The pharmacological actions of sotalol, (-)-propranolol and prazosin on norepinephrine (NE) concentration and creatine kinase (CK) activity in the coronary sinus blood of the ischemic heart were studied in open-chest dogs. A 60 min occlusion of the left anterior descending coronary artery was followed by a reperfusion period of 30 min. In saline-treated dogs, a significant increase in coronary sinus NE concentration occurring 30 s after the onset of reperfusion was followed by a rapid decrease to the initial value within 15 min. CK activity increased gradually and continuously starting 5 min after the beginning of reperfusion. A good correlation (r = 0.9, n = 8, P less than 0.05) was obtained in saline-treated dogs when the calculated slope of the time-activity curves for CK release was plotted against the corresponding peak concentration of NE. The increase in coronary sinus NE concentration upon reperfusion was accompanied by an increased arrhythmic ratio. Sotalol (5 mg/kg i.v.) diminished the increase in coronary sinus NE concentration along with a significant decrease in the arrhythmic ratio. The administration of either (-)-propranolol (0.1 mg/kg i.v.) or prazosin (1 mg/kg i.v.) did not significantly affect the increase in coronary sinus NE concentration. The arrhythmic ratio was significantly reduced by prazosin but not by (-)-propranolol. The rise in coronary sinus CK activity was significantly diminished in the presence of either sotalol, (-)-propranolol or prazosin. These results suggest that the occurrence of severe ventricular arrhythmias upon reperfusion may be related to the action of the increased myocardial NE on the cardiac alpha-adrenoceptors. The increased coronary sinus CK activity suggests that increased cardiac sympathetic activation may accelerate or aggravate the myocardial damage. We conclude that the antiarrythmic effect of sotalol may be due at least in part to its inhibitory action on the release of cardiac NE upon reperfusion.