Chronic hypertension pathophysiology

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Assistant Editor-In-Chief:Yazan Daaboul, Serge Korjian, Rim Halaby

Overview

Although the pathophysiology of secondary hypertension is known, there is still much debate about the true pathogenesis of primary (essential) hypertension. It is now conceded that hypertension is caused by multiple genetic and environmental factors with varying roles between individuals .

Pathophysiology

Cardiac Output and Peripheral Vascular Resistance

• Patients with hypertension usually have an increased peripheral vascular resistance, which is determined largely by the arterioles which are known for their relative increase in wall thickness determined basically by the smooth muscle cells.
• Intracellular calcium concentrations are increased causing vasoconstriction.
• This vasoconstriction is multifactorial but is ultimately linked to continuous increase in intracellular calcium.
• Prolonged constriction contributes to the overall structural damage to arterioles and consequential elevation of blood pressure.
• Notably, the cardiac output in hypertensive patients is generally normal. With age, decreased compliance of central arteries predominates, thus contributing mostly to systolic hypertension in the elderly.

Renin-Angiotensin Aldosterone System (RAAS)

• While the systemic role of RAAS shows little evidence of contribution; local release of renin-angiotensin in the kidney, heart, and arteries seems to play a much more important role in the pathogenesis of hypertension .
• Angiotensin II constricts resistance vessels, directly stimulates renal sodium reabsorption, activates aldosterone to increase sodium reabsorption, helps release antidiuretic hormone (ADH), and promotes sympathetic activity of the autonomic nervous system .
• Aldosterone increases sodium reabsorption by increasing the quantity of open sodium channels in the luminal membrane of the principal cells of the collecting tubules in the kidney.
• Furthermore, aldosterone has a nongenomic effect in increasing fibrosis, collagen deposition, inflammation, and cardiovascular remodeling .

Autonomic Nervous System

• Exact role of sympathetic nervous system in hypertension remains controversial.
• Effect of beta and alpha-blockers as anti-hypertensive agents validates that sympathetic nervous system is, at least partially, involved in hypertension.
• There is ample evidence that norepinephrine concentrations and rate of norepinephrine spillover from sympathetic nerve terminals are markedly elevated in patients with essential hypertension.
• Humoral, metabolic, reflex, and central mechanisms of adrenergic activation are all contributory to characterizing hypertension.

Role of Pressure Natriuresis and Renal Damage

• Pressure natriuresis is the effect of arterial pressure on sodium excretion. Experimental evidence has shown that pressure natriuresis is impaired in hypertension even without significant variations in renal blood flow or changes in glomerular filtration rate (GFR).
• In non-hypertensive patients, the increased blood pressure is countered by activation of the renal pressure natriuresis to allow maintenance of normal sodium balance and blood pressure . In hypertensive patients, however, pressure natriuresis seems to be permanently set at a higher BP threshold, whereby an inappropriately normal sodium excretion rate is maintained despite the high blood pressure values.
• Renal damage follows via loss of nephron function leading to a vicious circle of further impairment of pressure natriuresis and elevated BP.

Endothelial Dysfunction

• The vascular endothelium plays an important vasoactive role via release of vasoactive substances, such as nitric oxide and endothelin.
• The cross-talk between the endothelium and the media is an important determinant of the function of the latter.
• Endothelial dysfunction and permanent endothelial structural changes seem to be responsible for irreversible changes of the vascular bed and of chronic hypertension.
• Furthermore, renal microvascular disease is currently hypothesized as an important factor leading to the development of hypertension .

Role of Vasoactive Substances

• Increased role of vasoconstrive substances, such as:
  • Endothelin: Potent local vasoactive peptide with vasoconstrictor properties. Development of endothelin receptor antagonist for the treatment of systemic hypertension has been discontinued because of teratogenicity, testicular atrophy, and hepatotoxicity.
  • Ouabain: Steroid-like substance that plays a role in sodium and calcium transport.

• Defect in vasodilatory substances, such as:
  • Nitric oxide: Potent vasodilator, whose role is diminished in hypertension.
  • Bradykinin: Potent vasodilator, inhibited by RAAS in hypertensive patients.
  • Atrial natriuretic peptide (ANP): Hormone secreted by cardiac atria in response to atrial stretch by increased blood volume. Physiologically, it induces natriuresis to decrease blood volume. .

Environmental Factors

• Obesity and metabolic syndrome play a major indirect role in the pathogenesis of hypertension by increasing renal tubular reabsorption, impairment of pressure natriuresis, and activation of sympathetic and RAAS .
• Emotional stress causes immediate, but transient, increase in blood pressure. Although stress, per se, has not been shown to cause hypertension, it has been hypothesized that stress contributes to development of hypertension and when risk factors of hypertension are accompanied by environmental stress, the outcome on blood pressure is worse.
• Similarly, depression seems to negatively affect hypertension, despite scarce scientific evidence. It remains controversial whether depression develops secondary to hypertension or causes it and whether antidepressant medications are the only etiology of hypertension in depression.

Shown below is an image that summarizes the pathophysiology of hypertension.

Pathogenesis of Essential Hypertension. Adapted from Oparil S, Zaman MA, Calhoun DA. Pathogenesis of Hypertension. Ann Intern Med. 2003, 139(9):761-76

Genetics

• Epidemiological studies suggest that genetic factors account for 30% of blood pressure variations in populations .
• The prevalence of hypertension in patients with family history is almost double than those with no family history.
• Examples of genetic hypertension where specific genetic mutations were identified include, but are not limited to, some forms of primary hyperaldosteronism, pseudohyperaldosteronism, Liddle Syndrome, and syndrome of apparent mineralocorticoid excess.

• Inherited cardiovascular risk factors must not be overlooked in the pathogenesis of hypertension .
• Gene therapy may be a promising novel therapeutic approach to treat hypertension .