Recognizing and treating two types of long-term vasoconstriction in hypertension.
Long considered a single clinical entity, essential hypertension is now recognized as a heterogeneous spectrum of pathophysiologic disturbances, based on extensive clinical, pharmacologic and biochemical evidence. Two distinctly different mechanisms for long-term vasoconstriction can be identified and quantified in the spectrum of patients with essential hypertension, although the causes of this group of disorders are still obscure. The first vasoconstrictor mechanism is renin-angiotensin mediated and involves an increase in vascular smooth muscle cytosolic free calcium mobilized from intracellular sites. The degree of activity of this mechanism can be assessed by plasma renin level and/or by the hypotensive response to circulating anti-renin-system drugs (such as CEI inhibitors and beta blockers). The second vasoconstrictor mechanism, on the other hand, is renin-independent. It appears to require antecedent renal sodium retention and to be related to abnormal membrane influx of calcium. A low plasma renin level identifies this kind of vasoconstriction, which is also characterized by a low serum ionized calcium. Low-renin vasoconstriction is correctable by sodium depletion or by calcium channel or alpha adrenergic blockade. Depending on the state of sodium balance, these two vasoconstrictor mechanisms contribute reciprocally to maintenance of arteriolar tone in models of experimental hypertension, normotensive and hypertensive people, and in the vasoconstriction of edematous states, such as congestive heart failure. One of the two mechanisms also sustains diastolic hypertension in the experimental and clinical forms of renovascular hypertension and primary aldosteronism. Thus, both experimentally and clinically, at the polar extremes of the range of plasma renin values, one of the two mechanisms predominates: it is possible that, in the medium range of renin values, both mechanisms contribute to vasoconstriction. In our proposed unifying, analytic model, arteriolar vasoconstriction is associated with increased intracellular calcium and decreased magnesium levels in vascular smooth muscle. In the vasoconstriction consequent to sodium-volume expansion, cytosolic calcium is increased by an increased membrane influx. In renin-mediated vasoconstriction, receptor-operated channels mobilize cytosolic calcium instead from intracellular stores. These interrelationships provide a basis for stratifying hypertensive patients pathophysiologically and for applying simpler, more specific, and more rational therapies. Thus, the array of modern pharmacologic agents can often be rationally directed at one or the other, or both, of these two vasoconstrictor mechanisms.