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3. Renin-angiotensin system activity - Renin, a proteolytic enzyme, is secreted by the juxtaglomerular cells surrounding afferent arterioles in response to a number of stimuli, including reduced renal perfusion pressure, diminished intravascular volume, circulating catecholamines, increased sympathetic nervous system activity, increased arteriolar stretch, and hypokalemia. Plasma renin levels are classified in relation to dietary sodium intake or urinary sodium excretion.

Renin acts on angiotensinogen to cleave off the ten-amino-acid peptide angiotensin I. This peptide is then acted upon by angiotensin-converting enzyme (ACE) to create the eight-amino-acid peptide angiotensin II, a potent vasoconstrictor and a major stimulant of aldosterone release from the adrenal glands. The incidence of hypertension and its complications may be increased in individuals with the DD genotype of the allele coding for ACE. Despite the role of this system in the regulation of blood pressure, it probably does not play a central role in the pathogenesis of most primary (essential) hypertension; although approximately 10% of patients have high levels, 60% have normal levels, and 30% have low levels. Black persons with hypertension and older patients tend to have lower plasma renin activity, which may be associated with expanded intravascular volume.

4. Defect in natriuresis - Normal individuals increase their renal sodium excretion in response to elevations in arterial pressure and to a sodium or volume load. Hypertensive patients, particularly when their blood pressure is controlled, exhibit a diminished ability to excrete a sodium load. This defect may result in increased plasma volume and hypertension. During chronic hypertension, a sodium load is usually handled normally.

5. Intracellular sodium and calcium - Intracellular Na+ is elevated in blood cells and other tissues in primary (essential) hypertension. This may result from abnormalities in Na+-K+ exchange and other Na+ transport mechanisms. An increase in intracellular Na+ may lead to increased intracellular Ca2+ concentrations as a result of facilitated exchange and might explain the increase in vascular smooth muscle tone that is characteristic of established hypertension.

6. Exacerbating factors - A number of conditions elevate blood pressure, especially in predisposed individuals. Obesity is associated with an increase in intravascular volume and an elevated cardiac output. Weight reduction lowers blood pressure modestly. The relationship between sodium intake and hypertension remains controversial, and some - not all - persons with hypertension respond to high salt intake with substantial increases in blood pressure. Patients with high normal or elevated blood pressures should consume no more than 100 mmol/d of salt (2.4 g of sodium, 6 g of sodium chloride daily).

Excessive use of alcohol also raises blood pressure, perhaps by increasing plasma catecholamines. Hypertension can be difficult to control in patients who consume more than 40 g of ethanol (two drinks) daily or drink in "binges." Cigarette smoking raises blood pressure, again by increasing plasma norepinephrine. Although the long-term effect of smoking on blood pressure is less clear, the synergistic effects of smoking and high blood pressure on cardiovascular risk are well documented. The relationship of exercise to hypertension is variable. Aerobic exercise lowers blood pressure in previously sedentary individuals, but increasingly strenuous exercise in already active subjects has less effect. The relationship between stress and hypertension is not established. Polycythemia, whether primary or due to diminished plasma volume, increases blood viscosity and may raise blood pressure. Nonsteroidal anti-inflammatory drugs (NSAIDs) produce increases in blood pressure averaging 5 mm Hg and are best avoided in patients with borderline or elevated blood pressures. Low potassium intake is associated with higher blood pressure in some patients; an intake of 90 mmol/d is recommended.

There is a growing recognition that the complex of abnormalities termed the "metabolic syndrome" is associated with both the development of hypertension and an increased risk of adverse cardiovascular outcomes. The metabolic syndrome (sometimes also called syndrome X or the "deadly quartet") consists of upper body obesity, hyperinsulinemia and insulin resistance, hypertriglyceridemia, and hypertension. Affected patients usually also have low high-density lipoprotein (HDL) cholesterol levels and have been found to have elevated catecholamines and inflammatory markers such as C-reactive protein. Patients with hypertension should be encouraged to follow the lifestyle changes listed in Table 11-2.

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* Chobanian AV, Bakris GL, Black HR, et al. Seventh report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure. Hypertension. 2003;42(6):1206-52. [Medline].