This investigation was undertaken to define the mechanism by which diltiazem protects against life-threatening, reperfusion-induced arrhythmias. Using an isolated retrogressively perfused rat heart preparation with transient coronary artery occlusion, we compared the effects of diltiazem in its active form (d-cis) to its stereo-isomer (1-cis). Pre-ischemic administration of d-diltiazem (5 x 10(-8), 5 x 10(-7), 5 x 10(-6) M) caused a dose-dependent reduction in ventricular arrhythmias upon reperfusion following 10 min of regional ischemia. The incidence of reperfusion-induced ventricular fibrillation (RVF) was 50%, 0% (p less than 0.05) and 0% (p less than 0.05) with 5 x 10(-8), 5 x 10(-7), 5 x 10(-6) M diltiazem, respectively, compared with 60% in the control group. Preischemic administration of the 1-isomer caused different dose-dependent reduction in RVF. With 5 x 10(-6) M, the 1-isomer also reduced the incidence of RVF to 0% (p less than 0.05). However below this concentration it was ineffective (67%). D-diltiazem (5 x 10(-7) and 5 x 10(-6) M) increased coronary flow from 11.5 +/- 1.9 ml/min to 15.3 +/- 1.6 ml/min (p less than 0.05) and 15.2 +/- 1.0 ml/min (p less than 0.05) respectively, prior to ischemia. In contrast, the same dose of the 1-isomer did not alter coronary flow. The highest dose (5 x 10(-6) M) of d-diltiazem decreased heart rate by approximately 30% during the reperfusion phase, but all other concentrations had no significant effects.(ABSTRACT TRUNCATED AT 250 WORDS)