The effectiveness of the calcium entry blocker bepridil in protecting the myocardium from ischemic injury, was assessed in a canine model of regional ischemia and in a feline model of global ischemia. Bepridil administration (5 mg/kg or 15 mg/kg/24 h intravenously) did not reduce ultimate infarct size as assessed in anesthetized, open-chest dogs subjected to 90 min of occlusion of the left circumflex coronary artery and 24 h of reperfusion. Bepridil (5 mg/kg administered intravenously to a blood donor cat) did not provide any protection of the isolated blood-perfused cat heart from 90 min of normothermic global ischemia and 60 min of reperfusion. Treatment of the perfused cat heart with bepridil did not prevent tissue accumulation of calcium or loss of tissue potassium and ATP. Bepridil, however, significantly reduced reperfusion tachyarrhythmias in the dog model for assessing ultimate infarct size and prevented reperfusion-induced ventricular fibrillation of the cat isolated heart. These results indicate that the calcium entry blocker, bepridil, as assessed in the models employed, does not protect the myocardium from ischemic reperfusion injury. However, it does prevent reperfusion-induced tachyarrhythmias and ventricular fibrillation.