We previously reported that ₂-adrenergic receptor (₂-AR) stimulation in Purkinje fibers in vitro prolongs action potential duration and suppresses -adrenergic-induced delayed afterdepolarizations and sustained triggered activities. We examined the effects of 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 -blocker group, 72% for the ₁-blocker group, and 12.5% for the ₁ + -blockers group (unopposed ₂-adrenergic activation). Direct ₂-AR stimulation with UK-14304 also prevented VT/VF. These effects were reversed by the 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 ₂-AR stimulation has a potent antiarrhythmic effect on ischemia-reperfusion-induced VT/VF in vivo and that this effect is not centrally mediated.