Alpha-Adrenergic receptor responsiveness has been reported to increase during myocardial ischemia, correlating with onset of malignant arrhythmias. If alpha-adrenoceptor mechanisms play a significant role in induction of life-threatening arrhythmias, inhibition of these receptors with specific alpha-adrenoceptor antagonists should protect against disturbances in cardiac rhythm. To test this hypothesis, we induced ventricular fibrillation (VF) in 21 mongrel dogs with healed myocardial infarctions (MI) by 2-min coronary artery occlusion during exercise. On a subsequent day, the exercise plus ischemia test was repeated after the alpha 1-adrenoceptor antagonist prazosin HCl (0.5 mg/kg intravenously, i.v.; n = 14) or the alpha 1A-adrenergic receptor subtype antagonist WB4101 (2.0 mg/kg i.v., n = 9). Prazosin elicited a significant reduction in left ventricular systolic pressure (LVSP, control 157.0 +/- 6.5 vs. prazosin 118.5 +/- 2.7 mm Hg) and prevented arrhythmias in 13 of 14 animals (chi square p < 0.001). No other hemodynamic parameters, either before or during the coronary occlusion, were altered by prazosin. WB4101 did not alter any hemodynamic parameters either before or during coronary artery occlusion, yet prevented VF in 7 of 9 animals (chi square p < 0.025), delaying onset of malignant arrhythmias in the remaining animals. A second control exercise plus ischemia test reproducibly induced VF in all animals. Together these data demonstrate that alpha-adrenoceptor antagonists can prevent VF independent of hemodynamic changes. In particular, the data suggest that activation of the alpha 1A-adrenergic receptor subtype may contribute importantly to development of malignant arrhythmias.(ABSTRACT TRUNCATED AT 250 WORDS)