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Background: Acute myocardial ischemia is an important cause of morbidity and mortality worldwide. The heart and other organs can be rendered more resistant to the deleterious effects of ischemia through a variety of preconditioning strategies, including treadmill exercise and brief ischemia of skeletal muscle. Some of the beneficial effects of these preconditioning strategies appear to be mediated by as-of-yet unidentified hormonal opioids., Objectives: To test the hypothesis that endogenous opioids of the enkephalin class are capable of improving ischemic tolerance and acting in a hormonal manner., Methods: In phase one of the investigation, the authors assessed the cardioprotective potential of all four known enkephalins. This was achieved by subjecting isolated buffer-perfused rabbit hearts to a 25-minute period of test ischemia and two hours of reperfusion (protocol 1) after receiving treatment with either saline vehicle (controls) or increasing concentrations of purified enkephalins. On the basis of results from these initial studies, the authors performed additional experiments (protocol 2) to determine whether Met5-enkephalin-Arg6-Phe7 (MEAP) could be absorbed from skeletal muscle and exert a cardioprotective effect. Specifically, MEAP or vehicle (controls) was given intramuscularly 24 hours before the hearts were harvested. A similar assessment of ischemic tolerance as described in protocol 1 was then performed. Postischemic myocardial viability (infarct size) was assessed in all cases by triphenyltetrazolium chloride (TTC) staining. Hemodynamic parameters and infarct sizes for concentration-dependence studies were compared by two-way analysis of variance, and infarct sizes from protocol 2 studies were compared by using Student's t-test (significance set at p < or = 0.05)., Results: Mean infarct size in control hearts (+/- SEM) was 33% (+/- 4%) and 36% (+/- 6%) for protocol 1 and 2, respectively. Of the four enkephalins tested in protocol 1, only MEAP treatment showed a tendency toward cardioprotection. Interestingly, an alternative enkephalin, methionine5-enkephalin-Arg6-Gly7-Leu8, tended to exert an injurious effect. In protocol 2, MEAP treatment 24 hours before ischemia significantly reduced infarct size (14% +/- 4%) compared with controls, suggesting that it can be released from muscle and exert a distant cardioprotective effect., Conclusions: When given either directly to the heart or absorbed from a distant tissue, MEAP induces cardioprotection, supporting the hypothesis that it can act as a hormonal modulator of ischemic tolerance.