We had previously reported that activation of histamine H-3-receptors (H3R) on cardiac adrenergic nerve terminals decreases norepinephrine (NE) overflow from ischemic hearts and alleviates reperfusion arrhythmias. Thus, we used transgenic mice lacking H3R (H3R-/-) to investigate whether ischemic arrhythmias might be more severe in H3R-/-hearts than in hearts with intact H3R (H3R+/+). We report a greater incidence and longer duration of ventricular fibrillation (VF) in H3R-/- hearts subjected to ischemia. VF duration was linearly correlated with NE overflow, suggesting a possible cause-effect relationship between magnitude of NE release and severity of reperfusion arrhythmias. Thus, our findings strengthen a protective antiarrhythmic role of H3R in myocardial ischemia. Since malignant tachyarrhythmias cause sudden death in ischemic heart disease, attenuation of NE release by selective H3R agonists may represent a new approach in the prevention and treatment of ischemic arrhythmias. (C) 2003 Elsevier Science (USA). All rights reserved.