Antihypertensive activity of ABBOTT-81282, a nonpeptide angiotensin II antagonist, in the renal hypertensive rat.
ABBOTT-81282, 4-(N-butyl-N-[(2-'-[1H-tetrazol-5yl]biphenyl-4-yl)methyl]ami no) pyrimidine-5-carboxylic acid is a novel nonpeptide angiotensin II (AII) antagonist. In vivo studies were performed to evaluate ABBOTT-81282 for its antihypertensive effect, pharmacological mechanism(s) of action, and cardiovascular safety. In the conscious renal artery-ligated (RAL) hypertensive rat, a model of high renin hypertension, ABBOTT-81282 (1-10 mg/kg p.o. and 0.1-1.0 mg/kg i.v.) lowered mean arterial pressure (MAP) in a dose-dependent manner with the ED30 values of 2.2 mg/kg for p.o. administration and 0.08 mg/kg for i.v. administration. At 10 mg/kg p.o., ABBOTT-81282 lowered blood pressure in the RAL rat (delta MAP 66 +/- 9 mm Hg from control MAP 167 +/- 7 mm Hg, n = 6) to a normotensive level (MAP, 115 +/- 5 mm Hg) for greater than 24 h and did not change heart rate. The i.v. administration of 1 mg/kg of ABBOTT-81282 also produced a sustained, long-lasting decrease (delta MAP 27-52 mm Hg) in blood pressure that was significantly different from the vehicle group at 8 h postdosing (143 +/- 3 mm Hg, n = 4 for ABBOTT-81282 vs. 181 +/- 3 mm Hg, n = 6 for vehicle group, p < 0.01). When blood pressure in the renal hypertensive rat was maximally lowered (delta MAP 72 +/- 9 mm Hg, n = 4) following the 1 mg/kg i.v. dose (cumulative) of ABBOTT-81282, additional administration of captopril (3 mg/kg i.v.) produced no further decline in blood pressure. In the conscious normotensive rat, 10 mg/kg p.o. of ABBOTT-81282 had no effect on basal MAP (119 +/- 3 vs. 115 +/- 4 mm Hg, pre- vs. 3.5 h postdosing, n = 4) and heart rate (364 +/- 18 vs. 363 +/- 14 beats/min, pre- vs. 3.5 h postdosing, n = 4) but inhibited the AII (0.1 micrograms/kg i.v.)-induced increase in MAP by 64-70%, while the MAP responses to norepinephrine (0.3 micrograms/kg i.v.), vasopressin (0.03 IU/kg i.v.) and bradykinin (3 micrograms/kg i.v.) remained intact. ABBOTT-81282 was also administered to conscious normotensive rats (n = 4) instrumented with ECG telemetry transmitters. At an i.v. dose of 10 mg/kg, which is 125 times greater than the i.v. ED30, ABBOTT-81282 caused a minimal decrease (< 14%) in MAP and had no effect on ECG waveforms. These data demonstrate that ABBOTT-81282 is a safe and efficacious antihypertensive agent with selective AII antagonism.(ABSTRACT TRUNCATED AT 400 WORDS)
Lee
J Y
JY
Pharmaceutical Products Division, Abbott Laboratories, Abbott Park, Ill.
Brune
M E
ME
Warner
R B
RB
Buckner
S B
SB
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 / Q000494:pharmacology / Q000627:therapeutic use*; D001713:Biphenyl Compounds / Q000627:therapeutic use*; D001794:Blood Pressure / Q000187:drug effects; D003243:Consciousness; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004562:Electrocardiography; D006339:Heart Rate / Q000187:drug effects; D006978:Hypertension, Renovascular / Q000188:drug therapy*; D007275:Injections, Intravenous; D008297:Male; D051381:Rats; D017207:Rats, Sprague-Dawley; D012083:Renin / Q000097:blood; D013777:Tetrazoles / Q000627:therapeutic use*
D000959:Antihypertensive Agents; D001713:Biphenyl Compounds; D013777:Tetrazoles; D000804:Angiotensin II; C082984:Abbott 81282; D012083:Renin