In vivo pharmacology of an angiotensin AT1 receptor antagonist with balanced affinity for angiotensin AT2 receptors

Abstract L-163,017 (6-[benzoylamino]-7-methyl-2-propyl-3-[(2′-( N -(3-methyl-1-butoxy)carbonylaminosulfonyl)[1,1′]-biphenyl-4-yl]-methyl]-3 H -imidazo-[4,5- b ] is a potent, orally active, nonpeptide angiotensin II receptor antagonist. Conscious rats and dogs were dosed p.o. and i.v.; in both species the plasma bioequivalents are similar at the angiotensin AT 1 and AT 2 receptor sites indicating balanced activity is maintained in vivo. L-163,017 prevents the pressor response to intravenous (i.v.) angiotensin II in the conscious rat, dog, and rhesus monkey. L-163,017 also significantly reduces blood pressure in a renin-dependent model of hypertension, similar to an angiotensin converting enzyme inhibitor (Enalapril) and an angiotensin AT 1 receptor-selective antagonist (L-159,282). These studies indicate that neither the angiotensin AT 2 receptor nor bradykinin is important in the acute antihypertensive activity of angiotensin converting enzyme inhibitors or angiotensin II receptor antagonists.