Abstract
Introduction: Opioids have been proposed as ischemic modulators and may regulate ischemic preconditioning. Clearly, exogenous opioids protect against myocardial ischemic injury. However, whether inducible endogenous opioids mediate myocardial ischemic protection has not been shown. The purpose of this study was to determine the presence and activity of constitutive and inducible in-vivo endogenous opioids in response to ischemia. Methods: Thirty-two rabbit hearts were cannulated in the Langendorff mode. Myocytes were isolated before, during and after 2 hours of global hypothermic (32°C) ischemia. These myocytes were examined for the kappa opioid receptor agonists dynorphin and met-enkephalin via radioimmunoassay (RIA). Opioid levels were measured at baseline, end-ischemia, and at 5 and 45 minutes after reperfusion. To further investigate endogenous opioids we also examined myocyte viability in a different cell preparation, as measured by trypan blue exclusion and LDH release. Untreated controls were compared to myocytes treated with 1mM of naltrindole, which blocks any endogenous opioid activity. No cells received any exogenous opioid. Results: The RIA levels of the opioids dynorphin and met-enkephalin are shown. The mean levels are in pg/ml, ± SD. ∗p < 0.05 vs. baseline. Additionally, at baseline myocytes were 82 ± 2% viable which fell to 60 ± 2% after ischemia. However, naltrindole (opioid blocked) myocytes dropped to <1% viable after the same ischemic insult. Also, LDH release was significantly higher in the natrindole myocytes. Conclusion: This study demonstrates the presence of constitutive regulatory endogenous opioids in myocardium. Importantly, ischemia resulted in elevated myocyte levels of kappa agonist peptides, and finally, opioid inhibition significantly decreased viability. This would suggest an inducible opioid modulation of myocyte viability and resistance to ischemia, further illustrating endogenous opioid protection.TABLE—ABSTRACT 1DynorphinMet-EnkephalinBaseline4.8 ± 1.13.7 ± 1.6Ischemia10.5 ± 1.4∗7.7 ± 2.8∗5 min reflow3.5 ± 2.16.4 ± 2.0∗45 min reflow0.7 ± 0.44.1 ± 1.3
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