CARDIOVASCULAR EFFECTS OF ORALLY-ADMINISTERED ABBOTT-81988, AN ANGIOTENSIN-II ANTAGONIST, IN CONSCIOUS SPONTANEOUSLY HYPERTENSIVE RATS

ABBOTT-81988 (A-81988), propyl-N(2'-[1H-tetrazol-5-yl]biphenyl-4yl)met hyl] amino) pyridine-3-carboxylic acid, a nonpeptide angiotensin II (A II) antagonist was studied in the conscious spontaneously hypertensive rate (SHR) (male, 18 to 21 weeks) for cardiovascular effects of oral administration. Oral A-81988 at 0.3 to 3 mg/kg produced a dose-related 10 to 29% decrease in mean arterial pressure (MAP) in SHR (control, 1 61 to 177 mm Hg; n = 19) for 12 to 24 h without changing heart rate. O ral A-81988 at 3 mg/kg daily maintained MAP in SHR at normotensive lev els (97 to 120 mm Hg) during a 5-day protocol with no rebound hyperten sion at termination of treatment. There was an increase in plasma reni n activity in nanograms AI/milliliter/hour in SHR treated with A-81988 (32 +/- 3, n = 6 v 5 +/- 2, n = 6 for vehicle) during its antihyperte nsive action. The oral potency of A-81988 was enhanced about 10-fold i n furose-mide-treated SHR. The pressor response to AII was inhibited s electively in SHR even after an 8-day treatment with A-81988 (similar to 3 mg/kg/day orally). Total peripheral resistance was lowered and ca rdiac output unchanged in SHR administered A-81988 (3 mg/kg/day orally for 2 days). A-81988 (3 mg/kg orally) did not cause orthostatic hypot ension in SHR. When SHR were given A-81988 at about 3 mg/kg daily for 4 weeks in drinking water, systolic blood pressure (control, 174 +/- 4 mm Hg: n = 6) remained at normotensive levels (similar to 113 to 132 mm Hg) throughout the treatment period, and both the left and right ve ntricular weights were reduced with no alteration in total cholesterol , high and low density lipoprotein cholesterol, and triglycerides. The oral antihypertensive efficacy demonstrated in this study indicates t hat A-81988 should be useful in the treatment of human essential hyper tension.