T

Edited by Naranjan S. Dhda, Ph.D., M.D. (Hon.), I3.Sc. (Hon.)

1. S. ~ o c ~ ~ u ~ , N. Takeda, M. Nagana, N. Dhalla (eds.): Volume 1: The Ischemic Heart, 1998. ISBN 0-7923-8205-X.

Edited by SEIBU MOCHIZUKI, M.D., Ph.D. Professor and Chairman Department of Medicine Aoto Hospital Jikei University School of Medicine Tokyo, Japan

NOBUAKIRA TAKEDA, M.D., Ph.D. Associate Professor Department of Internal Medicine Aoto Hospital Jikei University School of Medicine Tokyo, Japan

MAKOTO NAGANO, M.D., Ph.D. Professor- Emeritus Jikei University School of Medicine Tokyo, Japan

NARANJAN S . DHALLA, Ph.D., M.D. (Hon.), D.Sc. (Hon.) Distinguished Professor and Director MRC Group in Experimental Cardiology Institute of Cardiovascular Sciences St. Boniface General Hospital Research Centre Faculty of Medicine, University of Manitoba Winnipeg, Canada

K L W E R ACADEMIC PUBLISHERS BOSTON

Distributors for North America: Kluwer Academic Publishers 101 Philip Drive Assinippi Park Nonvell, Massachusetts 02061 USA

Distributors for al l other countries: Kluwer Academic Publishers Group Distribution Centre Post Office Box 322 3300 AH Dordrecht, THE NETHERLANDS

Library of Congress Cataloging-in-Publication Data

Copyright 0 1998 by Kluwer Academic Publishers

All rights reserved. No part of this publication may be reproduced, stored in a retrieval system or transmitted in any form or by any means, mechanical, photo-copying, recording, or otherwise, without the prior written permission of the publisher, Kluwer Academic Publishers, 101 Philip Drive, Assinippi Park, Nonvell, Massachusetts 02061

Printed on acid9i.e paper.

PRINTED IN THE UNITED STATES OF AMERICA

CONTENTS

I.

Contributing Authors xi Dedication xl Preface h i i Acknowledgments xlv

P ~ T H O P ~ S I O ~ O G I C MEC-SMS OF I S C ~ ~ - ~ P E ~ U S I O N 1PJJUR.Y

1.

2.

3.

4.

5 .

Function of Cardiac Myocytes in Ischemic Heart Disease: Comparative Changes in Right and Left Ventricular Cells 3 SIAN E. HARDING, FEDERICA DEL MONTE, AND PHILIP A. POOLE-WILSON

Remodeling of Cardiac Myocytes in Chronic Heart Disease 13 A. MARTIN GERDES

Hibernating Myocardium 23 ROBERTO FERRARI

Length-Dependent Modulation of Cardlac Muscle Contractility in Normoxia, Hypoxia, and Acidosis: Possible Implications for Ischemia 33 KENICHI HONGO, ED WHITE, AND CLIVE H. ORCHARD

Roles of Superoxide, Nitric Oxide, and Peroxpitrite in Various Pathological Conditions 41 HIDEYUKI ISHIDA, MINHAZ UDDIN MOHAMMED, ZHI SU, MINAKO FUJISHIMA, AND HIROE NAKAZAWA

vi Contents

6.

7.

8,

9.

10.

11.

12.

13,

14.

15,

16.

17,

18,

Real-Time Measurement of Nitric Oxide in Coronary Transient Myocardial Ischemia and Repedusion 57

Outflow During

YOSHIAKI FUKUHIRO, SEIICHI MOCHIZUKI, MASAMI GOTO, TAKASHI FUJIWARA, TAIJI MURAKAMI, HROSHI INADA, HISAO MASAKI, ICHIRO MORITA, AND FUMIHIKO KAJIYA

Production of Hydrogen Peroxide During H~poxia-Reoxygena~on in Isolated Myocytes 67 RYUJI UEDA, NOBURU KONNO, MASAKI NAKATANI, TOSHIKI IWATA, YOSHIHISA ARATA, KATSUMITI IIJIMA, KAZUAKI NISHIO, EIICHI GESHI, TOSHIKUNI YANAGISHITA, TAKASHI KATAGIRI, AND YASUMITSU NAKAI

Oxygen Free Radicals Enhance Ergonovine-Induced Canine Coronary Vasoconstriction 77 TAKU KONNO, TAKU MATSUBARA, SHOICHI IMAI, MIKIO NAKAZAWA, YUTAKA YOSHIDA, TOMOYUKI HORI, KEISOKE SUZUKI, TORU IDA, KOTARO HIGUCHI, YUSUKE TAMURA, MASARU YAMAZOE, AND YOSHIFUSA AIZAWA

Structure and Expression of Calponin in Arterial Smooth Muscle Cells 87 HISAKO YAMAMURA, WATARU IKEDA, NOBUHIKO SHIBATA, NOBUHISA AWATA, AND KATSUHITO TAKAHASHI

Status of P-Adrenocepton, G-Proteins, and Adenylyl Cyclase in Ischemic Heart Disease 97 NAMNJAN S . DHALLA, SUJATA PERSAD, VINCENZO PANAGIA, SEIBU MOCHIZUKI, AND ROBERT E. BEAMlSH

Oxygen ons sump ti on and Mitochondrial Membrane Potential in Postischemic Myocardium 125 KAZUAKl NISHIO, NOBURU KONNO, YOSHIHISA ARATA, RYUJI UEDA, KATUMITI IIJIMA, TOSWIKI IWATA, AND TAKASHI KATAGIRI

Pathophysi~lo~cal Behavior of the Myocar~um in Acute Ischemia and Reperhsion, With Special Emphasis on the Sarcoplasmic Reticulum 137 TAKASHI KATAGIRI, EIICHI GESHI, HIROHISA ARATA, HARUHIKO ISHIOKA, SEIJI ITOH, AND NOBURU KONNO

Ca2+ Ion Shifts In Vivo in Reversible and Irreversible Ischemic Injury 151 ROBERT B. JENNINGS AND CHARLES STEENBERGEN

Ionic Mechanism of Reperfhsion Injury 177 MICHAEL J. SHATTOCK

Mechanism of Inhibition of Na+-H' Exchanger (NHE1) by ATP letion: Implications For Myocardial Ischemia 189

TOSHITARO IKEDA, SHIGEO WAKABAYASHI, AND MUNEKAZU SHIGEKAWA

The Source and Fate of Protons in the Repedused Ischemic Heart 199 GARY D. LOPASCHUK AND ALEXANDER S . CLANACHAN

Intracellular Calcium Regulation in Cardiac Cells During Acidosis 215 CESARE M.N. TERRACCIANO AND KENNETH MACLEOD

Intracellular pH Regulation and Myocardial Ischemia-Repedusion Injury 241 DANIELLE FEUVRAY

Contents vii

19. Regulation of [Na+ll and [Ca2*], During Myocardial Ischemia and Reperfusion in a Single-Cell Model 249 HIDEHARU HAYASHIi HIROSHI SATOH, HIDEKI KATOH , TAKURO NAKAMURAi SHIRO SUGIYAMA, AND HAJIME TERADA

20. ATP-Sensitive Potassium Channels and M y o c a r ~ ~ Ischemia 265 CANWEN JIANG, PHILIP A. POOLE-WILSON, AND SEIBU MOCHIZUKI

11. ING ANXI P R ~ T ~ C T I O N OF ION INJURY

21. Early and Delayed Protection Against Ventricular A ~ h y t ~ a s Induced by Preconditioning 279 AGNES VEGH, ADRIENN KIS, JULIUS GY PAPP, AND JAMES R. PARRATT

22. Effects of Is Preconditioning on Na4-Ca2+ Exchan 305 in Isolated Pedused Rat Hearts

SNINGO SEKI, HlROYUKI OKUMURA, TAKEHIKO IZUMI, FUMIKO OKAZAKI, SATOSHI TAKEDA, MASAYUKI TANIGUCHI, IKUO TANIGUCHI, AND SEIBU MOCHIZUKI

23. Long-Term But Not Short-Term Gardioprotection Can Be Induced by Preconditioning in Hypercholesterole~a 3 17 L A S Z L ~ SZEKERES, P, FERDINANDY, I, NAGY, AND z. szr~vAssu

24. Contribution of Endogenous Catecholamines to Preconditioning: Is It Through Facilitation of Adenosine Production? 327 KATSUO SUZUKI, AKIHITO TSUCHIDA, AND TETSUJI MIURA

25. Hypoxic reconditioning of Isolated Cardiomyocytes of Adult Rat 337 MICHIKO NOJIRI, KOUICHI TANONAKA, KEN-ICHI YABE, AND SATOSHI TAKE0

26. Pharmacologic~ Modi~cation of Ischemic Preconditioning During Percutaneous Transluminal Coronary Angioplasry 35 1 TETSUYA UEDA, KAZUHIKO HASWIMURA, YASUHIKO MATSU-URA, YOJI KATO, TAKENORI YASUDA, ISAO MOM, AND YOSHIYUKI KIJIMA

27. Protection Against Injury During Myocardial Ischemia and Reperfusion: Concepts and Strategies 357 DAVID J. HEARSE

28. Mechanisms of Cardioprotective EEFects of Propranolol Against Repedusion Injury 367 BRUCE KOWALUK, NEELAM KNAPER, CLAUD10 RIGATTO, VINCE PALACE, AND PAWAN K, SINGAL

29. Manganes~ Superoxide Disrnutase Induced by Extracellular Stress Enhances Myocardial Tolerance to Ischemia-Repe~usion 379 TSUNEHIKO KUZUYA, MASASHI NISHIDA, SHIRO HOSHIDA, NOBUSHIGE YAMASHITA, MASATSUGU HORI, AND MICHIHIKO TADA

30. Thioctic Acid Prevents Oxidative Damage in Isolated Cardiac Myocytes 387 HANS-GEORG OLBRICH, P. GRABISCH, T. DTCKFELD, I. HENKE, AND E. MUTSCHLER

viii Contents

31.

32.

33.

34.

35.

36.

37.

38.

39.

40.

41.

42.

Transfection of Heat-Shock Protein 70 Enhances Myocardial Tolerance to Ischemia: Evidence for a Role of HSP70 in Ischemia-Reperfusion Injury 399 YOSHIKI SAWA, KEN SUZUKI, YASUFUMI KANEDA, KEISHI KADOBA, HONG-ZHI BAI,

KOJI KAGISAKI, RYUICHI MORISHITA, AND HIKARU MATSUDA

Calcium But Not hniloride Improves the Mechanical Function of Repedused One-Week-Old Rabbit Hearts 41 1 SHINJI TERAMACHI, TOSHIYUKI ITOI, AND ZENSHIRO ONOUCHI

Effects of BIBR-277, an Angiotensin-I1 Type-1 Receptor Antagonist, on Ischemic Myocardial Stunning in Dogs 423 TOHRU NAKAI, KUMI SATOH, ATSUKO YAMAMOTO, KATSUJI HOSHI, AND KAZUO ICHIHARA

Reperhion 12 Hours, Mter Coronary Occlusion Salvages Myocardium in Dogs: Studies in a Single-Heart Model 433 AKIO KIMURA, KINJI ISHIKAWA, IWAO OGAWA, HIRONARI KOKA, SHOJI NAKAI, MASAHIKO INAGAKI, MASARU MIYATAKA, TAKAYA HASEGAWA, AND RYO KATORI

Ecto-5'-nucleotidase and Cardioprotection 441 MASAFUMI KITAKAZE, TETSUO MINAMINO, KOICHI NODE, HIROSHI SATO, YASUNORI UEDA, HIROSHI ASANUMA, HIROHARU FUNAYA, KOICHI ITO, TSUNEHIKO KUZUYA, AND MASATSUGU HORI

Limitation of Stunning in Dog Myocardium by the NucleosideNucleotide Mixture OG-VI 451 SEIICHIRO KANO, YASUNAGA OKAZAKI, TOHRU NAKAI, KUMI SATOH, KATSUJI HOSHI, HIDEAKI KOHRI, AND KAZUO ICHIHARA

Decrease in Myocardial Ischemic Tolerance with Aging in Fischer 344 Rats 461 MASATO TANI, KEN SHINMURA, HIROSHI HASEGAWA, YUKAKO SUGANUMA, AND YOKO HAYASHI

Underpehsion Injury in Diabetic Rat Hearts: Effects of Norepinephri~e and/or Insulin on Stiffness Increase and Abnormal Energy Metabolism 473 MAKIE HIGUCHI, KANAKO MIYAGI, AND MATAO SAKANASHI

Do Ketone Bodies Contribute to Protection Against Damage Caused by Both Myocardial Ischemia and Reperfusion Injury? 501 KIYOTAKA SATO, TAKASHI MASUDA, SHINICHIROU YAMAMOTO, NARIHISA MATSUYAMA, SHINYA KAWABATA, AND TOHRU IZUMI

Effect of Basic Fibroblast Growth Factor on the Regional Myocardial Blood Flow of Acutely Idarcted Myocardium in Experimental Anirnals

Intramyocardial Injection of Basic Fibroblast Growth Factor Increased Regional Myocardial Blood Flow and Salvaged Infarcted Myocardium in Dogs

511 KINJI ISHIKAWA

519 MASARU MIYATAKA, KINJI ISHIKAWA, IWAO OGAWA, HIRONARI KOKA, SHOJI NAKAI,

HIROFUMI KINO, MASAHKO INAGAKI, AKIO KIMURA, TAKAYA HASEGAWA, KOJI KITAYAMA, AND RYO KATORI

EEect of Basic Fibroblast Growth Factor on the Regional Myocardial Blood Flow in Acutely Idircted Myocardium in Rats 525 MASAHIICO INAGAKI, KINJI ISHIKAWA, IWAO OGAWA, AKIO KIMURA, MASARU

MIYATAKA, TAKAYA HASEGAWA, KOJI KITAYAMA, AND RYO KATORI

Contents ix

43. Gene Therapy for Myocardial Idarction 531 RYUICHI MORISHITA, MOTOKUNI AOKI, HIDETSUGU MATSUSHITA, YASUFUMI KANEDA,

JITSUO HIGAKI, AND TOSHIO OGIHARA

44. Adenovirac Vectors as Experimental and Therapeutic Tools

45. Prevention of Transplantation-Associated Arteriosclerosis by Anti-adhesion

545 ANTHONY ROSENZWEIG AND TAKASHI MATSUI

Therapy 551 MITSUAKI ISOBE AND JUN-ICHI SUZUKI

Index 563

c

Yoshifusa kzawa First ~ e p a ~ ~ e n t of Internal M ~ d i ~ i n e

ta ~ n i v e r s i ~ School of ~ e ~ ~ i n ~ 1-754 ~ ~ a ~ i - ~ a c h i Niigata5 951 Japan

~ o ~ o k u n i Aoki ~ ~ ~ ~ ~ ~ r n ~ ~ ~ of Geriatric ~ ~ ~ i ~ i ~ e Osaka U n i v ~ r s i ~ M e ~ i ~ ~ School Suita, Osaka, 565 Japan

Hirohisa Arata Third ~ e ~ a ~ ~ ~ n t of Internal Medicine Showa ~ n i v e ~ s i ~ School of Me~icine 1-5-8 Hatanodai, ~ ~ i n a ~ a ~ a - k ~ Tokyo, 142 Japan

Yos~ i~ i sa Arata Third ~ ~ p a r t ~ ~ n t of Internal Medicine Showa University School of Medicine 1-5-8 Hatan~dai, Shina Tokyo, 142 Japan

xii Contributing Authors

Hiroshi Asanuma First Department of Medicine Osaka University School of Medicine 2-2 Yamada-oka Suita, Osaka, 565 Japan

Nobuhisa Awata Department of Medicine Osaka Medical Center for Cancer and Cardiovascular Diseases 1-3-3 Nakamichi, Higashinari-ku Osaka, 537 Japan

Hong-Zhi Bai First Department of Surgery Institute for Cellular and Molecular Biology Osaka University Medical School

Suita, Osaka, 565 Japan

Robert E. Beamish Institute of Cardiovascular Sciences St. Boniface General Hospital Research Centre 351 Tache Avenue Winnipeg, MB R2H 2A6 Canada

Alexander S. Clanachan Cardiovascular Disease Research Group 423 Heritage Medical Research Centre Departments of Pediatrics and Pharmacology Faculty of Medicine UniveBity of Alberta Edmonton, AB T6G 2S2 Canada

Federica del Monte Cardiac Medicine Imperial College School of Medicine at the National Heart & Lung Institute Dovehouse Street London, SW3 6LY England, UK

Contributing Authors xiii

Naranjan S. Dhalla Institute of Cardiovascular Sciences St. Boniface General Hospital Research Centre 351 Tache Avenue Winnipeg, MI3 R2H 2A6 Canada

T. Dickfeld Medizinische U n i k IV Abteilung Fur Kardiologie Theodor-S tern-Kai 7 60596 Frankfurt a m Main Germany

P. Ferdinandy Department of Biochemistry Albert Szent-GyZirgyi Medical University Kazinczy u.2 €3-6720 Szeged Hungary

Roberto Ferrari Cattedra di Cardiologia Universita’ degli studi di Brescia c/o Spedali Civili P. le Spedali Civili, 1 25 123 Brescia IdY

Danielle Feuvray Laboratoire de Physiologie Cellulaire Universiti: Paris XI, Bit 443 91405 Orsay Cedex 91405 France

Minako Fujishima Department of Physiology Tokai University Isehara, 259-1 1 Japan

Takashi Fujiwara Department of Thoracic & Cardiovascular Surgery Kawasaki Medical School 577 Matsushima, Kurashiki Okayama, 701-01 Japan

~ o s h i a ~ ~ u ~ u h i r o D e p a ~ ~ e n t of Thoracic & ~ a r ~ o v ~ c u l ~ Surgery

of M e ~ c i n e School of ~ e d i c i n e

Suita, Osaka, 565 Japan

A, M a ~ i n Gerdes ~ e p ~ ~ e n t of ~ n a ~ o ~ y and Structural Biolo Universi~ of South Dakota 414 E. Clark Street V e d i o n , SD 57069 USA

Eiichi Geshi Third D e p a ~ e n t of Internal Medicine Shovva Universi~ School of Medicine 1-5-8 Watanodai, Shi~a~avva-~u Tokyo, 142

~ a s a ~ Goto Medical E n ~ n e ~ ~ n ~ & Systems Cardiolo ~ a w a ~ a ~ M e ~ c ~ School 577 Matsushi~ , Kurashiki Qkayama, 701-01

P. Erabisch Medizi~sche Klinik IV

Japan

Japan

60596 Frankfixrt am Main Germany

Sian E. Harding Cardiac Medicine ~ m ~ e ~ ~ College School of M ~ ~ c i n e at the National Heart & Lung Institute Dovehouse Street London, England SW3 6LY United Kingdom

Contributing Authars xv

Hiroshi Hasegawa ~ e p a ~ ~ e n t o ric Medicine Keio Universi 35 Shinanomachi, Shinjuk Tokyo, 160 Japan

First D ~ p a ~ e n t of M ~ ~ ~ i n e Kink ~ ~ i v e ~ i ~ School of Medicine Osakasayama Osaka, 589 Japan

Kazuhiko ~ a s h i ~ u r a ~ ~ ~ o v ~ c u l a r Division Ishinkai Yao General. Hospital Osaka, 581 Japan

~ i d e h a ~ Wayashi

~ a ~ a m a t s u Universi~ School of medicine 3600 Handa-cho ~amamatsu 43 1-3 1 Japan

Yoko Hayashi Depa~ment of Geriatric Medicine Keio University School of Medicine 3 5 S h i n a ~ o ~ a c hi, S hinj uku-Ku Tokyo, 160 Japan

David J. Hearse ~ardiova~cular Research The Rayne Institute

United Kingdom

I, Henke M e ~ i z i ~ s ~ h e Klinik IT! Abteilung fiir ~ a r d i o l o ~ e Theodor-Ste~-Kai 7 60596 Frankfurt am Main ~ ~ ~ a ~ y

mi Contributing Authors

Jitsuo Higaki Department of Geriatric Medicine Osaka University Medical School 2-2 Yamada-oka Suita, Osaka, 565 Japan

Kotaro Higuchi First Department of Internal Medicine Niigata University School of Medicine 1-754 Asahi-machi Niigata, 951 Japan

Makie Higuchi Department of Pharmacology School of Medicine University of the Ryukps Okinawa, 903-01 Japan

Kenichi Hongo Department of Internal Medicine (4) The Jikei University School of Medicine 3-25-8 Nishis~nbashi, Minato-ku Tokyo, 105 Japan

~asatsugu Hori First Department of Medicine Osaka University Medical School 2-2 Yamada-oka Suita, Osaka, 565 Japan

Tomoyuki Hori First Department of Internal Medicine Niigata University School of Medicine 1-754 Asahi-machi Niigata, 951 Japan

Contributing Authors xvii

Katsuji Hoshi Department of Pharmacology Hokkaido College of Pharmacy Otaru 047-02 Japan

Shiro Eloshida First Department of Medicine Osaka University Medical School 2-2 Uamada-oka Suita, Osaka, 565 Japan

Kazuo Ichihara Department of Pharmacology Hokkaido College of Pharmacy Otaru, 047-02 Japan

Tom Ida First Department of Internal Medicine Niigata University School of Medicine 1-754 Asahi-machi Niigata, 951 Japan

Katsumiti Iijirna Third Department of Internal Medicine Showa University School of Medicine 1-5-8 Hatanodai, Shingawa-ku Tokyo, 142 Japan

Katumiti Iijima Third Department of Internal Medicine Showa University School of Medicine 1-5-8 Hatanodai, Shinagawa-ku Tokyo, 142 Japan

Toshitaro Ikeda Department of Molecular Physiology National Cardiovascular Center Research Institute Fujishiro-dai 5 Suita, Osaka, 565 Japan

xdii Contributing Authors

Wataru Ikeda R e ~ a ~ m e n t of Medicine Osaka Me&cd Center far Ca~cer and Car~iovaseu~a~ Diseases 1-3-3 N a ~ a ~ c h i , Hi~ashinari-~u Osaka 537 Japan Shoiehi fmai D~par tm~nt of Pharmacology Niigata University School of ~ ~ d i c i n ~ 1-754 ~ ~ ~ i - ~ a e h i

Hiroshi Inada ~ e ~ a ~ m e n t of Thoracic & ~a~diovascular Surgery Kawasa~ Medical School 5’77 ~ a t s u s h ~ ~ a , ~ ~ r a s h i ~ Okaya~a, 701-01 Japan

Osaka, 589

H i d ~ y u ~ Ishida Department o f Physiology Takai University Isehara, 259-1 1

Japan

Japan Kinji fshikawa First ~ e p a ~ m e n t of Medicine finki ~ n i ~ e r s i ~ School of Medicine Osakasayama Osaka, 589 Japan

Haruhik~ Ishioka Third Department of Internal Medicine Showa ~ n i v e ~ s i ~ School of Medicine 1-5-8 Hatanadai, Shina Tokyo, 142 Japan

Contributing Authors xix

Mitsuaki Isobe First Department of Internal Medicine Shinshu University School of Medicine 3-1-1 Asahi ~ a t s ~ r n o t o 390 Japan

Koichi Ito First D e p a ~ m ~ n t of Medicine Osaka University School of Medicine 2-2 Yarnada-oka Suita, Osaka, 565 Japan

Seiji Itoh Third D ~ p a ~ m e n t of Internal Medicine Showa University School of Medicine 1-5-8 Hatanodai, S h ~ n a ~ ~ w a - k ~ Tokyo, 142 Japan

Toshiyuki Itoi Division of Pediatrics Children’s Research Hospital Kyoto Prefectural University of Medicine Kajiicho 465, Mirokoji, Kawaramachi K ~ ~ o k u ~ Kyoto, 602 Japan

Toshiki Iwata Third Department of Internal Medicine Showa ~ n i v ~ r s i t y School of Medicine 1-5-8 Matanod~, Shinagawa-ku Tokyo, 142 Japan

Takehiko Izumi Fourth Depart~ent of Internal Medicine Aoto Hospital Jikei University School of Medicine 6-41-2 Aoto, Kats~shika-ku Tokyo, 125 Japan

XX Contributing Authors

Tohru Izumi Department of Internal Medicine and Cardiology Kitasato University School of Medicine 1-15-1 Kitasato Sagamihara, 228 Japan

Robert B. Jennings Department of Pathology Duke University Medical Center P.O. Box 3712 Durham, NC 27710-0001 USA

Canwen Jiang Department of Gene Transfer Research Genzyme Corporation Framingham, MA USA

Keishi Kadoba First Department of Surgery Institute for Cellular and Molecular Biology Osaka University Medical School 2-2 Yamada-oka Suita, Osaka, 565 Japan

Koji Kagisaki First Department of Surgery Institute for Cellular and Molecular Biology Osaka University Medical School 2-2 Yamada-oka Suita, Osaka, 565 Japan

Fumihiko Kajiya Medical Engineering & Systems Cardiology Kawasaki Medical School 577 Matsushima, Kurashiki Okayama, 701-01 Japan

Contributing Authors xxi

Yasufumi Kaneda First Department of Surgery Institute for Cellular and Molecular Biology Osaka University Medical School 2-2 Yamada-oka Suita, Osaka, 565 Japan

Seiichiro Kano Department of Phamcology Hokkaido College of Pharrnacy Otaru, 047-02 Japan

Takashi Katagiri Third Department of Internal Medicine Showa University School of Medicine 1-5-8 Watanodai, Shinagawa-ku Tokyo, 142 Japan

Yoji Kato Cardiovascular Division Ishinkai Yao General Hospital Osaka, 581 Japan

Hideki Katoh Third Department of Internal Medicine Hamamatsu University School of Medicine 3600 Wanda-cho Hamamatsu, 431-31 Japan

Ryo Katori First Departrnent of Medicine Kinki University School of Medicine Osakasayrna Osaka, 589 Japan

Shinya Kawabata Department of Internal Medicine and Cardiology Kitasato University School of Medicine 1-15-1 Ktasato Sagamihara, 228 Japan

xxii Contributing Authors

Neelam Khaper Institute of Cardiovascular Sciences St. Boniface General Hospital Research Centre 351 Tache Avenue ~ i n n i p e ~ , MB R2H 2A6 Canada

Yoshiyuki Kijima Department of Cardiology

shi-osaka Municipal Hospital 2-3-1 Mikuriya Minami, Higashi-Osaka Osaka, 577 Japan &io Gmura First Department of Medicine Kink University School of Medicine Osakasa~ama Osaka, 589 Japan Hirofumi Kino First Department of Medicine Kink University School of Medicine Osakasay a m Osaka, 589 Japan Adrienn Kis ~ e ~ a r t m e n t of Pharmacology Albert S z e ~ t - ~ y ~ r ~ i Medical University Dom ter 12 H-6701 Szeged Hungary

Masafumi Kitakaze First Department of Mehcine Osaka University School of Medicine 2-2 Yamadaoka Suita, Osaka, 565 Japan

Koji Kitayama First Department of Medicine Kinki University School of Medicine ~ s ~ k a s a y a ~ Osaka, 589 Japan

Hideaki Kohri Department of Pharmacology Section Nutrition Research Institute Otsuka Pharmaceutical Factory, Inc.,

Narato, 772 Japan

Hironari Koka First Department of Medicine Kinki University School of Medicine Osakasayama Osaka, 589 Japan

Nobura Konno Third Department of Internal Medicine Showa university School of Medicine 1-5-8 Hatanodai, Shinagawa-ku Tokyo, 142 Japan

Taku Konno First Department of Internal Medicine Niigata University School of Medicine 1-754 Asahi-machi Niigata, 951 Japan

Bruce Kowaluk Institute of Cardiovascular Sciences St. Boniface General Hospital Research Centre 351 Tache Avenue Winnipeg, MB R 2 H 2A6 Canada

Tsunehiko Kuzuya First Department of Medicine Osaka University Medical School £**•*& x amacia*"Oi£a ouita, vJsaKa, j t o Japan

Gary D. Lopaschuk Cardiovascular Disease Research Group 423 Heritage Medical Research Centre Department of Pediatrics and Pharmacology The University of Alberta Edmonton, Alberta T6G 2S2 v^anacia

Contributing Authors sd i i

xxiv Contributing Authors

Kenneth T. MacLeod Imperial College School of Medicine at National Heart & Lung Institute Cardiac Medicine Dovehouse Street London, England SW3 6LY United Kingdom

Hisao Masaki Department of Thoracic & Cardiovascular Surgery Kawasaki Medical School 57’7 Matsushima, Kurashiki Okayama, 701-01 Japan

Takashi Masuda Department of Internal Medicine and Cardiology Kitasato University School of Medicine 1-15-1 Kitasato Sagarnihara, 228 Japan

Taku Matsubara First Department of Internal Medicine Niigata University School of Medicine 1-754 Asahi-machi Niigata, 951 Japan

Hikaru Matsu~a First Department of Surgery Institute for Cellular and Molecular Biology Osaka Universty Medical School 2-2 Yamada-oka Suita, Osaka, 565 Japan

Takashi Matsui Massachusetts General Hospital Cardiovascular Research Center Mailcode: 1494201 149 13th Street Charlestown, MA 02129-2060 USA

Contributing Authors xxv

Yasuhiko Matsu-ura Cardiovascular Division Ishinkai Yao General Hospital Osaka, 581 Japan

Hidetsugu Matsushita Department of Geriatric Medicine Osaka University Medical School 2-2 Yamada-oka Suita, Osaka, 565 Japan

Narihisa Matsuyama Department of Internal Medicine and Cardiology Kitasato University School of Medicine 1-15-1 Kitasato Sagamihara, 228 Japan

Tetsuo M i n a ~ n o First Department of Medicine Osaka University School of Medicine 2-2 Yamada-oka Suita, Osaka, 565 Japan

Tetsuji Miura Second Department of Internal Medicine Sapporo Medical University School of Medicine South-1 West-16, Chuo-ku Sapporo, 060 Japan

Kanako Miyagi Department of Pharrnacology School of Medicine University of the Ryukyus Okinawa 903-01 Japan

Masaru Miyataka First Department of Medicine Kinki University School of Medicine Osakasayama Osaka, 589 Japan

xxvi Contributing Authors

Seibu Mochizuki Fourth Department of Internal Medicine Aoto Hospital Jikei University School of Medicine 6-14-2 Aoto, Katsushika-ku Tokyo, 125 Japan

Seiichi Mochizuki Medical Engineering & Systems Cardiology Kawasaki Medical School 577 Matsushi~a, Kurashiki O ~ a y a ~ a , 701-01 Japan

Minhaz Uddin Mohammed Department of Physiology Tokai University Isehara, 259-1 1 Japan

Isao Mori Cardiovascular Division Ishinkai Yao General Hospital Osaka, 581 Japan

Ryuichi Morishita Department of Geriatric Medicine Osaka University Medical School 2-2 Y arnada-oka Suita, Osaka, 565 Japan

Ichiro Morita Department of Thoracic & Cardiovascular Surgery Kawasaki Medical School 577 Matsushirna, Kurashiki Okayama, 701-01 Japan

Taiji Murakarni Department of Thoracic & Cardiovascular Surgery Kawasaki Medical School 577 Matsushima, Kurashiki Okayama, 701-01 Japan

Contributing Authors

E. Mutschler ~harma~olo~sches Institut &r Natu~issenscha~ler Johann Wolfgang Goethe-Universitat Frankfkrt am Main Germany

I. N a g First Department of Medicine Albert Szent-Gyorgyi Medllcal University H-6720 Szeged Hungary

Shoji Nakai First Department of Medicine Kinki University School of Medicine Osakasayama Osaka, 589 Japan

Tohru Nakai Department of Pharmacology Hokkaido College of Pharmacy Otaru, 047-02 Japan

Yasumitsu Nakai First Department of Anatomy Showa University School of Medicine 1 -5-8 Hatanodai, S hinagawa- ku Tokyo, 142 Japan

Takuro Nakamura Third Department of Internal Medicine Hamamatsu University School of Medicine 3600 Handa-cho Hamamatsu, 43 1-3 1 Japan

Masaki Nakatani Third Department of Internal Medicine Showa University School of Medicine 1-5-8 Hatanodai, Shinagawa-ku Tokyo, 142 JaPm

d i Contributing Authors

Hiroe Nakazawa Department of Physiology Tokai University Isehara, 259-1 1 Japan

Mikio Nakazawa Department of Pharmacology Niigata University School of Medicine 1-754 As&-machi Niigata, 951 Japan

Masashi Nishida First Department of Medicine Osaka University Medical School 2-2 Yarnada-oka Suita, Osaka, 565 Japan

Kazuaki Nishio Third Department of Internal Medicine Showa University School of Medicine 1-5-8 Hatanodai, Shinagawa-ku Tokyo, 142 Japan

Koichi Node First Department of Medicine Osaka University School of Medicine 2-2 Yamada-oka Suita, Osaka, 565 Japan

Michiko Nojiri Department of Pharmacology Tokyo University of Pharmacy & Life Science School of Pharmacy 1432- 1 Horinouchi Hachioji, Tokyo, 192-03 Japan

Contributing Authors d

Iwao Ogawa First Department of Medicine Kinki University School of Medicine Osakasayama Osaka, 589 Japan

Toshio Ogihara Department of Geriatric Medicine Osaka University Medical School 2-2 Yamada-oka Suita, Osaka, 565 Japan

Fumiko Okazaki Fourth Department of Internal Medicine Aoto Hospital Jikei University School of Medicine 6-41-2 Aoto, Katsushika-ku Tokyo, 125 Japan

Yasunaga Okazaki Departmeqt of Surgery I1 Kochi Medical School Nankoku, 783 Japan

Hiroyuki Okumura Fourth Department of Internal Medicine Aoto Hospital Jikei University School of Medicine 6-41-2 Aoto, Katsushika-ku Tokyo, 125 Japan

Hans-Georg Olbrich Medizinische Klinik IV Abteilung fur Kardiologie Theodor-Stern-Kai 7 60596 Frankfkrt am Main Germany

xxx C ~ n ~ b u t i n g Authors

Zenshiro Onouchi Division of Pediatrics Children’s Research Haspital Kyoto Prefectural University of Medicine Kajiicho 465, Hirokoji, ~ a w a r a ~ a c h i Kamigyoku, Kyoto, 602 Japan

Clive H. Orchard Department of Phys io lo~ U n i v e ~ s i ~ of Leeds Leeds LS2 9JT United Kingdom

Vince Palace Institute of Cardiovascular Sciences St. Boniface General Hospital Research Centre 351 Tache Avenue Winnipeg, MB R2H 2A6 Canada

~ i n c e n z o Panagia ~ n s t i ~ u ~ ~ of Cardiovascular Sciences St. Boniface General Hospital Research Centre 351 Tache Avenue ~ i n n i p e ~ , MB R2H 2A6 Canada

Julius Gy Papp Department of Pharmacology Albert Szent-Gyorgyi Medical University Dom ter 12 H-6701 Szeged Hungary

James R. Parratt ~ e p a ~ m e ~ t s of Physiology and Pharmacology ~ n i v e r s i ~ of Strathclyde Glasgow, Scotland United Kmgdom

Sujata Persad Institute of Cardiovascular Sciences St. Boniface General Hospital Research Centre 351 Tache Avenue Winnipeg, MB R2H 2116 Canada

Contributing Authors xxxi

Philip A. Poole-Wilson Department of Cardiac Medicine Imperial College School of Medicine at the National Heart & Lung Institute University of London Dovehouse Street London, England SW3 6LY United Kingdom

Claudio Rigatto Institute of Cardiovascular Sciences St. Boniface General Hospitd Research Centre 351 Tache Avenue Winnipeg, MB R2H 2A6 Canada

Anthony Rosenzweig Massachusetts General Hospital Cardiovascular Research Center Mailcode: 1494201 149 13th Street Charlestown, MA 02129-2060 USA

Matao Sakanashi Department of Pharmacology School of Medicine University of the Ryukyus Qkinawa, 903-01 Japan

Hiroshi Sat0 First Department of Medicine Osaka University School of Medicine 2-2 Yamada-oka Suita, Osaka, 565 Japan

Kiyotaka Sat0 Department of Internal Medicine and Cardiology Kitasato University School of Medicine 1-15-1 Kitasato Sagarnihara, 228 Japan

4 Contributing Authors

Hiroshi Satoh Third Department of Internal Medicine Hamamatsu University School of Medicine 3600 Handa-cho Hamamatsu, 43 1-3 1 Japan

Kumi Satoh Department of Pharmacology Hokkaido College of Pharmacy O t a ~ , 047-02 Japan

Yoshiki Sawa First Department of Surgery Osaka University 2-2 Yamada-oka Suita, Osaka, 565 Japan

Shingo Seki Department of Internal Medicine Aoto Hospital Jikei University School of Medicine 6-41-2 Aoto, Katsushika-ku Tokyo, 125 Japan

Michael J. Shattock Cardiovascular Research The R a p e Institute St. Thomas’ Hospital London, England SEl 7EH United Kingdom

Nobuhiko Shibata Department of Medicine Osaka Medical Center for Cancer and Cardiovascular Diseases 1-3-3 Nakarnichi, Higashinari-ku Osaka, 537 Japan

Munekazu Shigekawa Department of Molecular Physiology National Cardiovascular Center Research Institute Fujishiro-dai 5 Suita, Osaka, 565 Japan

Contributing Authors d i

Ken Shinmura Department of Geriatric Medicine Keio University School of Medicine 35 S hinanomachi, Shinjuku-ku Tokyo, 160 Japan

Pawan K. Singal Institute of Cardiovascular Sciences St. Boniface General Hospital Research Centre 351 Tache Avenue Winnipeg, MB R2H 2A6 Canada

Charles Steenbergen Department of Pathology Duke University Medical Center P.O. Box 3712 Durham, NC 277 10-0001 USA

Zhi Su Department of Physiology Tokai University Isehara, 259-1 1 Japan

Yukako Suganuma Department of Geriatric Medicine Keio University School of Medicine 35 Shinanomachi, Shinjuku-ku Tokyo, 160 Japan

Shiho Sugiyama Third Department of Internal Medicine Hamamatsu University School of Medicine

Hamamatsu, 431-31 ' 3600 Handa-cho

Japan

Jun-ichi Suzuki First Department of Internal Medicine Shinshu University School of Medicine 3-1-1 Asahi Matsumoto 390 Japan

d v C o n t ~ b ~ t i ~ g Authors

Katsuo Suzuki Second Department of Internal Medicine Sapporo Medical University School of Medicine South-1 West-16, Chuo-ku Sapporo, 060 Japan

Keisuke SuzuI.4 Department of Medicine Ritasato University School of Medicine Kitasato Japan

Ken Suzuki First Department of Surgery Institute for Cellular and Molecular Biology Osaka University Medical School 2-2 Yamada-oka Suita, Osaka, 565 Japan

Liszl6 Szekeres Institute of Pharmacology Albert Szent-Gyorgyi Medical University Kazinczy u.2 H-6720 Szeged Hungary

z. szilvrissy First Department of Medicine Albert Szent-Gyorgyi Medical University Kazinczy u.2

Hungary M-6720 Szeged

Michihiko Tada Department of Medicine and Pathophysiology Osaka University Medical School 2-2 Yamada-oka Suita, Osaka, 565 Japan

C o ~ ~ b u t i n g Authors x m v

Katsuhito Takahashi Department of Medicine Osaka Medical Center for Cancer and Cardiovascular Diseases 1-3-3 N a k d c h i , H i ~ s h i n a ~ - k u Osaka, 537’ Japan

Satoshi Takeda Fourth Department of Internal Medicine Aoto Hospital, Jikei University School of Medicine 6-41-2 Aoto, Katsushika-ku Tokyo, 125 Japan

Satoshi Takeo Department of Pharmacology Tokyo University of Pharmacy & Life Science School of Pharmacy 1432-1 Horinouchi Hachioji, Tokyo, 192-03 Japan

Yusuke Tamura First Department of Internal Medicine Niigata University School of Medicine 1-754 Asahi-machi Niigata, 951 Japan

Masato Tani Department of Geriatric Medicine Keio University School of Medicine 35 S hinanornachi, S hinjuku-ku Tokyo, 160 Japan

Ikuo Taniguchi Fourth Department of Internal Medicine Aoto Hospital Jikei University School of Medicine 6-41-2 Aoto, Katsushika-ku Tokyo, 125 Japan

xxmi Contributing Authors

Masayuki Taniguchi Fourth Department of Internal Medicine Aoto Hospital Jikei University School of Medicine 6-41-2 Aoto, Katsushika-ku Tokyo, 125 Japan

Kouichi Tanonaka Department of Pharmacology Tokyo University of Pharmacy & Life Science School of Pharmacy 1432-1 Horinouchi Hachioji, Tokyo, 192-03 Japan

Hajime Terada Third Department of Internal Medicine Hamamatsu University School of Medicine 3600 Handa-cho Hamamatsu, 43 1-3 1 Japan

Shinji Teramachi Division of Pediatrics Children’s Research Hospital Kyoto Prefectural University of Medicine Kajiicho 465, Hirokoji, Kawaramachi K a ~ ~ o ~ u , Kyoto, 602 Japan

Cesare M.N. Terracciano Imperial College School of Medicine at National Heart & Lung Institute Cardiac Medicine Dovehouse Street London, England SW3 6LY United IGngdom

Akihito Tsuchida Second Department of Internal Medicine Sapporo Medical University School of Medicine South-1 West-16, Chuo-ku Sapporo, 060 Japan

Contributing Authors xxxvii

Ryuji Ueda Third Department of Internal Medicine Showa University School of Medicine 1-5-8, Hatanodai, Shinagawa-ku Tokyo, 142

Tetsuya Ueda Cardiovascular Division Ishinkai Yao General Hospital Osaka, 581

Japan

Japan Yasunori Ueda First Department of Medicine Osaka University School of Medicine 2-2 Yamada-oka Suita, Osaka, 565 Japan Agnes Vegh Department of Pharmacology Albert-Szent-Gyorgyi Medical University Dom ter 12 H-6701 Szeged Hungary

Shigeo Wakabayashi Department of Molecular Physiology National Cardiovascular Center Research Institute Fujishiro-chi 5 Suita, Osaka, 565 Japan Ed White Department of Physiology University of Leeds Leeds, LS2 9JT United Kingdom

Ken-ichi Yabe Department of Pharmacology Tokyo University of Pharmacy 8z Life Science School of Pharmacy 1432-1 Horinouchi Hachioji, Tokyo, 192-03 Japan

d i i Contributing Authors

Atsuko Yamamoto Depart~ent of Pharmacology ~ o k ~ ~ d o College of Pharmacy Otam, 04'7-02 Japan

Shinichi~ou Yammoto D e ~ ~ ~ e n t of Internal Medicine and Cardiology Kitasato ~ n i v e ~ i ~ School of ~ e d i c i n e 1-15-1 Kitasato S a ~ a ~ h a r a , 228 Japan

Wisako Ya~amura

Osaka Medical Center for Cancer and Cardiovascular Diseases 1-3-3 ~ a k a ~ ~ h i , Hi Osaka, 537 Japan

ment of Medicine

No~ushige Ya~ashita First ~ e p a r t ~ ~ n t of Medicine Osaka University Medical School 2-2 Y a ~ ~ d a ~ o k a Suita, Osaka, 565 Japan

Masaru Yamazoe First D e p a ~ ~ e n t of Internal Medicine Niigata University School of Medicine 1-754 Asahi-machi

Japan

~ o s h i k ~ ~ i Y anagishita Third Department of Internal Medicine Showa University School of Medicine 1-5-8 ~ a t a n o d ~ , S h i n a ~ a ~ a - ~ u Tokyo, 142 Japan

Takenori Yasuda Cardiovascular Division

Osaka, 581 ai Yao General Hospital

Japan

Contributing Authors xxxix

Yutaka Yoshida Department of Pharmacology Niigata University School of Medicine 1-754 Asahi-machi Niigata, 951 Japan

Robert B. Jennings, M.D.

This book is dedicated to Dr. Robert Jennings, James B. Duke Professor of Pathology at the Duke University Medical Center, for his pioneering work in the area of ische~a-repe~sion injury in the heart. His leadership in promoting cardiovascular research and the scientific basis for cardiology throughout the world in his capacity as President of the International Society for Heart Research (19’78- 1980) as well as Chairman of the Council of Cardiac Metabolism of the International Society and Federation of Cardiology (1986-1992) is acknowledged.

ROBERT B. JENNINGS: A MAN WITH A GREAT 'VISION AND C O ~ ~ I T ~ N T TO THE SERVICE OF CARDIOVASCULAR ~ ~ I C I N E

Robert Burgess Jennings was born on December 14, 1926, in Baltimore and obtained his B.S., M.S., and M.D. degrees from Northwestern University in 1947, 1949 and 1950, respectively. He served in the Department of Pathology at the Northwestern University Medical School as Instructor (1953-1956), Assistant Professor (1 956-1960), Associate Professor (1 960-1 963), Professor (1 963-1 969), and Professor and Chairman (1969-1975). In 1975, he moved to the Duke University Medical Center as Professor and Chairman of the Pathology Department, where he was appointed James B. Duke Professor of Pathology in 1980. At both Northwestern University and Duke University, he developed strong educational and research programs. He trained numerous fellows in cardiovascular pathology who are actively engaged in understanding the pathophysiolo~ of heart disease.

Dr. Jennings is an excellent investigator in the field of cardiac pathology. As early as 1953, he set out to discover the cellular, metabolic, and molecular events that result in the death of ischemic cardiomyocytes. He observed dramatic changes in Na+, K+, and Ca2+ in the ischemic heart and showed release of cardiac enzymes such as glutamic oxaloacetic transaminase and lactic dehydrogenase upon occluding the coronary artery for a brief period. His well-thought-out and elegant experiments revealed a defect in the ability of the ischemic heart to metabolize glucose. Not only did he lay out the concept of reversible and irreversible ischemic injury to the heart but he also provided convincing evidence for the existence of these two phases of myocardial ischemia. Irreversibly damaged cardiomyocytes were reported by him to exhibit a very unusual form of necrosis in which the cells were swollen and

xlii Robert B. Jennings

contained enormous contraction bands. Thus, his seminal experimental work on the temporary occlusion of the coronary artery for diEerent durations laid the foundation for therapeutic egects of early reperfixsion of the ischemic heart by thrombolysis, coronary bypass surgery, or angioplasty.

Dr. Robert Jennings is a man of great vision and extraordinary ~ o ~ t ~ e n t to the promotion of cardiovascular science. It is no secret that he is known for his keen sense of direction and for the development of logic that enables others to follow his arguments on subjects rangi~g from science to philos~phy. He challenges and inspires others to do great and difficult tasks. Nonetheless, he enjoys helping others to achieve their potential and demands excellence, During his Presidency of the International Society for Heart Research (1 97’8-1 980), he developed rules and regulations for improving the function of this Society. As Chairman of the Council of Cardiac Metabolism of the International Society and Federation of Cardiology (1 986-1 9929, he promoted cardiovascular education throughout the world. In addition to the Peter Harris Award for Distinguished Investigators in the field of heart research and the Distinguished Achievement Award of the Society of Cardiovascular Pathology, he has been honored several times for his contributions in the field of ischemic heart disease. We believe that the dedication of The ~ s c h e ~ i ~ Heart to Robert Jennings is a fitting tribute to this ~utstanding human being.

own that ischemic heart disease is a major health problem in the world, Over the past three decades, impressive progress in the fields of pathogenesis, prevention, and therapy of ischemic heart disease has resulted in a marked decline (korn about 65% to 40%) in mor ta l i~ in the Western world; however, the incidence of this devastating disease is on the rise in developing countries. It has

t several risk factors, such as high cholesterol, cigarette smoking, diabetes, hypertension^ obesity, lack of exercise, and stress, ~ r ~ ~ o t e the occurrence of ischemic heart disease as a consequence of both the f o ~ a t i o n of cholesterol plague and/or thrombosis in the coronary arteries and the development of coronary spasm. These ou tco~es result in reduction of the blood supply to myocardium, depending upon the site of occlusion in the coro associated with derangement of cardiac ~etabolism and cellular s ~ ~ t u r e " Myocar- dial ischemia under acute conditions leads to the develo~ment of heart dys~nction and a ~ h y t h ~ i a s as a consequence of a shift in the in~~cellular concentrati~n of cations as well as a deficiency of high-ene phosphate stores in the myocardium. Prolonged ischemia results in the development of myocardial infarction ever the scar size is about or more than 30% of the ventricular wall, con failure occurs within two to five years. Thus, two basic problems are bein investigated in the area of ischemic heart disease, namely, acute myocardial ischemia and myocardial infarction. While the biochemical changes in the heart due to acute myocardial ischemia are almost identified, a great deal of work regarding the sequence of events &om angina and cardiac hypertrophy to congestive heart failure

xliv Preface

due to myocardial infarction remains to be carried out in the ftuture. In particular, it is noteworthy to point out that not only does a defect occur in the contractile machinery of the ischemic heart but also a loss of adrenergic support to the heart becomes evident during the development of congestive heart failure due to myocar- dial infarction.

Although restoration of blood supply to the ischemic myocardium by angioplasty, coronary bypass, and/or thrombolysis can be seen to produce beneficial effects, the outcome for the patient seems to depend upon the time taken to establish the coronary flow to the ischemic myocardium. In fact, another problem, namely, repefision injury, sets in if the blood flow is not restored within a certain critical time. Most of the research in this area has revealed that reperfusion of the ischemic heart results in the formation of oxyradicals and oxidants, and this oxidative stress appears to play an important role in the genesis of massive arrhythmias as well as additional ultrastructural damage, membrane defects, and contractile abnormalities. The exact mechanism of ischemia-repefision injury have not been described; however, Ca2+-handling abnormalities in cardiomyocytes have been identified as one of the major targets for preventing ischemia-reperfusion injury. In this regard, diEerent f3-adrenergic receptor blocking agents and Ca2+ antagonists have proven to be usefiil. In addition, brief episodes of ischemia-Ischemic Preconditioning-have also been shown to attenuate the eEects of ischemia-repefision injury, but the mechanism of the cardioprotective actions of ischemic preconditioning are poorly understood.

A symposium on “The Ischemic Heart” was organized in Tokyo on November 19-21, 1996, for an in-depth discussion of a wide variety of issues in the field of ischemic heart disease, For this book, selected speakers from this syrnposium were invited to contribute papers emphasizing their experiences on diverse issues in the area of ischemic heart disease. We have organized their contributions in two sections, narnely, 1) Pathophysiologic Mechanisms of Ischemia-Repe~sion Injury, and 2) Preconditioning and Protection of Ischemia-Repe~sion Injury. It is our contention that the 45 chapters assembled for this book provide up-to-date infoma- tion concerning the current concepts of ischernia-reperfusion injury, the sequence of events resulting in the loss of contractile dysftunction, the mechanisms of cardioprotection by several drugs, and the role of ischemic preconditioning in attenuating problems associated with ischemia-reperfusion injury. We believe this book will be helpful to both students and scientists as well as to clinical cardiologists and cardiovascular surgeons dealing with ischemic heart disease.

Seibu Mochizuki, Tokyo Nobuakira Takeda, Tokyo

Makoto Nagano, Tokyo Naranjan S . Dhalla, Winnipeg

The conference on the Ischemic Heart was sponsored by the International Society and Federation of Cardiology, for which we are indeed gratefid. The financial support for this meeting was kindly provided by several Japanese pharmaceutical industries. It would have been virtually impossible to organize this conference without the advice of Drs. Philip Poole-Wilson and Howard Morgan, who served as members of the International Advisory Board. The help of Ms. Susan Zettler in the preparation of this book is highly appreciated. Special thanks are due to Mr. Robert Holland and Ms. Melissa Ramondetta and their editorial s t a at IUuvver Academic Publishers for their patience, interest, and hard work in assembling this volume.

T c

Edited by SEIBU MOCHIZUKI, M.D., Ph.D. Professor and Chairman Department of Medicine Aoto Hospital Jikei University School of Medicine Tokyo, Japan

NOBUAKIRA TAKEDA, M.D., Ph,D. Associate Professor Department of Internal Medicine Aoto Hospital Jikei University School of Medicine Tokyo, Japan

MAKOTO NAGANO, M.D., Ph.D. Professor Emeritus Jikei University School of Medicine Tokyo, Japan

NARANJAN S. DHALLA, Ph.D., M.D. (Son.), D.Sc. (Hon,) Distinguished Professor and Director MRC Group in Experimental Cardiology Institute of Cardiovascular Sciences St. BonitBce General Hospital Research Centre Faculty of Medicine, University of Manitoba Winnipeg, Canada

ISLUWER ACADEMIC PUBLISHERS, BOSTON