PROTECTIVE EFFECTS OF DILTIAZEM DURING MYOCARDIAL ISCHEMIA IN ISOLATED CAT HEARTS

Abstract

The protective effects of diltiazem, a Ca channel blocker, were studied in isolated, blood-perfused cat hearts subjected to 60 or 90 min of global ischemia, followed by reperfusion for 60 or 120 min, respectively. Ischemia-induced alterations of left ventricular (LV) developed pressure (DP) and compliance, measured with an intraventricular fluid-filled latex balloon, were correlated with respiratory activity in vitro of mitochondria isolated from ischemic-reperfused LV myocardium. Nontreated isolated hearts sustained severe declines of LVDP due to 60 (-50 .+-. 8%) and 90 min (-83 .+-. 7%) of ischemia; diltiazem-treated hearts demonstrated only minor losses of LVDP (-17 .+-. 8 and -26 .+-. 2%). Diltiazem prevented losses of compliance caused by 60 or 90 min of ischemia, which were severe in nontreated hearts after the latter period of ischemia. The progressive deterioration of mechanical function observed in nontreated hearts was paralleled by depressed mitochondrial O2 consumption and respiratory control. The respiratory activity of mitochondria isolated from diltiazem-treated hearts resembled that of control nonischemic cat heart mitochondria. Diltiazem prevented significant elevations of tissue and mitochondrial Ca2+ content, reflecting inhibition of Ca2+ influx during ischemia and reperfusion. Recovery of ATP levels was greater after 60 min each of ischemia and reperfusion in diltiazem-treated hearts. Diltiazem exerts direct, cardioprotective effects during myocardial ischemia, presumably by inhibiting transmembrane Ca2+ fluxes.