Angiotensin receptors: Physiology and pharmacology

The renin‐angiotensin system is critical for regulating extracellular fluid volume and blood pressure. Angiotensin II, the active peptide hormone produced by the renin enzymatic cascade, sustains vascular volume and blood pressure by constricting vessels, stimulating adrenal aldosterone secretion, increasing renal tubular sodium absorption, activating the sympathetic nervous system, and increasing cardiac contractility. These actions are a disability in the pathophysiologic states of hypertension and congestive heart failure (CHF), however, since reactive increases in renal renin and angiotensin II stimulate sympathetic activity and renal sodium retention, leading consequently to circulatory volume overload. The actions of angiotensin II are mediated by its interactions with specific cell‐surface angiotensin II receptors, namely, AT 1 and AT 2 ; most cardiovascular actions of angiotensin II come from its interaction with the AT 1 receptor. Angiotensin‐converting enzyme (ACE) inhibitors and angiotensin‐II‐receptor blockers antagonize the actions of the reninangiotensin axis, neutralizing its effects on hypertension and heart failure. Losartan is the first oral, nonpeptide, selective AT 1 ‐receptor blocker to be approved. Clinical trials show it to be effective and well tolerated as therapy for hypertension and CHF. Data obtained thus far suggest ACE inhibitors and AT 1 ‐receptor blockers have similar efficacy for treating these conditions, but the receptor blockers appear to produce fewer adverse effects. Whether the sustained increase in angiotensin II concentrations after AT 1 ‐receptor antagonism produces deleterious effects is not known. The concern is that these high levels may stimulate unblocked AT 2 receptors; the effect of that stimulation may not be important, however.