The beneficial effect of a calcium channel blocker, Diltiazem, on the ischemic-reperfused heart

Diltiazem-HCl,^® a potent calcium channel blocker, was found to be effective in moderating the harmful effects of reperfusion on the severely ischemic myocardium. In isolated working rat heart preparations it was found that 120 min of global ischemia followed by 15 min of reperfusion resulted in a massive leakage of creatine phosphokinase into the coronary effluent, and in many cases, in fibrillation and/or contracture. Left ventricular end-diastolic pressure increased sharply during reperfusion in these hearts. Reperfusion did not affect tissue ATP levels, but did increase creatine phosphate somewhat. When Diltiazem was added to the perfusate (final concentration 0.4 μm) 5 min prior to re-establishment of flow, the deleterious effects of reperfusion were greatly reduced. None of the hearts fibrillated on reperfusion, and none developed contracture. Left-ventricular end-diastolic pressure was increased only slightly in these hearts. The amount of creatine phosphokinase released into the coronary effluent during re-flow was only one-half that which was released by hearts reperfused in the absence of Diltiazem. In the Diltiazem-treated hearts reperfusion restored creatine phosphate to near-normal levels, although ATP levels were not increased. The beneficial effects of Diltiazem are probably related to its ability to reduce the rapid and massive mitochondrial calcium overloading which normally accompanies reperfusion of severely ischemic myocardium.