We determined the effect of the calcium antagonistic agent, diltiazem hydrochloride upon ischemia-reperfusion injury in the dog. Ischemia was produced by occluding the left anterior descending artery for 40 min. Subsequent reperfusion was accomplished for 120 min by virtue of removal of the occlusion. Sixteen of the dogs studied were randomly assigned to diltiazem (D)-treated group (n = 8) and saline (S)-treated group (n = 8). D in saline was intravenously infused at a concentration of 3 mcq/kg/min starting 15 min after the occlusion. Myocardial blood flow (MBF) was measured using hydrogen gas clearance method. Infarct size was quantified as percent myocardium at risk by triphenyltetrazolium chloride staining. D administration caused a slight decline in mean aortic pressure, heart rate, and heart rate X systolic blood pressure throughout the periods of occlusion and reperfusion. However, there was no significant difference observed in both groups of dogs. MBF to ischemic myocardium was not significantly enhanced by D during ischemia. After 5 min of reperfusion subepicardial MBF was increased in group S, indicating a tendency towards reactive hyperemia. After 120 min of reperfusion there was a significant reduction in subendocardial MBF in group S and the transmural blood flow ratio was 1.23 +/- 0.59 in group D as compared with 0.53 +/- 0.39 in group S (p less than 0.05). The infarcted area as a percentage of the risk area was considerably smaller in group D than in group S (27.5 +/- 3.0 vs 47.0 +/- 6.5%, p less than 0.05). D markedly reduced the elevation of tissue calcium especially in the subendocardium. These findings suggest that D reduces the ultimate infarct size through the beneficial effect on ischemia-reperfusion injury.