We previously reported that alpha(2)-adrenergic receptor (alpha(2)-AR) stimulation in Purkinje fibers in vitro prolongs action potential duration and suppresses beta-adrenergic-induced delayed afterdepolarizations and sustained triggered activities. We examined the effects of alpha(2)-AR stimulation on reperfusion-induced ventricular arrhythmias [ventricular tachycardia/ventricular fibrillation (VT/VF)] in vivo. Arterial blood pressure, heart rate, surface electrocardiogram, and renal sympathetic nerve activities were recorded simultaneously in Sprague-Dawley rats. The incidence of VT/VF was 87.5% for controls, 50% for the beta-blocker group, 72% for the alpha(1)-blocker group, and 12.5% for the alpha(1) + beta-blockers group (unopposed alpha(2)-adrenergic activation). Direct alpha(2)-AR stimulation with UK-14304 also prevented VT/VF. These effects were reversed by the alpha(2)-adrenergic antagonist yohimbine. Increases in renal sympathetic nerve activity were associated with left anterior descending coronary artery ligation and reperfusion (33 +/- 1.5 and 62 +/- 1.7% over baseline, respectively) in controls. Similar patterns were observed among all experimental groups irrespective of the incidence of VT/VF on reperfusion. We conclude that alpha(2)-AR stimulation has a potent antiarrhythmic effect on ischemia-reperfusion-induced VT/VF in vivo and that this effect is not centrally mediated.