Pharmacology of Antagonists of Angiotensin I and II

Abstract

The octapeptide analogues 8-Cys-AII, 8-Ile-AII, 4-Phe-8-Tyr-AII, and p-fluoro-4-Phe-AII were potent competitive antagonists of angiotensin I and II (AI and AII) in rat uterus strips, whereas the decapeptide analogues 4-Phe-8-Tyr-AI and 8-Ile-AI were weak antagonists, 8-Cys-AII and 8-Ile-AII were potent antagonists of the rise in blood pressure induced by angiotensin, although 4-Phe-8-Tyr-AII and p-fluoro-4-Phe-AII were less potent antagonists. AI was rapidly converted and was equipotent to AII in vivo, but 8-Ile-AI was a hundred times less potent than 8-Ile-AII. However, some conversion of 8-Ile-AI did occur, since SQ 20881 (an inhibitor of angiotensin-converting enzyme) markedly diminished the All antagonistic action of 8-Ile-AI. The decapeptides AI, 8-Ile-AI, and 4-Phe-8-Tyr-AI were potent competitive antagonists of the hydrolysis of hippurylhistidylleucine by converting enzyme in vitro. Infusion of the octapeptide and the decapeptide angiotensin analogues resulted in a significant lowering of the blood pressure in anesthetized rats treated with phenoxybenzamine and propranolol and made acutely hypertensive by unclamping a renal pedicle that had been temporarily occluded. The decapeptide analogues, therefore, can function as inhibitors of angiotensin-converting enzyme and simultaneously generate octapeptide antagonists in vivo.