BW A575C: pharmacological profile in vivo of a novel angiotensin converting enzyme inhibitor and beta-blocker.
The novel compound BW A575C, N-(1-(S)-carboxy-5-[4-(3-isopropylamino-2-(R,S)-hydroxypropoxy)-indole-2 - carboxamido]pentyl)-(R,S)-alanyl-(S)-proline, is a potent angiotensin converting enzyme (ACE) inhibitor and beta-blocker in vitro. It was therefore of considerable interest to establish whether this novel pharmacological profile was maintained in vivo. In conscious instrumented normotensive rats and dogs, intravenous and oral administration of BW A575C causes a dose-dependent rightward displacement of the pressor dose-response curve to angiotensin I (dose ratio of 29.5 and 16.1 in rats and dogs, respectively, at 1.0 mg/kg i.v.) and the tachycardia dose-response curve to isoprenaline (dose ratio of 3.1 and 8.0 in rats and dogs, respectively, at 1.0 mg/kg i.v.). In these experiments BW A575C is approximately 2-10 times more active as an ACE inhibitor than as a beta-blocker. In conscious instrumented acute renovascular hypertensive dogs, where plasma renin activity is elevated 10-fold, BW A575C (1.0 mg/kg i.v.) causes a reduction in blood pressure of 35% within 10 min of injection, which is sustained for up to 4 h. This reduction in blood pressure is accompanied by a consistent, but nonsignificant, reduction in heart rate. These results confirm the novel pharmacological profile of BW A575C in vivo and demonstrate that this compound is an effective antihypertensive agent in a renin-dependent model of hypertension.
Cambridge
D
D
Department of Pharmacology, Wellcome Research Laboratories, Beckenham, Kent, England.
Allan
G
G
Hardy
G W
GW
Follenfant
M J
MJ
Ford
A
A
Oliver
P L
PL
D000319:Adrenergic beta-Antagonists / Q000494:pharmacology*; D000803:Angiotensin I / Q000494:pharmacology; D000806:Angiotensin-Converting Enzyme Inhibitors / Q000494:pharmacology*; D000818:Animals; D001794:Blood Pressure / Q000187:drug effects; D004285:Dogs; D006339:Heart Rate / Q000187:drug effects; D006978:Hypertension, Renovascular / Q000188:drug therapy / Q000503:physiopathology; D007211:Indoles / Q000494:pharmacology*; D007545:Isoproterenol / Q000494:pharmacology; D008297:Male; D011412:Propanolamines / Q000494:pharmacology*; D051381:Rats; D011919:Rats, Inbred Strains
D000319:Adrenergic beta-Antagonists; D000806:Angiotensin-Converting Enzyme Inhibitors; D007211:Indoles; D011412:Propanolamines; C055304:BW-A 575C; D000803:Angiotensin I; D007545:Isoproterenol