No abstract

FPL 63547, in its active diacid form, was a potent inhibitor of rabbit lung angiotensin converting enzyme (ACE) in vitro (IC50 0.51 nm). In conscious normotensive dogs, FPL 63547 (10–300 μg kg−1 i.v.) produced prolonged, dose‐related inhibition of plasma ACE activity and angiotensin I pressor responses, without affecting basal blood pressure, heart rate or pressor responses to angiotensin II. In anaesthetized dogs, FPL 63547 diacid (3–300 μg kg−1 i.v. cumulatively) produced dose‐related increases in cardiac output accompanied by falls in total peripheral resistance indicative of vasodilatation. Mild stimulation of cardiac rate and contractility was also observed. Enalapril diacid had a similar profile. FPL 63547 was a highly effective antihypertensive agent after oral administration to spontaneously hypertensive rats (SHR) pretreated with a diuretic. It lowered systolic blood pressure (SBP) on acute administration over the range 3 × 10−7–10−5 mol kg−1 p.o. (⋍ 0.13–4.5 mg kg−1 p.o.). FPL 63547 was more potent than other ACE inhibitors tested, threshold active doses for lisinopril, enalapril and captopril being 10−6, 10−6 and 3 × 10−5 mol kg−1 p.o., respectively. The antihypertensive effects of FPL 63547, unlike those of enalapril and captopril, were of long duration. The antihypertensive efficacy of FPL 63547 was also observed following chronic oral administration. A dose of 0.5 mg kg−1 day−1 once daily for 23 days produced a sustained reduction of SBP. By the end of the treatment period, SBP was significantly lowered both pre‐ and post‐dose, i.e. effective 24 h control had been achieved. The profile of FPL 63547 is consistent with it being a potent, selective and long‐acting ACE inhibitor. As an antihypertensive agent in SHR it compared favourably with other members of this class with respect to potency and duration of action.