Morphine enhances pharmacological preconditioning by isoflurane: role of mitochondrial K(ATP) channels and opioid receptors.
BACKGROUND
Adenosine triphosphate-regulated potassium channels mediate protection against myocardial infarction produced by volatile anesthetics and opioids. We tested the hypothesis that morphine enhances the protective effect of isoflurane by activating mitochondrial adenosine triphosphate-regulated potassium channels and opioid receptors.


METHODS
Barbiturate-anesthetized rats (n = 131) were instrumented for measurement of hemodynamics and subjected to a 30 min coronary artery occlusion followed by 2 h of reperfusion. Myocardial infarct size was determined using triphenyltetrazolium staining. Rats were randomly assigned to receive 0.9% saline, isoflurane (0.5 and 1.0 minimum alveolar concentration [MAC]), morphine (0.1 and 0.3 mg/kg), or morphine (0.3 mg/kg) plus isoflurane (1.0 MAC). Isoflurane was administered for 30 min and discontinued 15 min before coronary occlusion. In eight additional groups of experiments, rats received 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) reduced infarct size (41 +/- 3%; n = 13 and 38 +/- 2% of the area at risk; n = 10, respectively) as compared to control experiments (59 +/- 2%; n = 10). Morphine plus isoflurane further decreased infarct size to 26 +/- 3% (n = 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 infarction 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.
Ludwig
Lynda M
LM
Department of Anesthesiology, the Medical College of Wisconsin, Milwaukee 53226, USA.
Patel
Hemal H
HH
Gross
Garrett J
GJ
Kersten
Judy R
JR
Pagel
Paul S
PS
Warltier
David C
DC
D000255:Adenosine Triphosphate / Q000494:pharmacology*; D000818:Animals; D004357:Drug Synergism; D019206:GTP-Binding Protein alpha Subunits, Gi-Go / Q000502:physiology; D006439:Hemodynamics / Q000187:drug effects; D019157:Ischemic Preconditioning, Myocardial / Q000379:methods*; D007530:Isoflurane / Q000494:pharmacology*; D008297:Male; D008928:Mitochondria / Q000502:physiology*; D009020:Morphine / Q000494:pharmacology*; D009203:Myocardial Infarction / Q000517:prevention & control; D009270:Naloxone / Q000494:pharmacology; D015221:Potassium Channels / Q000502:physiology*; D011493:Protein Kinase C / Q000502:physiology; D051381:Rats; D017208:Rats, Wistar; D011957:Receptors, Opioid / Q000502:physiology*
D015221:Potassium Channels; D011957:Receptors, Opioid; D009270:Naloxone; D009020:Morphine; D000255:Adenosine Triphosphate; D007530:Isoflurane; D011493:Protein Kinase C; D019206:GTP-Binding Protein alpha Subunits, Gi-Go