Morphine Enhances Pharmacological Preconditioning by Isoflurane

Abstract

Background: Adenosine triphosphate–regulated potassium channels mediate protection against myocardial infarction pro- duced by volatile anesthetics and opioids. We tested the hypoth- esis that morphine enhances the protective effect of isoflurane by activating mitochondrial adenosine triphosphate–regulated potassium channels and opioid receptors. Methods: Barbiturate-anesthetized rats (n ⴝ 131) were instru- mented for measurement of hemodynamics and subjected to a 30 min coronary artery occlusion followed by2hof reperfu- sion. Myocardial infarct size was determined using triphenyl- tetrazolium staining. Rats were randomly assigned to receive 0.9% saline, isoflurane (0.5 and 1.0 minimum alveolar con- centration [MAC]), morphine (0.1 and 0.3 mg/kg), or morphine (0.3 mg/kg) plus isoflurane (1.0 MAC). Isoflurane was adminis- tered for 30 min and discontinued 15 min before coronary occlusion. In eight additional groups of experiments, rats re- ceived 5-hydroxydecanoic acid (5-HD; 10 mg/kg) or naloxone (6 mg/kg) in the presence or absence of isoflurane, morphine, and morphine plus isoflurane. Results: Isoflurane (1.0 MAC) and morphine (0.3 mg/kg) re- duced infarct size (41 ⴞ 3%; n ⴝ 13 and 38 ⴞ 2% of the area at risk; n ⴝ 10, respectively) as compared to control experiments (59 ⴞ 2%; n ⴝ 10). Morphine plus isoflurane further decreased infarct size to 26 ⴞ 3% (n ⴝ 11). 5-HD and naloxone alone did not affect infarct size, but abolished cardioprotection produced by isoflurane, morphine, and morphine plus isoflurane. Conclusions: Combined administration of isoflurane and morphine enhances the protection against myocardial infarc- tion to a greater extent than either drug alone. This beneficial effect is mediated by mitochondrial adenosine triphosphate– regulated potassium channels and opioid receptors in vivo.