Cardiac arrhythmias are ameliorated by local inhibition of angiotensin formation and bradykinin degradation with the converting-enzyme inhibitor ramipril

Abstract

We investigated the influence of the angiotensin-converting enzyme (ACE) inhibitor ramipril on cardiac arrhythmias in guinea pigs and rats. Ramiprilat, the active moiety of ramipril, did not influence action potentials of isolated guinea-pig papillary muscle or rabbit sinus node, thereby excluding cellular electrophysiological evidence of anti-arrhythmic properties. Ramipril protected against cardiac arrhythmias induced by digoxin infusion in guinea pigs. This effect was comparable with that of lidocaine. In isolated perfused ischemic working rat hearts, angiotensin (ANG) I (3 x 10(-9) M/l) and ANG II (1 x 10(-9) M/l) aggravated reperfusion arrhythmias, accompanied by deterioration of cardiodynamic and metabolic events. Bradykinin (BK) (1 x 10(-10)-1 x 10(-8) M/l), in contrast, protected against reperfusion arrhythmias, which corresponded to an increase in energy-rich phosphates and glycogen stores and a decrease in lactate levels in myocardial tissue. Identical changes were seen in hearts from rats pretreated with ramipril (1 mg/kg PO) or perfused with ramiprilat (2.58 x 10(-7)-2.58 x 10(-5) M/l). Local ACE inhibition in these ischemic hearts antagonized ANG I but not ANG II effects and enhanced BK effects. The BK antagonist D-Arg-(Hyp2, Thi5,8, D-Phe7)BK abolished the beneficial effects of BK, ramipril, and ramiprilat. Increased concentrations of BK or ramiprilat were able to reverse the antagonism. The antiarrhythmic agent nicainoprol, a fast-sodium-channel blocking drug (class Ib), also protected isolated rat hearts against reperfusion arrhythmias, but was without beneficial effects on cardiac hemodynamics and biochemical parameters, in contrast to the ACE inhibitor. These results suggest that the beneficial effects of the ACE inhibitor ramipril on digoxin and reperfusion arrhythmias are not mediated by their direct actions on ionic channels in the cell membrane. It seems that other factors are responsible for its beneficial effects on reperfusion arrhythmias, cardiac function, and metabolism, which are associated with a reduction in ANG II generation and BK degradation by local ACE inhibition in the heart.