Previously, our laboratory has shown that opioid receptors are involved in ischemic preconditioning (PC) in the intact rat heart; however, it is not known whether this cardioprotection is mediated by central or peripheral mechanisms. To test this hypothesis, both naloxone (NL), the non-selective opioid receptor antagonist and naloxone methiodide (QNL), its quaternary derivative which does not cross the blood-brain barrier, were used to determine if opioid receptor-induced myocardial protection occurs via a central or peripheral locus of action in inactin-anesthetized, open-chested, Wistar rats. In group I, the control group was subjected to 30 min of occlusion and 2 h of reperfusion. In group II, ischemic PC was elicited by three 5-min occlusion periods interspersed with 5 min of reperfusion. In group III, QNL (10 mg/kg, i.v.) was administered 10 min before the 30 min of occlusion. Groups IV and V consisted of a dose-response effect of QNL on ischemic PC in which QNL (0.3 or 10 mg/kg, i.v., respectively) was given 10 min prior to ischemic PC. In addition, in groups VI and VII, one of two doses of naloxone (1 or 3 mg/kg, i.v.) was administered 10 min before ischemic PC. Infarct size (IS) as a percentage of the area at risk (AAR) was determined by tetrazolium staining. Ischemic PC reduced IS to 9 +/- 2% (P < 0.05) v control (53 +/- 4%). The low dose of QNL partially blocked the cardioprotective effect of ischemic PC; whereas the high dose completely abolished its cardioprotective effect. The high dose of QNL had no effect on IS alone. Similarly, the low dose of NL did not antagonize the cardioprotective effect of ischemic PC; however, the high dose completely abolished ischemic PC. These results indicate that the cardioprotective effect of ischemic preconditioning is mediated by a peripheral opioid receptor mechanism in the intact rat heart.