We investigated the effects of diltiazem cardioplegia on myocardial function and infarct size in the region of the left anterior descending artery after acute occlusion and reperfusion during cardiopulmonary bypass. Sheep (30 kg) were subjected to 1 hour of regional myocardial ischemia by occlusion of the left anterior descending artery and assigned to a control (n = 8) or experimental group (n = 5). Control animals were placed on cardiopulmonary bypass and the heart arrested with potassium cardioplegia. The left anterior descending artery was released and two additional doses of 100 ml of cardioplegic solution were infused during the total cross-clamp time of 30 minutes. The animals were then weaned from bypass after 1 hour and beating, working reperfusion maintained for an additional 4 hours. The experimental group followed the same protocol except that the cardioplegic solution contained diltiazem (1.4 mg/L). Segmental myocardial function was determined by pairs of ultrasonic crystals in the area at risk, control segment, and minor axis. Global contractility was determined from maximum derivative of left ventricular pressure and cardiac output. The area at risk was determined by injecting monastral blue dye into the left atrium with the left anterior descending artery briefly reoccluded, and the area of necrosis was determined by measuring with a planimeter non-triphenyltetrazolium chloride stained areas in the sectioned left ventricle. After 5 hours of reperfusion, not only did the diltiazem group demonstrate better global contractility as defined by the derivative of left ventricular pressure (1853 +/- 292 versus 979 +/- 191, p = 0.05) but, in addition, the systolic shortening in the ischemic area improved significantly when compared with the control group (9.4 +/- 4 versus 2.13 +/- 0.77, p = 0.05). The group receiving diltiazem cardioplegia had an area of necrosis to area at risk ratio of 31.4% +/- 3%, which was significantly better than this ratio in the control group of 60.75% +/- 7% (p = 0.01). Diltiazem cardioplegia results in improved global and segmental contractility and limits the infarct size after occlusion of the left anterior descending artery and surgical reperfusion.