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ANESTHETIC PHARMACOLOGY

Xenon Preconditioning: The Role of Prosurvival Signaling, Mitochondrial Permeability Transition and Bioenergetics in Rats

Yasushi Mio, MD^*, Yon Hee Shim, MD^*, Ebony Richards, BS^*, Zeljko J. Bosnjak, PhD^*, Paul S. Pagel, MD, PhD^*, and Martin Bienengraeber, PhD^*

From the *Department of Anesthesiology, Medical College of Wisconsin, Milwaukee, Wisconsin; Department of Anesthesiology, Jikei University School of Medicine, Tokyo, Japan; and Department of Pharmacology and Toxicology, Medical College of Wisconsin, Milwaukee; Wisconsin.

Address correspondence and reprint requests to Martin Bienengraeber, PhD, Department of Anesthesiology, Medical College of Wisconsin, 8701 Watertown Plank Rd., Milwaukee, WI 53226. Address e-mail to mbieneng{at}mcw.edu.

BACKGROUND: Similar 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.

METHODS: Male 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 β (GSK-3β) phosphorylation and isolation of mitochondria. Mitochondrial oxygen consumption before and after hypoxia/reoxygenation and mitochondrial permeability transition pore opening were determined.

RESULTS: Xenon 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-3β. Xenon pretreatment preserved state 3 respiration of isolated mitochondria compared with the results obtained in the absence of the gas. The Ca²⁺ concentration required to induce mitochondrial membrane depolarization was larger in the presence compared with the absence of xenon pretreatment (78 ± 17 and 56 ± 17 µM, respectively). The phosphoinositol-3-kinase-kinase inhibitor wortmannin blocked the effect of xenon on infarct size and respiration.

CONCLUSIONS: These results indicate that xenon preconditioning reduces myocardial infarct size, phosphorylates Akt, and GSK-3β, preserves mitochondrial function, and inhibits Ca²⁺-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.