USE OF ANGIOTENSIN-II ANTAGONISTS IN HUMAN HEART-FAILURE - FUNCTION OF THE SUBTYPE-1 RECEPTOR

Therapeutic inhibition of angiotensin II: In human heart failure, specific inhibition of the cardiac effects of angiotensin II in addition to inhibition of the circulating renin-angiotensin system is an important therapeutic goal. Angiotensin II receptor subtype 1 (AT(1)) antagonists have been developed to specifically and selectively block the AT(1) receptor and provide a more complete blockade of angiotensin II production with a marked improvement in side effects. Results of clinical studies: Clinical studies have shown beneficial effects from AT(1) receptor antagonists. In a single dose study in patients with heart failure, the AT(1) antagonist losartan decreased mean arterial pressure and pulmonary arterial pressure and increased the cardiac index, with maximal effects at 25 mg/day. The administration of losartan for 12 weeks also produced favorable hemodynamic and clinical results. The neurohormonal effects of AT(1) receptor antagonists lead to decreases in plasma norepinephrine, aldosterone and atrial natriuretic peptide and an increase in plasma angiotensin II levels. Effect of receptor subtype: The direct myocardial effects of angiotensin II and AT(1) receptor antagonists in human hearts are determined by angiotensin receptor subtypes, their localization and regulation. We found that the receptor subtype AT(2) represents the dominant receptor in normal and failing human myocardium. Angiotensin Il receptors were found on isolated human cardiac fibroblasts where angiotensin II stimulated cellular proliferation via an as yet undetermined subtype. In end-stage human heart failure, angiotensin II receptors are characteristically downregulated at the protein and messenger RNA level. In a chronic rat model, the AT(1) receptor antagonist losartan led to a downregulation of angiotensin If receptors in the liver, kidney, adrenal cortex and medulla. Downregulation of these receptors may represent an important mechanism by which AT(1) receptor antagonists and angiotensin converting enzyme (ACE) inhibitors act to inhibit the renin-angiotensin system. Conclusions: AT(1) receptor antagonists may inhibit the formation of plasma and tissue angiotensin II in heart failure to some extent. They may act synergistically with ACE inhibitors to inhibit renin-angiotensin systems completely. However, more basic data are needed to understand the effects, particularly in human myocardium.