Isoflurane preconditions myocardium against infarction via activation of inhibitory guanine nucleotide binding proteins

Abstract

Background: Isoflurane-induced myocardial protection during ischemia is mediated by adenosine triphosphate-regulated potassium (K(ATP)) channels; however, the intracellular signal transduction cascade responsible for this process has been incompletely evaluated. The authors tested the hypothesis that isoflurane reduces myocardial infarct size through a G(i) protein- mediated process. Methods: Forty-eight hours after pretreatment with vehicle (0.9% saline) or the G(i) protein inhibitor pertussis toxin (10 μg/kg intravenously), barbiturate-anesthetized dogs (n = 43) were instrumented for measurement of aortic and left ventricular pressures and maximum rate of increase of left ventricular pressure. All dogs were subjected to a 60-min left anterior descending coronary artery occlusion followed by 3-h reperfusion. In four separate groups, vehicle- or pertussis toxin-pretreated dogs were studied with or without administration of 1 minimum alveolar concentration isoflurane. In two additional groups, dogs received the direct K(ATP) channel agonist nicorandil (100 μg/kg bolus and 10 μg · kg-1 · min-1 intravenous infusion) in the presence or absence of pertussis toxin pretreatment. Myocardial perfusion and infarct size were measured with radioactive microspheres and triphenyltetrazolium staining, respectively. Results: Isoflurane significantly (P < 0.05) decreased infarct size to 7 ± 2% of the area at risk compared with control experiments (26 ± 2%). Pertussis toxin pretreatment alone had no effects on myocardial infarct size (31 ± 4%) but blocked the beneficial effects of isoflurane (21 ± 3%). Nicorandil decreased infarct size (11 ± 2%), but, in contrast to isoflurane, this effect was independent of pertussis toxin pretreatment (11 ± 1%). Conclusion: Isoflurane reduces myocardial infarct size by a G(i) protein- mediated mechanism in vivo.