Essensial Hypertension Pathogenesis and Pathophsiology

8/8/2019 Essensial Hypertension Pathogenesis and Pathophsiology

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L E A D I N G A R T I C L E

* Senior Resident

** Professor

Department of Nephrology,

All India Institute of Medical Sciences,New Delhi-110 029.

Essential Hypertension Pathogenesis and Pathophysiology

Sanjay Vikrant*, SC Tiwari**

Population studies suggest the blood pressure (BP)

is a continuous variable, with no absolute dividing

line between normal and abnormal values1. High

blood pressure is a leading risk factor for heart

disease, stroke, and kidney failure. This correlation

is more robust with systolic than with diastolic BP2.

Even when BP is lowered by antihypertensive

medication, the associated reduction in the

incidence of coronary heart disease lags behind

that of stroke3.

There is a widely held misconception that

hypertension is a single disease that can be treated

with a single recipe. Hypertension is a

heterogenous disorder in which patients can be

stratified by pathophysiologic characteristics that

have a direct bearing on the efficacy of specifically

targeted antihypertensive medications, on the

detection of potentially curable forms of

hypertension, and on the risk of cardiovascular

complications4.

Essential hypertension is characterised by a

sustained systolic pressure of greater than 140 mm

Hg and a diastolic BP at greater than 90 mm Hg

and by some characteristics listed in Table I.

The pressure required to move blood through the

circulatory bed is provided by pumping action of

the heart (cardiac output; CO) and the tone of

the arteries (peripheral resistance; PR). Each of

these primary determinants of the blood pressure

is, in turn, determined by the interaction of the

exceedingly complex series of factors6 displayed

in part in figure 1.

Hypertension has been attributed to abnormalities

in virtually every one of these factors. It is unlikely

that all of these factors are operative in any given

patient; but multiple hypotheses may prove to be

correct, since the haemodynamic hallmark of

primary hypertension a persistently elevated

vascular resistance may be reached through a

number of different paths. Before the final

destination, these may converge into either

structural thickening of the vessel walls or

functional vasoconstriction. Moreover, individual

factors often interact, and the interactions are

proving to be increasingly complex. For instance,

insulin resistance is present even before

hypertension develops in those who are genetically

predisposed, the resultant hyperinsulinaemia is

associated with sodium sensitivity, obesity, and

increased sympathetic drive as well as impaired

endothelium - dependent vascular resistance8.

Table I : Pathophysiologic characteristics of

essential hypertension5.

No known cause

Diastolic pressure repeatedly > 90 mm Hg

Total peripheral resistance usually increased

Pulse pressure possibly increased or decreased

Cardiac output normal, or elevated in some,

possibly early in the disease

Cardiac work increased

Altered renal physiology, with accelerated

natriuresis and reduced renal blood flow

Normal blood flow to most regions; diminishedrenal and skin blood flow and increased

muscle flow may develop

Plasma volume reduced (may be inversely

related to diastolic pressure)

Hyper-reactivity of pressure to stress, abnormal

vascular reactivity and impaired circulatory

homeostasis.

Role of genetics

The variations in BP that are genetically determinedare termed inherited BP. Although, we do not


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know which genes cause BP to vary, we know from

family studies that inherited BP can range from

low normal BP to severe hypertension. Although,

it has frequently been indicated that the causes of

essential hypertension are not known, this is onlypartially true because we have little information

on genetic variations or genes that are over-

expressed or under-expressed as well as the

intermediary phenotypes that they regulate to

cause high BP. Factors that increase BP, such as

obesity and high alcohol and salt intake are called

hypertensinogenic factors; some of these factors

have inherited, behavioural, and environmental

components. Inherited BP could be considered as

the core BP, whereas hypertensinogenic factors

cause BP to increase above the range of inheritedBPs. Further, there are interactions between

genetics and environmental factors that influence

intermediary phenotypes such as sympathetic

nerve activity, renin angiotensin aldosterone and

renin - kallikrein - kinin systems and endothelial

factors, which is turn influence other intermediary

phenotypes such as sodium excretion, vascular

reactivity, and cardiac cartractility. These and many

other intermediary phenotypes determine total

vascular resistance and cardiac output and

consequently BP9.

The identification of variants (allelic) genes that

contribute to the development of hypertension is

complicated by the fact that the 2 phenotypes that

determine BP, i.e., cardiac output and total

peripheral resistance, are controlled by

intermediary phenotypes, including the autonomic

nervous system, vasopressor/vasodepressor

hormones, the structure of the cardiovascular

system, body fluid volume and renal function, and

many others. Furthermore, these intermediary

phenotypes are also controlled by complex

mechanisms including BP itself10. Thus there are

many genes that could participate in the

development of hypertension.

The influence of genes on BP has been suggested

by family studies demonstrating associations of

BP among siblings and between parents and

children. There is better association among BP

values in biological children than in adopted

children and in identical as opposed to non-

identical twins. BP variability attributed to all

genetic factors varies from 25% in pedigree studies

to 65% in twin studies. Furthermore, genetic factorsalso influence behavioural pattern, which might

lead to BP elevation. For example, a tendency

towards obesity or alcoholism will be influenced

by both genetic and environmental factors, thus

the proportion of BP variability caused by

inheritance is difficult to determine and may vary

in different populations.

Mutations in at least 10 genes have been shown

to raise or lower BP through common pathways

by increasing or decreasing salt and water

reabsorption by the nephron11,12. The genetic

mutations responsible for 3 rare forms of

mendellian (monogenic) hypertension syndromes

- gluco-corticoid remediable aldosteronism (GRA),

Liddles syndrome, and apparent

mineralocorticoid excess (AME) has been

identified, whereas in a fourth, autosomal

dominant hypertension with brachydactyly the

gene is not yet identified but has been mapped to

chromosome 12 (12 p). Subtle variations in one

of these genes may also cause some forms ofessential hypertension.

Polymorphisms and mutations in genes such as

angiotensin gene, angiotensin converting enzyme,

B2 adrenergic receptor, adducin, angiotensinase

C, renin binding proteins, G-protein B3 subunit,

atrial natriuretic factor, and the insulin receptor

have also been linked to the development of

essential hypertension; however, most of them

show a weak association if any, and most of these

studies need further confirmation.

Cardiac output

An increased cardiac output has been found in

some young, borderline hypertensives who may

display a hyperkinetic circulation. If it is responsible

for the hypertension, the increase in cardiac output

could logically arise in two ways : either from an

increase in fluid volume (preload) or from an

increase in contractility from neural stimulation of

Journal, Indian Academy of Clinical Medicine Vol. 2, No. 3 July-September 2001 141


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142 Journal, Indian Academy of Clinical Medicine Vol. 2, No. 3 July-September 2001

the heart (Fig 1 ). However, even if it is involved in

initiation of hypertension, the increased cardiac

output likely does not persist, since the typical

haemodynamic finding in established

hypertension is an elevated peripheral resistance

and normal cardiac output13.

Significant increases in left ventricular mass have

been recognised in the still normotensive children

of hypertensive parents14,15. Such ventricular

hypertrophy has generally been considered a

compensatory mechanism to increased vascular

resistance (after load). However, it could reflect a

primary response to repeated neural stimulation

and, thereby, could be an initiating mechanism

for hypertension16 as well as amplifier of cardiac

output that reinforces the elevation of BP upstream

from the constricted arteriolar bed17.

An increased circulatory fluid volume (preload)

could induce hypertension by increasing cardiac

output. However, in most studies, patients with

established hypertension have a lower blood

volume and total exchangeable sodium than do

normal subjects18.

Autoregulation

The pattern of initially high cardiac output giving

way to persistently elevated peripheral resistance

has been observed in a few people and many

animals with experimental hypertension. When

animals with markedly reduced renal tissue are

given volume loads, the blood pressure rises

initially as a consequence of the high cardiac

output but within a few days, peripheral resistance

rises, and the cardiac output returns to near basal

levels19.

This changeover has been interpreted as reflecting

an intrinsic property of the vascular bed to regulate

the flow of blood, depending on the metabolic

need of tissues. This process, called

autoregulation, has been described20 and

demonstrated experimentally21. With increased

cardiac output, more blood flows through the

tissues than is required, and the increased flow

delivers extra nutrients or removes additional

Fig. 1 : Some of the factors involved in the control of blood pressure that affect the basic equation : blood pressure - cardiac

output x peripheral resistance.


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metabolic products; in response, the vessels

constrict, decreasing blood flow and returning the

balance of supply and demand to normal. Thus

the peripheral resistance increases and remains

high by the rapid induction of structural thickeningof resistance vessels.

Similar conversion from an initially high cardiac

output to a later increased peripheral resistance

has been shown in hypertensive people22. But the

role of autoregulation has been questioned by

various reasons. These include the finding that

patients with increased cardiac output also have

increased oxygen consumption rather than lower

level that should be seen if there was overperfusion

of tissues, as entailed in autoregulation concept.

Nonetheless, the auto-regulatory model does

explain the course of hypertension, in volume

expanded animals and people, particularly in the

presence of reduced renal mass.

Excess sodium intake

Excess sodium intake induces hypertension by

increasing fluid volume and preload, thereby

increasing cardiac output. Sodium excess may

increase blood pressure in multiple other ways as

well; affects vascular reactivity23 and renalfunction24. Diets in non-primitive societies contain

many times the daily adult sodium requirements,

an amount that is beyond the threshold level

needed to induce hypertension. Only part of the

population may be susceptible to the deleterious

effects of this high sodium intake, presumably

because these individuals have an additional renal

defect in sodium excretion25.

Epidemiologic evidence

The epidemiologic evidence incriminating an

excess of sodium goes as follows :

Primitive people from widely different parts of

the world who do not eat sodium have no

hypertension, nor does their BP rise with age,

as it does in all other industrialised

populations26,27.

If primitive people who are free from

hypertension adopt modern life styles,

including increased intake of sodium, then their

BP rises and hypertension appears28,29.

In population studies, a significant correlation

between the level of salt intake and frequencyof hypertension has been found30,31. In the

Intersalt study, which measured 24-hours urine

electrolytes and BP in 10,079 men and women

aged 20 to 59 in 52 places around the

world32,33, there was a positive correlation

between sodium excretion and both systolic

blood pressure (SBP) and diastolic blood

pressure (DBP), but a more significant

association between sodium excretion and the

changes in BP with age.

Experimental evidence

When hypertensive patients are on sodium

restricted diet, their BP falls34,35.

Short periods of increased NaCl intake has

been shown to raise BP in normotensives,

especially genetically predisposed animals36,37.

In randomised controlled studies of hundreds

of patients with high normal blood pressure,

those patients who moderately restricted their

sodium intake for 36 months38 to 5 years39,

had lower blood pressure and a decreased

incidence of hypertension than did the patients

who did not reduce their sodium intake.

A high sodium intake may activate a number

of pressure mechanisms40, viz., increases in

intraellular calcium41 and plasma

catecholamines42, worsening of insulin

resistance43, and a paradoxical rise in atrial

natriuretic peptide23.

Sensitivity of sodium

Since almost everyone in western countries ingests

a high sodium diet, the fact that only about half

will develop hypertension suggests a variable

degree of blood pressure sensitivity to sodium.

Although, obviously both heredity and interactions

with other environmental exposures may be

involved44, Weinberger et al45 defined sodium


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sensitivity as a 10mm Hg or greater decrease in

mean blood pressure from the level measured

after 4 hour infusion of 2 L normal saline

compared to the level measured the morning after

1 day of a 10 mmol sodium diet, during whichthree oral doses of furosemide were given at 10

AM, 2 PM, and 6 PM. Using this criteria they found

that 51% of hypertensives, but only 26% of

normotensive were sodium sensitive. Multiple

mechanisms of sodium sensitivity has been

proposed, viz., defect in renal sodium excretion24,

increased activity of the sodium hydrogen

exchanger46, increased sympathetic nervous

system activity47, increased calcium entry into

vascular smooth muscle41, impaired nitric oxide

synthesis48. Blacks have greater frequency of saltsensitivity. Salt sensitivity45 increases with age, and

perhaps more in women than in men50. In a recent

study Fujiwora et alreported that modulation of

NO synthesis by salt intake may be involved in a

mechanism for salt sensitivity in human

hypertension51.

Altered renal physiology

In essential hypertension, physiologic and

pathologic renal changes often precede changesidentifiable in other organs, but whether they

precede or follow the onset of the hypertension

itself has not been determined. The earliest

physiologic lesion of essential hypertension is

vascular, GFR is maintained; whereas total renal

blood flow is reduced (increased filtration fraction).

This pattern may be explained by diffuse,

predominantly efferent but also afferent,

vasoconstriction of all nephrons or, alternatively,

by selective afferent vasoconstriction with diversion

of blood away from some nephrons to maintainnear normal GFR. This renal vasoconstriction is

reversible and could lead to reduced pressure and

flow in the post glomerular circulation, which may

predispose to increased tubule Na+

reabsorption52,53.

Abnormal renal sodium transport

Body volume varies directly with total body Na+,

because Na+ is the predominant extracellular

solute that retains water within the extracellular

space. One primary function of the kidneys is to

regulate Na+ and water excretions, and

consequently, they play a dominant role in the longterm control of BP. To achieve this goal, two

important renal mechanisms are utilised. One

mechanism regulates extra cellular fluid volume

by coupling increases or decreases in urinary

excretion of Na+ and water, and the related

changes in renal perfusion pressure. This

phenomenon has been referred to a pressure

natriuresis and pressure diuresis54 (Fig. 2).

The second mechanism employs the renin-

angiotensin - aldosterone system, which directly

controls peripheral vascular resistance and renal

reabsorption of Na+ and water55.

Renal sodium retention

Essential hypertension is due primarily to an

abnormal kidney which has an unwillingness to

excrete sodium56.

Various investigations have proposed different

hypotheses to explain for abnormal renal sodium

retention as the initiating event for hypertension.

Resetting of pressure natriuresis

Guyton considers the regulation of body fluid

volume by the kidneys to be the dominant

mechanism for the long term control of blood

pressure, the only one of many regulatory controls

to have sustained and infinite power57,19.

Therefore, if hypertension develops, something

must be amiss with the pressure natriuresis control

mechanism or else the BP would return to normal.

Under normal conditions, the perfusion pressure

is around 100 mm Hg, sodium excretion is about

150 mEq/day, and these two mechanisms are in

a remarkably balanced state. The curve relating

arterial pressure to sodium excretion is steep19.

As Guyton and co-workers have shown, either the

entire curve can be shifted to the right or the slope

can be depressed, depending on the type of renal

insult, which inturn, is reflected by varying sensitivity


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to sodium58.

Cross transplantation studies in animal models59

and in humans60,61 have shown that the alteration

in renal function responsible for the resetting of

the pressure natriuresis curve is inherited.

Reduced nephron number

Brenneret al62 advanced the hypothesis that the

nephron endowment at birth is inversely relatedto the risk of developing hypertension later in life.

The congenital reduction in the number of

nephrons or in the filtration surface area (FSA)

per glomerulus, limits the ability to excrete sodium,

raises the blood pressure, and setting off a vicious

circle, whereby systemic hypertension begets

glomerular hypertension which begets more

systemic hypertension63 (Fig. 3).

These investigators point out that as many as 40%

of individuals under age 30 have fewer than thepresumably normal number of nephrons (600,000

per kidney) and speculate that those individuals,

whose congenital nephron numbers fall in the

lower range, constitute the population subsets that

exhibit enhanced susceptibility to the development

of essential hypertension. Similarly, a decrease

in filtration surface, reflected in a decreased

glomerular diameter or capillary basement

membrane surface area may be responsible for

an increased susceptibility to hypertension even

in the presence of a normal nephron number.

The congenital decrease in filtration surface has

been put forward as a possible explanation for

observed differences in susceptibility to

hypertension among genetic populations as well

as in blacks, women, and older people, all of

whom may have smaller kidneys or fewer

functioning nephrons64,96.

Fig. 2 : Proposed mechanism of pressure natriuresis.

Fig. 3 : A diagram of the hypothesis that the risks ofdeveloping essential hypertension and progressive renal injury

in adult life are increased as a result of congenital

oligonephropathy, or an inborn deficit of FSA, caused by

impaired renal development. Low birth weight, caused by

intrauterine growth retardation and/or prematurity, contributes

to the oligonephropathy. Systemic and glomerular

hypertension in later life results in progressive glomerularsclerosis, further reducing FSA and perpetuating a vicious circle

that leads, in the extreme, to end-stage renal failure63.


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Acquired natriuretic hormone

The Guyton hypothesis allows for a normal blood

volume despite an elevated pressure, in keeping

with most volume measurements in hypertensive

patients65. The next hypothesis requires an initiallyexpanded plasma volume that, after an inhibition

of renal sodium reabsorption, is allowed to return

to normal.

Ouabain, an endogenous digitalis like inhibitor

of sodium pump, which arises when plasma

volume is expanded, increases intracellular sodium

and mobilises calcium from intracellular stores.

Blaustein has formulated an overall scheme for

this acquired compensatory mechanism for renal

sodium retention, which could be a cause of

essential hypertension (Fig. 4)66

.

Renin-angiotensin - aldosterone

system

Renin may play a critical role in the pathogenesis

of most hypertension, a view long espoused by

Laragh67.

Fig. 4 : Diagram showing various feedback loops that may be involved in the rise in blood pressure that accompanies the

attempt to prevent plasma volume expansion when excessive sodium is ingested relative to the innate ability of the

kidneys to excrete a sodium load. The increase in intracellular sodium is the direct result of the inhibition of the Na+ pump

by ouabain; the increase in intracellular calcium is then mediated by the Na+/Ca2+ exchanger as a result of the rise insodium. (+) positive feedback loop; (), negative feedback loop; ADH antidiuretic hormone; ANP, atrial natriuretic peptides;

[Na+] intracellular sodium concentration; [Ca2+], intracellular calcium concentration66.


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Fig. 5 is a schematic overview of the renin-

angiotensin system showing its major components,

the regulators of renin release and the primary

effects of angiotensin II (AII) excluding the All

receptors.

Although, low renin levels are expected in essential

hypertension, the majority of patients with essential

hypertension do not have low suppression renin

angiotensin levels but inappropriately normal

or even elevated PRA levels. Indeed, when renin

profiling is correctly performed and indexed in

patients with essential hypertension, about 20%

are found to have high renin values, and about

30% have low renin values, with the remaining

half distributed between these two extremes68.

It seems likely that this mechanism is abnormally

activated in many patients with essential

hypertension, and at least three mechanisms have

been offered : nephron heterogeneity, non

modulation, and increased sympathetic drive.

Nephron heterogenecity with unsuppressible

renin secretion and impaired natriuresis as

cause of essential hypertension:

Within the kidneys, there exists a functional and

structural basis for the abnormal renin secretion

Fig. 5 : Schematic representation of the renin-angiotensin system, showing the major regulators of renin release, the biochemical

cascade leading to AII, and the major effects of AII. CNS, central nervous system, ECFV, extracellular fluid volume.


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and impaired Na+ excretion that are characteristic

of hypertensive states54 (Table II)69.

Table II : Hypothesis - there is nephron

heterogeneity in essential hypertension69.

1. There are ischaemic nephrons with impaired

sodium excretion intermingled with adapting

hyperfiltering hypernatriuretic nephrons.

2. Renin secretion is high from ischaemic

nephrons and low from hyperfiltering

nephrons.

3. The inappropriate circulating renin-

angiotensin level impairs sodium excretion

because:

a. In the adapting hypernatriuretic nephrons

i . I t increases tubular sodium

reabsorption.

ii. It enhances tubuloglomerular feedback

- mediated afferent constriction.

b. As the circulating renin level is diluted by

non-participation of adapting nephrons, it

becomes inadequate to support efferent

tone in hypoperfused nephrons.

4. A loss of nephron number with age and from

ischaemia further impairs sodium excretion.

Non-modulation

This has been proposed by Williams and

Hollenberg for normal renin and high renin levels

seen in nearly half of hypertensive patients due to

defective feed-back regulation of the renin -

angiotensin system within the kidneys and the

adrenal glands70.

Normal individuals modulate the responsiveness

of their AII target tissues with their level of dietary

sodium intake. With sodium restriction, the

adrenal secretion of aldosterone is enhanced

and vascular responses are reduced, with

sodium loading, the adrenal response is

suppressed, and vascular response are

enhanced, particularly within the renal

circulation. With sodium restriction, renal blood

flow (RBF) is reduced, facilitating sodium

conservation; with sodium loading, RBF is

increased, promoting sodium excretion. These

changes are mediated mainly by changes in All

level, increasing with sodium restriction and

decreasing with sodium loading.

Non-modulation is characterised by abnormaladrenal and renal responses to All infusions and

salt loads71. These findings have been attributed

to an abnormally regulated and rather fixed level

of AII, that, in the adrenal tissues, does not increase

aldosterone secretion in response to sodium

restriction and, in the renal circulation, does not

allow renal blood flow to increase with sodium

loading. The hypothesis that there is an abnormally

regulated, fixed local All concentration in these

modulators received support from the correction

of both the adrenal and renal defects after

suppression of All by ACE-inhibitors.

Non-modulation in the face of relatively high

dietary sodium intake could explain the

pathogenesis of sodium sensitive hypertension and

provide a more targeted, rational therapy for

correction. Moreover, a lower prevalence of non-

modulation has been found in young women,

suggesting that female sex hormones may confer

protection against this genotypic predisposition to

hypertension72.

Low renin essential hypertension

Although low renin levels are expected in the

absence of one or another of the previously

described circumstances, a great deal of work has

been done to uncover special mechanisms,

prognoses, and therapy for hypertension with low

renin.

The possible mechanisms for low renin

hypertension include volume expansion with or

without mineral corticoid excess but majority of

careful analyses fail to indicate volume expansion73

or increased levels of mineralocorticoids74. Recent

studies by Fishar75et al focus on adrenal and

pressure responsiveness to angiotensin II (ang. II)

as a function of dietary salt intake in patients with

low renin hypertension, normal renin hypertension,

and normal controls. There were striking functional


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similarities between normal renin hypertension

and non-modulating essential hypertension with

normal plasma renin activity, including :

(i) Salt sensitivity of the blood pressure,

(ii) blunted plasma aldosterone responses to ang.

II infusion and upright posture after 5 days of

rigid dietary sodium restriction, and

(iii) relatively low basal plasma aldosterone levels.

These differences compared to normal controls

and modulating hypertensive subjects

disappeared when dietary salt intake was

increased to 200 mEq/day, consistent with

suppression of plasma ang. II activity during

high salt intake with resensitization of ang. II

receptors and improved ang. II responsiveness.

Fig. 6 : High blood pressure mechanisms80

If so, perhaps the blunted responsiveness to

ang. II during sodium restriction could reflect

the continuing generation of ang. II, with

angiotensin receptor down regulation in these

subjects.

Mutations in the HSD II B2 gene causes a rare

monogenic juvenile hypertensive syndrome

called apparent mineralocorticoid excess (AME).In AME, compromised II. HSD enzyme activity

results in over stimulation of the mineralo

corticoid receptor (MR) by cortisol; causing

sodium retention, hypokalaemia, and salt

dependent hypertension76,77.

There is evidence that an impaired II

hydroxysteroid dehydrogenase (II B HSD2

activity) type 2 may play a role in the


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pathogenesis of essential hypertension in some

patients and this may be genetically determined.

Because 40% of patients with essential

hypertension have low renin levels, a number

of these patients may have a mild form of AME.Furthermore, as spironolactone causes ready

remission, it is important to seek the diagnosis

by genetic and clinical studies. The prevalence

of mutations of II HSD2 in general population

of patients with essential hypertension is

presently unknown. The epidemiology of such

mutations is relevant for two reasons. First, the

prevalence is important in order to define the

cost-benefit ratio for screening patients with low

renin-low aldosterone hypertension. Second, the

accurate diagnosis of AME should permit thedesign of more specific therapies for patients

with this disease76,77.

Two forms of vasoconstriction in essential

hypertension:

Two forms of vasoconstriction, one mediated by

renin and other by Na+ - volume forces, seen

in extreme forms of hypertension also operate

in essential hypertension. Laragh and co-

workers78,79 have long attached a great deal of

significance to various PRA levels found inpatients with essential hypertension. According

to this view, the levels of renin can identify the

relative contribution of vasoconstriction and

body fluid expansion to pathogenesis of

hypertension. According to the bipolar

vasoconstriction - volume analysis, arteriolar

vasoconstriction by AII is predominantly

responsible for the hypertension in patients with

high renin, whereas volume expansion is

predominantly responsible in those with low

renin. Though, both lead to increasedperipheral resistance, which is the common

characteristic of all hypertension. The similarity

ends there, however, because the conditions

imposed by these two agents are radically

different in their implications for risk, survival,

and treatment (Fig. 6)80.

Fig. 7 : The spectrum of hypertensive disorders stratified according to their renin-sodium relationship. Normal subjects, as

indicated by the equation at the bottom of the figure, maintain and defend normotension by curtailing renal renin secretion inreaction to a rise in sodium intake or autonomic vasoconstriction, or by proportionally increasing renin secretion in the face of

either Na+ depletion or hypotension from fluid or blood loss or a neurogenic fall in blood pressure. Hypertensive subjects sustain

their higher blood pressures by renal secretion of too much renin for their Na+ volume states, or by renal retention of too much

Na+ (Volume) for their renin level, which often fails to fully turn off as it does in normal subjects. High renin hypertensive patients

are proportionately more vasoconstricted with poor tissue perfusion and therefore most susceptible to cardiovascular tissue

ischaemic damage. BP = blood pressure; PRA = plasma renin activity.


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The predominance of activity of either pole

depresses activity at other, whereas both

vasoconstrictive forces may well assert their

influence when renin levels are in the medium

range.

Human hypertensive disorders as a

spectrum of abnormal plasma renal-sodium

volume products

Normotension is sustained and defended by

fluctuation of PRA according to salt intake and

Na+ balance. Human hypertensive states are

characterised by excessive renal renin secretion

and thus PRA for the concurrent state of Na+

balance (i.e., by a spectrum of abnormally high

plasma renin levels) for the Na+ -volume status

or vice versa, i.e., renal retention of too much

Na+ (Volume) for their renin level which often

fail to fully turn off as it does in normal subjects69

(Fig. 7).

Stress and sympathetic overactivity

As shown in Figure 1 an excess of renin-angiotensin activity could interact with the

sympathetic nervous system (SNS) to mediate

most of its effects. On the other hand, stress

may activate the SNS directly; and SNS

overactivity in turn, may interact with high

sodium intake, the renin-angiotensin system,

and insulin resistance among the other possible

mechanisms. Considerable evidence, supports

increased SNS activity in early hypertension and,

even more impressively, in the still normotensive

offspring of hypertensive parents, among whoma large number are l ikely to develop

hypertension.

Fig. 8 : Indications that an increased sympathetic outflow may be key factor in primary hypertension. The outflow is increased

when arterial baroreceptors are reset so that they exert less inhibition on the vasomotor center. The resetting could be due to

genetic changes in the endothelial lining of the carotid sinus and aortic arch and/or at the vasomotor centers. The increased

sympathetic outflow may be further enhanced by stress. As a consequence of this neurohumoral excitation, the systemic vascular

resistance is increased. In addition, the endothelial cells in the resistance blood vessel may secrete less vasodilator and more

vasoconstrictor substances, thus compounding the vasoconstriction. Furthermore, mitogens produced in endothelial cells andalso released from platelets, together with norepinephrine, can cause proliferation of the vascular smooth muscle with a further

aggravation of the systemic vasoconstriction82.


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Baroreceptor dysfunction

The baroreceptors when activated by a rise in BP

or central venous pressure, respectively, normally

reduce heart rate and lower blood pressure by

vagal stimulation and sympathetic inhibition.When hypertension is sustained, these reflexes are

reset rapidly from both structural and functional

changes so that given increase is BP evokes less

decrease in heart rate81. Shepherd postulates that

the decreased inhibition of the vasomotor center

resulting from resetting of arterial baroreceptors

(mechano receptors) may be responsible for

increased sympathetic out flow and thereby in the

perpetuation of hypertension (Fig. 8)82.

Stress : People exposed to repeated psychogenicstresses may develop hypertension more frequently

than otherwise similar people not so stressed.

The blood pressure remained normal among

nuns in a secluded order over a 20 years

period, whereas it rose with age in women

living nearby in the outside world83.

Annual rate of developing hypertension is 5.6

times greater among air traffic controllers, who

work under high level of psychological stress,

than non professional pilots84.

Among healthy employed men, job strain

(defined as high psychological demands and

low decision latitude on the job) is associated

with 3.1 times greater odds ratio for

hypertension, an increased left ventricular mass

index by echocardiography85, and higher

awake ambulatory blood pressure86.

People may become hypertensive not just

because they are more stressed, but because

they respond differently to stress. Greater

cardiovascular and sympathetic nervous

reactivities to various laboratory stresses have

been documented in hypertensives and in

normotensive at higher risk of developing

hypertension87,88,89, extending even to a greater

anticipatory BP response while awaiting an

exercise stress test90.

Despite the rather impressive body of literature,

the role of mental stress in the development

of hypertension remains uncertain. Its effects

are likely to depend on an interaction of at

least three factors: the nature of the stressor,

its perception by the individual, and theindividuals physiological susceptibility91.

The role of acquired tubulointerstitial disease

in the pathogenesis of salt dependent

hypertension92

It proposes that hypertension has two phases : an

early phase in which elevations in blood pressure

(BP) are mainly episodic and are mediated by a

hyperactive SNS or RAS, and a second phase in

which BP is persistently elevated and that is

primarily mediated by an impaired ability of thekidney to excrete salt, NaCl. The transition from

the first phase to the second occurs as a

consequence of catecholamine induced elevations

in BP that preferentially damage regions of the

kidney (juxtamedullary and medullary regions) that

do not autoregulate well to changes in renal

perfusion pressure (Fig. 9)92.

This may be the major mechanism for the

development of salt-dependent hypertension, and

particularly for the hypertension associated withblacks, aging, and obesity. Thus, essential

hypertension may be a type of acquired

tubulointerstitial renal disease.

Hypertension may result from entry into the

pathway at other stages :

i Interstitial damage due to other mechanisms:

Hypercalcaemia, chronic pyelonephritis,

obstruction, heavy metals (lead), radiation, or

associated with gout.

ii Mechanisms that directly compromise renalmedullary blood flow-Cyclosporine, analgesic

abuse, genetic reduction in medullary blood

flow in spontaneously hypertensive rats (SHR).

iii Directly resulting in decreased sodium

excretion.

Liddles syndrome, glucocorticoid - remediable

aldosteronism, and the syndrome of apparent

mineralocorticoid excess, and a genetic reduction


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in nephron numbers.

In conclusion, this hypothesis links early, episodic,

salt independent hypertension with the later

development of a persistent salt dependent

hypertension with the new concept that it ismediated by acquired tubulointerstitial and

peritubular capillary injury. A strength of the

hypothesis is that it unites many prior hypotheses

into one pathway; including that of Julius on the

role of the sympathetic nervous system in early

hypertension93, of Cowley et al on the role of

medullary ischaemia94, of Sealey and Laragh on

activation of the renin-angiotensin II system69, of

Guyton et alon impaired pressure natriuresis54,

of Kurokawa on enhanced TG feedback95 and

Mackenzie, Lawler and Brenner on reduced

nephron number96. In addition, it potentially

provides answers to many questions not easily

addressed by other individual hypothesis.

Peripheral resistance

Multiple factors affect peripheral resistance (Fig.

1). Main determinant of sustained elevated BP

is increase in peripheral resistance which resides

in precapillary vessels with a lumen diameter

of less than 500 m97. In human hypertensionand in experimental animal models of

hypertension, structural changes in these

resistance vessels are commonly observed. In

patients with essential hypertension, the

characteristic findings include :

1. Decreased lumen diameter and,

2. Increased ratio of the diameter of vascular

smooth muscle layer of the vessel (tunica

media) to lumen diameter, referred to as the

media to lumen ratio.

According to Poiseulles law, vascular resistance

is positively related to both the viscosity of blood

and the length of arterial system and negatively

to the fourth power of the luminal radius. Since

neither viscosity nor length are much, if at all,

altered and the small change in luminal radius

can have such a major effect, it is apparent that

the increased vascular resistance seen in

Fig. 9 : Scheme for pathogenesis of salt dependent

hypertension. The hypothesis proposes that early

hypertension is episodic and is mediated by a hyperactivesympathetic nervous system or activated renin-angiotensin

system. The acute norepinephrine or angiotensin II

mediated elevation in BP are transmitted to the peritubular

capillaries of the kidney in association with a reduction in

blood flow secondary to the vasoconstrictive properties

of these substances. Capil lary damage and

tubulointerstitial injury with fibrosis results. The localischaemia stimulates [(adenosine, local angiotensin II,

renal nerve sympathetic activity (RSNA)] or inhibits [(nitricoxide (NO), prostaglandins, dopamine] vasoactive

mediators, resulting in NaCl reabsorption due to enhanced

tubuloglomerular feeback. The capillary damage and

increase in renal vascular resistance also blunts the

pressure natriuresis mechanism. The consequences of both

enhanced tubuloglomerular feedback and impairedpressure natriuresis is an acquired functional defect in

NaCl excretion. This results in a resetting of the pressure

natriuresis curve to a higher pressure in order to restore

sodium balance back to normal92.


15/22


established hypertension must reflect changes in

the calibre of the small resistance arteries and

arterioles98.

The increase in media to lumen ratio of the

resistance vessels occurs by the addition of materialto the outer or inner surfaces of the blood vessel

wall97. This process requires growth (either

hyperplasia or hypertrophy) of the cellular

components of the blood vessel wall and results

in an increase in its cross-sectional area. An

alternative process, referred to as vascular

remodelling, can result in an increased media to

lumen ratio through the rearrangement of the

existing material without an increase in the cross

sectional area of the vessel. For this to occur, a

reduction in the external diameter of the blood

vessel is required. In human essential hypertension,

there is increasing evidence to support the view

that vascular remodelling rather than growth, is

the predominant change occurring in resistance

vessels.

Cell membrane alterations

There is a body of evidence that shows that the

cell membranes of hypertensive animals and, less

Fig. 10 : Hypotheses linking abnormal ionic fluxes to increased

peripheral resistance through increase in cell sodium, calcium,

or pH.

Fig. 11 : A flow diagram illustrating the link between Na+/H+ exchanger activation and essential hypertension104.


16/22


convincingly, of hypertensive people are altered

in a primary manner, allowing abnormal

movements of ions and thereby changing the

intracellular environment to favour contraction and

growth (Fig. 10)99

. These primary alterations aredifferentiated from the secondary inhibition of the

Na+/K+-ATPase pump by ouabain, which is

secreted after volume expansion and, as described

earlier, is a possible mechanism for renal sodium

retention.

Abnormalities of the physical properties of the

membrane and of multiple transport systems have

been implicated in the pathogenesis of

hypertension100. Most relate to vascular smooth

muscle cells, but since such cells are not available

for study in humans, surrogates such as red and

while blood cells are used. Transport systems

present in the cell membrane of erythrocytes that

control the movement of sodium and potassium

to maintain the marked differences in

concentration of these ions on the outside and

inside of cells, which in turn provides the elector

chemical gradients needed for various cell

functions101,102.

There is evidence that the sodium hydrogen

exchanger is stimulated in hypertensive patients

either by an increased cellular calcium load or

enhanced external calcium entry. An increased

Na+/H+ exchanger could play a significant role

in the pathogenesis of hypertension, both by

stimulating vascular tone and cell growth and

possibly by increasing sodium reabsorption in

renal proximal tubule cells (Fig. 11)104.

RBC membranes from hypertensives have an

increased cholesterol : phospholipid ratio in

association with high sodium lithium transport(SLC)105 and increased ratios of fatty acid

metabolites to precursors compared to those

from age matched normotensives100 . Such

changes in lipids produce a high membrane

microviscosity and decrease in fluidity106, which

may be responsible for increased permeability

to sodium and other alterations in sodium

transport107.

Endothelial dysfunction

Nitric Oxide (NO) is the primary endogenous

vasodilator (Fig. 12)108. Although, the role of

NO in the regulation of BP is uncertain, several

studies have reported its influence on BP andrenal haemodynamics109. In healthy human

subjects, inhibition of NO synthase by N-

monomethyl-L-arginine acutely increased BP,

peripheral vascular resistance, and fractional

excretion of Na+110.

NO is tonical ly active in the medullary

circulation, so that reducing NO production or

vascular responsiveness, reportedly enhances

the pressure natriuresis response, followed by

reductions in papillary blood flow, renalinterstitial hydrostatic pressure, and Na+

excretion by almost 30%, without corresponding

changes in total or cortical RBF or GFR109. This

mechanism may contribute to the blunted

pressure natriuresis reported in experimental

models.

Endothel in : Endothel in is among the

Fig. 12 : Nitric oxide in arterial smooth muscle. A messenger

molecule such as acetylcholine binds its receptor on an

endothelial cell, activating inward calcium currents. Calcium

binds to calmodulin and activates endothelial cell nitric oxide

synthase, which converts arginine plus oxygen into citrulline

and nitric oxide. Nitric oxide diffuses out of the endothelialcell into an adjacent smooth muscle cell and activates

guanylate cyclase by binding to the iron in its haeme group.

The increase in cyclic guanosine monophosphate (cGNP)

causes smooth muscle relaxation and thus vasodilation. GTP

- guanosine triphosphate.


17/22


vasoconstrictors yet to be identified. Its

actions are mediated through two types of

receptors, ETA

and ETB, both of which are

located on vascular smooth muscle. An orally

active mixed endothelium receptor antagonistbosentan, reduced BP in hypertensive patients

to a level that was comparable to enalapril111.

Bosentan has also been reported to block the

effects of an infusion of angiotensin II on BP

and renal blood flow in rats112.This raises the

issue of whether a component of these

angiotensin II actions may be mediated by

endothelin.

Obesity

Hypertension is more common in obese

people. Obese individuals have higher

cardiac output, stroke volume, and central

and total blood volume and lower peripheral

resistance than non obese individuals with

similar blood pressure113. The increase in

card iac output is propor t ional to the

expansion of body mass and may be the

primary reason for the rise in BP 114. The

prevalence of hypertension increased equallywith increasing BMI, degree of upper body

obesity, and fasting insulin levels115 (Fig. 13).

Insulin resistance and hyper-

insulinaemia

Higher insulin levels are associated with more

hypertension, and many possible mechanisms

may explain the association. (Table III)116.

The hypertension that is more common in

obese people may arise in large part fromthe insul in res is tance and resul tant

hyperinsulinaemia that results from the

increased mass of fat. However, rather

unexpectedly, insulin resistance may also be

involved in hypertension in non-obese people

Fig. 13 : Overall scheme for the mechanisms by which obesity, if predominantly upper body or visceral in location, could promote

diabetes, dyslipidaemia and hypertension via hyperinsulinaemia.


18/22


as wel l 11 7. The explanat ion for insu l in

resistance found in as many as half of non-

obese hypertensive, however is not obvious

and may involve one or more aspects of

insulins action (Table IV ).

Table III : Proposed mechanisms by which

insulin resistance and/or hyperinsulinaemia

may lead to increased blood pressure.

Enhanced renal sodium and water reabsorption.

Increased blood pressure sensitivity to

dietary salt intake

Augmentation of the pressure and

aldosterone responses to AII

Changes in transmembrane electrolyte

transport

a. Increased intracellular sodium

b. Decreased Na+/K+ - ATPase activity

c. Increased intracellular Ca2+ pump activity

Increased intracellular Ca2+ accumulation

Stimulation of growth factors, especially in

Fig. 14 : The left panel represents insulins action in normal humans. Although insulin causes marked increases in sympatheticneural out flow, which would be expected to increase blood pressure, it also causes vasodilation, which would decrease blood

pressure. The net effect of these two opposing influences is no change or slight decrease in blood pressure. There may be an

imbalance between the sympathetic and vascular actions of insulin in conditions such as obesity and hypertension. As shown in

the right panel, insulin may cause potentiated sympathetic activation or attenuated vasodilation. An imbalance between these

pressure and depressor actions of insulin may result in elevated blood pressure119.

vascular smooth muscle.

Stimulation of sympathetic nervous activity

Reduced synthesis of vasodilatory

prostaglandins

Impaired vasodilationIncreased secretion of endothelin

Effects of hyperinsulinaemia on blood

pressure :

Figure 13, portrays three ways by which the

hyper insul inaemia that develops as a

consequence of insul in resistance and

reduced clearance could induce hypertension.

Other mechanisms have been proposed

(Table III). Of these, impaired endothelium -

dependent vasodilation may be particularlyimportant 11 8 Insul in normal ly acts as a

vasodilator119-121. It has been shown that

al though insul in increases sympathetic

activity, the effect is normally overridden by

the direct vasodilatory effect of insulin (Fig.

14 )119.


19/22


Table IV : Factors that may induce insulin resistance in hypertension.

Aspect Normal site of action Effect of hypertension

Insulin delivery Capillary bed Vasoconstriction; attenuated vasodilation, capillary

rarefaction

Insulin transport Interstitium Impaired transport

Insulin action muscle fibre Genetic or acquired increase in type 2B fibres,

hormonal interference with insulin effects, decreased

transport protein.

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Essensial Hypertension Pathogenesis and Pathophsiology

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