Effects of diltiazem (10(-5) M) on the calcium paradox were studied in isolated, perfused rat hearts. After 4 min of calcium-free perfusion, the hearts were reperfused with medium containing 2.5 mM calcium for 15 min at 37 degrees C. During this perfusion, the coronary flow rate was maintained either high (10 ml/min) to produce severe tissue injury of calcium paradox or low (5 ml/min) to produce mild injury. In the high flow rate group, administration of diltiazem during the calcium-free period and calcium-repletion period failed to reduce the overall level of tissue injury caused by calcium-repletion. In the low coronary flow rate group, diltiazem markedly prevented the development of the calcium paradox, in terms of calcium-induced creatine kinase release, recovery of contractile tension development, tissue high-energy phosphate stores and tissue calcium accumulation. These events were irrespective of whether the drug was administered only during the calcium-free period, the calcium-free period and initial 2 min of the calcium-repletion period or the calcium-free period and totality of the calcium-repletion period. Thus, diltiazem appears to exert its protective effect against the mild calcium paradox phenomenon by regulating the ionic environment of myocardial cells during the calcium-free period.