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 values
1
. 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 BP
2
.
Even when BP is lowered by antihypertensive
medication, the associated reduction in the
incidence of coronary heart disease lags behind
that of stroke
3
.
There is a widely held misconception that
hypertension is a single disease that can be treated
wi th a si ngl e reci pe. Hypertensi on i s 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
detecti on of potenti al l y curabl e forms of
hypertension, and on the risk of cardiovascular
complications
4
.
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 factors
6
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 resistance
8
.
Table I : Pathophysiologic characteristics of
essential hypertension
5
.
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; diminished
renal 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 determined
are termed inherited BP. Although, we do not
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 only
partially 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 inherited
BPs. 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 BP
9
.
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
peri pheral resi stance, are control l ed 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 itself
10
. Thus there are
many genes that coul d parti ci pate i n 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 factors
also 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 nephron
11,12
. The genetic
mutations responsible for 3 rare forms of
mendellian (monogenic) hypertension syndromes
- gluco-corticoid remediable aldosteronism (GRA),
Li ddl e s 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 of
essential 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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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
haemodynami c fi ndi ng i n establ i shed
hypertension is an elevated peripheral resistance
and normal cardiac output
13
.
Significant increases in left ventricular mass have
been recognised in the still normotensive children
of hypertensive parents
14,15
. 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 hypertension
16
as well as amplifier of cardiac
output that reinforces the elevation of BP upstream
from the constricted arteriolar bed
17
.
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 subjects
18
.
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
levels
19
.
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 ti ssues. Thi s process, cal l ed
autoregulation, has been described
20
and
demonstrated experimentally
21
. With increased
cardiac output, more blood flows through the
tissues than is required, and the increased flow
delivers extra nutrients or removes additional
Fig. 1 : Some of the factors involved in the control of blood pressure that affect the basic equation : blood pressure - cardiac
output x peripheral resistance.
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metabolic products; in response, the vessels
constrict, decreasing blood flow and returning the
balance of supply and demand to normal. Thus
the peripheral resistance increases and remains
high by the rapid induction of structural thickening
of resistance vessels.
Similar conversion from an initially high cardiac
output to a later increased peripheral resistance
has been shown in hypertensive people
22
. 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 reactivity
23
and renal
function
24
. 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 excretion
25
.
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 i t does i n al l other i ndustri al i sed
populations
26,27
.
If pri mi ti ve peopl e who are free from
hypertension adopt modern life styles,
including increased intake of sodium, then their
BP rises and hypertension appears
28,29
.
In population studies, a significant correlation
between the level of salt intake and frequency
of hypertension has been found
30,31
. 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
world
32,33
, 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 falls
34,35
.
Short periods of increased NaCl intake has
been shown to raise BP in normotensives,
especially genetically predisposed animals
36,37
.
In randomised controlled studies of hundreds
of patients with high normal blood pressure,
those patients who moderately restricted their
sodium intake for 36 months
38
to 5 years
39
,
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 mechanisms
40
, viz., increases in
i ntrael l ul ar cal ci um
41
and pl asma
catecholamines
42
, worsening of insulin
resistance
43
, and a paradoxical rise in atrial
natriuretic peptide
23
.
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
involved
44
, Weinberger et al
45
defined sodium
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sensitivity as a 10mm Hg or greater decrease in
mean blood pressure from the level measured
after 4 hour infusion of 2 L normal saline
compared to the level measured the morning after
1 day of a 10 mmol sodium diet, during which
three 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 excretion
24
,
increased activity of the sodium hydrogen
exchanger
46
, increased sympathetic nervous
system activity
47
, increased calcium entry into
vascular smooth muscle
41
, impaired nitric oxide
synthesis
48
. Blacks have greater frequency of salt
sensitivity. Salt sensitivity
45
increases with age, and
perhaps more in women than in men
50
. In a recent
study Fujiwora et al reported that modulation of
NO synthesis by salt intake may be involved in a
mechani sm for sal t sensi ti vi ty i n human
hypertension
51
.
Altered renal physiology
In essential hypertension, physiologic and
pathologic renal changes often precede changes
identifiable 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,
predomi nantl y efferent but al so afferent,
vasoconstriction of all nephrons or, alternatively,
by selective afferent vasoconstriction with diversion
of blood away from some nephrons to maintain
near normal GFR. This renal vasoconstriction is
reversible and could lead to reduced pressure and
flow in the post glomerular circulation, which may
predi spose to i ncreased tubul e Na+
reabsorption
52,53
.
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
regul ate Na+ and water excreti ons, and
consequently, they play a dominant role in the long
term 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 diuresis
54
(Fig. 2).
The second mechanism employs the renin-
angiotensin - aldosterone system, which directly
controls peripheral vascular resistance and renal
reabsorption of Na+ and water
55
.
Renal sodium retention
Essential hypertension is due primarily to an
abnormal kidney which has an unwillingness to
excrete sodium
56
.
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 sustai ned and i nfi ni te power
57,19
.
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 steep
19
.
As Guyton and co-workers have shown, either the
entire curve can be shifted to the right or the slope
can be depressed, depending on the type of renal
insult, which inturn, is reflected by varying sensitivity
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to sodium
58
.
Cross transplantation studies in animal models
59
and in humans
60,61
have shown that the alteration
in renal function responsible for the resetting of
the pressure natriuresis curve is inherited.
Reduced nephron number
Brenner et al
62
advanced the hypothesis that the
nephron endowment at birth is inversely related
to 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 hypertension
63
(Fig. 3).
These investigators point out that as many as 40%
of individuals under age 30 have fewer than the
presumably 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 di fferences i n suscepti bi l i ty to
hypertension among genetic populations as well
as in blacks, women, and older people, all of
whom may have smaller kidneys or fewer
functioning nephrons
64,96
.
Fig. 2 : Proposed mechanism of pressure natriuresis.
Fig. 3 : A diagram of the hypothesis that the risks of
developing 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 ol i gonephropathy. Systemi c and gl omerul ar
hypertension in later life results in progressive glomerular
sclerosis, further reducing FSA and perpetuating a vicious circle
that leads, in the extreme, to end-stage renal failure
63
.
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Acquired natriuretic hormone
The Guyton hypothesis allows for a normal blood
volume despite an elevated pressure, in keeping
with most volume measurements in hypertensive
patients
65
. The next hypothesis requires an initially
expanded 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
.
Reni n-angi otensi n - al dosterone
system
Renin may play a critical role in the pathogenesis
of most hypertension, a view long espoused by
Laragh
67
.
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
+
/Ca
2+
exchanger as a result of the rise in
sodium. (+) positive feedback loop; (), negative feedback loop; ADH antidiuretic hormone; ANP, atrial natriuretic peptides;
[Na
+
] intracellular sodium concentration; [Ca
2+
], intracellular calcium concentration
66
.
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Fig. 5 is a schematic overview of the renin-
angiotensin system showing its major components,
the regulators of renin release and the primary
effects of angiotensin II (AII) excluding the All
receptors.
Although, low renin levels are expected in essential
hypertension, the majority of patients with essential
hypertension do not have low suppression renin
angiotensin levels but inappropriately normal
or even elevated PRA levels. Indeed, when renin
profiling is correctly performed and indexed in
patients with essential hypertension, about 20%
are found to have high renin values, and about
30% have low renin values, with the remaining
half distributed between these two extremes
68
.
It seems likely that this mechanism is abnormally
activated in many patients with essential
hypertension, and at least three mechanisms have
been offered : nephron heterogeneity, non
modulation, and increased sympathetic drive.
Nephron heterogenecity with unsuppressible
renin secretion and impaired natriuresis as
cause of essential hypertension:
Within the kidneys, there exists a functional and
structural basis for the abnormal renin secretion
Fig. 5 : Schematic representation of the renin-angiotensin system, showing the major regulators of renin release, the biochemical
cascade leading to AII, and the major effects of AII. CNS, central nervous system, ECFV, extracellular fluid volume.
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and impaired Na+ excretion that are characteristic
of hypertensive states
54
(Table II)
69
.
Tabl e II : Hypothesi s - there i s nephron
heterogeneity in essential hypertension
69
.
1. There are ischaemic nephrons with impaired
sodium excretion intermingled with adapting
hyperfiltering hypernatriuretic nephrons.
2. Renin secretion is high from ischaemic
nephrons and l ow from hyperfi l teri ng
nephrons.
3. The i nappropri ate ci rcul ati ng reni n-
angiotensin level impairs sodium excretion
because:
a. In the adapting hypernatriuretic nephrons
i. It i ncreases tubul ar sodi um
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-modul ati on
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 glands
70
.
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
sodi um l oadi ng, the adrenal response i s
suppressed, and vascul ar response are
enhanced, part i cul arl y wi t hi n t he 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 abnormal
adrenal and renal responses to All infusions and
salt loads
71
. 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
di etary sodi um i ntake coul d expl ai n 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
hypertension
72
.
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 possi bl e mechani sms for l ow reni n
hypertension include volume expansion with or
without mineral corticoid excess but majority of
careful analyses fail to indicate volume expansion
73
or increased levels of mineralocorticoids
74
. Recent
studies by Fishar
75
et al focus on adrenal and
pressure responsiveness to angiotensin II (ang. II)
as a function of dietary salt intake in patients with
low renin hypertension, normal renin hypertension,
and normal controls. There were striking functional
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similarities between normal renin hypertension
and non-modulating essential hypertension with
normal plasma renin activity, including :
(i) Salt sensitivity of the blood pressure,
(ii) blunted plasma aldosterone responses to ang.
II infusion and upright posture after 5 days of
rigid dietary sodium restriction, and
(iii) relatively low basal plasma aldosterone levels.
These differences compared to normal controls
and modul at i ng hypert ensi ve subj ect s
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 mechanisms
80
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 hypertension
76,77
.
There i s evi dence t hat an i mpai red I I
hydroxysteroid dehydrogenase (II B HSD2
act i vi t y) t ype 2 may pl ay a rol e i n t he
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pathogenesis of essential hypertension in some
patients and this may be genetically determined.
Because 40% of pat i ent s wi t h essent i al
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 the
design of more specific therapies for patients
with this disease
76,77
.
Two forms of vasoconstriction in essential
hypertensi on:
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-
workers
78,79
have long attached a great deal of
significance to various PRA levels found in
patients with essential hypertension. According
to this view, the levels of renin can identify the
relative contribution of vasoconstriction and
body fl ui d expansi on to pathogenesi s of
hypert ensi on. Accordi ng t o t he bi pol ar
vasoconstriction - volume analysis, arteriolar
vasoconstri cti on by AII i s predomi nantl y
responsible for the hypertension in patients with
high renin, whereas volume expansion is
predominantly responsible in those with low
reni n. Though, bot h l ead t o i ncreased
peripheral 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 in
reaction 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 hypert ensi ve di sorders 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 subjects
69
(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 acti vate the SNS di rectl y; 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 whom
a l arge number are l i kel y t o devel op
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 and
also released from platelets, together with norepinephrine, can cause proliferation of the vascular smooth muscle with a further
aggravation of the systemic vasoconstriction
82
.
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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 rate
81
. 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 psychogenic
stresses 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 world
83
.
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 pilots
84
.
Among healthy employed men, job strain
(defined as high psychological demands and
low decision latitude on the job) is associated
wi th 3.1 ti mes greater odds rati o for
hypertension, an increased left ventricular mass
index by echocardiography
85
, and higher
awake ambulatory blood pressure
86
.
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
hypertension
87,88,89
, extending even to a greater
anticipatory BP response while awaiting an
exercise stress test
90
.
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 the
individuals physiological susceptibility
91
.
The role of acquired tubulointerstitial disease
i n the pathogenesi s of sal t dependent
hypertension
92
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 the
kidney 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 with
blacks, aging, and obesity. Thus, essential
hypertensi on may be a type of acqui red
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 renal
medullary 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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July-September 2001 153

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 is
mediated 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
hypertension
93
, of Cowley et al on the role of
medullary ischaemia
94
, of Sealey and Laragh on
activation of the renin-angiotensin II system
69
, of
Guyton et al on impaired pressure natriuresis
54
,
of Kurokawa on enhanced TG feedback
95
and
Mackenzie, Lawler and Brenner on reduced
nephron number
96
. 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 m
97
. In human hypertension
and i n experi ment al ani mal model s of
hypertension, structural changes in these
resistance vessels are commonly observed. In
pati ents wi th essenti al hypertensi on, 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
hypertensi on. The hypothesi s proposes that earl y
hypertension is episodic and is mediated by a hyperactive
sympathetic 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 t hese subst ances. Capi l l ary damage and
tubulointerstitial injury with fibrosis results. The local
ischaemia stimulates [(adenosine, local angiotensin II,
renal nerve sympathetic activity (RSNA)] or inhibits [(nitric
oxi de (NO), prostagl andi ns, dopami ne] vasoacti ve
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 impaired
pressure 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 normal
92
.
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July-September 2001
established hypertension must reflect changes in
the calibre of the small resistance arteries and
arterioles
98
.
The increase in media to lumen ratio of the
resistance vessels occurs by the addition of material
to the outer or inner surfaces of the blood vessel
wall
97
. 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 hypertension
104
.
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July-September 2001 155

convincingly, of hypertensive people are altered
i n a pri mary manner, al l owi ng abnormal
movements of ions and thereby changing the
intracellular environment to favour contraction and
growth (Fig. 10)
99
. These primary alterations are
differentiated 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 i mpl i cated i n the pathogenesi s of
hypertension
100
. 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 mai ntai n the marked di fferences i n
concentration of these ions on the outside and
inside of cells, which in turn provides the elector
chemical gradients needed for various cell
functions
101,102
.
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 normotensives
100
. Such
changes in lipids produce a high membrane
microviscosity and decrease in fluidity
106
, which
may be responsible for increased permeability
to sodium and other alterations in sodium
transport
107
.
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 and
renal haemodynamics
109
. 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 i s t oni cal l y act i ve i n t he medul l ary
circulation, so that reducing NO production or
vascular responsiveness, reportedly enhances
the pressure natriuresis response, followed by
reducti ons i n papi l l ary bl ood fl ow, renal
interstitial hydrostatic pressure, and Na+
excretion by almost 30%, without corresponding
changes in total or cortical RBF or GFR
109
. This
mechanism may contribute to the blunted
pressure natriuresis reported in experimental
models.
Endot hel i n : Endot hel i n i s among t he
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 endothelial
cell 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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vasoconstri ctors yet to be i denti fi ed. Its
actions are mediated through two types of
receptors, ET
A
and ET
B
, both of which are
located on vascular smooth muscle. An orally
active mixed endothelium receptor antagonist
bosentan, reduced BP in hypertensive patients
to a level that was comparable to enalapril
111
.
Bosentan has also been reported to block the
effects of an infusion of angiotensin II on BP
and renal blood flow in rats
112
.

This raises the
i ssue of whet her a component of t hese
angiotensin II actions may be mediated by
endothelin.
Obesity
Hypertensi on i s more common i n obese
peopl e. Obese i ndi vi dual s have hi gher
cardiac output, stroke volume, and central
and total blood volume and lower peripheral
resistance than non obese individuals with
similar blood pressure
113
. The increase in
car di ac out put i s pr opor t i onal t o t he
expansion of body mass and may be the
primary reason for the rise in BP
114
. The
prevalence of hypertension increased equally
with increasing BMI, degree of upper body
obesity, and fasting insulin levels
115
(Fig. 13).
Insul i n resi stance 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 from
t he i nsul i n r esi st ance and r esul t ant
hyperi nsul i naemi a t hat resul t s f rom t he
i ncreased mass of f at . However, rat her
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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July-September 2001 157

as wel l
117
. The expl anat i on f or i nsul i n
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
Augment at i on of t he pressure and
aldosterone responses to AII
Changes in transmembrane electrolyte
transport
a. Increased intracellular sodium
b. Decreased Na
+
/K
+
- ATPase activity
c. Increased intracellular Ca
2+
pump activity
Increased intracellular Ca
2+
accumulation
Stimulation of growth factors, especially in
Fig. 14 : The left panel represents insulins action in normal humans. Although insulin causes marked increases in sympathetic
neural 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 pressure
119
.
vascular smooth muscle.
Stimulation of sympathetic nervous activity
Reduced synt hesi s of vasodi l at ory
prostaglandins
Impaired vasodilation
Increased secretion of endothelin
Effects of hyperi nsul i naemi a on bl ood
pressure :
Figure 13, portrays three ways by which the
hyper i nsul i naemi a t hat devel ops as a
consequence of i nsul i n r esi st ance and
reduced clearance could induce hypertension.
Other mechani sms have been proposed
(Table III). Of these, impaired endothelium -
dependent vasodilation may be particularly
i mpor t ant
118
I nsul i n nor mal l y act s as a
vasodi l ator
119-121
. It has been shown that
al t hough i nsul i n i ncreases sympat het i c
activity, the effect is normally overridden by
the direct vasodilatory effect of insulin (Fig.
14 )
119
.
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July-September 2001
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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