The cardioprotective effects of lidoflazine, a drug with calcium homeostatic properties, were investigated in dogs subjected to 1 hour of normothermic global ischemia, followed by reperfusion. None of the eight control dogs could be weaned from the extracorporeal bypass, confirming the severity of the ischemic model. All eight acutely pretreated dogs showed rapid recovery from the prolonged ischemic arrest and could support their own circulation. Recovery of preischemic values was 95% for systolic aortic pressure, 71% for diastolic aortic pressure, 99% for left ventricular dP/dt max and 80% for cardiac output. Light and electron microscopy and calcium cytochemistry were performed on left ventricular biopsies taken before, during and after ischemic arrest. In the control dogs, loss of structural integrity of the sarcolemma and mitochondria was prominent at the end of the ischemic period. Intracellular edema, hypercontraction of sarcomeres and great accumulation of calcium in severely damaged mitochondria occurred after 5 and 30 minutes of reperfusion. In the lidoflazine-treated dogs, such lesions were largely prevented during the ischemic period and completely reversed after reperfusion. These observations suggest that the tolerance of ischemia is markedly augmented by lidoflazine.