Morphine enhances isoflurane-induced postconditioning against myocardial infarction: the role of phosphatidylinositol-3-kinase and opioid receptors in rabbits |
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Authors: | Weihrauch Dorothee Krolikowski John G Bienengraeber Martin Kersten Judy R Warltier David C Pagel Paul S |
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Affiliation: | Department of Anesthesiology, Medical College of Wisconsin and Clement J. Zablocki Veterans Affairs Medical Center, Milwaukee, Wisconsin 53226, USA. |
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Abstract: | Isoflurane reduces myocardial infarct size during early reperfusion by activating phosphatidylinositol-3-kinase (PI3K) signaling. We tested the hypothesis that this cardioprotection against reperfusion injury is enhanced by morphine and that a decrease in apoptosis plays a role in preservation of myocardial viability. Rabbits (n = 108) instrumented for hemodynamic measurement and subjected to a 30-min coronary occlusion followed by 3 h reperfusion received 0.9% saline, the selective PI3K inhibitor wortmannin (0.6 mg/kg), or the nonselective opioid antagonist naloxone (6 mg/kg) before coronary occlusion in the presence or absence of isoflurane (0.5 or 1.0 MAC), morphine (0.05 or 0.1 mg/kg), or their combination administered for 3 min before and 2 min after reperfusion. Infarct size was determined using triphenyltetrazolium staining and apoptosis assessed using cytochrome c translocation and Terminal Deoxynucleotidyl Transferase-Mediated dUTP Nick End Labeling (TUNEL) staining of left ventricular myocardium in situ. Isoflurane (1.0 but not 0.5 MAC) and morphine (0.1 but not 0.05 mg/kg) reduced (P < 0.05) infarct size (mean +/- sd 21% +/- 4%, 44% +/- 6%, 19% +/- 4%, and 41% +/- 6% of left ventricular area at risk, respectively) as compared with control (41% +/- 4%). The combination of 0.5 MAC isoflurane and 0.05 mg/kg morphine also decreased infarct size (18% +/- 9%). Wortmannin and naloxone alone did not affect infarct size but blocked the protection produced by isoflurane, morphine, and their combination. Isoflurane and morphine reduced cytochrome c translocation and TUNEL staining. The results indicate that morphine enhances isoflurane-induced postconditioning by activating PI3K and opioid receptors in vivo. A reduction in apoptotic cell death contributes to preservation of myocardial integrity during postconditioning by isoflurane. IMPLICATIONS: The results of this study indicate that morphine enhances isoflurane-induced postconditioning by activating phosphatidylinositol-3-kinase and opioid receptors in vivo. A reduction in apoptotic cell death contributes to preservation of myocardial integrity during postconditioning by isoflurane and morphine. |
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