PATHOPHYSIOLOGY The pathophysiology of primary hypertension is heterogeneous but ultimately

exerts its effects through the two primary determinants of BP: cardiac output (CO) and peripheral
resistance (PR). The processes influencing these two determinants are numerous and complex, and
although the underlying cause of primary hypertension remains unknown, it is most likely multifactorial.
As a review of these mechanisms is beyond the scope of this text, readers are referred to other
sources.11 The development of primary hypertension involves interplay between genetic and
environmental factors interacting with multiple physiological systems including neural, renal, hormonal,
and vascular. Further complicating this is that an individual’s phenotype of primary hypertension (eg,
diastolic hypertension in middle-aged individuals, isolated systolic hypertension in the elderly, and
obesity-related hypertension) may have different

contributing mechanisms.11 Because of these complexities, no final common pathway has been
identified and a single target for the treatment of primary hypertension remains elusive. Therefore,
guidelines for the selection of specific therapeutic agents allow the clinician some flexibility in choices.

Genetic Factors Although multiple genetic polymorphisms have been associated with relatively small
effects on systolic BP (SBP), diastolic BP (DBP), and response to antihypertensive medications,
replications of these findings in large populations are elusive. Consequently, the information available to
date is far from sufficient to provide any practical guidance for clinicians.11 Nevertheless, genetic basis
of variability in response to drug therapy continues to be pursued. Environmental Factors In contrast
with genetic factors, environmental factors contributing to hypertension are well characterized.
Cigarette smoking (cigars and smokeless tobacco) and caffeine cause transient increases in BP via
norepinephrine release and, in the case of caffeine, by its antagonism of vasodilatory adenosine
receptors. Acute alcohol ingestion may have a variable effect (increased due to sympathetic nerve
activity or lowering due to vasodilation) which is transient, whereas chronic heavy consumption of
alcohol and binge drinking raises the risk of hypertension.11,14 Many other environmental factors have
been shown or been proposed to influence BP and, in some cases, contribute to the development of
hypertension. These include obesity, physical inactivity, fetal environment (eg, maternal malnutrition,
increased fetal exposure to maternal glucocorticoids), postnatal weight gain, premature birth and low
birth weight, potassium and magnesium depletion, vitamin D deficiency, and environmental toxins (eg,
lead).11

Neural Mechanisms Overactivity of the sympathetic nervous system (SNS) in the early stages of primary
hypertension manifests as increased heart rate, CO, and peripheral vasoconstriction. Despite this, recent
outcome trials of agents targeting the SNS (α- and β-adrenergic blockers) have not performed as well as
other classes of drugs. Nevertheless, strategies aimed at targeting the SNS continue to be pursued with
specific interest in invasive strategies aimed at resistant hypertension.11

Renal Mechanisms The contribution of sodium to the development of primary hypertension is related to
excess sodium intake and/or abnormal

sodium excretion by the kidneys.11 However, it is generally accepted that dietary salt is associated with
increases in BP that can be lowered with reduction of sodium intake,15 particularly in

individuals deemed salt sensitive.16 For example, 29% of participants in the Dietary Approaches to Stop
Hypertension (DASH)-Sodium trial were deemed to be salt sensitive and responded to reductions in salt
intake.16,17 Current guidelines suggest there is a threshold effect of sodium intake on BP in the range of
50 to 100 mmol/day (1.2–2.4 g). However, these recommendations may require modification based on
contemporary investigations.18 Although population-wide based reduction in dietary sodium intake via
global policies has been widely advocated as an approach to reduce hypertension and cardiovascular
disease (CVD), the need for further scientific investigation of salt restriction persists. Hormonal
Mechanisms Renin is produced and stored in the juxtaglomerular cells of the kidney, and its release is
stimulated by impaired renal perfusion, salt depletion, and β1-adrenergic stimulation. The release of
renin is the rate-limiting step in the eventual formation of angiotensin II, which is a potent
vasoconstrictor (Figure 5–2).11 The role of the renin-angiotensin-aldosterone system (RAAS) in primary
hypertension is supported by the presence of high levels of renin, suggesting the system is
inappropriately activated. Proposed mechanisms include increased sympathetic drive, defective
regulation of the RAAS (nonmodulation), and the existence of a subpopulation of ischemic nephrons
that release excess renin.11 However, there are also patients with primary hypertension and low levels
of renin which suggests alternative mechanisms, unrelated to renin levels or activity, may be in play.
Thus, although uncommon in general practice, plasma renin activity (PRA) measurements may be
utilized to guide antihypertensive therapy selection. In fact, it has been demonstrated that patients with
low PRA (less than 0.65 ng/mL/hour [0.18 ng/L/s]) respond preferentially to diuretics, aldosterone
antagonists, and calcium channel blockers (CCBs), whereas those with higher PRA levels respond
preferentially to renin-mediated therapies such as β-blockers, angiotensin-converting enzyme inhibitors
(ACE-Is), angiotensin receptor blockers (ARBs), and direct renin inhibitors.4 However, use of PRA
measurements to guide therapy is not without controversy and the reader is referred to other sources
for more information on the subject.7 FIGURE 5–2. Diagram of the renin-angiotensin-aldosterone
system (RAAS), a key system involved in the modulation of blood pressure. The diagram depicts the
pathways involved in the action of various antihypertensive agents including angiotensin-converting
enzyme (ACE) inhibitors, ARBs, diuretics, and aldosterone antagonists. By inhibiting the action of ACE,
ACE inhibitors reduce both the formation of the vasoconstrictors angiotensin II and the degradation of
vasodilation substances including bradykinin. ARBs primarily act through inhibition of the action of
angiotensin II on the angiotensin-I receptors that modulate vasoconstriction. Aldosterone antagonists
directly inhibit the action of aldosterone; diuretics affect sodium and water retention at a renal level.
(ARB, angiotensin receptor blockers; AT1, angiotensin-1.) (From Victor RG, Kaplan NM. Kaplan’s Clinical
Hypertension, 10th ed. Philadelphia, PA: Wolters Kluwer Lippincott Williams & Wilkins Health, 2010.)

Vascular Mechanisms Elevated peripheral arterial resistance is the hemodynamic hallmark of primary
hypertension. The increase in PR typically observed may be due to a reduction in arterial lumen size as a
result of vascular remodeling. This remodeling, or change in vascular tone, may be modulated by various
endotheliumderived vasoactive substances, growth factors, and cytokines. This increase in arterial
stiffness or reduced compliance results in the observed increase in systolic BP.11 Contributing
Comorbidities Several comorbidities have a high concurrence with the presence of hypertension leading
to a higher risk of target organ damage, cardiovascular morbidity and mortality, and overall health care
costs. Specifically, these include the presence of diabetes mellitus (DM), dyslipidemia, obesity, and CKD.
As such, the assessment of global cardiovascular risk in all patients with hypertension should be part of
the management plan while also pursuing target BPs through nonpharmacologic and pharmacologic
means.6

MEASUREMENT OF BLOOD PRESSURE Appropriate technique in measuring BP is a vital component to

the diagnosis and management of hypertension. Accurate measurement of a patient’s BP requires the
control of factors that may influence variability in the measure. Failure to consider these factors,
including body position, cuff size, device selection, auscultatory technique and dietary intake prior to the
visit, may lead to misclassification and thus inaccurate assessments of risk. Clinicians should instruct
patients to avoid exercise, alcohol, caffeine, or nicotine consumption 30 minutes before BP
measurement. Patients should be sitting comfortably with their back supported and arm free of
constrictive clothing with legs uncrossed and feet flat on the floor for a minimum of 5 minutes before
the first reading. Systolic and diastolic BP tend to increase when the cuff size is too small. Ideally, the
cuff bladder should encircle at least 80% of the arm’s circumference to ensure a more accurate
measurement of BP.19 To reduce deviations in BP measurement in the clinic, the patient and clinician
should not talk during BP readings. The measurement arm is supported and positioned at heart level. If a
mercury or aneroid device is used, then the palpatory method must be used first to estimate the SBP.20
If an automated device is used, this is not necessary. After the patient’s cuff is inflated above the systolic
pressure, the pressure indicator should drop at a rate of 2 to 3 mm Hg/s. A stethoscope placed over the
brachial artery in the antecubital fossa identifies the first and last audible Korotkoff sounds, which
should be taken as systolic and diastolic pressure, respectively. A minimum of two readings at least 1
minute apart are then averaged. If measurements vary by more than 5 mm Hg between the two
readings, then one or two additional BP measurements are collected and the multiple readings
averaged. BP classification is based on the average of two or more properly measured BP readings on
each of two or more office visits. Details and further recommendations for accurate measurement of BP
in special populations can be found elsewhere.6,19 Finally, the measurement of clinic or office BPs is
often poorly correlated with assessments of BP in other settings. Consequently, under select
circumstances, clinicians are increasingly using 24-hour ABPM, AOBP monitoring and HBP monitoring.
These tools are useful in identifying patients with white coat hypertension or in the case of 24-hour
ABPM, elevations of BP during the night. They may also aid in the management of refractory
hypertension with minor target organ damage, those with suspected autonomic neuropathy, those with
hypotensive symptoms, and patients with large differences between home and clinic BP measurements.
Benefits derived from these additional modes of BP monitoring may be of greater prognostic
significance than traditional office-based measurements.5,20

PATOFISIOLOGY

Severalhumoralabnormalitiesmaybeinvolvedinthedevelopmentof essential hypertension. These

abnormalities may involve the RAAS, natriuretic hormone, and hyperinsulinemia.

THE RENIN-ANGIOTENSIN-ALDOSTERONE SYSTEM (RAAS) The RAAS is a complex endogenous system

that is involved with mostregulatorycomponentsofarterialBP.Activationandregulation are governed
primarily by the kidney (Fig. 13–1). The RAAS regulates sodium, potassium, and fluid balance. Therefore,
this system significantly influences vascular tone and sympathetic nervous system activity and is the
most influential contributor to the homeostatic regulation of BP. Renin is an enzyme that is stored in the
juxtaglomerular cells, which are located in the afferent arterioles of the kidney. The release
ofreninismodulatedbyseveralfactors:intrarenalfactors(e.g.,renal
perfusionpressure,catecholamines,andangiotensinII)andextrarenal factors (e.g., sodium, chloride, and
potassium). Juxtaglomerularcellsfunctionasabaroreceptor-sensingdevice. Decreased renal artery
pressure and kidney blood flow are sensed by these cells and stimulate secretion of renin. The
juxtaglomerular apparatus also includes a group of specialized distal tubule cells

referred to collectively as the macula densa. A decrease in sodium and chloride delivered to the distal
tubule stimulates renin release. Catecholamines increase renin release probably by directly
stimulatingsympatheticnervesontheafferentarteriolesthat,inturn,activate the juxtaglomerular cells.
Decreased serum potassium and/or intracellular calcium is detected by the juxtaglomerular cells,
resulting in renin secretion. Renin catalyzes the conversion of angiotensinogen to
angiotensinIintheblood.AngiotensinIisthenconvertedtoangiotensin IIbyangiotensin-
convertingenzyme(ACE).Afterbindingtospecific receptors(classifiedaseitherAT1 orAT2
subtypes),angiotensinIIexerts biologic effects in several tissues. The AT1 receptor is located in brain,
kidney, myocardium, peripheral vasculature, and the adrenal glands. These receptors mediate most
responses that are critical to cardiovascular and kidney function. The AT2 receptor is located in adrenal
medullary tissue, uterus, and brain. Stimulation of the AT2 receptor does not influence BP regulation.
Circulating angiotensin II can elevate BP through pressor and volume effects. The pressor effects include
direct vasoconstriction, stimulation of catecholamine release from the adrenal medulla, and centrally
mediated increases in sympathetic nervous system activity. Angiotensin II also stimulates aldosterone
synthesis from the adrenal cortex. This leads to sodium and water reabsorption that increases plasma
volume, total peripheral resistance, and ultimately,
BP.Clearly,anydisturbanceinthebodythatleadstoactivationofthe RAAS could explain chronic
hypertension. The heart and brain contain a local RAAS. In the heart, angiotensin II is also generated by
a second enzyme, angiotensin I convertase (human chymase). This enzyme is not blocked by ACE
inhibition.ActivationofthemyocardialRAASincreasescardiaccontractility and stimulates cardiac
hypertrophy. In the brain, angiotensinIImodulatestheproductionandreleaseofhypothalamicandpituitary
hormones and enhances sympathetic outflow from the medulla oblongata. Peripheral tissues can locally
generate biologically active angiotensin peptides, which may explain the increased vascular resistance
seen in hypertension. Some evidence suggests that angiotensin produced by local tissue may interact
with other humoral regulators andendothelium-derivedgrowthfactorstostimulatevascularsmooth
muscle growth and metabolism. These angiotensin peptides may, in
fact,instigateincreasedvascularresistanceinlowplasmareninforms
ofhypertension.ComponentsofthetissueRAASalsomayberesponsible for the long-term hypertrophic
abnormalities seen with hypertension (left ventricular hypertrophy, vascular smooth muscle
hypertrophy, and glomerular hypertrophy).

NATRIURETIC HORMONE Natriuretic hormone inhibits sodium and potassium ATPase and thus interferes
with sodium transport across cell membranes. Inherited defects in the kidney’s ability to eliminate
sodium can cause an increasedbloodvolume.Acompensatoryincreaseintheconcentration of circulating
natriuretic hormone theoretically could increase urinary excretion of sodium and water. However, this
same hormone is also thought to block the active transport of sodium out of arteriolar smooth muscle
cells. The increased intracellular concentration of sodium ultimately would increase vascular tone and
BP.

INSULIN RESISTANCE AND HYPERINSULINEMIA

Evidencehaslinkedinsulinresistanceandhyperinsulinemiawiththe
developmentofhypertension,sometimesreferredtoasthemetabolic