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.