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

Therapeutic inhibition of angiotensin II: In human heart failure, spec ific inhibition of the cardiac effects of angiotensin II in addition t o inhibition of the circulating renin-angiotensin system is an importa nt therapeutic goal. Angiotensin II receptor subtype 1 (AT(1)) antagon ists have been developed to specifically and selectively block the AT( 1) receptor and provide a more complete blockade of angiotensin II pro duction with a marked improvement in side effects. Results of clinical studies: Clinical studies have shown beneficial effects from AT(1) re ceptor antagonists. In a single dose study in patients with heart fail ure, the AT(1) antagonist losartan decreased mean arterial pressure an d pulmonary arterial pressure and increased the cardiac index, with ma ximal effects at 25 mg/day. The administration of losartan for 12 week s also produced favorable hemodynamic and clinical results. The neuroh ormonal effects of AT(1) receptor antagonists lead to decreases in pla sma 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 ant agonists in human hearts are determined by angiotensin receptor subtyp es, their localization and regulation. We found that the receptor subt ype AT(2) represents the dominant receptor in normal and failing human myocardium. Angiotensin Il receptors were found on isolated human car diac fibroblasts where angiotensin II stimulated cellular proliferatio n 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) re ceptor antagonist losartan led to a downregulation of angiotensin If r eceptors in the liver, kidney, adrenal cortex and medulla. Downregulat ion of these receptors may represent an important mechanism by which A T(1) receptor antagonists and angiotensin converting enzyme (ACE) inhi bitors act to inhibit the renin-angiotensin system. Conclusions: AT(1) receptor antagonists may inhibit the formation of plasma and tissue a ngiotensin II in heart failure to some extent. They may act synergisti cally with ACE inhibitors to inhibit renin-angiotensin systems complet ely. However, more basic data are needed to understand the effects, pa rticularly in human myocardium.