Effects of Diltiazem on Extent of Ultimate Myocardial Injury Resulting from Temporary Coronary Artery Occlusion in Dogs

SUMMARYThe calcium antagonist, diltiazem, was evaluated for its ability to reduce the extent of myocardial injury resulting from 90 min of left circumflex (LCX) coronary artery occlusion in anesthetized dogs. Administration of diltiazem (0.75 mg/kg over 10 min, followed by 600 μg/kg/h for 4 h) was initiated 30 min prior to LCX occlusion. Regional myocardial blood flow (RMBF) was measured with radioactive microspheres 30 min after LCX occlusion, and at 45 min and 24 h after reperfusion. At 24 h, after obtaining hemodynamic and RMBF measurements, excised hearts were processed by perfusion staining to determine the percent of left ventricle (LV) perfused by LCX (area at risk) and infarct size, with triphenyltetrazolium chloride. Infarct size, expressed as a percentage of the area at risk, was significantly lower in the diltiazem-treated group compared to the control group (27 ± 4 vs. 42 ± 5%, respectively). The area at risk, expressed as a percentage of left ventricular mass, was similar in both groups [41 ± 2 and 44 ± 3% (area at risk—LV)]. In addition, the marked elevation of tissue Ca content in noninfarcted and infarcted myocardium within the area at risk (18 ± 2 and 42 ± 8 μmol Ca/g) in control animals was attenuated by diltiazem (6 ± 3 and 18 ± 8 μmol Ca/g). Diltiazem did not increase blood flow to ischemic myocardium during LCX occlusion. However, reflow to the inner layers of formerly ischemic myocardium during reperfusion was significantly greater in diltiazem-treated dogs. Both arterial blood pressure and heart rate were significantly lower in the diltiazem-treated group. In addition, mortality (1 vs. 4) and occurrence of ventricular arrhythmias during reperfusion were lower in diltiazem-treated dogs. The data suggest that diltiazem reduces myocardial ischemic injury by lowering myocardial oxygen demands indirectly via favorable hemodynamic alterations, and directly by limiting transmembrane Ca fluxes during ischemia and reperfusion.