Using an isolated rat heart preparation as a model of cardiopulmonary bypass and ischemic arrest, the effects of the addition of the calcium antagonist, diltiazem, to St. Thomas' cardioplegic Solution were investigated. Under conditions of normothermic ischemic arrest (37 ° C, 35 min), the addition of diltiazem improved the protective properties of the St. Thomas' cardioplegic Solution. Moreover, studies with varying concentrations produced a bell-shaped dose-response curve for diltiazem with its optimal concentration at 0.5 μmoles/Iiter (0.21 mg/liter) when postischemic recovery of aortic flow was improved from 53.2 ± 4.3% to 79.2 ± 4.4% (p<0.01) and postischemic creatine kinase leakage was reduced by approximately 40%. Despite this marked additional protection when ischemic arrest was normothermic, diltiazem afforded no improvement in protection under conditions of hypothermic (20 °C, 180 min) ischemic arrest.