In vivo pharmacology of an angiotensin AT(1) receptor antagonist with balanced affinity for angiotensin AT(2) receptors

L-163,017 (6-[benzoylamino]-7-methyl-2-propyl-3-[[2'-(N-(3-methyl-1-butoxy)carbonylaminosulfonyl)[1,1]-biphenyl-4-yl]-methyl]-3H-imidazo[4,5-b]pyridine) 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, and AT, receptor sites indicating balanced activity is maintained in vivo. L-163,017 prevents the presser 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, 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.