Essential Hypertension – Pathogenesis and Pathophysiology

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

* Senior Resident** ProfessorDepartment of Nephrology,All India Institute of Medical Sciences,New Delhi-110 029.

Essential Hypertension – Pathogenesis and PathophysiologySanjay Vikrant*, SC Tiwari**

Population studies suggest the blood pressure (BP)is a continuous variable, with no absolute dividingline between normal and abnormal values1. Highblood pressure is a leading risk factor for heartdisease, stroke, and kidney failure. This correlationis more robust with systolic than with diastolic BP2.Even when BP is lowered by antihypertensivemedication, the associated reduction in theincidence of coronary heart disease lags behindthat of stroke3.

There is a widely held misconception thathypertension is a single disease that can be treatedwith a single recipe. Hypertension is aheterogenous disorder in which patients can bestratified by pathophysiologic characteristics thathave a direct bearing on the efficacy of specificallytargeted antihypertensive medications, on thedetection of potentially curable forms ofhypertension, and on the risk of cardiovascularcomplications4.

Essential hypertension is characterised by asustained systolic pressure of greater than 140 mmHg and a diastolic BP at greater than 90 mm Hgand by some characteristics listed in Table I.

The pressure required to move blood through thecirculatory bed is provided by pumping action ofthe heart (cardiac output; CO) and the tone ofthe arteries (peripheral resistance; PR). Each ofthese primary determinants of the blood pressureis, in turn, determined by the interaction of the“exceedingly complex series of factors”6 displayedin part in figure 1.

Hypertension has been attributed to abnormalitiesin virtually every one of these factors. It is unlikely

that all of these factors are operative in any givenpatient; but multiple hypotheses may prove to becorrect, since the haemodynamic hallmark ofprimary hypertension – a persistently elevatedvascular resistance – may be reached through anumber of different paths. Before the finaldestination, these may converge into eitherstructural thickening of the vessel walls orfunctional vasoconstriction. Moreover, individualfactors often interact, and the interactions areproving to be increasingly complex. For instance,insulin resistance is present even beforehypertension develops in those who are geneticallypredisposed, the resultant hyperinsulinaemia isassociated with sodium sensitivity, obesity, andincreased sympathetic drive as well as impairedendothelium - dependent vascular resistance8.

Table I : Pathophysiologic characteristics ofessential hypertension5.No known causeDiastolic pressure repeatedly > 90 mm HgTotal peripheral resistance usually increasedPulse pressure possibly increased or decreased

Cardiac output normal, or elevated in some,possibly early in the diseaseCardiac work increasedAltered renal physiology, with acceleratednatriuresis and reduced renal blood flowNormal blood flow to most regions; diminishedrenal and skin blood flow and increasedmuscle flow may developPlasma volume reduced (may be inverselyrelated to diastolic pressure)Hyper-reactivity of pressure to stress, abnormalvascular reactivity and impaired circulatoryhomeostasis.

Role of geneticsThe variations in BP that are genetically determinedare termed “inherited BP”. Although, we do not

know which genes cause BP to vary, we know fromfamily studies that inherited BP can range fromlow normal BP to severe hypertension. Although,it has frequently been indicated that the causes ofessential hypertension are not known, this is onlypartially true because we have little informationon genetic variations or genes that are over-expressed or under-expressed as well as theintermediary phenotypes that they regulate tocause high BP. Factors that increase BP, such asobesity and high alcohol and salt intake are called“hypertensinogenic factors”; some of these factorshave inherited, behavioural, and environmentalcomponents. Inherited BP could be considered asthe core BP, whereas hypertensinogenic factorscause BP to increase above the range of inheritedBPs. Further, there are interactions betweengenetics and environmental factors that influenceintermediary phenotypes such as sympatheticnerve activity, renin angiotensin aldosterone andrenin - kallikrein - kinin systems and endothelialfactors, which is turn influence other intermediaryphenotypes such as sodium excretion, vascularreactivity, and cardiac cartractility. These and manyother intermediary phenotypes determine totalvascular resistance and cardiac output andconsequently BP9.

The identification of variants (allelic) genes thatcontribute to the development of hypertension iscomplicated by the fact that the 2 phenotypes thatdetermine BP, i.e., cardiac output and totalperipheral resistance, are controlled byintermediary phenotypes, including the autonomicnervous system, vasopressor/vasodepressorhormones, the structure of the cardiovascularsystem, body fluid volume and renal function, andmany others. Furthermore, these intermediaryphenotypes are also controlled by complexmechanisms including BP itself10. Thus there aremany genes that could participate in thedevelopment of hypertension.

The influence of genes on BP has been suggestedby family studies demonstrating associations ofBP among siblings and between parents andchildren. There is better association among BP

values in biological children than in adoptedchildren and in identical as opposed to non-identical twins. BP variability attributed to allgenetic factors varies from 25% in pedigree studiesto 65% in twin studies. Furthermore, genetic factorsalso influence behavioural pattern, which mightlead to BP elevation. For example, a tendencytowards obesity or alcoholism will be influencedby both genetic and environmental factors, thusthe proportion of BP variability caused byinheritance is difficult to determine and may varyin different populations.

Mutations in at least 10 genes have been shownto raise or lower BP through common pathwaysby increasing or decreasing salt and waterreabsorption by the nephron11,12. The geneticmutations responsible for 3 rare forms ofmendellian (monogenic) hypertension syndromes- gluco-corticoid remediable aldosteronism (GRA),Liddle’s syndrome, and apparentmineralocorticoid excess (AME) has beenidentified, whereas in a fourth, autosomaldominant hypertension with brachydactyly thegene is not yet identified but has been mapped tochromosome 12 (12 p). Subtle variations in oneof these genes may also cause some forms of“essential” hypertension.

Polymorphisms and mutations in genes such asangiotensin gene, angiotensin converting enzyme,B2 adrenergic receptor, adducin, angiotensinaseC, renin binding proteins, G-protein B3 subunit,atrial natriuretic factor, and the insulin receptorhave also been linked to the development ofessential hypertension; however, most of themshow a weak association if any, and most of thesestudies need further confirmation.

Cardiac outputAn increased cardiac output has been found insome young, borderline hypertensives who maydisplay a hyperkinetic circulation. If it is responsiblefor the hypertension, the increase in cardiac outputcould logically arise in two ways : either from anincrease in fluid volume (preload) or from anincrease in contractility from neural stimulation of

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

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

the heart (Fig 1 ). However, even if it is involved ininitiation of hypertension, the increased cardiacoutput likely does not persist, since the typicalhaemodynamic finding in establishedhypertension is an elevated peripheral resistanceand normal cardiac output13.

Significant increases in left ventricular mass havebeen recognised in the still normotensive childrenof hypertensive parents14,15. Such ventricularhypertrophy has generally been considered acompensatory mechanism to increased vascularresistance (after load). However, it could reflect aprimary response to repeated neural stimulationand, thereby, could be an initiating mechanismfor hypertension16 as well as amplifier of cardiacoutput that reinforces the elevation of BP upstreamfrom the constricted arteriolar bed17.

An increased circulatory fluid volume (preload)could induce hypertension by increasing cardiacoutput. However, in most studies, patients withestablished hypertension have a lower bloodvolume and total exchangeable sodium than do

normal subjects18.

AutoregulationThe pattern of initially high cardiac output givingway to persistently elevated peripheral resistancehas been observed in a few people and manyanimals with experimental hypertension. Whenanimals with markedly reduced renal tissue aregiven volume loads, the blood pressure risesinitially as a consequence of the high cardiacoutput but within a few days, peripheral resistancerises, and the cardiac output returns to near basallevels19.

This changeover has been interpreted as reflectingan intrinsic property of the vascular bed to regulatethe flow of blood, depending on the metabolicneed of tissues. This process, calledautoregulation, has been described20 anddemonstrated experimentally21. With increasedcardiac output, more blood flows through thetissues than is required, and the increased flowdelivers 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 - cardiacoutput x peripheral resistance.


metabolic products; in response, the vesselsconstrict, decreasing blood flow and returning thebalance of supply and demand to normal. Thusthe peripheral resistance increases and remainshigh by the rapid induction of structural thickeningof resistance vessels.

Similar conversion from an initially high cardiacoutput to a later increased peripheral resistancehas been shown in hypertensive people22. But therole of autoregulation has been questioned byvarious reasons. These include the finding thatpatients with increased cardiac output also haveincreased oxygen consumption rather than lowerlevel that should be seen if there was overperfusionof tissues, as entailed in autoregulation concept.Nonetheless, the auto-regulatory model doesexplain the course of hypertension, in volumeexpanded animals and people, particularly in thepresence of reduced renal mass.

Excess sodium intakeExcess sodium intake induces hypertension byincreasing fluid volume and preload, therebyincreasing cardiac output. Sodium excess mayincrease blood pressure in multiple other ways aswell; affects vascular reactivity23 and renalfunction24. Diets in non-primitive societies containmany times the daily adult sodium requirements,an amount that is beyond the threshold levelneeded to induce hypertension. Only part of thepopulation may be susceptible to the deleteriouseffects of this high sodium intake, presumablybecause these individuals have an additional renaldefect in sodium excretion25.

Epidemiologic evidenceThe epidemiologic evidence incriminating anexcess of sodium goes as follows :� Primitive people from widely different parts of

the world who do not eat sodium have nohypertension, nor does their BP rise with age,as it does in all other industrialisedpopulations26,27.

� If primitive people who are free from

hypertension adopt modern life styles,including increased intake of sodium, then theirBP rises and hypertension appears28,29.

� In population studies, a significant correlationbetween the level of salt intake and frequencyof hypertension has been found30,31. In theIntersalt study, which measured 24-hours urineelectrolytes and BP in 10,079 men and womenaged 20 to 59 in 52 places around theworld32,33, there was a positive correlationbetween sodium excretion and both systolicblood pressure (SBP) and diastolic bloodpressure (DBP), but a more significantassociation between sodium excretion and thechanges 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 hundredsof patients with high normal blood pressure,those patients who moderately restricted theirsodium intake for 36 months38 to 5 years39,had lower blood pressure and a decreasedincidence of hypertension than did the patientswho did not reduce their sodium intake.

� A high sodium intake may activate a numberof pressure mechanisms40, viz., increases inintraellular calcium41 and plasmacatecholamines42, worsening of insulinresistance43, and a paradoxical rise in atrialnatriuretic peptide23.

Sensitivity of sodiumSince almost everyone in western countries ingestsa high sodium diet, the fact that only about halfwill develop hypertension suggests a variabledegree of blood pressure sensitivity to sodium.Although, obviously both heredity and interactionswith other environmental exposures may beinvolved44, Weinberger et al45 defined sodium


sensitivity as a 10mm Hg or greater decrease inmean blood pressure from the level measuredafter 4 hour infusion of 2 L normal salinecompared to the level measured the morning after1 day of a 10 mmol sodium diet, during whichthree oral doses of furosemide were given at 10AM, 2 PM, and 6 PM. Using this criteria they foundthat 51% of hypertensives, but only 26% ofnormotensive were sodium sensitive. Multiplemechanisms of sodium sensitivity has beenproposed, viz., defect in renal sodium excretion24,increased activity of the sodium hydrogenexchanger46, increased sympathetic nervoussystem activity47, increased calcium entry intovascular smooth muscle41, impaired nitric oxidesynthesis48. Blacks have greater frequency of saltsensitivity. Salt sensitivity45 increases with age, andperhaps more in women than in men50. In a recentstudy Fujiwora et al reported that modulation ofNO synthesis by salt intake may be involved in amechanism for salt sensitivity in humanhypertension51.

Altered renal physiologyIn essential hypertension, physiologic andpathologic renal changes often precede changesidentifiable in other organs, but whether theyprecede or follow the onset of the hypertensionitself has not been determined. The earliestphysiologic lesion of essential hypertension isvascular, GFR is maintained; whereas total renalblood 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 diversionof blood away from some nephrons to maintainnear normal GFR. This renal vasoconstriction isreversible and could lead to reduced pressure andflow in the post glomerular circulation, which maypredispose to increased tubule Na+reabsorption52,53.

Abnormal renal sodium transport

Body volume varies directly with total body Na+,

because Na+ is the predominant extracellularsolute that retains water within the extracellularspace. One primary function of the kidneys is toregulate Na+ and water excretions, andconsequently, they play a dominant role in the longterm control of BP. To achieve this goal, twoimportant renal mechanisms are utilised. Onemechanism regulates extra cellular fluid volumeby coupling increases or decreases in urinaryexcretion of Na+ and water, and the relatedchanges in renal perfusion pressure. Thisphenomenon has been referred to a pressurenatriuresis and pressure diuresis54 (Fig. 2).

The second mechanism employs the renin-angiotensin - aldosterone system, which directlycontrols peripheral vascular resistance and renalreabsorption of Na+ and water55.

Renal sodium retention

Essential hypertension is due primarily to anabnormal kidney which has an unwillingness toexcrete sodium56.

Various investigations have proposed differenthypotheses to explain for abnormal renal sodiumretention as the initiating event for hypertension.

Resetting of pressure natriuresis

Guyton considers the regulation of body fluidvolume by the kidneys to be the dominantmechanism for the long term control of bloodpressure, the only one of many regulatory controlsto have sustained and infinite power57,19.Therefore, if hypertension develops, somethingmust be amiss with the pressure natriuresis controlmechanism or else the BP would return to normal.

Under normal conditions, the perfusion pressureis around 100 mm Hg, sodium excretion is about150 mEq/day, and these two mechanisms are ina remarkably balanced state. The curve relatingarterial pressure to sodium excretion is steep19.As Guyton and co-workers have shown, either theentire curve can be shifted to the right or the slopecan be depressed, depending on the type of renalinsult, which inturn, is reflected by varying sensitivity


to sodium58.

Cross transplantation studies in animal models59

and in humans60,61 have shown that the alterationin renal function responsible for the resetting ofthe pressure natriuresis curve is inherited.

Reduced nephron number

Brenner et al62 advanced the hypothesis that thenephron endowment at birth is inversely relatedto the risk of developing hypertension later in life.The congenital reduction in the number ofnephrons or in the filtration surface area (FSA)per glomerulus, limits the ability to excrete sodium,raises the blood pressure, and setting off a viciouscircle, whereby systemic hypertension begetsglomerular hypertension which begets moresystemic 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 (600,000per kidney) and “speculate that those individuals,whose congenital nephron numbers fall in thelower range, constitute the population subsets thatexhibit enhanced susceptibility to the developmentof essential hypertension”. Similarly, a decreasein filtration surface, reflected in a decreasedglomerular diameter or capillary basementmembrane surface area may be responsible for

an increased susceptibility to hypertension evenin the presence of a normal nephron number.

The congenital decrease in filtration surface hasbeen put forward as a possible explanation forobserved differences in susceptibility tohypertension among genetic populations as wellas in blacks, women, and older people, all ofwhom may have smaller kidneys or fewerfunctioning 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 injuryin adult life are increased as a result of congenitaloligonephropathy, or an inborn deficit of FSA, caused byimpaired renal development. Low birth weight, caused byintrauterine growth retardation and/or prematurity, contributesto the oligonephropathy. Systemic and glomerularhypertension in later life results in progressive glomerularsclerosis, further reducing FSA and perpetuating a vicious circlethat leads, in the extreme, to end-stage renal failure63.


Acquired natriuretic hormoneThe Guyton hypothesis allows for a normal bloodvolume despite an elevated pressure, in keepingwith most volume measurements in hypertensivepatients65. The next hypothesis requires an initiallyexpanded plasma volume that, after an inhibitionof renal sodium reabsorption, is allowed to returnto normal.

Ouabain, an endogenous digitalis like inhibitorof sodium pump, which arises when plasmavolume is expanded, increases intracellular sodium

and mobilises calcium from intracellular stores.Blaustein has formulated an overall scheme forthis acquired compensatory mechanism for renalsodium retention, which could be a cause ofessential hypertension (Fig. 4)66.

Renin-angiotensin - aldosteronesystemRenin may play a critical role in the pathogenesisof most hypertension, a view long espoused byLaragh67.

Fig. 4 : Diagram showing various feedback loops that may be involved in the rise in blood pressure that accompanies theattempt to prevent plasma volume expansion when excessive sodium is ingested relative to the innate ability of thekidneys to excrete a sodium load. The increase in intracellular sodium is the direct result of the inhibition of the Na+ pumpby 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.


Fig. 5 is a schematic overview of the renin-angiotensin system showing its major components,the regulators of renin release and the primaryeffects of angiotensin II (AII) excluding the Allreceptors.

Although, low renin levels are expected in essentialhypertension, the majority of patients with essentialhypertension do not have low suppression reninangiotensin levels but “inappropriately” normalor even elevated PRA levels. Indeed, when reninprofiling is correctly performed and indexed inpatients with essential hypertension, about 20%are found to have high renin values, and about

30% have low renin values, with the remaininghalf distributed between these two extremes68.

It seems likely that this mechanism is abnormallyactivated in many patients with essentialhypertension, and at least three mechanisms havebeen offered : nephron heterogeneity, nonmodulation, and increased sympathetic drive.

Nephron heterogenecity with unsuppressiblerenin secretion and impaired natriuresis ascause of essential hypertension:

Within the kidneys, there exists a functional andstructural basis for the abnormal renin secretion

Fig. 5 : Schematic representation of the renin-angiotensin system, showing the major regulators of renin release, the biochemicalcascade leading to AII, and the major effects of AII. CNS, central nervous system, ECFV, extracellular fluid volume.


and impaired Na+ excretion that are characteristicof hypertensive states54 (Table II)69.

Table II : Hypothesis - there is nephronheterogeneity in essential hypertension69.1. There are ischaemic nephrons with impaired

sodium excretion intermingled with adaptinghyperfiltering hypernatriuretic nephrons.

2. Renin secretion is high from ischaemicnephrons and low from hyperfilteringnephrons.

3. The inappropriate circulating renin-angiotensin level impairs sodium excretionbecause:a. In the adapting hypernatriuretic nephrons

i. It increases tubular sodiumreabsorption.

ii. It enhances tubuloglomerular feedback- mediated afferent constriction.

b. As the circulating renin level is diluted bynon-participation of adapting nephrons, itbecomes inadequate to support efferenttone in hypoperfused nephrons.

4. A loss of nephron number with age and fromischaemia further impairs sodium excretion.

Non-modulationThis has been proposed by Williams andHollenberg for normal renin and high renin levelsseen in nearly half of hypertensive patients due todefective feed-back regulation of the renin -angiotensin system within the kidneys and theadrenal glands70.

Normal individuals modulate the responsivenessof their AII target tissues with their level of dietarysodium intake. With sodium restriction, theadrenal secretion of aldosterone is enhancedand vascular responses are reduced, withsodium loading, the adrenal response issuppressed, and vascular response areenhanced, part icularly within the renalcirculation. With sodium restriction, renal bloodflow (RBF) is reduced, facilitating sodiumconservation; with sodium loading, RBF is

increased, promoting sodium excretion. Thesechanges are mediated mainly by changes in Alllevel, increasing with sodium restriction anddecreasing with sodium loading.

Non-modulation is characterised by abnormaladrenal and renal responses to All infusions andsalt loads71. These findings have been attributedto an abnormally regulated and rather fixed levelof AII, that, in the adrenal tissues, does not increasealdosterone secretion in response to sodiumrestriction and, in the renal circulation, does notallow renal blood flow to increase with sodiumloading. The hypothesis that there is an abnormallyregulated, fixed local All concentration in thesemodulators received support from the correctionof both the adrenal and renal defects aftersuppression of All by ACE-inhibitors.

Non-modulation in the face of relatively highdietary sodium intake could explain thepathogenesis of sodium sensitive hypertension andprovide a more targeted, rational therapy forcorrection. Moreover, a lower prevalence of non-modulation has been found in young women,suggesting that female sex hormones may conferprotection against this genotypic predisposition tohypertension72.

Low renin essential hypertensionAlthough low renin levels are expected in theabsence of one or another of the previouslydescribed circumstances, a great deal of work hasbeen done to uncover special mechanisms,prognoses, and therapy for hypertension with lowrenin.

The possible mechanisms for low reninhypertension include volume expansion with orwithout mineral corticoid excess but majority ofcareful analyses fail to indicate volume expansion73

or increased levels of mineralocorticoids74. Recentstudies by Fishar75 et al focus on adrenal andpressure responsiveness to angiotensin II (ang. II)as a function of dietary salt intake in patients withlow renin hypertension, normal renin hypertension,and normal controls. There were striking functional


similarities between normal renin hypertensionand non-modulating essential hypertension withnormal 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 ofrigid dietary sodium restriction, and

(iii) relatively low basal plasma aldosterone levels.

These differences compared to normal controlsand modulat ing hypertensive subjectsdisappeared when dietary salt intake wasincreased to 200 mEq/day, consistent withsuppression of plasma ang. II activity duringhigh salt intake with resensitization of ang. IIreceptors and improved ang. II responsiveness.

Fig. 6 : High blood pressure mechanisms80

If so, perhaps the blunted responsiveness toang. II during sodium restriction could reflectthe continuing generation of ang. II, withangiotensin receptor down regulation in thesesubjects.Mutations in the HSD II B2 gene causes a raremonogenic juvenile hypertensive syndromecalled apparent mineralocorticoid excess (AME).In AME, compromised II. HSD enzyme activityresults in over stimulation of the mineralocorticoid receptor (MR) by cortisol; causingsodium retention, hypokalaemia, and saltdependent hypertension76,77.There is evidence that an impaired IIhydroxysteroid dehydrogenase (II B HSD2activi ty) type 2 may play a role in the


pathogenesis of essential hypertension in somepatients and this may be genetically determined.Because 40% of patients with essentialhypertension have low renin levels, a numberof these patients may have a mild form of AME.Furthermore, as spironolactone causes readyremission, it is important to seek the diagnosisby genetic and clinical studies. The prevalenceof mutations of II HSD2 in general populationof patients with essential hypertension ispresently unknown. The epidemiology of suchmutations is relevant for two reasons. First, theprevalence is important in order to define thecost-benefit ratio for screening patients with lowrenin-low aldosterone hypertension. Second, theaccurate diagnosis of AME should permit thedesign of more specific therapies for patientswith this disease76,77.

Two forms of vasoconstriction in essentialhypertension:

Two forms of vasoconstriction, one mediated by

renin and other by Na+ - volume forces, seenin extreme forms of hypertension also operatein essential hypertension. Laragh and co-workers78,79 have long attached a great deal ofsignificance to various PRA levels found inpatients with essential hypertension. Accordingto this view, the levels of renin can identify therelative contribution of vasoconstriction andbody fluid expansion to pathogenesis ofhypertension. According to the “bipolarvasoconstriction - volume analysis,” arteriolarvasoconstriction by AII is predominantlyresponsible for the hypertension in patients withhigh renin, whereas volume expansion ispredominantly responsible in those with lowrenin. Though, both lead to increasedperipheral resistance, which is the commoncharacteristic of all hypertension. The similarityends there, however, because the conditionsimposed by these two agents are radicallydifferent 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, asindicated 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 ofeither Na+ depletion or hypotension from fluid or blood loss or a neurogenic fall in blood pressure. Hypertensive subjects sustaintheir higher blood pressures by renal secretion of too much renin for their Na+ volume states, or by renal retention of too muchNa+ (Volume) for their renin level, which often fails to fully turn off as it does in normal subjects. High renin hypertensive patientsare proportionately more vasoconstricted with poor tissue perfusion and therefore most susceptible to cardiovascular tissueischaemic damage. BP = blood pressure; PRA = plasma renin activity.


The predominance of activity of either poledepresses activity at other, whereas bothvasoconstrictive forces may well assert theirinfluence when renin levels are in the mediumrange.

Human hypertensive disorders as aspectrum of abnormal plasma renal-sodiumvolume products

Normotension is sustained and defended byfluctuation of PRA according to salt intake andNa+ balance. Human hypertensive states arecharacterised by excessive renal renin secretionand thus PRA for the concurrent state of Na+balance (i.e., by a spectrum of abnormally highplasma renin levels) for the Na+ -volume statusor vice versa, i.e., renal retention of too muchNa+ (Volume) for their renin level which often

fail to fully turn off as it does in normal subjects69

(Fig. 7).

Stress and sympathetic overactivityAs shown in Figure 1 an excess of renin-angiotensin activity could interact with thesympathetic nervous system (SNS) to mediatemost of its effects. On the other hand, stressmay activate the SNS directly; and SNSoveractivity in turn, may interact with highsodium intake, the renin-angiotensin system,and insulin resistance among the other possiblemechanisms. Considerable evidence, supportsincreased SNS activity in early hypertension and,even more impressively, in the still normotensiveoffspring of hypertensive parents, among whoma large number are l ikely to develophypertension.

Fig. 8 : Indications that an increased sympathetic outflow may be key factor in primary hypertension. The outflow is increasedwhen arterial baroreceptors are reset so that they exert less inhibition on the vasomotor center. The resetting could be due togenetic changes in the endothelial lining of the carotid sinus and aortic arch and/or at the vasomotor centers. The increasedsympathetic outflow may be further enhanced by stress. As a consequence of this neurohumoral excitation, the systemic vascularresistance is increased. In addition, the endothelial cells in the resistance blood vessel may secrete less vasodilator and morevasoconstrictor 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 furtheraggravation of the systemic vasoconstriction82.


Baroreceptor dysfunctionThe baroreceptors when activated by a rise in BPor central venous pressure, respectively, normallyreduce heart rate and lower blood pressure byvagal stimulation and sympathetic inhibition.When hypertension is sustained, these reflexes arereset rapidly from both structural and functionalchanges so that given increase is BP evokes lessdecrease in heart rate81. Shepherd postulates thatthe decreased inhibition of the vasomotor centerresulting from resetting of arterial baroreceptors(mechano receptors) may be responsible forincreased sympathetic out flow and thereby in theperpetuation of hypertension (Fig. 8)82.

Stress : People exposed to repeated psychogenicstresses may develop hypertension more frequentlythan otherwise similar people not so stressed.

� The blood pressure remained normal amongnuns in a secluded order over a 20 yearsperiod, whereas it rose with age in womenliving nearby in the outside world83.

� Annual rate of developing hypertension is 5.6times greater among air traffic controllers, whowork under high level of psychological stress,than non professional pilots84.

� Among healthy employed men, job strain(defined as high psychological demands andlow decision latitude on the job) is associatedwith 3.1 times greater odds ratio forhypertension, an increased left ventricular massindex by echocardiography85, and higherawake ambulatory blood pressure86.

� People may become hypertensive not justbecause they are more stressed, but becausethey respond differently to stress. Greatercardiovascular and sympathetic nervousreactivities to various laboratory stresses havebeen documented in hypertensives and innormotensive at higher risk of developinghypertension87,88,89, extending even to a greateranticipatory BP response while awaiting anexercise stress test90.

� Despite the rather impressive body of literature,

the role of mental stress in the developmentof hypertension remains uncertain. Its effectsare likely to depend on an interaction of atleast three factors: the nature of the stressor,its perception by the individual, and theindividual’s physiological susceptibility91.

The role of acquired tubulointerstitial diseasein the pathogenesis of salt dependenthypertension92

It proposes that hypertension has two phases : anearly phase in which elevations in blood pressure(BP) are mainly episodic and are mediated by ahyperactive SNS or RAS, and a second phase inwhich BP is persistently elevated and that isprimarily mediated by an impaired ability of thekidney to excrete salt, NaCl. The transition fromthe first phase to the second occurs as aconsequence of catecholamine induced elevationsin BP that preferentially damage regions of thekidney (juxtamedullary and medullary regions) thatdo not autoregulate well to changes in renalperfusion pressure (Fig. 9)92.

This may be the major mechanism for thedevelopment of salt-dependent hypertension, andparticularly for the hypertension associated withblacks, aging, and obesity. Thus, essentialhypertension may be a type of acquiredtubulointerstitial renal disease.

Hypertension may result from entry into thepathway at other stages :

i Interstitial damage due to other mechanisms:Hypercalcaemia, chronic pyelonephritis,obstruction, heavy metals (lead), radiation, orassociated with gout.

ii Mechanisms that directly compromise renalmedullary blood flow-Cyclosporine, analgesicabuse, genetic reduction in medullary bloodflow in spontaneously hypertensive rats (SHR).

iii Directly resulting in decreased sodiumexcretion.

Liddle’s syndrome, glucocorticoid - remediablealdosteronism, and the syndrome of apparentmineralocorticoid excess, and a genetic reduction


in nephron numbers.

In conclusion, this hypothesis links early, episodic,salt independent hypertension with the laterdevelopment of a persistent salt dependenthypertension with the new concept that it ismediated by acquired tubulointerstitial andperitubular capillary injury. A strength of thehypothesis is that it unites many prior hypothesesinto one pathway; including that of Julius on therole of the sympathetic nervous system in earlyhypertension93, of Cowley et al on the role ofmedullary ischaemia94, of Sealey and Laragh onactivation of the renin-angiotensin II system69, ofGuyton et al on impaired pressure natriuresis54,of Kurokawa on enhanced TG feedback95 andMackenzie, Lawler and Brenner on reducednephron number96. In addition, it potentiallyprovides answers to many questions not easilyaddressed by other individual hypothesis.

Peripheral resistanceMultiple factors affect peripheral resistance (Fig.1). Main determinant of sustained elevated BPis increase in peripheral resistance which residesin precapillary vessels with a lumen diameterof less than 500 µm97. In human hypertensionand in experimental animal models ofhypertension, structural changes in theseresistance vessels are commonly observed. Inpatients with essential hypertension, thecharacteristic findings include :1. Decreased lumen diameter and,2. Increased ratio of the diameter of vascular

smooth muscle layer of the vessel (tunicamedia) to lumen diameter, referred to as themedia to lumen ratio.

According to Poiseulle’s law, vascular resistanceis positively related to both the viscosity of bloodand the length of arterial system and negativelyto the fourth power of the luminal radius. Sinceneither viscosity nor length are much, if at all,altered and the small change in luminal radiuscan have such a major effect, it is apparent thatthe increased vascular resistance seen in

Fig. 9 : Scheme for pathogenesis of salt dependenthypertension. The hypothesis proposes that earlyhypertension is episodic and is mediated by a hyperactivesympathetic nervous system or activated renin-angiotensinsystem. The acute norepinephrine or angiotensin IImediated elevation in BP are transmitted to the peritubularcapillaries of the kidney in association with a reduction inblood flow secondary to the vasoconstrictive propertiesof these substances. Capi l lary damage andtubulointerstitial injury with fibrosis results. The localischaemia stimulates [(adenosine, local angiotensin II,renal nerve sympathetic activity (RSNA)] or inhibits [(nitricoxide (NO), prostaglandins, dopamine] vasoactivemediators, resulting in NaCl reabsorption due to enhancedtubuloglomerular feeback. The capillary damage andincrease in renal vascular resistance also blunts thepressure natriuresis mechanism. The consequences of bothenhanced tubuloglomerular feedback and impairedpressure natriuresis is an acquired functional defect inNaCl excretion. This results in a resetting of the pressure–natriuresis curve to a higher pressure in order to restoresodium balance back to normal92.


established hypertension must reflect changes inthe calibre of the small resistance arteries andarterioles98.

The increase in media to lumen ratio of theresistance vessels occurs by the addition of materialto the outer or inner surfaces of the blood vesselwall97. This process requires growth (eitherhyperplasia or hypertrophy) of the cellularcomponents of the blood vessel wall and resultsin an increase in it’s cross-sectional area. Analternative process, referred to as vascularremodelling, can result in an increased media tolumen ratio through the rearrangement of theexisting material without an increase in the crosssectional area of the vessel. For this to occur, areduction in the external diameter of the bloodvessel is required. In human essential hypertension,there is increasing evidence to support the viewthat vascular remodelling rather than growth, isthe predominant change occurring in resistancevessels.

Cell membrane alterationsThere is a body of evidence that shows that thecell membranes of hypertensive animals and, less

Fig. 10 : Hypotheses linking abnormal ionic fluxes to increasedperipheral 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.


convincingly, of hypertensive people are alteredin a primary manner, allowing abnormalmovements of ions and thereby changing theintracellular environment to favour contraction andgrowth (Fig. 10)99. These primary alterations aredifferentiated from the secondary inhibition of theNa+/K+-ATPase pump by ouabain, which issecreted after volume expansion and, as describedearlier, is a possible mechanism for renal sodiumretention.

Abnormalities of the physical properties of themembrane and of multiple transport systems havebeen implicated in the pathogenesis ofhypertension100. Most relate to vascular smoothmuscle cells, but since such cells are not availablefor study in humans, surrogates such as red andwhile blood cells are used. Transport systemspresent in the cell membrane of erythrocytes thatcontrol the movement of sodium and potassiumto maintain the marked differences inconcentration of these ions on the outside andinside of cells, which in turn provides the electorchemical gradients needed for various cellfunctions101,102.

There is evidence that the sodium hydrogenexchanger is stimulated in hypertensive patientseither by an increased cellular calcium load orenhanced external calcium entry. An increasedNa+/H+ exchanger could play a significant rolein the pathogenesis of hypertension, both bystimulating vascular tone and cell growth andpossibly by increasing sodium reabsorption inrenal proximal tubule cells (Fig. 11)104.

RBC membranes from hypertensives have anincreased cholesterol : phospholipid ratio inassociation with high sodium lithium transport(SLC)105 and increased ratios of fatty acidmetabolites to precursors compared to thosefrom age matched normotensives100. Suchchanges in lipids produce a high membranemicroviscosity and decrease in fluidity106, whichmay be responsible for increased permeabilityto sodium and other alterations in sodiumtransport107.

Endothelial dysfunctionNitric Oxide (NO) is the primary endogenousvasodilator (Fig. 12)108. Although, the role ofNO in the regulation of BP is uncertain, severalstudies have reported its influence on BP andrenal haemodynamics109. In healthy humansubjects, inhibition of NO synthase by N-monomethyl-L-arginine acutely increased BP,peripheral vascular resistance, and fractionalexcretion of Na+110.

NO is tonical ly act ive in the medullarycirculation, so that reducing NO production orvascular responsiveness, reportedly enhancesthe pressure natriuresis response, followed byreductions in papil lary blood flow, renalinterstitial hydrostatic pressure, and Na+excretion by almost 30%, without correspondingchanges in total or cortical RBF or GFR109. Thismechanism may contribute to the bluntedpressure natriuresis reported in experimentalmodels.

Endothe l in : Endothe l in is among the

Fig. 12 : Nitric oxide in arterial smooth muscle. A messengermolecule such as acetylcholine binds its receptor on anendothelial cell, activating inward calcium currents. Calciumbinds to calmodulin and activates endothelial cell nitric oxidesynthase, which converts arginine plus oxygen into citrullineand nitric oxide. Nitric oxide diffuses out of the endothelialcell into an adjacent smooth muscle cell and activatesguanylate 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.


vasoconstrictors yet to be identif ied. Itsactions are mediated through two types ofreceptors, ETA and ETB, both of which arelocated on vascular smooth muscle. An orallyactive mixed endothelium receptor antagonistbosentan, reduced BP in hypertensive patientsto a level that was comparable to enalapril111.Bosentan has also been reported to block theeffects of an infusion of angiotensin II on BPand renal blood flow in rats112. This raises theissue of whether a component of theseangiotensin II actions may be mediated byendothelin.

ObesityHypertension is more common in obesepeople. Obese indiv iduals have highercardiac output, stroke volume, and centraland total blood volume and lower peripheralresistance than non obese individuals with

similar blood pressure113. The increase incard iac output is propor t iona l to theexpansion of body mass and may be theprimary reason for the rise in BP114. Theprevalence of hypertension increased equallywith increasing BMI, degree of upper bodyobesity, and fasting insulin levels115 (Fig. 13).

Insulin resistance and hyper-insulinaemiaHigher insulin levels are associated with morehypertension, and many possible mechanismsmay explain the association. (Table III)116.The hypertension that is more common inobese people may arise in large part fromthe insu l in res is tance and resu l tan thyperinsul inaemia that results from theincreased mass of fat. However, ratherunexpectedly, insulin resistance may also beinvolved 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 promotediabetes, dyslipidaemia and hypertension via hyperinsulinaemia.


as wel l 117. The exp lanat ion for insu l inresistance found in as many as half of non-obese hypertensive, however is not obviousand may involve one or more aspects ofinsulin’s action (Table IV ).

Table III : Proposed mechanisms by whichinsulin resistance and/or hyperinsulinaemiamay lead to increased blood pressure.Enhanced renal sodium and water reabsorption.

Increased blood pressure sensitivity todietary salt intakeAugmentation of the pressure andaldosterone responses to AIIChanges in transmembrane electrolytetransport

a. Increased intracellular sodiumb. Decreased Na+/K+ - ATPase activityc. Increased intracellular Ca2+ pump activityIncreased intracellular Ca2+ accumulation

Stimulation of growth factors, especially in

Fig. 14 : The left panel represents insulin’s 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 bloodpressure. The net effect of these two opposing influences is no change or slight decrease in blood pressure. There may be animbalance between the sympathetic and vascular actions of insulin in conditions such as obesity and hypertension. As shown inthe right panel, insulin may cause potentiated sympathetic activation or attenuated vasodilation. An imbalance between thesepressure and depressor actions of insulin may result in elevated blood pressure119.

vascular smooth muscle.Stimulation of sympathetic nervous activityReduced synthesis of vasodi latoryprostaglandinsImpaired vasodilationIncreased secretion of endothelin

Effects of hyperinsulinaemia on bloodpressure :Figure 13, portrays three ways by which thehyper insu l inaemia that deve lops as aconsequence of insul in resistance andreduced clearance could induce hypertension.Other mechanisms have been proposed(Table III). Of these, impaired endothelium -dependent vasodilation may be particularlyimportant118 Insul in normal ly acts as avasodilator119-121. It has been shown thatal though insul in increases sympathet icactivity, the effect is normally overridden bythe direct vasodilatory effect of insulin (Fig.14 )119.


Table IV : Factors that may induce insulin resistance in hypertension.Aspect Normal site of action Effect of hypertensionInsulin delivery Capillary bed Vasoconstriction; attenuated vasodilation, capillary

rarefactionInsulin transport Interstitium Impaired transportInsulin action muscle fibre Genetic or acquired increase in type 2B fibres,

hormonal interference with insulin effects, decreasedtransport protein.

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Essential Hypertension – Pathogenesis and Pathophysiology

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