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

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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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    Journal, Indian Academy of Clinical Medicine Vol. 2, No. 3 July-September 2001 143

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

    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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    Journal, Indian Academy of Clinical Medicine Vol. 2, No. 3 July-September 2001 145

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

    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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    Journal, Indian Academy of Clinical Medicine Vol. 2, No. 3 July-September 2001 147

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

    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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    Journal, Indian Academy of Clinical Medicine Vol. 2, No. 3 July-September 2001 149

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

    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.

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    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.

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    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.

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    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.

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    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.

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    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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