and parental history of hypertension. Even so, the predictive model was significantly improved by adding systolic pressure reactivity as a fourth pre­dictor variable (R2 increased from 0.25 to 0.37). Thus, systolic pressure re­activity was found to yield additional predictive information about subsequent blood pressure beyond that provided by more traditional risk factors.

Diastolic blood pressure at follow-up was not reliably predicted by the model based on the three standard clinical measures. This failure is particularly important because an elevation in diastolic pressure in most cases establishes the clinical diagnosis of hypertension. A predictive model combining heart rate reactivity and diastolic pressure reactivity together with resting diastolic pressure did, however, strongly predict follow-up diastolic pressure levels (R2 = 0.37), with each of the three predictor variables contnbuting signifi­cantly to the model. The observation that diastolic reactivity was a significant addition in predicting follow-up diastolic pressure is consistent with the prior report by Borghi et aL (1986). This observation also complements prior findings by Parker, Croft, Cresanta, Freedman, Burke, Webber, and Berenson (1987), which showed that peak blood pressure level during three physical stressors is an important predictor of blood pressure among children after a three-year

HIGH CARDIOVASCULAR REACTIVITY 287

follow-up interval even after partialling out the effects of resting blood pres­sure.

Nevertheless, the strongest predictor of follow-up blood pressure levels among the reactivity measures was heart rate reactivity. Heart rate reactivity was a significant joint contributor in the three-component model predicting follow-up diastolic pressure described above. In addition, heart rate reactivity was also the only significant individual predictor of follow-up diastolic pressure (R2 = 0.18), showing a stronger relationship to later diastolic levels than any of the standard clinical measures or any of the other reactivity measures. High heart rate reactors defined at age 18 to 22 were found to show higher stetho­scopic and ambulatory systolic and diastolic pressures at follow-up than former low heart rate reactors (Figures 2 and 3). It is worth noting that these high and low heart rate reactors had virtually identical baseline blood pressure levels when initially tested. Thus, high heart rate reactivity was associated with evidence of a rise in blood pressure over this first decade of early adulthood.

Although somewhat speculative, one reasonable explanation for why heart rate reactivity should predict eventual blood pressure outcomes better than blood pressure reactivity is relatively simple. The active coping reaction time task used as a stressor in this study has been shown to elicit an increase in beta-adrenergic activity that increases heart rate and cardiac output but lowers total peripheral resistance due to beta-receptor-mediated vasodilation (Obrist, Gaebelein, Teller, Langer, Grignolo, Light, & McCubbin, 1978; Sherwood, Allen, Obrist, & Langer, 1986). Subjects who show a greater increase in sympa­thetic activity during this task should therefore show larger increases in heart rate; however, since blood pressure response would be influenced in opposite directions by increased cardiac output but decreased vascular resistance, the greater sympathetic activity shown by these subjects would not always result in a greater pressor response, particularly for diastolic pressure. Other re­search has indicated that high myocardial reactivity to a similar reaction time task is associated with similarly high reactivity to other stressors and to the same stressor over time spans as long as several months (Sherwood, Dolan, & Light, 1990a; Sherwood, Turner, Light, & Blumenthal, 1990b; Turner, Sher­wood, & Light, 1990; see also Chapter 1). Based on this evidence of stability of reactivity, it is highly plausible that an individual who manifests high sympa­thetic reactivity to mental challenges from early adulthood onward may develop hypertension from the effects of sympathetic activity on myocardial, vascular, and/or renal function.

INTEGRATION OF FINDINGS TO DATE AND RECOMMENDATIONS FOR FUTURE PROSPECTIVE STUDIES

To summarize the available prospective research on reactivity, there have clearly been few studies completed at this time. With the exception of some

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CHAPl'ER FIFTEEN

£-£ HIGH HR REACTORS ("=15)

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HIGH CARDIOVASCULAR REACTMTY 289

early research using the cold pressor as a stressor, however, the results have unifonnly indicated that high cardiovascular reactivity is a predictor of higher blood pressure levels and/or hypertension development at follow-up. The ob­servations from studies attempting to control for other risk factors, including family history of hypertension, resting level of blood pressure, and obesity, have consistently indicated that high reactivity is an independent predictor. The studies also suggest that high reactivity may be more strongly related to hypertension with an onset before age 45, but more investigations with a longer follow-up interval are needed to replicate this finding.

The studies reviewed previously have not yielded a consistent picture in terms of which cardiovascular index of reactivity is the best predictor. Menkes et al. (1989) obtained a significant relationship to hypertension only with sys­tolic reactivity while Borghi et al. (1986) observed a similar relationship only with diastolic reactivity and Light et al. (1992) observed predictive relationships to blood pressure levels with heart rate reactivity and, to a lesser extent, both systolic and diastolic reactivity. One possible explanation for these apparent inconsistencies is that the stressors used in all cases were different, ranging from the cold pressor (which is known to act predominantly via alpha-receptor activity that induces greater vasoconstriction) to an active coping reaction time task (which acts primarily via beta-receptor activity inducing enhanced cardiac output and lesser vasoconstriction; see Bolli, Amann, Hulthen, Kiowski, & Buhler, 1981; Sherwood et al., 1986). If one assumes that the goal of each of the reactivity assessments was not to detect the subjects with the greatest increase in any single cardiovascular index but the subjects with the greatest increase in generalized sympathetic activity, it is reasonable that the single index that reflects such activity best would be blood pressure for the cold pressor test and heart rate (or cardiac output) for the reaction time task.

Given the gaps in the present findings, it is certainly not yet established that high cardiovascular reactivity contributes in a direct causal fashion to hypertension development. Yet, can even an ideally designed prospective study in humans provide clear confirming or disconfirming evidence on this issue? The literature on animal models of stress-induced hypertension is relevant as a guide. The borderline hypertensive rat (Lawler, Cox, Sanders, & Mitchell, 1988) is one example of these models. Early studies with this rat, which is the offspring of one hypertensive and one normotensive parent, showed that it develops sustained and irreversible hypertension if exposed chronically to a stressful shock-shock conflict task but not if simply handled or placed daily in the experimental apparatus. Thus, in this genetically susceptible animal, stress exposure can play a causal role in hypertension development. Later studies, however, revealed that this animal also develops hypertension when placed on a high-salt diet without exposure to stress. Furthermore; exercise in the form of daily swimming prevented stress-induced hypertension. This means that either environmental factor, frequent stress exposure alone, or high-salt diet alone is sufficient to induce hypertension in this animal!

290 CHAPI'ER FIFTEEN

If we try to reexamine these findings according to a hypothetical scenario using the limitations of human prospective research, the difficulty of inferring causality becomes obvious. Our data are comprised of the following: (1) Young borderline hypertensive rats can be shown to be hyperreactive to stress ex­posure compared to rats with a different genetic make-up. (2) At follow-up, a majority of the borderline hypertensive animals have developed hypertension while none of the other rat strain has done so. If we were unaware of the direct manipulations of stress exposure in some animals and dietary salt intake in others, we might be led to the conclusion that hyperreactivity during chronic stress exposure played a causal role in the hypertension development of all borderline hypertensive rats and that those that did not become hypertensive were not exposed to sufficient stress. In some cases, we would be correct, but for the cases of animals fed a high-salt diet or for those stressed but also exercised, we would be wrong. Knowledge of the other important influences, diet and exercise, as well as knowledge of chronic stress exposure is needed to generate the correct interpretation of multiple causality.

It is obvious that longitUdinal human research over several decades cannot employ direct control over environmental factors, such as stress exposure, salt intake, and exercise habits. The compromise that must be substituted is to document the influence of these factors, regularly and as often as possible. The most powerful demonstration of the predictive power of reactivity to date is the study by Menkes and colleagues (1989), owing in part to its large sample, excellent retrieval rate on follow-up, and very long follow-up interval. These are all elements to strive for in an ideal prospective study. Additionally, its use of annual surveys is yet another unique and useful procedure that should be imitated in future research. In future projects, these surveys might be used to document individual differences in life stressors, diet, and exercise that may interact with reactivity to influence blood pressure outcomes. In­formation on life stressors should not be limited to major life events, such as loss of job or spouse, but should include ways of quantifying chronic sources of stress, such as job strain (Schnall, Pieper, Schwartz, Karasek, Schlussel, De­vereux, Ganau, Alderman, Warren, & Pcikering, 1990), lack of social support in the workplace or at home (Strogatz & James, 1986), and related factors. If such information were documented on an annual basis, along with hypertension status and recent blood pressure level, it would provide an impressive data base from which to assess the relative impact of stress exposure versus other influences.

The ideal prospective study should also build on our earlier observations in regard to reactivity assessments. Since previous studies have successfully demonstrated that reactivity measures are good predictors using a variety of stressors, and since it appears most desirable to document which individuals show greater sympathetic nervous system reactivity rather than just greater pressor response to a single task, there are strong arguments in favor of testing reactivity to a full battery of stressors. This battery should include stressors of

HIGH CARDIOVASCULAR REACTMTY 291

different kinds, including those that tend to evoke greater alpha-adrenergic activity (like the cold pressor test) and those that evoke greater beta-adrener­gic reactivity (like the reaction time task). It should definitely include one or more stressors that realistically elicit behaviors similar to common daily life events at work and at home, such as mentally engaging tasks or role play dealing with an interpersonal conflict situation. In addition, it might be most useful to assess reactivity to both active and passive coping stressors since these events tend to evoke different hemodynamic patterns, yet high myocar­dial and high vascular reactors have been shown to be consistent in the relative responses to these different events (Sherwood et al, 1990a).

Since prior investigations have suggested that reactivity is strongest as a predictor of hypertension prior to age 45, the ideal prospective study should initially test subjects early in development, preferably before age 25. A large sample may be obtained by using a multicenter approach or by the Menkes et al (1989) method of entering a new cohort each year. The most essential final ingredient for the ideal prospective study is, of course, patience. With an approach of obtaining updated survey data annually, shorter term outcomes may be easily tested, but the final goal should be a follow-up interval averaging 25 to 30 years at minimum.

With this approach in mind, it would be possible to test a number of new hypotheses. The first would be to test whether those individuals who show the most consistently high sympathetic reactivity (based on responses across all stressors, with greater weight given to the single cardiovascular index that shows the greatest percentage increase during each specific stressor) had an increased incidence of subsequent hypertension. The second would be to test whether this increased incidence of hypertension is evident only in those high sympathetic reactors who subsequently have reported above-average life stress on the annual surveys. This second test would actually provide the more definitive evidence that stress exposure and chronic bouts of high reactivity contribute directly to pathogenic changes. Third, the reactivity measures to various stressors might be compared to determine whether reactivity to a single stressor is a stronger predictor of later hypertension than reactivity to other stressors or the combined sympathetic reactivity measure. Fourth, fail­ure to recover to baseline levels after the end of stress should also be evaluated for its predictive power. Finally, the independence of predictive relationships from other risk factors, including family history, resting blood pressure, dietary salt intake, and exercise habits, should be assessed, along with interactions of these factors with reactivity.

It is the hope of the authors that a consensus will soon be reached among scientists in our field that major prospective evaluations of the long-term significance of high cardiovascular reactivity are not only warranted but man­dated. It is further hoped that scientists with vision, dedication, and exceptional tolerance for delay of gratification will soon begin working to address this high-priority research need.

292 CHAPl'ER FIFTEEN

ACKNOWLEDGMENTS

Portions of this chapter describe research supported by NIH grants 18976 and RROOO46.

REFERENCES

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Bolli, P., Amann, F. W., Hulthen, L., Kiowski, W., & Buhler, F. R. (1981). Elevated plasma adrenaline reflects sympathetic overactivity and enhanced alpha-adrenoceptor-mediated vas0-

constriction in essential hypertension. Clinical Science, 61, 161s-1648. Borghi, C., Costa, F. V., Boschi, S., Mussi, A, & Ambrosioni, E. (1986). Predictors of stable

hypertension in young borderline subjects: A five-year follow-up study. Journal of Cardio­vascular Pho:r",n,cology, 8(5),8138-8141.

Eich, R. H., & Jacobsen, E. C. (1967). Vascular reactivity in medical students followed for 10 years. Journal of Chronic Diseases, 20, 583-592.

Falkner, B., Kushner, H., Onesti, G., & Angeiakos, E. T. (1981). Cardiovascular characteristics in adolescents who develop essential hypertension. H~ 9, 521-527.

Harlan, W. R., Osborne, R. K., & Graybiel, A (1964). Prognostic value of the cold pressor test and the basal blood pressure: Based on an eighteen-year follow-up study. American Journal of Cardiology, 19, 6&1-687.

Hines, E. A, Jr. (1940). 8ignificance of vascular hyperreaction as measured by the cold pressor test. American Heart JoumaJ. 19, 408-416.

Hines, E. A, Jr., & Brown, G. E. (1936). The cold pressor test for measuring the reactibility of the blood pressure: Data concerning 571 normal and hypertensive subjects. American Heart JoumaJ. 11, 1-9.

Horwitz, R. I. (1984). Methodologic standards and the clinical usefulness of the cold pressor test: Editorial. H~ 6, 295-296.

Lawler, J. E., Cox, R. H., Sanders, B. J., & Mitchell, V. P. (1988). The borderline hypertensive rat: A model for studying the mechanisms of environmentally induced hypertension. Health Psychology, 7, 137-147.

Light, K. C., Dolan, C. A, Davis, M. R., & 8herwood, A (1992). Cardiovascular responses to an active coping challenge as predictors of blood pressure patterns 10-15 years later. Psychoso­matic Medicine, 54, 217-230.

Manuck, S. B., Kasprowicz, A L., & Muldoon, M. F. (1990). Behaviorally evoked cardiovascular reactivity and hypertension: Conceptual issues and potential associations. Annals of Behav­ioral Medicine, If, 17-29.

Menkes, M. S., Matthews, K. A, Krantz, D. S., Lundberg, V., Mead, L. A, Qaqish, B., Liang, K.-Y., Thomas, C. B., & Pearson, T. A (1989). Cardiovascular reactivity to the cold pressor test as a predictor of hypertension. H~ 14, 524-530.

Obrist, P. A, Gaebelein, C. J., Teller, E. S., Langer, A W., Grignolo, A, Light, K. C., & McCubbin, J. A (1978). The relationship among heart rate, carotid dP/dt, and blood pressure in humans as a function of the type of stress. Psychophysiology, 15, 102-115.

Parker, F. C., Croft, J. B., Cresanta, J. L., Freedman, D. S., Burke, G. L., Webber, L. S., & Berenson, G. S. (1987). The association between cardiovascular response tasks and future blood pressure levels in children: Bogalusa Heart Study. American Heart JoumaJ. 119, 1174-1179.

Pickering, T. G., & Gerin, W. (1990). Cardiovascular reactivity in the laboratory and the role of behavioral factors in hypertension: A critical review. Annals of Behavioml Medicine, If, 3-16.

HIGH CARDIOVASCULAR REACTMTY 293

Schanll, P. L., Pieper, C., Schwartz, J. E., Karasek, R. A, Schlussel, Y., Devereux, R. B., Ganau, A, Aldennan, M., Warren, K., & Pickering, T. G. (1990). The relationship between "job strain," work place diastolic blood pressure, and left ventricular mass index: Results of a case-control study. Journal of the American Medical Association, 263, 1919-1935.

Sherwood, A, Allen, M. T., Obrist, P. A, & Langer, A W. (1986). Evaluation of beta-adrenergic infiuences on cardiovascular and metabolic adjustments to physical and psychological stress. Psychophysiology,23,89-104.

Sherwood, A, Dolan, C. A, & Light, K. C. (l990a). Hemodynamics of blood pressure responses during active and passive coping. Psychophysiology, 27, 656-668.

Sherwood, A, Turner, J. R., Light, K. C., & Blumenthal, J. A (l990b). Temporal stability of the hemodynamics of cardiovascular reactivity. International Journal of Psychophysiology, 10, 95-98.

Strogatz, D. S., & James, S. A (1986). Social support and hypertension among blacks and whites in a rural, southern community. American Journal of Epidemiology, 124, 949-956.

Turner, J. R., Sherwood, A, & Light, K. C. (1990). Generalization of cardiovascular response: Supportive evidence for the reactivity hypothesis. International Journal of Psychophysiol­ogy, 11, 207-212.

Wood, D. L., Sheps, S. G., Elveback, L. R., & Schirger, A (1984). Cold pressor test as a predictor of hypertension. Hypertension, 6, 301-306.

Index

Active coping, 9, 10, 168 Activity Preference Questionnaire, 108 Adenosine triphosphate, 269, 270 Adolescents. See Children and adolescents Adrenergic receptors, SNS monitoring, 43-

44 Aerobic exercise, and cardiovascular re­

actiNity, 212-213 Aerobic fitness, and ambulatory blood pres­

sure, 54 Age

and ambulatory blood pressure, 53 and catecholamine levels, 36

Aggression, 113 Aldosterone, factors in secretion of, 58 Aldosteronism, and ambulatory blood pres-

sure, 58 Ambulatory blood pressure

affecting factors aerobic fitness, 54 age, 53 blood pressure profile, 53 electrolyte intake and regulation, 55 gender, 53 hypothalamo-pituitary-adrenal system,

57-58 physical demands, 52 race, 54

Ambulatory blood pressure (continued) affecting factors (continued)

renin-angiotensin system, 56-07 sympathetic nervous system, 66

invasive measurement of, 73--75 prediction from laboratory studies, 66-68 situations for highest and lowest levels, 52 typical pattern, 51-52

Anger, 109-110 and cardiovascular reactivity, 109-110 coping methods, 109, 110 measurement of, 109, 110

Anger Expression Scale, 110 Angiotensin II, and blood pressure, 57 Antihypertensive therapy, and catecholamine

levels, 37 Anxiety, 108-109

and cardiovascular reactivity, 108-109 measurement of, 108 situational anxiety, 108 stress reactivity in children/adolescents,

197-198

Blacks aerobic fitness and ambulatory blood

pressure, 54 African traditions of, 138 and John Henryism, 136-137

295

296

Blacks (continued) model for investigation of reactivity, 131-

139 coping resources, 138-139 genetic factors, 137-138 psychological factors, 136-137 sodium effects, 134-136 sympathetic nervous system effects, 133-

134 types of stressors, 132-133

predictors of hypertension blood pressure status, 129 family history, 1~129 personality, 129-130

and psychological stress, 16 responses compared to whites cardiovascu­

lar responses, 126-127 catecholamines, 127-128 neuropeptides, 128

socioeconomic factors and hypertension, 133, 137

and sodium excretion, 55, 252 stressors of, 131, 135 stress reactivity in children/adolescents,

191-192 Blood pressure

ambulatory. See Ambulatory blood pressure cardiovascular reactivity, individual differ-

ences, 10-12 and exercise, 15 and kidneys, ~248, 270-272 to measure cardiovascular reactivity, 7 and posture, 24-25 and stress, 15-16

Body surface area, stress reactivity in chil­dren/adolescents, 191

Borderline hypertension, 174-180 cold pressor studies, 179 exercise response, 178 exercise studies, 176

and physical stressors, 177 hyperkinetic circulatory state, 175 life stress responses, 179-180 and mental stressors, 177, 180 phannacologic challenge, effects of, 176 relationship to lett-ventricular mass, 178-

179 resting blood pressure, 177-178 risk factors for hypertension, 174-175

Caffeine, and catecholamine levels, 36-37 Cardiac output, 8 Cardiac preejection period, 8

Cardiovascular reactivity assessment of

administration of stressors, 8-10 physiological measurement, 7-8

biological theory of, 4-6 and hypertension, 275-277 individual differences

INDEX

blood pressure and heart rate responses, 10-12

hemodynamic response patterns, 12-14 individual differences and research, 4 past research, characteristics of, 90 psychological factors, 14-17

coronary-prone personality, 99-100 life events, 99 pathophysiology, 14-16 psychosomatic factors, 16-17 social support, 96-97

situational stability in responses, 19-25 extraneous influences, 24-25 laboratory-field generalization, 22-24 laboratory intertask consistency, 20-

22 stimuli used in research, 5 temporal stability in responses, 17-19 twin studies, 91-95 use of term, 3, 4, 167

Cardiovascular structural changes, and hyper­tension, 178-179,268

Catecholamines, 33-38 affecting factors

age,36 antihypertensive therapy, 37 caffeine, 36-37 hypertension, 34-35 meditation, 35-36 menstrual cycle, 38 race,34-35,I27-128 sodium, 34-35 Type A behavior, 35 type of stressor, 37-38

naloxone, effect ·on, 232 in pregnancy, 155 stress reactivity in children/adolescents,

192-193 Central nervous system, excitation, and hy­

pertension risk, 267-268 Children and adolescents

stress reactivity affective states, 197-198 and body surface area, 191 dietary factors, 193-195 family history, 1~190

INDEX

Children and adolescents (continued) stress reactivity (continued)

gender dift'erences, 190-191 honnonal activity, 192-193 racial dift'erences, 191-192 sexual maturation, 191 stressors, 195-196 Type A behavior, 196

structural factors and hypertension risk, 269

Chromogranin A, SNS monitoring, 39-40 Cold pressor tasks

and borderline hypertensives, 179 as predictor of hypertension, 282-283 reactivity studies, 9, 12, 18, 70, 173

Competitive personality, 112-113 and cardiovascular reactivity, 112-113

COPE,114 Coping, 113-114

active coping, 9, 10, 168 with anger, 109, 110 and blacks, 138-139 denial as. 114 measurement of, 114

Coronary-prone personality, 99-100 twin studies, 99-100

Critical period, in development of hyper­tension, 273-274

Cushing's syndrome and ambulatory blood pressure, 57-58 cause of, 57

Cyclic AMP, SNS monitoring, 42 Cynical mistrust

characteristics of, 107 measurement of, 107

Denial, as coping method, 114 Denial of Illness Scale, 114 Diet

cardiovascular responses to high and low sodium diet, 255-258

stress reactivity in children/adolescents, 193-195

Dominant personality, 112 and cardiovascular reactivity, 112

Dopamine beta-hydroxylase, and SNS mon­itoring, 39-40

Electrocardiogram, 7 Electrolyte intake, and ambulatory blood

pressure, 55 Emotionality, and emotional and motivational

arousal, 113

Epinephrine, centers of production of, 34 Essential hypertension

definition of, 222 developmental approach to, 222 research limitations, 223

297

and sympathetic nervous system, 223-224 Estrogen replacement therapy, and stress re­

sponse, 159-160 Exercise

blood pressure increase, 15 compared to psychological stress response,

5,6,15 exercise studies

acute aerobic exercise, 212-213 borderline hypertension study, 176, 178 cross-sectional studies, 208-209 hypertension reactivity study, 172-173 longitudinal studies, 210-212 and nonnotensives, 178

exercise testing ACSM guidelines, 206 protocols used, 206

methodological issues in study of, 204-205 exercise testing, 206-207 fitness assessment, 205-206 psychophysiological measures, 207-208 statistical approach used, 208 stress reactivity testing, 207

and .opioid neuropeptides, 236-238 positive effects of, 203-204, 235-236

Fear of failure, 115-116 Fight or flight

damage from, 16 and sympathetic nervous system, 4

Fitness assessment, 205-206 Follicle-stimulating honnone

and menopause, 156 and menstrual cYcle, 151

Framingham Type A scale, 115

Gender dift'erences and ambulatory blood pressure, 53 and coronary mortality, 148 stress reactivity in children/adolescents,

190-19l in stress response, 148-150 and Type A behavior, 116

Genes blacks and hypertension, 128-129, 137-138 and cardiovascular reactivity, twin studies,

91-95 gene-disease relationship, 88

298

Genes (continued) and hypertension, 169-170,274-275 and life events, 99 limits of genetic effects, 97-98 and obesity, 98 and resting blood pressure, 274-275 stress reactivity in children/adolescents,

189-190

Heart rate cardiovascular reactivity, individual differ­

ences, 1~12 comparisons, in reactivity studies, 170 as predictor of hypertension, 286--287

Heart transplant, and ambulatory blood pres­sure, 56

Hemodynamic response patterns, cardiova­scular reactivity, individual differences, 12-14

Hormones. See Reproductive hormones and stress

Hostility, 9-10, 11~111 and cardiovascular reactivity, 11~111 and catecholamine levels, 35 cynical mistrust, 107 potential for hostility, 11~111 stress reactivity in children/adolescents,

197-198 HR index, 72 Hyperkinetic circulatory state, in borderline

hypertensives, 175 Hypertension

blacks, 125-126 borderline. See Borderline hypertension and cardiovascular reactivity, 275-277 and catecholamine levels, 34-35 correlates of hyperreactivity in, 188 effects of, 166, 167-168, 2~270 essential. See Essential hypertension genetic factors, 169-170,274-275 hypertensive profile, 53 model of development of

activation of central and autonomic ner-vous system, 267-268

assumptions in, 266-267 critical period in development of, 273-274 flowchart of model, 266 and interactions of smooth muscle, 272-

273 renal factors, 27~272 structural adaptation in, 268-270

reactivity studies cold pressor studies, 173

INDEX

Hypertension (continued) reactivity studies (continued)

diastolic blood pressure, 171 exercise studies, 172-173 heart rate comparisons, 170 identification of hyperreactive subjects,

167 mental and psychomotor challenges, 173-

174 pharmacologic studies, 172 rationale for studies, 169 systolic blood pressure, 170 types of taskslstressors used, 168

white coat hypertension, 53 Hypotbalamo-pituitary-adrenal system

and ambulatory blood pressure, 57-58 opioid inhibition of, ~235

Impedance cardiography, to measure cardio­vascular reactivity, 7-8

Individual differences and autonomic nervous system activity,

223 cardiovascular reactivity

blood pressure and heart rate responses, 1~12

hemodynamic response patterns, 12-14 past research, characteristics of, 90 twin studies, 91-95

and research, 4 Inoculation effect, 195-196 Intertask consistency, cardiovascular re­

activity, ~22 Intrinsic sympathomimetic activity, nature of,

37

Jenkins Activity Survey (JAS), 106, 115, 116 John Henryism, and blacks, 136-137

Kidneys renal transplantation studies, 271 role in blood pressure, 246-248, 27~272

Laboratory stress testing and average ambulatory levels, 66-68 connection between lab and ambulatory re­

sponses,77-80 invasive measurement of ambulatory blood

pressure, 73-75 laboratory-field generalizations, 22-24 laboratory intertask consistency, 2~22 laboratory temporal stability, 17-19 prediction of real-life variability, ~73

INDEX

Laboratory stress testing (continued) prediction of response to real-life stressor,

75-76 self-monitored casual blood pressure, 65-66

Left-ventricular mass enlargement, and blood pressure, 178-179,268

Life events, and genes, 99 Life stress

and risk of hypertension, 179-180 stress reactivity in children/adolescents, 195

Little and Fisher Denial Scale, 114 Locus of control

internal and external and cardiovascular re­activity, 107

meaning of, 106 Luteinizing hormone

and menopause, 156 and menstrual cycle, 151-152

Manifest Anxiety Scale, 108 Marlow~rowne Social Desirability Scale,

108 Mate selection, and health behaviors, 96 Maximal exercise test, 206 Mean arterial blood pressure, measure of, 8 Meditation, and catecholamine levels, 35-36 Menopause

average age of, 155 and cardiovascular reactivity, 156-157 hormonal changes, pre-menopausal period,

156 Menstrual cycle

cardiovascular reactivity, 152-153 and biochemical measures, 153-154 and phase for study, 154

and catecholamine levels, 38 events of, 151-152 and stress, 152-154

Mental arithmetic test as predictor of hypertension, 284 reactivity studies, 11, 13-14, 18, 19, 20

Mental challenges and borderline hypertensives, 177, 180 as predictor of hypertension, 283-285 in reactivity studies, 173-174

Mirror trace tasks, reactivity studies, 12, 19 Multidimensional Coping Inventory, 114

Naloxone effect on catecholamines, 232 effect on pituitary hormones, 232, 235

N europeptides, blacks compared to whites, 128 Neuropeptide Y, SNS monitoring, 40

Norepinephrine, 34 increases in exercise studies, 172 SNS monitoring, 40-41 and type ofstressor, 12-13

Novaco anger scale, 109

299

Nulliparity, and coronary heart disease, 155

Obesity, and genes, 98 Opioid neuropeptides

individual differences and aerobic exercise, 235-238 blood pressure and orthostatic stressors, ~230

blood pressure and psychological stres­sors, 225--229

opioid inhibition of sympathoadreno­medullary and hypothalamo-pituitary­adrenocortical axes, 230-235

and stress reactivity, 224-225 Oral contraceptives, and stress responses,

158-159 Orthostatic stressors, and blood pressure,

~230

Ovulation, nature of, 152

Parathyroid glands, and blood pressure, 271-272

Personality aggressive personality, 113 angry personality, 109-110 anxious personality, 108-109 blacks, and hypertension, 129-130 choice and dispositional characteristics, 95-

96 competitive personality, 112-113 coping styles, 113-114 coronary-prone personality, 99-100 cynical mistrust, 107 dominant personality, 112 and emotionaVmotivational arousal, 104-105 hostile personality, 110-111 interactions between personality character­

istics, 118 and locus of control, 1~107 personality characteristics

definition of, 104 short-lived versus enduring, 104

power seeking personality, 112 and situation interaction, 117 stress reactivity in children/adolescents,

196-198 temperament and emotional arousal, 113 Type A behavior, 114-117

300

Phannacologic studies borderline hypertension study, 176 reactivity studies, 172

Pheochromocytoma, and hypertension, 56 Physical activity

and ambulatory blood pressure, 52, 54 and borderline hypertensives, 177 See also Exercise

Pituitary honnones, naloxone, effect on, 232, 235

Platelets, catecholamine content, 41 Posture

and borderline hypertensives, 177 and cardiovascular reactivity, 24-25

Potassium, stress reactivity in children/adole­scents, 194-195

Power seeking personality, 112 and cardiovascular reactivity, 112

Pregnancy, reproductive honnones and stress, 165

Prevailing state hypothesis, 167 Psychological factors

cardiovascular reactivity, 14-17 pathophysiology, 14-16 psychosomatic factors, 16-17 social support, 96-97

choice and dispositional characteristics, 95-96

mate selection and health behaviors, 96 stress and sympathetic outflow, 16 See also Personality

Psychological stress and blacks, 16, 136-137 and blood pressure, 225-229 compared to exercise response, 5, 6 and sympathetic nervous system, 5-6

Psychomotor challenges, in reactivity studies, 174

Puberty reproductive honnones and stress, 150-

151 stress reactivity in children/adolescents,

191, 192-193 Pupillometry, SNS monitoring, 41-42

Race and ambulatory blood pressure, 54 and catecholamine levels, 34-35 stress reactivity in children/adolescents,

191-192 Reaction time test, reactivity studies, 5, 9,11,

12,19 Recurrent activation hypothesis, 167

INDEX

Relaxation and catecholamine levels, 35-36 and pupillary sensitivity, 41-42

Renal-body fluid system, and blood pressure, 65

Renin functions of, 56-57 high-renin persons, 57 SNS monitoring, 42

Renin-angiotensin-aldosterone system and ambulatory blood pressure, 56-57 stress reactivity in children/adolescents, 193

Reproductive honnones and stress during menopause, 155-157 during pregnancy, 165 during puberty, 150-151 and estrogen replacement therapy, 159-160 and menstrual cycle, 152-154 and oral contraceptive users, 158-159

Resting blood pressure of borderline hypertensives, 177-178 heritabilityof,274-275

Situation, situation interaction and person­ality, 117

Situational stability and cardiovascular reactivity, 19-25

extraneous influences, 24-25 laboratory-field generalization, 22-24 laboratory intertask consistency, 20-22

16 Personality Factor Questionnaire, 108 Social anxiety, 108 Social Competence Interview, 10 Social support, effects on health, 96-97 Sodium

and ambulatory blood pressure, 65 and catecholamine levels, 34-35 effects on blood pressure, 245, 246-248 excretion and blacks, 65, 252 high and low sodium diet, cardiovascular

responses, 255-258 salt-sensitivity, 65 sensitivity in children, 193-194 sodium retention, nature of, 247 sodium sensitivity, nature of, 247 stress exposure and sodium excretion, 248-

255 animal models, 248-250 in man, 250-255

and vascular reactivity in blacks, 134-136 Speech Stressor task, 12, 76-76 State-Trait Anxiety Inventory, 108 Stress Interview, 10

INDEX

Stressors of Black Americans, 131, 132-133, 135 and catecholamine levels, 37-38 exercise compared to psychological stress

response, 5, 6, 15 to measure cardiovascular reactivity, 5, 8-

10 stress reactivity in children/adolescents,

195-196 types used in research, 5, 9, 10

Submaximal exercise tests, 206 Sympathetic nervous system

and ambulatory blood pressure, 56 catecholamine response to stress, 33-38 and essential hypertension, 223-224 and fight or flight, 4-5 measures of

adrenergic receptors, 43-44 chromagranin A, 39-40 direct sympathetic nerve monitoring, 38-

39 neuropeptide Y, 40 norepinephrine phannacokinetics, ~1 plasma cyclic AMP, 42 plasma renin, 42 platelet catecholamine content, 41 puJdlloID~,41-42

and psychological stress, 5-6,16 racial differences in, 127-128, 131

Sympathoadrenomedullary function, opioid in­lubition of, 200-235

Temperament and emotional and motivational arousal,

113 and emotional arousal, 113

Temporal stability, and cardiovascular re-activity, 17-19

Test anxiety, 108 Thematic Apperception Test, 112 Thrustone Temperament Scale, 113

301

Time factors, and catecholamine levels, 37-38 Total peripheral resistance, 8 Twin studies

of cardiovascular reactivity, 91-95 coronary-prone personality, 99-100 of obesity, 98

Type A behavior, 114-117 and cardiovascular reactivity, 114-117 and catecholamine levels, 35 characteristics of, 114 in children/adolescents, 196 compared to Type B behavior, 115 fear of failure of, 115-116 gender differences, 116 measurement of, 115 and pupil size, 41 situstions related to, 115

Type B behavior, compared to Type A be­havior,115

Ways of Coping Questionnaire, 114 White coat hypertension, 63