Changes in tissue lactate, ATP, and cytosolic free calcium (Cai) were examined in isolated, perfused rat hearts receiving 20 min of zero-flow global ischemia (37 degrees C). Addition of diltiazem before ischemia caused a concentration-dependent decrease in lactate accumulation. This effect was not mediated by modulation of norepinephrine release since depletion of catecholamines by reserpine did not alter lactate accumulation, and diltiazem treatment reduced lactate accumulation in catecholamine-depleted hearts. Diltiazem-treated hearts showed a concentration-dependent decrease in tissue ATP utilization that was associated with the decrease in tissue lactate during ischemia. Basal time averaged Cai, determined by fluorine NMR using 5FBAPTA, was 620 nM. Diltiazem (0.9 microM) decreased this value to 489 nM and reduced heart rate and maximum pressure developed (81.3 and 53.9% of control, respectively) before ischemia. Cai increased fourfold between 9 and 15 min of ischemia in hearts receiving no drug, while there was no increase in Cai in diltiazem-treated hearts. These results show that diltiazem reduces the use of ATP and therefore production of lactate during ischemia, and indicate a relationship between preservation of ATP and maintenance of Cai that may be important in the beneficial effects of diltiazem during myocardial ischemia.