• Yasushi Mio, Yon Hee Shim, Ebony Richards, Zeljko J Bosnjak, Paul S Pagel, and Martin Bienengraeber.
• Department of Anesthesiology, Medical College of Wisconsin, 8701 Watertown Plank Rd., Milwaukee, WI 53226, USA.
• Anesth. Analg. 2009 Mar 1;108(3):858-66.

BackgroundSimilar to volatile anesthetics, the anesthetic noble gas xenon protects the heart from ischemia/reperfusion injury, but the mechanisms responsible for this phenomenon are not fully understood. We tested the hypothesis that xenon-induced cardioprotection is mediated by prosurvival signaling kinases that target mitochondria.MethodsMale Wistar rats instrumented for hemodynamic measurements were subjected to a 30 min left anterior descending coronary artery occlusion and 2 h reperfusion. Rats were randomly assigned to receive 70% nitrogen/30% oxygen (control) or three 5-min cycles of 70% xenon/30% oxygen interspersed with the oxygen/nitrogen mixture administered for 5 min followed by a 15 min memory period. Myocardial infarct size was measured using triphenyltetrazolium staining. Additional hearts from control and xenon-pretreated rats were excised for Western blotting of Akt and glycogen synthase kinase 3 beta (GSK-3beta) phosphorylation and isolation of mitochondria. Mitochondrial oxygen consumption before and after hypoxia/reoxygenation and mitochondrial permeability transition pore opening were determined.ResultsXenon significantly (P < 0.05) reduced myocardial infarct size compared with control (32 +/- 4 and 59% +/- 4% of the left ventricular area at risk; mean +/- sd) and enhanced phosphorylation of Akt and GSK-3beta. Xenon pretreatment preserved state 3 respiration of isolated mitochondria compared with the results obtained in the absence of the gas. The Ca(2+) concentration required to induce mitochondrial membrane depolarization was larger in the presence compared with the absence of xenon pretreatment (78 +/- 17 and 56 +/- 17 microM, respectively). The phosphoinositol-3-kinase-kinase inhibitor wortmannin blocked the effect of xenon on infarct size and respiration.ConclusionsThese results indicate that xenon preconditioning reduces myocardial infarct size, phosphorylates Akt, and GSK-3beta, preserves mitochondrial function, and inhibits Ca(2+)-induced mitochondrial permeability transition pore opening. These data suggest that xenon-induced cardioprotection occurs because of activation of prosurvival signaling that targets mitochondria and renders them less vulnerable to ischemia-reperfusion injury.

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