Adenosine appears to mediate the preconditioning-induced reduction in infarct size in rabbits and dogs, but little is known about the role of adenosine in preconditioning-induced protection against ischemia-induced arrhythmias. We compared the effects of preconditioning induced by 2 cycles of 5 min of global ischemia and 2 cycles of 5 min of perfusion with either adenosine (100 μmol/L) or the adenosine A1-selective agonist 2-chloro-N6-cyclopentyladenosine (CCPA, 100 nmol/L) in protecting against ischemia-induced arrhythmias in Langendorff-perfused rat hearts. Preconditioning reduced the incidence of ventricular tachycardia (VT) from 100 to 58% and the incidence of sustained VT or ventricular fibrillation (VF) from 92 to 33%. Perfusion with adenosine reduced the incidence of VT from 100 to 55%, the incidence of VF from 67 to 9% and the incidence of sustained VT or VF from 92 to 9%. CCPA reduced the incidence of sustained VT or VF from 92 to 25%. These interventions provided a true reduction in the severity of arrhythmias, rather than merely a delay in the onset. Our results suggest that the stimulation of A1 receptor by adenosine is involved in triggering ischemic preconditioning-induced protection against ischemia-induced arrhythmias in rats. (Jpn Circ J 1996; 60: 341 - 348)