The objective of this research was to investigate the role of opioids in myocardial protection of the large mammalian heart. A porcine isolated working heart model of swine was carefully characterized and various opioid agonists were administered prior to inducing global ischemia. An acute coronary occlusion model was developed to investigate the effects of opioid preconditioning on regional ischemia, in particular infarct size, myocardial function, and arrhythmias. The results of these studies suggest a specific role of d-receptor agonists in myocardial protection in large mammalian hearts.