Experimental cardiovascular benefits of angiotensin-converting enzyme inhibitors: beyond blood pressure reduction.

In an attempt to separate the cardiac effects of converting-enzyme (CE) inhibition from those on blood pressure, experiments were performed in rats and dogs with nonantihypertensive (subhypotensive) doses of the CE inhibitor ramipril. (a) Left ventricular hypertrophy: Rats with aortic constriction treated with a nonantihypertensive dose of ramipril (10 micrograms/kg/day) for 6 weeks showed the same prevention and regression of cardiac hypertrophy as groups receiving the antihypertensive dose of 1 mg/kg/day. Comparable results were obtained in animals treated for 1 year. (b) Ischemia-reperfusion injuries: In rats, subchronic oral administration of ramipril in a subhypotensive dose (10 micrograms/kg/day) prevented ex vivo postischemic reperfusion arrhythmias and improved cardiodynamic and metabolic parameters. Almost complete inhibition of cardiac CE was achieved with this low dose. (c) Acute myocardial infarction: Ramiprilat (40 ng/kg/min) was infused for 6 h into the left coronary artery of anesthetized dogs with a ligation of the descending branch of this artery. This route and the low dose were chosen to achieve local cardiac effects without affecting systemic hemodynamics. Ramiprilat significantly reduced the infarct area expressed as a percentage of the area at risk. This cardioprotective effect of ramiprilat was mimicked by bradykinin and abolished by coadministration of a bradykinin antagonist. Thus, factors beyond blood pressure reduction and load changes may add to the cardiovascular benefits of CE inhibitors. This may indicate local (cardiac) paracrine and/or autocrine effects of the renin-angiotensin system and/or participation of kinins.