Cardiovascular effects of orally administered ABBOTT-81988, an angiotensin II antagonist, in conscious spontaneously hypertensive rats.
ABBOTT-81988 (A-81988), 2-(N-propyl-N[(2'-[1H-tetrazol-5-yl]biphenyl- 4yl)methyl] amino) pyridine-3-carboxylic acid, a nonpeptide angiotensin II (AII) 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, 161 to 177 mm Hg; n = 19) for 12 to 24 h without changing heart rate. Oral A-81988 at 3 mg/kg daily maintained MAP in SHR at normotensive levels (97 to 120 mm Hg) during a 5-day protocol with no rebound hypertension at termination of treatment. There was an increase in plasma renin 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 antihypertensive action. The oral potency of A-81988 was enhanced about 10-fold in furosemide-treated SHR. The pressor response to AII was inhibited selectively in SHR even after an 8-day treatment with A-81988 (approximately 3 mg/kg/day orally). Total peripheral resistance was lowered and cardiac 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 hypotension in SHR.(ABSTRACT TRUNCATED AT 250 WORDS)
Lee
J Y
JY
Pharmaceutical Products Division, Abbott Laboratories, Abbott Park, Illinois 60064.
Warner
R B
RB
Brune
M E
ME
Adler
A L
AL
Winn
M
M
De
B
B
Zydowsky
T M
TM
Opgenorth
T J
TJ
Kerkman
D J
DJ
DeBernardis
J F
JF
D000284:Administration, Oral; D000804:Angiotensin II / Q000037:antagonists & inhibitors*; D000818:Animals; D000959:Antihypertensive Agents / Q000008:administration & dosage / Q000494:pharmacology*; D001794:Blood Pressure / Q000187:drug effects; D006339:Heart Rate / Q000187:drug effects; D006439:Hemodynamics / Q000187:drug effects*; D006973:Hypertension / Q000188:drug therapy*; D008297:Male; D009539:Nicotinic Acids / Q000008:administration & dosage / Q000494:pharmacology*; D051381:Rats; D011918:Rats, Inbred SHR; D013777:Tetrazoles / Q000008:administration & dosage / Q000494:pharmacology*
D000959:Antihypertensive Agents; D009539:Nicotinic Acids; D013777:Tetrazoles; D000804:Angiotensin II; C081174:A 81988