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CARDIOVASCULAR ANESTHESIA

Morphine Enhances Isoflurane-Induced Postconditioning Against Myocardial Infarction: The Role of Phosphatidylinositol-3-Kinase and Opioid Receptors in Rabbits

Departments of Anesthesiology, Pharmacology and Toxicology, and Medicine (Division of Cardiovascular Diseases), the Medical College of Wisconsin and the Clement J. Zablocki Veterans Affairs Medical Center, Milwaukee, Wisconsin, and the Department of Biomedical Engineering, Marquette University, Milwaukee, Wisconsin.

Address correspondence and reprint requests to Paul S. Pagel, MD, PhD, Medical College of Wisconsin, MEB-M4280, 8701 Watertown Plank Road, Milwaukee, WI 53226. Address electronic mail to pspagel{at}mcw.edu.

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.

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