Release of cardiac histamine by immunologic and pharmacologic stimuli is known to provoke ventricular arrhythmias. Augmented histamine efflux from ischemic myocardium has been proposed but remains controversial. The purpose of this study was to determine whether cardiac histamine efflux is precipitated by coronary artery occlusion and if so, whether histamine efflux is associated with the development of early ischemic ventricular arrhythmias. The left anterior descending coronary artery was occluded while recording a continuous electrocardiogram and coronary sinus blood was sampled frequently during the first 30 min of coronary artery occlusion in pentobarbital-anesthetized, open-chest dogs. Coronary sinus histamine concentration rose from a mean baseline of 0.06 +/- 0.10 ng/ml (+/- SD) before coronary artery occlusion to a mean peak of 0.61 +/- 0.40 ng/ml after coronary artery occlusion (p less than 0.0001; n = 14). The median peak coronary sinus histamine concentration was significantly greater in dogs that suffered ventricular fibrillation after coronary artery occlusion (n = 4) than in those that did not (n = 10) (0.86 ng/ml vs. 0.37 ng/ml; p = 0.05). The area under the coronary sinus histamine concentration-vs.-time curve ("total cardiac histamine efflux") correlated directly with the total number of ventricular premature contractions during the first 30 min after coronary artery occlusion (r = 0.81; p less than 0.005; n = 10), and with infarct size (r = 0.91; p less than 0.01; n = 6). Thus, during acute myocardial ischemia, the coronary sinus histamine concentration increases simultaneously with the development of early ischemic ventricular arrhythmias and in proportion to their severity.