Cardiac and renovascular effects in the anaesthetized dog of BW A575C: a novel angiotensin converting enzyme inhibitor with beta-adrenoceptor blocking properties

Abstract

1. In the anaesthetized open-chest dog, BW A575C (N-(1-(S)-carboxy-5-[4(3- isopropylamino-2-(R,S)-hydroxypropoxy)indole-2- carboxamido]pentyl)-(R,S)-alanyl-(S)-proline) causes a dose-dependent inhibition of the isoprenaline response (increased cardiac rate). In this preparation BW A575C is approximately 50 times less active than propranolol, and 500 times less active than pindolol at the cardiac beta 1-adrenoceptor. 2. At equieffective cardiac beta 1-adrenoceptor blocking doses in the anaesthetized, open-chest dog, BW A575C (5.0 mg kg-1, i.v.) significantly reduces diastolic blood pressure and reduces cardiac contractility and rate. By contrast, propranolol (0.1 mg kg-1, i.v.) and pindolol (0.01 mg kg-1, i.v.) have little effect on diastolic blood pressure, but significantly reduce cardiac contractility and rate. The effects of BW A575C on cardiac rate are not significantly different from those of propranolol and pindolol, but its effects on cardiac contractility are significantly less than those of propranolol. BW A575C also produces some increase in left ventricular internal dimensions at end-diastole. This small cardiac dilatation is not significantly different from that observed with pindolol but is significantly less than that of propranolol. 3. In the anaesthetized closed-chest dog, BW A575C causes a dose-dependent inhibition of the angiotensin I pressor response. In this preparation BW A575C is approximately equiactive with enalapril at preventing the pressor response due to conversion of exogenous angiotensin I to angiotensin II (inhibition of angiotensin converting enzyme (ACE)). 4. At equieffective ACE-inhibition doses in the anaesthetized, closed-chest dog, BW A575C (1.0 mg kg-1 by i.v. infusion) significantly reduces diastolic blood pressure, cardiac contractility and rate, whereas enalapril (1.0 mg kg-1 by i.v. infusion) only significantly reduces diastolic blood pressure. This blood pressure lowering effect of enalapril is not significantly different from that of BW A575C. In this preparation BW A575C and enalapril also significantly increase renal blood flow, and renal excretion of urine and Na+. There is however no significant difference between their renovascular effects. 5. These studies demonstrate that BW A575C produces changes in cardiac and renovascular function which can be ascribed to its being an ACE-inhibitor and a beta-adrenoceptor blocking agent. The combination of these pharmacological properties results in a fall in blood pressure without compromising either cardiac performance or renal function.