The effects of calcium channel antagonists and an agonist on susceptibility to ventricular fibrillation were investigated using chronically instrumented dogs with a healed anterior wall myocardial infarction. Three to 4 weeks after the infarction, a 2-min coronary occlusion was initiated during the last minute of exercise and continued for 1 min after cessation of exercise. Twenty-two dogs developed ventricular fibrillation (susceptible) whereas the remaining 14 animals did not (resistant) during this exercise plus ischemia test. The exercise plus ischemia test was repeated in the susceptible dogs after the following treatments: verapamil (n = 17, 250 micrograms/kg), nifedipine (n = 9, 10 and 100 micrograms/kg) and magnesium sulfate (n = 9, 100 mg/kg). Verapamil prevented ventricular fibrillation in all dogs whereas the high dose of nifedipine protected eight of nine animals; the low dose of nifedipine protected one of nine animals and magnesium sulfate protected seven of nine dogs. Finally, the calcium channel agonist Bay K8644 (n = 9, 30 micrograms/kg) was given to resistant animals. All resistant dogs developed ventricular fibrillation when the exercise plus ischemia test was repeated after Bay K8644. These data suggest that calcium entry may play a critical role in the development of arrhythmias during ischemia, with increased calcium entry provoking arrhythmias and calcium entry blockade preventing the lethal events.