In an effort to determine whether the beneficial effect of calcium blocking drugs occurs only during ischemia or during reperfusion as well, anesthetized dogs were subjected to 3 hours of occlusion of the left anterior descending coronary artery followed by 3 hours of reperfusion. In protocol A, intracoronary verapamil (0.01 mg/kg/min) was begun 90 minutes after coronary occlusion and continued for 1 hour into the reperfusion phase (n = 6) while a control group received an infusion of saline solution (n = 6). In vivo area at risk determined by dye injection was 29 +/- 3% of the left ventricle (+/- standard error of the mean) in the control group and 30 +/- 3% in the verapamil group (difference not significant [NS]), whereas the area of necrosis determined by triphenyltetrazolium staining and expressed as a percent of area at risk was smaller in the verapamil group (29 +/- 8%) than in the control group (57 +/- 8%, p less than 0.05). In protocol B, verapamil infusion into the left anterior descending coronary was begun 5 minutes before blood reperfusion and continued throughout the 3-hour reperfusion phase. Area at risk was similar in both groups (control, 25 +/- 1%, n = 8; verapamil, 28 +/- 2%, n = 8, NS); area of necrosis expressed as a percentage of area at risk was 49 +/- 6% in the control group and 45 +/- 10% in the verapamil group (NS). Therefore, calcium blockade of ischemic myocytes delays death and enhances salvage produced by reperfusion. However, calcium blockade begun after prolonged coronary occlusion does not enhance reperfusion-induced myocardial salvage.