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Pathogenesis of Hypertension

Suzanne Oparil, MD; M. Amin Zaman, MD; and David A. Calhoun, MD
[+] Article and Author Information

From University of Alabama at Birmingham, Birmingham, Alabama.


Potential Financial Conflicts of Interest:Consultancies: S. Oparil (Bristol Myers-Squibb, Biovail, Merck & Co., Pfizer, Reliant, Sanofi, Novartis, The Salt Institute, Wyeth); Grants received: S. Oparil (Abbott Laboratories, AstraZeneca, Aventis, Boehringer Ingelheim, Bristol Myers-Squibb, Eli Lilly, Forest Laboratories, GlaxoSmithKline, King, Novartis [Ciba], Merck & Co., Pfizer, Sanofi/BioClin, Schering-Plough, Schwarz Pharma, Scios, Inc., G.D. Searle, Wyeth, Sankyo, Solvay, Encysive).

Requests for Single Reprints: Suzanne Oparil, MD, Department of Medicine, Division of Cardiovascular Diseases, University of Alabama at Birmingham, Zeigler Building 1034, 703 19th Street South, Birmingham, AL 35294.

Current Author Addresses: Drs. Oparil, Zaman, and Calhoun: Department of Medicine, Division of Cardiovascular Diseases, University of Alabama at Birmingham, Zeigler Building 1034, 703 19th Street South, Birmingham, AL 35294.


Ann Intern Med. 2003;139(9):761-776. doi:10.7326/0003-4819-139-9-200311040-00011
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Evidence for genetic influence on blood pressure comes from various sources. Twin studies document greater concordance of blood pressures in monozygotic than dizygotic twins (6), and population studies show greater similarity in blood pressure within families than between families (7). The latter observation is not attributable to only a shared environment since adoption studies demonstrate greater concordance of blood pressure among biological siblings than adoptive siblings living in the same household (8). Furthermore, single genes can have major effects on blood pressure, accounting for the rare Mendelian forms of high and low blood pressure (3). Although identifiable single-gene mutations account for only a small percentage of hypertension cases, study of these rare disorders may elucidate pathophysiologic mechanisms that predispose to more common forms of hypertension and may suggest novel therapeutic approaches (3). Mutations in 10 genes that cause Mendelian forms of human hypertension and 9 genes that cause hypotension have been described to date, as reviewed by Lifton and colleagues (3, 9) (Figure 2). These mutations affect blood pressure by altering renal salt handling, reinforcing the hypothesis of Guyton (5) that the development of hypertension depends on genetically determined renal dysfunction with resultant salt and water retention (2).

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Figure 1.
Pathophysiologic mechanisms of hypertension.(2)

AME = apparent mineralocorticoid excess; CNS = central nervous system; GRA = glucocorticoid-remediable aldosteronism. Reproduced with permission from Crawford and DiMarco .

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Figure 2.
Mutations altering blood pressure in humans.NaClTALDCTCCTredblue(3)

A diagram of a nephron, the filtering unit of the kidney, is shown. The molecular pathways mediating sodium chloride ( ) reabsorption in individual renal cells in the thick ascending limb ( ) of the Henle's loop, distal convoluted tubule ( ), and the cortical collecting tubule ( ) are indicated, along with the pathway of the renin–angiotensin system, the major regulator of renal salt reabsorption. Inherited diseases affecting these pathways are indicated (hypertensive disorders [ ] and hypotensive disorders [ ]). 11β-HSD2 = 11β-hydroxysteroid dehydrogenase-2; ACE = angiotensin-converting enzyme; AME = apparent mineralcorticoid excess; ANG = angiotensin; DOC = deoxycorticosterone; GRA = glucocorticoid-remediable aldosteronism; MR = mineralocorticoid receptor; PHA1 = pseudohypoaldosteronism type 1; PT = proximal tubule. Reproduced from Lifton et al. , with permission from Elsevier Science.

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Figure 3.
Role of the sympathetic nervous system in the pathogenesis of cardiovascular diseases.(29)

Reproduced from Brook and Julius , with permission from Elsevier Science.

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Figure 4.
How remodeling can modify the cross-sections of blood vessels.(57)

The starting point is the vessel at the center. Remodeling can be hypertrophic (increase of cross-sectional area), eutrophic (for example, no change in cross-sectional area), or hypotrophic (decrease of cross-sectional area). These forms of remodeling can be inward (reduction in lumen diameter) or outward (for example, increase in lumen diameter). Reproduced with permission from Mulvany et al. .

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Figure 5.
A pathway for the development of salt-sensitive hypertension.GFRK i (4)

The development of salt-sensitive hypertension is proposed to occur in 3 phases. In the first phase, the kidney is structurally normal and sodium is excreted normally. However, the kidney may be exposed to various stimuli that result in renal vasoconstriction, such as hyperactivity of the sympathetic nervous system or intermittent stimulation of the renin–angiotensin system. During this phase, the patient may have either normal blood pressure or borderline hypertension, which (if present) is salt-resistant. In the second phase, subtle renal injury develops, impairing sodium excretion and increasing blood pressure. This phase is initiated by ischemia of the tubules, which results in interstitial inflammation (involving mononuclear-leukocyte infiltration and oxidant generation), which in turn leads to the local generation of vasoconstrictors, such as angiotensin II, and a reduction in the local expression of vasodilators, especially nitric oxide. In addition, renal vasoconstriction leads to the development of preglomerular arteriolopathy, in which the arterioles are both thickened (because of smooth-muscle cell proliferation) and constricted. The resulting increase in renal vascular resistance and decrease in renal blood flow perpetuate the tubular ischemia, and the glomerular vasoconstriction lowers the single-nephron glomerular filtration rate ( ) and the glomerular ultrafiltration coefficient ( ). These changes result in decreased sodium filtration by the glomerulus. The imbalance in the expression of vasoconstrictors and vasodilators favoring vasoconstriction also leads to increased sodium reabsorption by the tubules; together, these changes lead to sodium retention and an increase in systemic blood pressure. In the third phase, the kidneys equilibrate at a higher blood pressure, allowing them to resume normal sodium handling. Specifically, as the blood pressure increases, there is an increase in renal perfusion pressure across the fixed arterial lesions. This increase helps to restore filtration and relieve the tubular ischemia, thereby correcting the local imbalance in vasoconstrictors and vasodilators and allowing sodium excretion to return toward normal levels. However, this process occurs at the expense of an increase in systemic blood pressure and hence a rightward shift in the pressure–natriuresis curve. In addition, this condition is not stable, since the increase in blood pressure may lead to a progression in the arteriolopathy, thereby initiating a vicious circle. During this phase, sodium sensitivity may be observed as a decrease in blood pressure when sodium intake is restricted, whereas increased sodium intake will have a lesser effect on blood pressure because of the intact but shifted balance between blood pressure and natriuresis. The early phase of this pathway may be bypassed in the presence of other mechanisms, such as primary tubulointerstitial disease, genetic alterations in sodium regulation and excretion, or a congenital reduction in nephron number that limits sodium filtration. Adapted with permission from Johnson et al. . Copyright © 2002 Massachusetts Medical Society. All rights reserved.

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Figure 6.
Simple tubular models of the systemic arterial system.Top.Middle.Bottom.left(78)

Normal distensibility and normal pulse wave velocity. Decreased distensibility but normal pulse wave velocity. Decreased distensibility with increased pulse wave velocity. The amplitude and contour of pressure waves that would be generated at the origin of these models by the same ventricular ejection (flow) waves are shown ( ). Decreased distensibility as such increases pressure wave amplitude, whereas increased wave velocity causes the reflected wave to return during the ventricular systole. Reproduced from Oparil and Weber , with permission from Elsevier Science.

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Figure 7.
Signal transduction pathways for mechanical stress in rat mesenteric small arteries.(86)

AT1-R = angiotensin II type 1 receptor; ERK1/2 = extracellular signal-regulated kinases 1 and 2; FAK = focal adhesion kinase; MEK = mitogen-activated protein kinase extracellular signal-regulated kinase; MMP = matrix metalloproteinase; PDGF = platelet-derived growth factor; PDGFβ-R = platelet-derived growth factor-β receptor (receptor tyrosine kinase); PKC = protein kinase C; PLC = phospholipase C; TK = tyrosine kinase. c-Src, Ras, and Raf are specific tyrosine kinases; Grb, Sch, and Sos are domain adaptor proteins; and α, β, and γ are G-protein subunits. Reproduced with permission from Mulvany .

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Figure 8.
The angiotension II types 1 (AT 1 ) and 2 (AT 2 ) receptors have generally opposing effects.121212NO1PAI-121

The AT receptor leads to vasoconstriction, cell growth, and cell proliferation; the AT receptor has the opposite effect, leading to vasodilation, antigrowth, and cell differentiation. The AT receptor is antinatriuretic; the AT receptor is natriuretic. The AT receptor stimulation results in free radicals; AT stimulation produces nitric oxide ( ) that can neutralize free radicals. The AT receptor induces plasminogen activator inhibitor-1 ( ) and other growth family pathways; the AT receptor does not. The angiotensin-receptor blockers bind to and block selectively at the AT receptor, promoting stimulation of the receptor by angiotensin II.

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Figure 9.
Mechanisms of angiotensin II (ANG II)–dependent, oxidant-mediated vascular damage.

ICAM = intercellular adhesion molecule; MCP-1 = monocyte chemoattractant protein-1; NO = nitric oxide; PAI-1 = plasminogen activator inhibitor-1; VCAM = vascular cell adhesion molecule.

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Figure 10.
Endothelial function in the normal vasculature and in the hypertensive vasculature.leftrighttopNOET A ET B bottomA(111)

Large conductance vessels ( ), for example, epicardial coronary arteries, and resistance arterioles ( ), are shown. In normal conductance arteries ( ), platelets and monocytes circulate freely, and oxidation of low-density lipoprotein is prevented by a preponderance of nitric oxide ( ) formation. At the level of the small arterioles, reduced vascular tone is maintained by constant release of nitric oxide. Endothelin-1 normally induces no vasoconstriction or only minimal vasoconstriction through stimulation of type A endothelin receptors ( ) located on smooth-muscle cells and contributes to basal nitric oxide release by stimulating type B endothelin receptors ( ) on endothelial cells. In the hypertensive microvasculature ( ), decreased activity of nitric oxide and enhanced ET -mediated vasoconstrictor activity of endothelin-1 result in increased vascular tone and medial hypertrophy, with a consequent increase in systemic vascular resistance. At the level of conductance arteries, a similar imbalance in the activity of endothelial factors leads to a proatherosclerotic milieu that is conducive to the oxidation of low-density lipoprotein, the adhesion and migration of monocytes, and the formation of foam cells. These activities ultimately lead to the development of atherosclerotic plaques, the rupture of which, in conjunction with enhanced platelet aggregation and impaired fibrinolysis, results in acute intravascular thrombosis, thus explaining the increased risk for cardiovascular events in patients with hypertension. These mechanisms may be operative in patients with high normal blood pressure and may contribute to their increased cardiovascular risk. Adapted with permission from Panza et al. .

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