To examine the effects of diltiazem on myocardial ischemia, 200 micrograms/kg of diltiazem were injected intravenously into anesthetized open-chest mongrel dogs 10 min after coronary ligation. This was followed by a continuous infusion of diltiazem at 10 micrograms/kg/min for 50 min. Regional myocardial blood flow (MBF) was measured by the hydrogen gas clearance method. Sixty minutes after ligation, myocardial specimens were taken from the areas where MBF was measured, and the ATP and CP contents were determined by the bioluminescence method. Simultaneously, mitochondria were isolated from the ischemic and nonischemic areas, and both the respiratory control index (RCI) and the rate of oxygen consumption in state III (QO2 III) were calculated. The aortic systolic pressure and heart rate of diltiazem treated and untreated dogs were not significantly different, and diltiazem did not increase the MBF in the area with a MBF below 40 ml/min/100 g. When MBF was 10 to 30 ml/min/100 g, the ATP content in the diltiazem treated hearts was significantly higher than that in the untreated dogs, whereas the CP content was not significantly changed. Thus, diltiazem administered after ischemia preserved ATP content in the ischemic myocardium with a MBF of 10 to 30 ml/min/100 g without significantly affecting the hemodynamics or MBF. This suggests that diltiazem exerts a cardioprotective effect by acting directly on the ischemic myocardium if it has an MBF above a certain level, even when the drug is administered after the onset of ischemia.