Protective effects on isolated hearts with developing infarction: Slow channel blockade by diltiazem versus beta-adrenoceptor antagonism by metoprolol

Abstract

Slow channel inhibitors (calcium antagonists) and beta-adrenoceptor antagonists may theoretically protect the infarcting myocardium by different mechanisms. Thus, beta-receptor antagonism reduces the oxygen demand by the combined effects of bradycardia, decreased arterial pressure, and reduced contractility, whereas slow channel inhibition chiefly increases coronary blood flow and decreases the afterload by peripheral vasodilation. The present study was designed to assess and compare the effects of the beta-receptor antagonist metoprolol with those of the calcium channel inhibitor diltiazem on cellular damage and mechanical function in the isolated working rat heart subject to coronary artery ligation. We compared the highest concentrations of both agents that could be tolerated in this preparation: diltiazem 4 × 10 − 7 M and metoprolol 10 −4 M. These concentrations were equally effective in reducing enzyme release, which was taken as an index of cellular damage, and in preserving high energy phosphate contents in the infarcting myocardium. However, the 2 agents exhibited opposite effects on coronary flow rates and mechanical function. Compared with diltiazem metoprolol reduced total coronary flow, cardiac output, and left ventricular work and efficiency immediately after coronary artery ligation. However, diltiazem even favorably influenced the mechanical performance of the isolated heart compared with that of untreated control hearts during the 60 minutes of regional myocardial ischemia. These benefits were similarly apparent when the hearts were paced to the rate of control hearts. The presumed mechanism was coronary vasodilation, because afterload increased as left ventricular power production increased in this model. These results suggest that slow channel inhibition by diltiazem has advantages over beta-receptor antagonism by metoprolol in protecting the infarcting myocardium and that further evaluation of diltiazem in other preparations is warranted.