The role of delta-opioid receptors in mediating ischemic preconditioning (IPC) in rats, rabbits, and pigs has been well-established; however, no studies have been performed in dogs. Therefore, the purpose of the present study was to determine if activation of delta-opioid receptors can mimic the cardioprotective effects of IPC in the canine heart and to determine if a nonselective opioid receptor antagonist could block IPC. All dogs were subjected to 60 minutes of left anterior descending (LAD) coronary artery occlusion and 3 hours of reperfusion. Ischemic preconditioning was produced by one 5-minute period of ischemia 10 minutes before LAD coronary artery occlusion. Infarct size (IS) expressed as a percent of the area at risk (AAR; IS/AAR) was determined by triphenyltetrazolium staining. Two selective delta-opioid receptor (DOR) agonists, TAN-67 and BW373U86, were administered by intracoronary infusion for 30 minutes before LAD occlusion and the opioid receptor antagonist naloxone was administered 30 minutes before IPC. Both TAN-67 and BW373U86 produced significant reductions in IS/AAR similar to that of IPC (control: 28+/-2.1; TAN: 12.3+/-2.2; IPC: 9.3+/-3.0: BW: 11.7+/-2.6). Naloxone attenuated the effect of IPC (control: 28+/-2.1; naloxone: 18.2+/-4.5). These results suggest that opioid receptors are important in IPC in dogs, and stimulation of delta-opioid receptors with selective agonists can mimic the cardioprotective effects of IPC and may have therapeutic potential.