In addition to well-known neurobehavioral effects, endogenous cannabinoids exert diverse cardiovascular actions. Recently, they have been suggested to protect the myocardium against ischemia/reperfusion injury. The aim of this study is to examine the contribution of endogenous cannabinoids to cardioprotection afforded by remote ischemic preconditioning. Three groups of remote preconditioned (15 min of mesenteric artery occlusion followed by 15 min of reperfusion) and three groups of sham-operated rats were included in the study. Animals were pretreated intravenously by vehicle, cannabinoid CB(1) (AM251, 1 mg/kg) or CB(2) (AM630, 1 mg/kg) receptor antagonist 15 min prior to remote preconditioning or sham operation. Myocardial injury was induced by 30 min of coronary artery occlusion followed by 2 h of reperfusion. The resultant arterial hypotension, ventricular arrhythmias, and infarct size were compared among the groups. Remote preconditioning exerted potent cardioprotection manifested as significant reductions in infarct size (P<0.001) as well as number and duration of arrhythmias (P<0.01, 0.01 and 0.05 for premature ventricular contractions, ventricular tachycardias and fibrillations; respectively). The cannabinoid CB(1) receptor antagonist pretreatment had no significant effect on ischemia-induced hypotension, arrhythmias or infarct size. On the other hand, the cannabinoid CB(2) receptor antagonist pretreatment abolished the protective effects of remote preconditioning on infarct size (P<0.01) and arrhythmias (P<0.01), without any significant effect on ischemia-induced hypotension. The results of this study suggest that endogenous cannabinoids, through acting on cannabinoid CB(2) receptors, are involved in the cardioprotective phenomenon of remote ischemic preconditioning, induced by mesenteric artery occlusion and reperfusion.