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 μ₁-opioid receptor agonist with δ₁-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.

Key Words: myocardial ischemia, preconditioning, helium, morphine, opioid receptor