CHARACTERIZATION OF ANTIHYPERTENSIVE ACTIVITY OF ABBOTT-81988, A NONPEPTIDE ANGIOTENSIN-II ANTAGONIST IN THE RENAL HYPERTENSIVE RAT

N[(2'-[1H-tetrazol-5-yl]biphenyl-4yl)methyl]amino) pyridine-3-carboxyl ic acid (ABBOTT-81988), a novel nonpeptide angiotensin II (AII) antago nist, was evaluated to characterize its antihypertensive activity in t he conscious renal hypertensive rat. Oral or i.v. administration of AB BOTT-81988 at 0.03 to 0.3 mg/kg produced a dose-dependent, sustained d ecrease in mean arterial pressure (MAP; control 162-173 mm Hg, n = 27) of similar to 20 to 70 mm Hg. At a dose of 0.3 mg/kg p.o., ABBOTT-819 88 lowered MAP to a normotensive level for more than 24 hr and did not change heart rate. During its antihypertensive effect (Delta MAP, -28 % similar to-35%), ABBOTT-81988 (0.1-0.3 mg/kg i.v.) decreased total p eripheral resistance (Delta resistance, -31% similar to-43%), and card iac output remained either unchanged or slightly elevated. ABBOTT-8198 8(0.3 mg/kg i.v.) produced an additional antihypertensive effect (Delt a MAP, -12 +/- 2%, n = 5) in captopril-pretreated (10 mg/kg i.v.) hype rtensive rats, but captopril (10 mg/kg i.v.) had no effect in ABBOTT-8 1988-pretreated (0.3 mg/ kg i.v.) rats. In the normotensive rat, ABBOT T-81988 (0.3 mg/ kg p.o.) had no effect on basal MAP, but it inhibited the AII-induced (0.1 mu g/kg i.v.) presser response by 51% to 91% for 24 hr, whereas the responses to norepinephrine (0.3 mu g/kg i.v;), va sopressin (0.03 IU/kg i.v.) and bradykinin (3 mu g/kg i.v.) were not a ffected. It is concluded that ABBOTT-81988 is a safe and efficacious A II antagonist that may have use in the treatment of human hypertension .