Pathophysiology of hypertension
Pathophysiology is a branch of medicine which explains the function of the body as it relates to diseases and conditions. The pathophysiology of hypertension is an area which attempts to explain mechanistically the causes of hypertension, which is a chronic disease characterized by elevation of blood pressure. Hypertension can be classified by cause as either essential (also known as primary or idiopathic) or secondary. About 90–95% of hypertension is essential hypertension.[1][2][3][4] Some authorities define essential hypertension as that which has no known explanation, while others define its cause as being due to overconsumption of sodium and underconsumption of potassium. Secondary hypertension indicates that the hypertension is a result of a specific underlying condition with a well-known mechanism, such as chronic kidney disease, narrowing of the aorta or kidney arteries, or endocrine disorders such as excess aldosterone, cortisol, or catecholamines. Persistent hypertension is a major risk factor for hypertensive heart disease, coronary artery disease, stroke, aortic aneurysm, peripheral artery disease, and chronic kidney disease.[5]
A diagram explaining factors affecting arterial pressure
Cardiac output and peripheral resistance are the two determinants of arterial pressure.[6] Cardiac output is determined by stroke volume and heart rate; stroke volume is related to myocardial contractility and to the size of the vascular compartment. Peripheral resistance is determined by functional and anatomic changes in small arteries and arterioles.
The pathophysiology of hypertension involves the impairment of renal pressure natriuresis, the feedback system in which high blood pressure induces an increase in sodium and water excretion by the kidney that leads to a reduction of the blood pressure.
Hypertension implies an increase in either cardiac outputo ortotal peripheral resistance (TPR). Essential hypertension
developing in young adults may be initiated by an increase In cardiac output, associated with signs of overactivity of The sympathetic nervous system; the blood pressure (BP) is labile, and the heart rate is increased. Later, the BP increases further because of a rise in TPR, with consequent return to a normal cardiac output. Most patients in clinical practice
with sustained hypertension have an elevated TPR accom-panied by constriction of resistance vessels. Through time, vascular remodeling contributes a structural component to vasoconstriction.
The abrupt left ventricular systole creates a shock wave that is reflected back from the peripheral resistance vessels and Reaches the ascending aorta during early diastole. It is often Visible in younger subjects as the dicrotic notch in tracings of Aortic pressure. With aging, there is loss of elasticity and an Increase in the tone of the resistance vessels. The pressure Wave is transmitted more rapidly within the arterial tree. Eventually, this shock wave in the aorta coincides with the upstroke
of the aortic systolic pressure wave, leading to an abrupt
increase in the height of the systolic BP. This largely accounts
for the frequent finding of isolated, or predominant, systolic
hypertension in the elderly. In contrast, systolic hypertension
in the young usually reflects an enhanced cardiac contractility
and output.
PATHOPHYSIOLOGY OF HYPERTENSION
INTEGRATION OF CARDIORENAL FUNCTION
The integration of cardiorenal function is illustrated by the
response of a normal person to standing. There is an abrupt
fall in venous return and hence in cardiac output that elicits
a baroreflex response, as resistance vessels contract to buffer
the immediate fall in BP, and capacitance vessels contract to
restore venous return. The outcome is only a small drop in
the systolic BP, with a modest rise in diastolic BP and heart
rate. During prolonged standing, increased renal sympa-
thetic nerve activity enhances the reabsorption of sodium
chloride (NaCl) and fluid by the renal tubules, as well as
the release of renin from the juxtaglomerular apparatus.
Renin release results in the subsequent generation of angio-
tensin II and aldosterone, which maintain the BP and the
volume of the circulation. In contrast, the BP of patients with
autonomic insufficiency declines progressively on standing,
sometimes to the point of syncope. These patients with auto-
nomic failure illustrate vividly the crucial importance of a
stable BP for efficient function of the brain, heart, and kid-
neys. Therefore, it is no surprise that evolution has provided
multiple, coordinated BP-regulatory processes. The under-
standing of the cause for a sustained change in BP, such as
hypertension, requires knowledge of a number of interre-
lated pathophysiologic processes. The most important and
best understood of these are discussed in this chapter.
RENAL MECHANISMS AND SALT BALANCE
The kidney has a unique role in BP regulation. Renal salt
and water retention sufficient to increase the extracellular
fluid (ECF) volume, blood volume, and mean circulatory
filling pressure enhances venous return, cardiac output, and
BP. The kidney is so effective in excreting excess NaCl and
fluid during periods of surfeit, or retaining them during
periods of deficit, that the ECF and blood volumes normally
vary less than 10% with changes in salt intake. Consequently,
the role of body fluids in hypertension is subtle. For example,
a tenfold increase in daily NaCl intake in normal subjects
increases ECF volume by only about 1 L (about 6%) and
normally produces no change, or only a small increase,
in BP. Conversely, a diet with no salt content leads to the
loss of approximately 1 L of body fluid over 3 to 5 days
and only a trivial fall in BP. Different effects can be seen in
patients with chronic kidney disease (CKD) whose BP often
increases with the level of salt intake. This “salt-sensitive”
component to BP increases progressively with loss of kidney
function in patients with vascular or glomerular kidney
disease. Among normotensive subjects, a salt-sensitive com-
ponent to BP is apparent in about 30% and appears to
have a genetic component. Salt sensitivity is almost twice as
frequent in patients with hypertension, and is particularly
common among African Americans, the elderly, and those
with CKD. It is generally associated with a lower level of
plasma renin activity (PRA).
What underlies salt sensitivity? The normal kidneys are
exquisitely sensitive to BP. A rise in mean arterial pressure
(MAP) of as little as 1 to 3 mm Hg elicits a subtle increase in
renal NaCl and fluid elimination. This “pressure natriuresis”
also works in reverse and conserves NaCl and fluid during
decreases in BP. It is rapid, quantitative, and fundamental
for normal homeostasis. It is primarily a result of changes
in tubular NaCl reabsorption rather than total renal blood
flow (RBF) or glomerular filtration rate (GFR). Indeed,
renal autoregulation maintains RBF and GFR remarkably
constant during modest changes in BP. The pressure natri-
uresis mechanism accurately adjusts salt excretion and body
fluids in persons with healthy kidneys across a range of BPs.
Two primary mechanisms of pressure natriuresis have been
identified.
First, in some studies in rats, a rise in renal perfusion pres-
sure increases blood flow selectively through the medulla,
which is not as tightly autoregulated as cortical blood flow.
This increase in pressure and flow enhances renal inter-
stitial hydraulic pressure throughout the kidney, which
reduces proximal tubule reabsorption and impairs fluid
return to the bloodstream. Therefore, net NaCl and fluid
reabsorption is diminished. Second, the degree of stretch
of the afferent arteriole regulates the secretion of renin into
the bloodstream and hence the generation of angiotensin
II. Therefore, an increase in BP that is transmitted to this
site reduces renin secretion. Angiotensin II coordinates the
body’s salt and fluid retention mechanisms by stimulating
thirst and enhancing NaCl and fluid reabsorption in the
proximal and distal nephron segments. By stimulating secre-
tion of aldosterone and arginine vasopressin, and inhibit-
ing atrial natriuretic peptide (ANP), angiotensin II further
enhances reabsorption in the distal tubules and collecting
ducts. Thus, during normal homeostasis, an increase in BP
is matched by a decrease in PRA. It follows that a normal or
elevated value for PRA in hypertension is effectively “inap-
propriate” for the level of BP, and is thereby contributing to
the maintenance of hypertension.
The relationships between long-term changes in salt
intake, the renin-angiotensin-aldosterone system (RAAS),
and BP are shown in Figure 65.1. Normal human subjects
regulate the RAAS closely with changes in salt intake. An
increase in salt intake brings about only a modest and tran-
sient rise in MAP, because the RAAS is suppressed and the
highly effective pressure natriuresis mechanism rapidly
increases renal NaCl and fluid elimination sufficiently to
restore a normal blood volume and BP. Expressed quanti-
tatively in Figure 65.1, the slope of the long-term increase
in NaCl excretion with BP is almost vertical. One factor con-
tributing to the steepness of this slope, or the gain of the
pressure natriuresis relationship, is the reciprocal changes
in the RAAS with BP that dictate appropriate alterations in
salt handling by the kidney. Therefore, when the RAAS is
artificially fixed, the slope of the pressure natriuresis rela-
tionship flattens resulting in salt sensitivity, displacement of
the set point, and a change in ambient BP. For example, an
infusion of angiotensin II into a normal subject raises the
BP. Because angiotensin II is being infused, the kidney can-
not suppress angiotensin II levels appropriately by reducing
renin secretion. Therefore, the pressure natriuresis mecha-
nism is prevented, and the BP elevation is sustained without
an effective and complete renal compensation. In contrast,
normal subjects treated with an angiotensin-converting
enzyme (ACE) inhibitor to block angiotensin II genera-
tion or an angiotensin receptor blocker (ARB) to block AT1
receptors have a fall in BP. Again, the kidney cannot stimulate
an appropriate effect of angiotensin II and aldosterone that
would be required to retain sufficient NaCl and fluid to
buffer the fall in BP. Therefore, when the RAAS is fixed, the
BP changes as a function of salt intake and becomes highly
“salt sensitive” (see Fig. 65.1). These studies demonstrate
the unique role of the RAAS in long-term BP regulation and
its importance in isolating BP from NaCl intake.
Some recent findings add complexity to these simple
relationships. Renin is also generated within the connecting
tubule and collecting ducts. This renal renin may contribute
to the very high level of angiotensin within the kidney that
does not share the same relationship with dietary salt. Animal
models of diabetes mellitus demonstrate an increase in local
angiotensin generation and action in the kidneys that may
contribute to the beneficial effects of ACE inhibitor and ARB
therapy despite low circulating renin levels. Other studies have
shown that prorenin, although not itself active, becomes acti-
vated after binding to a renin receptor in the tissues where
novel signaling adds another component to the effects of the
RAAS. This is important, because conventional RAAS antago-
nists may not block these actions. It is generally considered
that the novel renin inhibitors do not block this renin receptor.
Four compelling lines of evidence implicate the kidney
and RAAS in long-term BP regulation. First, kidney trans-
plantation studies in rats showed that a normotensive animal
SECTION 12 — HYPERTENSION
that received a kidney from a hypertensive animal become
hypertensive, and vice versa. Similarly, human kidney trans-
plant recipients frequently become hypertensive if they
receive a kidney from a hypertensive donor. Apparently, the
kidney in hypertension is programmed to retain salt and
water inappropriately for a normal level of BP, thereby reset-
ting the pressure natriuresis to a higher level of BP and dic-
tating the appearance of hypertension in the recipient even
if the neurohumoral environment is that of normotension.
Nevertheless, recent studies in gene-deleted or transgenic
mice subjected to kidney transplantation concluded that the
increase in BP during prolonged infusion of angiotensin II
was mediated by the combined effects within the kidney and
the systemic circulation, most likely involving the brain. A
second observation was that the BP was normally reduced 5%
to 20% by an ACE inhibitor, an ARB, an aldosterone receptor
antagonist, or a renin inhibitor. The fall in BP was greatest
in those with elevated PRA values, and it was enhanced by
dietary salt restriction or concurrent use of diuretic drugs
(see Fig. 65.1). Third, almost 90% of patients approaching
end-stage renal disease (ESRD) have hypertension. Fourth,
the major monogenetic causes of human hypertension
involve genes that activate RAAS signaling (such as gluco-
corticoid remediable hypertension) or renal sodium transport
(such as Liddle syndrome).
TOTAL-BODY AUTOREGULATION
An increase in cardiac output necessarily increases peripheral
blood flow. However, each organ has intrinsic mechanisms
that adapt its blood flow to its metabolic needs. Therefore,
over time, an increase in cardiac output is translated into
an increase in TPR. The outcome is that organ blood flow is
maintained, but hypertension becomes sustained. This total-
body autoregulation is demonstrated in human subjects who
are given salt-retaining mineralocorticosteroid hormones.
An initial rise in cardiac output is translated in most indi-
viduals into sustained hypertension and an elevated TPR over
5 to 15 days.
STRUCTURAL COMPONENTS TO HYPERTENSION
Hypertension causes not only hypertrophic or eutrophic
remodeling in the distributing and resistance vessels and
the heart, but also fibrotic and sclerotic changes in the
glomeruli and interstitium of the kidney. Hypertrophy
of resistance vessels limits the ratio of lumen to wall, and
dictates a fixed component to TPR. This is evidenced by a
higher TPR in hypertensive subjects during maximal vasodi-
latation. Moreover, thickened and hypertrophied resistance
vessels have greater reductions in vessel diameter during
vasoconstrictor stimulation. This is apparent as an increase
in vascular reactivity to pressor agents. Remodeling of resis-
tance arterioles diminishes their response to changes in
perfusion pressure. This manifests as a blunted myogenic
response contributing to incomplete autoregulation of
RBF, thereby adding a component of barotrauma to hyper-
tensive kidney damage. Sclerotic and fibrotic changes in the
glomeruli and renal interstitium, combined with hypertro-
phy of the afferent arterioles, limit the sensing of BP in the
juxtaglomerular apparatus and interstitium of the kidney.
This blunts renin release and pressure natriuresis, thereby
contributing to salt sensitivity and sustained hypertension.
Rats receiving intermittent weak electrical stimulation of
the hypothalamus initially had an abrupt increase in BP fol-
lowed by a sudden fall after the cessation of the stimulus.
However, eventually the baseline BP increased in parallel
with the appearance of hypertrophy of the resistance ves-
sels. These structural components may explain why it often
takes weeks or months to achieve maximal antihypertensive
action from a drug, a reduction in salt intake, or correction
of a renal artery stenosis or hyperaldosteronism. Vascular
and left ventricular hypertrophy is largely, but usually not
completely, reversible during treatment of hypertension,
whereas fibrotic and sclerotic changes are not.
SYMPATHETIC NERVOUS SYSTEM, BRAIN,
AND BAROREFLEXES
A rise in BP diminishes the baroreflex, reduces the tone of
the sympathetic nervous system, and increases the tone of
the parasympathetic nervous system. Paradoxically, human
hypertension is often associated with an increase in heart
rate, maintained or increased plasma catecholamine levels,
and an increase in directly measured sympathetic nerve dis-
charge despite the stimulus to the baroreceptors. What is
the cause of this inappropriate activation of the sympathetic
nervous system in hypertension? Studies in animals show
that the baroreflex “resets” to the ambient level of BP after
2 to 5 days. Baroreflex no longer continues to “fight” the
elevated BP, but defends it at the new higher level. Much of
this adaptation occurs within the baroreceptors themselves.
With aging and atherosclerosis, the walls of the carotid sinus
and other baroreflex sensing sites become less distensible.
Therefore, the BP is less effective in stretching the afferent
nerve endings, and the sensitivity of the baroreflex is dimin-
ished. This may contribute to the enhanced sympathetic
nerve activity and increased plasma catecholamines that are
characteristic of elderly hypertensive subjects. Additionally,
animal models have identified central mechanisms that alter
the gain of the baroreflex process, and therefore the sym-
pathetic tone, in hypertension. The importance of central
mechanisms in human hypertension is apparent from the
effectiveness of drugs, such as clonidine, that act within the
brain to decrease the sympathetic tone. The kidneys them-
selves contain barosensitive and chemosensitive nerves that
can regulate the sympathetic nervous system. Patients with
ESRD on hemodialysis experienced an increased sympa-
thetic nervous system discharge and increased BP that were
not apparent after bilateral nephrectomy. This suggested
that the renal nerves were maintaining enhanced sympa-
thetic tone. Recently, the success of radiofrequency ablation
of the renal nerves in improving BP control in patients with
drug resistant hypertension further illustrates the impor-
tance of the renal nerves in setting the long-term level of BP
in human subjects.
ENDOTHELIUM AND OXIDATIVE STRESS
Calcium-mobilizing agonists such as bradykinin or ace-
tylcholine, as well as shear forces produced by the flow of
blood, release endothelium-dependent relaxing factors,
predominantly nitric oxide (NO). NO has a half-life of only
a few seconds because of inactivation by oxyhemoglobin or
active oxygen species (ROS) such as superoxide anion
(O2
−). Humans with essential hypertension have defects
in endothelium-dependent relaxing factor responses of
peripheral vessels and also diminished NO generation.
One underlying mechanism is oxidative stress. Excessive
O2
− formation inactivates NO, leading to a functional NO
deficiency. Another mechanism is the appearance of inhibi-
tors of nitric oxide synthase (NOS), including asymmetric
dimethyl arginine (ADMA). Finally, atherosclerosis, pro-
longed hypertension, or the development of malignant
hypertension causes structural changes in the endothelium
that limit NO generation further. In the kidney, NO inhibits
renal NaCl reabsorption in the loop of Henle and collect-
ing ducts. Therefore, NO deficiency not only induces vaso-
constriction but also diminishes renal pressure natriuresis.
Functional NO deficiency in large blood vessels contributes
to vascular inflammation and atherosclerosis.
GENETIC CONTRIBUTIONS
The heritability of human hypertension can be assessed
from differences in the concordance of hypertension
between identical twins (who share all genes and a similar
environment) versus nonidentical twins (who share only a
similar environment). These studies suggested that genetic
factors contributed less than half of the risk for developing
hypertension in modern humans. Studies in mice with tar-
geted disruption of individual genes or insertions of extra
copies of genes provided direct evidence of the critical
regulatory roles for certain gene products in hypertension.
Deletions of the gene in mice for endothelial NOS leads to
salt-dependent hypertension. The BP of mice decreases with
the number of copies of the gene encoding ACE. These are
compelling examples of circumstances in which a single
gene can sustain hypertension. However, there is increasing
recognition of the complexity and importance of gene–
gene interactions and the crucial effects of the genetic back-
ground on the changes in BP that accompany insertion or
deletion of a gene.
Currently, there is evidence that certain individual gene
defects can contribute to human essential hypertension.
However, the net effect on BP is small. Certain rare forms
of hereditary hypertension are caused by single-gene
defects. For example, dexamethasone-suppressible hyper-
aldosteronism is caused by a chimeric rearrangement of
the gene encoding aldosterone synthase that renders the
enzyme responsive to adrenocorticotropic hormone. Liddle
syndrome is caused by a mutation in the gene encoding
one component of the endothelial sodium channel that
is expressed in the distal convoluted tubule. The mutated
form has lost its normal regulation, leading to a permanent
“open state” of the sodium channel that dictates inappro-
priate renal NaCl retention and salt-sensitive, low-renin
hypertension (see Chapters 9, 39, and 67).
IMPLICATED MEDIATORS OF HYPERTENSION
Alterations in the synthesis, secretion, degradation, or action
of numerous substances are implicated in certain categories
of hypertension. The most important of these are described
in the following paragraphs.
RENIN, ANGIOTENSIN II, AND ALDOSTERONE
The PRA is not appropriately suppressed in most patients
with essential hypertension, and it is increased above normal
values in approximately 15%. Subjects with normal or high
PRA have a greater antihypertensive response to single-
agent therapy with an ACE inhibitor, an ARB, or a β-blocker
than patients with low-renin hypertension, who respond
notably to salt restriction and diuretic therapy. The RAAS is
particularly important in the maintenance of BP in patients
with renovascular hypertension, although its importance
wanes during the chronic phase when structural alterations
in blood vessels or damage in the kidney dictate a RAAS-
independent component to the hypertension.
SYMPATHETIC NERVOUS SYSTEM AND
CATECHOLAMINES
Pheochromocytoma is a catecholamine-secreting tumor,
often occurring in the adrenal medulla, that increases
plasma catecholamines tenfold to 1000-fold. However,
even such extraordinary increases in pressor amines are
rarely fatal, because an intact renal pressure natriuresis
mechanism reduces the blood volume, thereby limiting
the rise in BP. Indeed, such patients can have orthostatic
hypotension between episodes of catecholamine secretion
(see Chapter 67).
An increased sympathetic nerve tone of resistance vessels
in human essential hypertension causes α1-receptor–mediated
vasoconstriction of the blood vessels and β1-receptor–mediated
increases in contractility and output of the heart that are
incompletely offset by β2-receptor–mediated vasorelaxation
of peripheral blood vessels. Increased sympathetic nerve dis-
charge to the kidney leads to α1-mediated enhancement of
NaCl reabsorption and β1-mediated renin release.
DOPAMINE
Dopamine is synthesized in the brain and renal tubular
epithelial cells independent of sympathetic nerves. Dopa-
mine synthesis in the kidney is enhanced during volume
expansion and contributes to decreased reabsorption of
NaCl in the proximal tubule. Defects in tubular dopamine
responsiveness are apparent in genetic models of hyper-
tension. Recent evidence relates single nucleotide poly-
morphisms of genes that regulate dopamine receptors to
human salt-sensitive hypertension.
ARACHIDONATE METABOLITES
Arachidonate is esterified as a phospholipid in cell mem-
branes. It is released by phospholipases that are activated
by agents such as angiotensin II. Three enzymes principally
metabolize arachidonate. Cyclooxygenase (COX) gener-
ates unstable intermediates whose subsequent metabolism
by specific enzymes yields prostaglandins that are either
generally vasodilative (e.g., prostaglandin I2 [PGI2]), vaso-
constrictive (e.g., thromboxane), or of mixed effect (e.g.,
PGE2). COX-1 is expressed in many tissues, including plate-
lets, resistance vessels, glomeruli, and cortical collecting
ducts. Inflammatory mediators induce COX-2. However, the
normal kidney is unusual in expressing substantial COX
hich is located in macula densa cells, tubules, renal med-
ullary interstitial cells, and arterioles. The net effect of
blocking COX-1 generally is to retain NaCl and fluid while
raising BP and dropping PRA. Blockade of COX-2 has little
effect on normal BP, but it can increase BP in those with
essential hypertension. Nonsteroidal antiinflammatory
agents exacerbate essential hypertension, blunt the anti-
hypertensive actions of most commonly used agents, pre-
dispose to acute kidney injury during periods of volume
depletion or hypotension, and blunt the natriuretic action
of loop diuretics. In contrast, aspirin reduces BP in patients
with renovascular hypertension, testifying to the prohyper-
tensive actions of thromboxane and other prostanoids that
activate the thromboxane-prostanoid receptor in this con-
dition. Metabolism of arachidonate by cytochrome P-450
monooxygenase yields 19,20-hydroxyeicosatetraenoic acid
(HETE), which is a vasoconstrictor of blood vessels but
inhibits tubular NaCl reabsorption. Metabolism by epoxy-
genase leads to epoxyeicosatrienoic acids (EETs), which are
powerful vasodilators and natriuretic agents. Arachidonate
metabolites act primarily as modulating agents in normal
physiology. Their role in human essential hypertension
remains elusive.
L-ARGININE-NITRIC OXIDE PATHWAY
Nitric oxide is generated by three isoforms of NOS that
are widely expressed in the body. NO interacts with many
heme-centered enzymes. Activation of guanylyl cyclase gen-
erates cyclic guanosine monophosphate, which is a powerful
vasorelaxant and inhibits NaCl reabsorption in the kidney.
Defects in NO generation in the endothelium of blood
vessels in human essential hypertension may contribute to
increased peripheral resistance, vascular remodeling, and
atherosclerosis, whereas defects in renal NO generation may
contribute to inappropriate renal NaCl retention and salt
sensitivity. NOS activity is reduced in hypertensive human
subjects and in those with CKD.
REACTIVE OXYGEN SPECIES
The incomplete reduction of molecular oxygen, either
by the respiratory chain during cellular respiration or by
oxidases such as nicotinamide adenine dinucleotide phos-
phate (NADPH) oxidase, yields ROS including O2
− and
generates peroxynitrite (ONOO−). ONOO− has long-lasting
effects through oxidizing and nitrosylating reactions.
Reaction of ROS with lipids yields oxidized low-density
lipoprotein (LDL), which promotes atherosclerosis, and
isoprostanes, which cause vasoconstriction, salt retention,
and platelet aggregation. ROS are difficult to quantitate,
but indirect evidence suggests that hypertension, especially
in the setting of CKD, is a state of oxidative stress. Drugs
that effectively reduce O2
− reduce BP in animal models of
hypertension, but they are largely unexamined in human
hypertension.
ENDOTHELINS
Endothelins are produced primarily by cells of the vascular
endothelium and collecting tubules. Discrete receptors
mediate either increased vascular resistance (type A) or
the release of NO and inhibition of NaCl reabsorption in
the collecting ducts (type B). Endothelin type A receptors
potentiate the vasoconstriction accompanying angiotensin
II infusion or blockade of NOS. Endothelin is released by
hypoxia, specific agonists such as angiotensin II, salt loading,
and cytokines. Nonspecific blockade of endothelin recep-
tors lowers BP in models of volume-expanded hypertension.
The role of endothelin in human essential hypertension is
unclear.
ATRIAL NATRIURETIC PEPTIDE
Atrial natriuretic peptide is released from the heart dur-
ing atrial stretch. It acts on receptors that increase GFR,
decrease NaCl reabsorption in the distal nephron, and
inhibit renin secretion. ANP is released during volume
expansion and contributes to the natriuretic response. Its
role in essential hypertension is unclear. Endopeptidase
inhibitors that block ANP degradation are natriuretic and
antihypertensive, but also inhibit the metabolism of kinins.
Although an increase in kinins may contribute to the fall
in BP with endopeptidase or ACE inhibitors, kinins can
cause an irritant cough or a more serious anaphylactoid
reaction.
PATHOGENESIS OF HYPERTENSION IN
CHRONIC KIDNEY DISEASE
With progression of CKD, the prevalence of salt-sensitive
hypertension increases in proportion to the fall in GFR.
Hypertension is almost universal in patients with CKD
caused by primary glomerular or vascular disease, whereas
those with primary tubulointerstitial disease may be normo-
tensive or, occasionally, salt losing.
With declining nephron number, CKD limits the ability
to adjust NaCl excretion rapidly and quantitatively during
changes in intake. The role of ECF volume expansion is appar-
ent from the ability of hemodialysis to lower BP in patients
with ESRD.
Additional mechanisms besides primary renal fluid
retention contribute to the increased TPR and hyperten-
sion in patients with CKD. The RAAS is often inappropri-
ately stimulated. The ESRD kidney generates abnormal
renal afferent nerve impulses, which entrain an increased
sympathetic nerve discharge that is reversed by bilateral
nephrectomy. Plasma levels of endothelin increase with kid-
ney failure. CKD induces oxidative stress, which contributes
to vascular disease and impaired endothelium-dependent
relaxing factor responses. A decreased generation of NO
from L-arginine follows the accumulation of ADMA, which
inhibits NOS. The thromboxane-prostanoid receptor is
activated and contributes to vasoconstriction and structural
damage.
Clearly, hypertension in CKD is multifactorial, but
volume expansion and salt sensitivity are predominant.
Pressor mechanisms mediated by angiotensin II, catechol-
amines, endothelin, or thromboxane-prostanoid receptors
become more potent during volume expansion. This fact
may underlie the importance of these systems in the ESRD
patients. Finally, many of the pathways that contribute to
hypertension in ESRD (such as impaired NO generation
and excessive production of endothelin, ROS, and ADMA)
also contribute to atherosclerosis, cardiac hypertrophy, and
progressive renal fibrosis and sclerosis. Indeed, in poorly
treated hypertension, kidney damage leads to additional
hypertension, which itself engenders further kidney damage,
generating a vicious spiral culminating in accelerated hyper-
tension, progressively diminishing kidney function, and the
requirement for renal replacement therapy. Therefore,
rational management of hypertension in CKD first entails
salt-depleting therapy with a salt-restricted diet and diuretic
therapy. Patients frequently require additional therapy to
combat the enhanced vasoconstriction and to attempt to
slow the rate of progression.
Pathophysiology is a branch of medicine which explains the function of the body as it relates to diseases and conditions. The pathophysiology of hypertension is an area which attempts to explain mechanistically the causes of hypertension, which is a chronic disease characterized by elevation of blood pressure. Hypertension can be classified by cause as either essential (also known as primary or idiopathic) or secondary. About 90–95% of hypertension is essential hypertension.[1][2][3][4] Some authorities define essential hypertension as that which has no known explanation, while others define its cause as being due to overconsumption of sodium and underconsumption of potassium. Secondary hypertension indicates that the hypertension is a result of a specific underlying condition with a well-known mechanism, such as chronic kidney disease, narrowing of the aorta or kidney arteries, or endocrine disorders such as excess aldosterone, cortisol, or catecholamines. Persistent hypertension is a major risk factor for hypertensive heart disease, coronary artery disease, stroke, aortic aneurysm, peripheral artery disease, and chronic kidney disease.[5]
A diagram explaining factors affecting arterial pressure
Cardiac output and peripheral resistance are the two determinants of arterial pressure.[6] Cardiac output is determined by stroke volume and heart rate; stroke volume is related to myocardial contractility and to the size of the vascular compartment. Peripheral resistance is determined by functional and anatomic changes in small arteries and arterioles.
The pathophysiology of hypertension involves the impairment of renal pressure natriuresis, the feedback system in which high blood pressure induces an increase in sodium and water excretion by the kidney that leads to a reduction of the blood pressure.
Hypertension implies an increase in either cardiac outputo ortotal peripheral resistance (TPR). Essential hypertension
developing in young adults may be initiated by an increase In cardiac output, associated with signs of overactivity of The sympathetic nervous system; the blood pressure (BP) is labile, and the heart rate is increased. Later, the BP increases further because of a rise in TPR, with consequent return to a normal cardiac output. Most patients in clinical practice
with sustained hypertension have an elevated TPR accom-panied by constriction of resistance vessels. Through time, vascular remodeling contributes a structural component to vasoconstriction.
The abrupt left ventricular systole creates a shock wave that is reflected back from the peripheral resistance vessels and Reaches the ascending aorta during early diastole. It is often Visible in younger subjects as the dicrotic notch in tracings of Aortic pressure. With aging, there is loss of elasticity and an Increase in the tone of the resistance vessels. The pressure Wave is transmitted more rapidly within the arterial tree. Eventually, this shock wave in the aorta coincides with the upstroke
of the aortic systolic pressure wave, leading to an abrupt
increase in the height of the systolic BP. This largely accounts
for the frequent finding of isolated, or predominant, systolic
hypertension in the elderly. In contrast, systolic hypertension
in the young usually reflects an enhanced cardiac contractility
and output.
PATHOPHYSIOLOGY OF HYPERTENSION
INTEGRATION OF CARDIORENAL FUNCTION
The integration of cardiorenal function is illustrated by the
response of a normal person to standing. There is an abrupt
fall in venous return and hence in cardiac output that elicits
a baroreflex response, as resistance vessels contract to buffer
the immediate fall in BP, and capacitance vessels contract to
restore venous return. The outcome is only a small drop in
the systolic BP, with a modest rise in diastolic BP and heart
rate. During prolonged standing, increased renal sympa-
thetic nerve activity enhances the reabsorption of sodium
chloride (NaCl) and fluid by the renal tubules, as well as
the release of renin from the juxtaglomerular apparatus.
Renin release results in the subsequent generation of angio-
tensin II and aldosterone, which maintain the BP and the
volume of the circulation. In contrast, the BP of patients with
autonomic insufficiency declines progressively on standing,
sometimes to the point of syncope. These patients with auto-
nomic failure illustrate vividly the crucial importance of a
stable BP for efficient function of the brain, heart, and kid-
neys. Therefore, it is no surprise that evolution has provided
multiple, coordinated BP-regulatory processes. The under-
standing of the cause for a sustained change in BP, such as
hypertension, requires knowledge of a number of interre-
lated pathophysiologic processes. The most important and
best understood of these are discussed in this chapter.
RENAL MECHANISMS AND SALT BALANCE
The kidney has a unique role in BP regulation. Renal salt
and water retention sufficient to increase the extracellular
fluid (ECF) volume, blood volume, and mean circulatory
filling pressure enhances venous return, cardiac output, and
BP. The kidney is so effective in excreting excess NaCl and
fluid during periods of surfeit, or retaining them during
periods of deficit, that the ECF and blood volumes normally
vary less than 10% with changes in salt intake. Consequently,
the role of body fluids in hypertension is subtle. For example,
a tenfold increase in daily NaCl intake in normal subjects
increases ECF volume by only about 1 L (about 6%) and
normally produces no change, or only a small increase,
in BP. Conversely, a diet with no salt content leads to the
loss of approximately 1 L of body fluid over 3 to 5 days
and only a trivial fall in BP. Different effects can be seen in
patients with chronic kidney disease (CKD) whose BP often
increases with the level of salt intake. This “salt-sensitive”
component to BP increases progressively with loss of kidney
function in patients with vascular or glomerular kidney
disease. Among normotensive subjects, a salt-sensitive com-
ponent to BP is apparent in about 30% and appears to
have a genetic component. Salt sensitivity is almost twice as
frequent in patients with hypertension, and is particularly
common among African Americans, the elderly, and those
with CKD. It is generally associated with a lower level of
plasma renin activity (PRA).
What underlies salt sensitivity? The normal kidneys are
exquisitely sensitive to BP. A rise in mean arterial pressure
(MAP) of as little as 1 to 3 mm Hg elicits a subtle increase in
renal NaCl and fluid elimination. This “pressure natriuresis”
also works in reverse and conserves NaCl and fluid during
decreases in BP. It is rapid, quantitative, and fundamental
for normal homeostasis. It is primarily a result of changes
in tubular NaCl reabsorption rather than total renal blood
flow (RBF) or glomerular filtration rate (GFR). Indeed,
renal autoregulation maintains RBF and GFR remarkably
constant during modest changes in BP. The pressure natri-
uresis mechanism accurately adjusts salt excretion and body
fluids in persons with healthy kidneys across a range of BPs.
Two primary mechanisms of pressure natriuresis have been
identified.
First, in some studies in rats, a rise in renal perfusion pres-
sure increases blood flow selectively through the medulla,
which is not as tightly autoregulated as cortical blood flow.
This increase in pressure and flow enhances renal inter-
stitial hydraulic pressure throughout the kidney, which
reduces proximal tubule reabsorption and impairs fluid
return to the bloodstream. Therefore, net NaCl and fluid
reabsorption is diminished. Second, the degree of stretch
of the afferent arteriole regulates the secretion of renin into
the bloodstream and hence the generation of angiotensin
II. Therefore, an increase in BP that is transmitted to this
site reduces renin secretion. Angiotensin II coordinates the
body’s salt and fluid retention mechanisms by stimulating
thirst and enhancing NaCl and fluid reabsorption in the
proximal and distal nephron segments. By stimulating secre-
tion of aldosterone and arginine vasopressin, and inhibit-
ing atrial natriuretic peptide (ANP), angiotensin II further
enhances reabsorption in the distal tubules and collecting
ducts. Thus, during normal homeostasis, an increase in BP
is matched by a decrease in PRA. It follows that a normal or
elevated value for PRA in hypertension is effectively “inap-
propriate” for the level of BP, and is thereby contributing to
the maintenance of hypertension.
The relationships between long-term changes in salt
intake, the renin-angiotensin-aldosterone system (RAAS),
and BP are shown in Figure 65.1. Normal human subjects
regulate the RAAS closely with changes in salt intake. An
increase in salt intake brings about only a modest and tran-
sient rise in MAP, because the RAAS is suppressed and the
highly effective pressure natriuresis mechanism rapidly
increases renal NaCl and fluid elimination sufficiently to
restore a normal blood volume and BP. Expressed quanti-
tatively in Figure 65.1, the slope of the long-term increase
in NaCl excretion with BP is almost vertical. One factor con-
tributing to the steepness of this slope, or the gain of the
pressure natriuresis relationship, is the reciprocal changes
in the RAAS with BP that dictate appropriate alterations in
salt handling by the kidney. Therefore, when the RAAS is
artificially fixed, the slope of the pressure natriuresis rela-
tionship flattens resulting in salt sensitivity, displacement of
the set point, and a change in ambient BP. For example, an
infusion of angiotensin II into a normal subject raises the
BP. Because angiotensin II is being infused, the kidney can-
not suppress angiotensin II levels appropriately by reducing
renin secretion. Therefore, the pressure natriuresis mecha-
nism is prevented, and the BP elevation is sustained without
an effective and complete renal compensation. In contrast,
normal subjects treated with an angiotensin-converting
enzyme (ACE) inhibitor to block angiotensin II genera-
tion or an angiotensin receptor blocker (ARB) to block AT1
receptors have a fall in BP. Again, the kidney cannot stimulate
an appropriate effect of angiotensin II and aldosterone that
would be required to retain sufficient NaCl and fluid to
buffer the fall in BP. Therefore, when the RAAS is fixed, the
BP changes as a function of salt intake and becomes highly
“salt sensitive” (see Fig. 65.1). These studies demonstrate
the unique role of the RAAS in long-term BP regulation and
its importance in isolating BP from NaCl intake.
Some recent findings add complexity to these simple
relationships. Renin is also generated within the connecting
tubule and collecting ducts. This renal renin may contribute
to the very high level of angiotensin within the kidney that
does not share the same relationship with dietary salt. Animal
models of diabetes mellitus demonstrate an increase in local
angiotensin generation and action in the kidneys that may
contribute to the beneficial effects of ACE inhibitor and ARB
therapy despite low circulating renin levels. Other studies have
shown that prorenin, although not itself active, becomes acti-
vated after binding to a renin receptor in the tissues where
novel signaling adds another component to the effects of the
RAAS. This is important, because conventional RAAS antago-
nists may not block these actions. It is generally considered
that the novel renin inhibitors do not block this renin receptor.
Four compelling lines of evidence implicate the kidney
and RAAS in long-term BP regulation. First, kidney trans-
plantation studies in rats showed that a normotensive animal
SECTION 12 — HYPERTENSION
that received a kidney from a hypertensive animal become
hypertensive, and vice versa. Similarly, human kidney trans-
plant recipients frequently become hypertensive if they
receive a kidney from a hypertensive donor. Apparently, the
kidney in hypertension is programmed to retain salt and
water inappropriately for a normal level of BP, thereby reset-
ting the pressure natriuresis to a higher level of BP and dic-
tating the appearance of hypertension in the recipient even
if the neurohumoral environment is that of normotension.
Nevertheless, recent studies in gene-deleted or transgenic
mice subjected to kidney transplantation concluded that the
increase in BP during prolonged infusion of angiotensin II
was mediated by the combined effects within the kidney and
the systemic circulation, most likely involving the brain. A
second observation was that the BP was normally reduced 5%
to 20% by an ACE inhibitor, an ARB, an aldosterone receptor
antagonist, or a renin inhibitor. The fall in BP was greatest
in those with elevated PRA values, and it was enhanced by
dietary salt restriction or concurrent use of diuretic drugs
(see Fig. 65.1). Third, almost 90% of patients approaching
end-stage renal disease (ESRD) have hypertension. Fourth,
the major monogenetic causes of human hypertension
involve genes that activate RAAS signaling (such as gluco-
corticoid remediable hypertension) or renal sodium transport
(such as Liddle syndrome).
TOTAL-BODY AUTOREGULATION
An increase in cardiac output necessarily increases peripheral
blood flow. However, each organ has intrinsic mechanisms
that adapt its blood flow to its metabolic needs. Therefore,
over time, an increase in cardiac output is translated into
an increase in TPR. The outcome is that organ blood flow is
maintained, but hypertension becomes sustained. This total-
body autoregulation is demonstrated in human subjects who
are given salt-retaining mineralocorticosteroid hormones.
An initial rise in cardiac output is translated in most indi-
viduals into sustained hypertension and an elevated TPR over
5 to 15 days.
STRUCTURAL COMPONENTS TO HYPERTENSION
Hypertension causes not only hypertrophic or eutrophic
remodeling in the distributing and resistance vessels and
the heart, but also fibrotic and sclerotic changes in the
glomeruli and interstitium of the kidney. Hypertrophy
of resistance vessels limits the ratio of lumen to wall, and
dictates a fixed component to TPR. This is evidenced by a
higher TPR in hypertensive subjects during maximal vasodi-
latation. Moreover, thickened and hypertrophied resistance
vessels have greater reductions in vessel diameter during
vasoconstrictor stimulation. This is apparent as an increase
in vascular reactivity to pressor agents. Remodeling of resis-
tance arterioles diminishes their response to changes in
perfusion pressure. This manifests as a blunted myogenic
response contributing to incomplete autoregulation of
RBF, thereby adding a component of barotrauma to hyper-
tensive kidney damage. Sclerotic and fibrotic changes in the
glomeruli and renal interstitium, combined with hypertro-
phy of the afferent arterioles, limit the sensing of BP in the
juxtaglomerular apparatus and interstitium of the kidney.
This blunts renin release and pressure natriuresis, thereby
contributing to salt sensitivity and sustained hypertension.
Rats receiving intermittent weak electrical stimulation of
the hypothalamus initially had an abrupt increase in BP fol-
lowed by a sudden fall after the cessation of the stimulus.
However, eventually the baseline BP increased in parallel
with the appearance of hypertrophy of the resistance ves-
sels. These structural components may explain why it often
takes weeks or months to achieve maximal antihypertensive
action from a drug, a reduction in salt intake, or correction
of a renal artery stenosis or hyperaldosteronism. Vascular
and left ventricular hypertrophy is largely, but usually not
completely, reversible during treatment of hypertension,
whereas fibrotic and sclerotic changes are not.
SYMPATHETIC NERVOUS SYSTEM, BRAIN,
AND BAROREFLEXES
A rise in BP diminishes the baroreflex, reduces the tone of
the sympathetic nervous system, and increases the tone of
the parasympathetic nervous system. Paradoxically, human
hypertension is often associated with an increase in heart
rate, maintained or increased plasma catecholamine levels,
and an increase in directly measured sympathetic nerve dis-
charge despite the stimulus to the baroreceptors. What is
the cause of this inappropriate activation of the sympathetic
nervous system in hypertension? Studies in animals show
that the baroreflex “resets” to the ambient level of BP after
2 to 5 days. Baroreflex no longer continues to “fight” the
elevated BP, but defends it at the new higher level. Much of
this adaptation occurs within the baroreceptors themselves.
With aging and atherosclerosis, the walls of the carotid sinus
and other baroreflex sensing sites become less distensible.
Therefore, the BP is less effective in stretching the afferent
nerve endings, and the sensitivity of the baroreflex is dimin-
ished. This may contribute to the enhanced sympathetic
nerve activity and increased plasma catecholamines that are
characteristic of elderly hypertensive subjects. Additionally,
animal models have identified central mechanisms that alter
the gain of the baroreflex process, and therefore the sym-
pathetic tone, in hypertension. The importance of central
mechanisms in human hypertension is apparent from the
effectiveness of drugs, such as clonidine, that act within the
brain to decrease the sympathetic tone. The kidneys them-
selves contain barosensitive and chemosensitive nerves that
can regulate the sympathetic nervous system. Patients with
ESRD on hemodialysis experienced an increased sympa-
thetic nervous system discharge and increased BP that were
not apparent after bilateral nephrectomy. This suggested
that the renal nerves were maintaining enhanced sympa-
thetic tone. Recently, the success of radiofrequency ablation
of the renal nerves in improving BP control in patients with
drug resistant hypertension further illustrates the impor-
tance of the renal nerves in setting the long-term level of BP
in human subjects.
ENDOTHELIUM AND OXIDATIVE STRESS
Calcium-mobilizing agonists such as bradykinin or ace-
tylcholine, as well as shear forces produced by the flow of
blood, release endothelium-dependent relaxing factors,
predominantly nitric oxide (NO). NO has a half-life of only
a few seconds because of inactivation by oxyhemoglobin or
active oxygen species (ROS) such as superoxide anion
(O2
−). Humans with essential hypertension have defects
in endothelium-dependent relaxing factor responses of
peripheral vessels and also diminished NO generation.
One underlying mechanism is oxidative stress. Excessive
O2
− formation inactivates NO, leading to a functional NO
deficiency. Another mechanism is the appearance of inhibi-
tors of nitric oxide synthase (NOS), including asymmetric
dimethyl arginine (ADMA). Finally, atherosclerosis, pro-
longed hypertension, or the development of malignant
hypertension causes structural changes in the endothelium
that limit NO generation further. In the kidney, NO inhibits
renal NaCl reabsorption in the loop of Henle and collect-
ing ducts. Therefore, NO deficiency not only induces vaso-
constriction but also diminishes renal pressure natriuresis.
Functional NO deficiency in large blood vessels contributes
to vascular inflammation and atherosclerosis.
GENETIC CONTRIBUTIONS
The heritability of human hypertension can be assessed
from differences in the concordance of hypertension
between identical twins (who share all genes and a similar
environment) versus nonidentical twins (who share only a
similar environment). These studies suggested that genetic
factors contributed less than half of the risk for developing
hypertension in modern humans. Studies in mice with tar-
geted disruption of individual genes or insertions of extra
copies of genes provided direct evidence of the critical
regulatory roles for certain gene products in hypertension.
Deletions of the gene in mice for endothelial NOS leads to
salt-dependent hypertension. The BP of mice decreases with
the number of copies of the gene encoding ACE. These are
compelling examples of circumstances in which a single
gene can sustain hypertension. However, there is increasing
recognition of the complexity and importance of gene–
gene interactions and the crucial effects of the genetic back-
ground on the changes in BP that accompany insertion or
deletion of a gene.
Currently, there is evidence that certain individual gene
defects can contribute to human essential hypertension.
However, the net effect on BP is small. Certain rare forms
of hereditary hypertension are caused by single-gene
defects. For example, dexamethasone-suppressible hyper-
aldosteronism is caused by a chimeric rearrangement of
the gene encoding aldosterone synthase that renders the
enzyme responsive to adrenocorticotropic hormone. Liddle
syndrome is caused by a mutation in the gene encoding
one component of the endothelial sodium channel that
is expressed in the distal convoluted tubule. The mutated
form has lost its normal regulation, leading to a permanent
“open state” of the sodium channel that dictates inappro-
priate renal NaCl retention and salt-sensitive, low-renin
hypertension (see Chapters 9, 39, and 67).
IMPLICATED MEDIATORS OF HYPERTENSION
Alterations in the synthesis, secretion, degradation, or action
of numerous substances are implicated in certain categories
of hypertension. The most important of these are described
in the following paragraphs.
RENIN, ANGIOTENSIN II, AND ALDOSTERONE
The PRA is not appropriately suppressed in most patients
with essential hypertension, and it is increased above normal
values in approximately 15%. Subjects with normal or high
PRA have a greater antihypertensive response to single-
agent therapy with an ACE inhibitor, an ARB, or a β-blocker
than patients with low-renin hypertension, who respond
notably to salt restriction and diuretic therapy. The RAAS is
particularly important in the maintenance of BP in patients
with renovascular hypertension, although its importance
wanes during the chronic phase when structural alterations
in blood vessels or damage in the kidney dictate a RAAS-
independent component to the hypertension.
SYMPATHETIC NERVOUS SYSTEM AND
CATECHOLAMINES
Pheochromocytoma is a catecholamine-secreting tumor,
often occurring in the adrenal medulla, that increases
plasma catecholamines tenfold to 1000-fold. However,
even such extraordinary increases in pressor amines are
rarely fatal, because an intact renal pressure natriuresis
mechanism reduces the blood volume, thereby limiting
the rise in BP. Indeed, such patients can have orthostatic
hypotension between episodes of catecholamine secretion
(see Chapter 67).
An increased sympathetic nerve tone of resistance vessels
in human essential hypertension causes α1-receptor–mediated
vasoconstriction of the blood vessels and β1-receptor–mediated
increases in contractility and output of the heart that are
incompletely offset by β2-receptor–mediated vasorelaxation
of peripheral blood vessels. Increased sympathetic nerve dis-
charge to the kidney leads to α1-mediated enhancement of
NaCl reabsorption and β1-mediated renin release.
DOPAMINE
Dopamine is synthesized in the brain and renal tubular
epithelial cells independent of sympathetic nerves. Dopa-
mine synthesis in the kidney is enhanced during volume
expansion and contributes to decreased reabsorption of
NaCl in the proximal tubule. Defects in tubular dopamine
responsiveness are apparent in genetic models of hyper-
tension. Recent evidence relates single nucleotide poly-
morphisms of genes that regulate dopamine receptors to
human salt-sensitive hypertension.
ARACHIDONATE METABOLITES
Arachidonate is esterified as a phospholipid in cell mem-
branes. It is released by phospholipases that are activated
by agents such as angiotensin II. Three enzymes principally
metabolize arachidonate. Cyclooxygenase (COX) gener-
ates unstable intermediates whose subsequent metabolism
by specific enzymes yields prostaglandins that are either
generally vasodilative (e.g., prostaglandin I2 [PGI2]), vaso-
constrictive (e.g., thromboxane), or of mixed effect (e.g.,
PGE2). COX-1 is expressed in many tissues, including plate-
lets, resistance vessels, glomeruli, and cortical collecting
ducts. Inflammatory mediators induce COX-2. However, the
normal kidney is unusual in expressing substantial COX
hich is located in macula densa cells, tubules, renal med-
ullary interstitial cells, and arterioles. The net effect of
blocking COX-1 generally is to retain NaCl and fluid while
raising BP and dropping PRA. Blockade of COX-2 has little
effect on normal BP, but it can increase BP in those with
essential hypertension. Nonsteroidal antiinflammatory
agents exacerbate essential hypertension, blunt the anti-
hypertensive actions of most commonly used agents, pre-
dispose to acute kidney injury during periods of volume
depletion or hypotension, and blunt the natriuretic action
of loop diuretics. In contrast, aspirin reduces BP in patients
with renovascular hypertension, testifying to the prohyper-
tensive actions of thromboxane and other prostanoids that
activate the thromboxane-prostanoid receptor in this con-
dition. Metabolism of arachidonate by cytochrome P-450
monooxygenase yields 19,20-hydroxyeicosatetraenoic acid
(HETE), which is a vasoconstrictor of blood vessels but
inhibits tubular NaCl reabsorption. Metabolism by epoxy-
genase leads to epoxyeicosatrienoic acids (EETs), which are
powerful vasodilators and natriuretic agents. Arachidonate
metabolites act primarily as modulating agents in normal
physiology. Their role in human essential hypertension
remains elusive.
L-ARGININE-NITRIC OXIDE PATHWAY
Nitric oxide is generated by three isoforms of NOS that
are widely expressed in the body. NO interacts with many
heme-centered enzymes. Activation of guanylyl cyclase gen-
erates cyclic guanosine monophosphate, which is a powerful
vasorelaxant and inhibits NaCl reabsorption in the kidney.
Defects in NO generation in the endothelium of blood
vessels in human essential hypertension may contribute to
increased peripheral resistance, vascular remodeling, and
atherosclerosis, whereas defects in renal NO generation may
contribute to inappropriate renal NaCl retention and salt
sensitivity. NOS activity is reduced in hypertensive human
subjects and in those with CKD.
REACTIVE OXYGEN SPECIES
The incomplete reduction of molecular oxygen, either
by the respiratory chain during cellular respiration or by
oxidases such as nicotinamide adenine dinucleotide phos-
phate (NADPH) oxidase, yields ROS including O2
− and
generates peroxynitrite (ONOO−). ONOO− has long-lasting
effects through oxidizing and nitrosylating reactions.
Reaction of ROS with lipids yields oxidized low-density
lipoprotein (LDL), which promotes atherosclerosis, and
isoprostanes, which cause vasoconstriction, salt retention,
and platelet aggregation. ROS are difficult to quantitate,
but indirect evidence suggests that hypertension, especially
in the setting of CKD, is a state of oxidative stress. Drugs
that effectively reduce O2
− reduce BP in animal models of
hypertension, but they are largely unexamined in human
hypertension.
ENDOTHELINS
Endothelins are produced primarily by cells of the vascular
endothelium and collecting tubules. Discrete receptors
mediate either increased vascular resistance (type A) or
the release of NO and inhibition of NaCl reabsorption in
the collecting ducts (type B). Endothelin type A receptors
potentiate the vasoconstriction accompanying angiotensin
II infusion or blockade of NOS. Endothelin is released by
hypoxia, specific agonists such as angiotensin II, salt loading,
and cytokines. Nonspecific blockade of endothelin recep-
tors lowers BP in models of volume-expanded hypertension.
The role of endothelin in human essential hypertension is
unclear.
ATRIAL NATRIURETIC PEPTIDE
Atrial natriuretic peptide is released from the heart dur-
ing atrial stretch. It acts on receptors that increase GFR,
decrease NaCl reabsorption in the distal nephron, and
inhibit renin secretion. ANP is released during volume
expansion and contributes to the natriuretic response. Its
role in essential hypertension is unclear. Endopeptidase
inhibitors that block ANP degradation are natriuretic and
antihypertensive, but also inhibit the metabolism of kinins.
Although an increase in kinins may contribute to the fall
in BP with endopeptidase or ACE inhibitors, kinins can
cause an irritant cough or a more serious anaphylactoid
reaction.
PATHOGENESIS OF HYPERTENSION IN
CHRONIC KIDNEY DISEASE
With progression of CKD, the prevalence of salt-sensitive
hypertension increases in proportion to the fall in GFR.
Hypertension is almost universal in patients with CKD
caused by primary glomerular or vascular disease, whereas
those with primary tubulointerstitial disease may be normo-
tensive or, occasionally, salt losing.
With declining nephron number, CKD limits the ability
to adjust NaCl excretion rapidly and quantitatively during
changes in intake. The role of ECF volume expansion is appar-
ent from the ability of hemodialysis to lower BP in patients
with ESRD.
Additional mechanisms besides primary renal fluid
retention contribute to the increased TPR and hyperten-
sion in patients with CKD. The RAAS is often inappropri-
ately stimulated. The ESRD kidney generates abnormal
renal afferent nerve impulses, which entrain an increased
sympathetic nerve discharge that is reversed by bilateral
nephrectomy. Plasma levels of endothelin increase with kid-
ney failure. CKD induces oxidative stress, which contributes
to vascular disease and impaired endothelium-dependent
relaxing factor responses. A decreased generation of NO
from L-arginine follows the accumulation of ADMA, which
inhibits NOS. The thromboxane-prostanoid receptor is
activated and contributes to vasoconstriction and structural
damage.
Clearly, hypertension in CKD is multifactorial, but
volume expansion and salt sensitivity are predominant.
Pressor mechanisms mediated by angiotensin II, catechol-
amines, endothelin, or thromboxane-prostanoid receptors
become more potent during volume expansion. This fact
may underlie the importance of these systems in the ESRD
patients. Finally, many of the pathways that contribute to
hypertension in ESRD (such as impaired NO generation
and excessive production of endothelin, ROS, and ADMA)
also contribute to atherosclerosis, cardiac hypertrophy, and
progressive renal fibrosis and sclerosis. Indeed, in poorly
treated hypertension, kidney damage leads to additional
hypertension, which itself engenders further kidney damage,
generating a vicious spiral culminating in accelerated hyper-
tension, progressively diminishing kidney function, and the
requirement for renal replacement therapy. Therefore,
rational management of hypertension in CKD first entails
salt-depleting therapy with a salt-restricted diet and diuretic
therapy. Patients frequently require additional therapy to
combat the enhanced vasoconstriction and to attempt to
slow the rate of progression.