Morphine Reduces the Threshold of Helium Preconditioning Against Myocardial Infarction: The Role of Opioid Receptors in Rabbits

Objectives: Brief, repetitive administration of helium before prolonged coronary artery occlusion and reperfusion protects myocardium against infarction. Opioid receptors mediate the cardioprotective effects of ischemic pre- and postconditioning, but whether these receptors also play a role in helium preconditioning is unknown. The authors tested the hypotheses that opioid receptors mediate helium preconditioning and that morphine (a mu(1)-opioid receptor agonist with delta(1)-opioid agonist properties) lowers the threshold of cardioprotection produced by helium in vivo. Design: A randomized, prospective study. Setting: A university research laboratory. Participants: Male New Zealand white rabbits. Interventions: Rabbits (n = 56) were instrumented for the measurement of systemic hemodynamics and subjected to a 30-minute left anterior descending coronary artery (LAD) occlusion and 3 hours of reperfusion. In separate experimental groups, rabbits (n = 6 or 7 per group) received 0.9% saline (control), 1 or 3 cycles of 70% helium-30% oxygen administered for 5 minutes interspersed with 5 minutes of an air-oxygen mixture, morphine (0.1 mg/kg intravenously), or the nonselective opioid antagonist naloxone (6 mg/kg intravenously) before LAD occlusion. Other groups of rabbits received 3 cycles of helium or 1 cycle of helium plus morphine (0.1 mg/kg) in the absence or presence of naloxone (6 mg/kg) before ischemia and reperfusion. Statistical analysis of data was performed with analysis of variance for repeated measures followed by Bonferroni modification of the Student t test. Measurements and Main Results: Myocardial infarct size was determined by using triphenyltetrazolium chloride staining and presented as a percentage of the left ventricular area at risk. Helium reduced myocardial infarct size in an exposure-related manner (36 +/- 6 [p > 0.05] and 25% +/- 4% [p < 0.05 v control] for 1 and 3 cycles of helium, respectively; data are mean +/- standard deviation) compared with control (44% +/- 7%). Morphine and naloxone alone did not affect infarct size (45 +/- 2 and 40% +/- 8%, respectively). The combination of 1 cycle of helium and morphine reduced infarct size (24% +/- 5%, p < 0.05 v control) to an equivalent degree as 3 cycles of helium. Naloxone pretreatment abolished cardioprotection produced by 3 cycles of helium (47% +/- 2%) and the combination of 1 cycle of helium plus morphine (45% +/- 4%). Conclusions: The results indicate that morphine lowers the threshold of helium preconditioning. Opioid receptors mediate helium preconditioning and its augmentation by morphine in vivo. (C) 2009 Elsevier Inc. All rights reserved