Use of angiotensin II antagonists in human heart failure: function of the subtype 1 receptor


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Abstract

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 (AT1) antagonists have been developed to specifically and selectively block the AT1 receptor and provide a more complete blockade of angiotensin II production with a marked improvement in side effectsResults of clinical studies:Clinical studies have shown beneficial effects from AT1 receptor antagonists. In a single dose study in patients with heart failure, the AT1 antagonist losartan decreased mean arterial pressure and pulmonary arterial pressure and increased the cardiac index, with maximal effects at 25mg/day. The administration of losartan for 12 weeks also produced favorable hemodynamic and clinical results. The neurohormonal effects of AT1 receptor antagonists lead to decreases in plasma norepinephrine, aldosterone and atrial natriuretic peptide and an increase in plasma angiotensin II levelsEffect of receptor subtype:The direct myocardial effects of angiotensin II and AT} receptor antagonists in human hearts are determined by angiotensin receptor subtypes, their localization and regulation. We found that the receptor subtype AT2 represents the dominant receptor in normal and failing human myocardium. Angiotensin II 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 AT1 receptor antagonist losartan led to a downregulation of angiotensin II receptors in the liver, kidney, adrenal cortex and medulla. Downregulation of these receptors may represent an important mechanism by which AT1 receptor antagonists and angiotensin converting enzyme (ACE) inhibitors act to inhibit the renin-angiotensin systemConclusions:AT1 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

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