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Xenon preconditioning: the role of prosurvival signaling, mitochondrial permeability transition and bioenergetics in rats. Anesth Analg 2009 Mar;108(3):858-66



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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 beta (GSK-3beta) 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-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.

CONCLUSIONS: These 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.

Author List

Mio Y, Shim YH, Richards E, Bosnjak ZJ, Pagel PS, Bienengraeber M


Zeljko J. Bosnjak PhD Professor in the Medicine department at Medical College of Wisconsin
Paul S. Pagel MD, PhD Professor in the Anesthesiology department at Medical College of Wisconsin

MESH terms used to index this publication - Major topics in bold

Anesthetics, Inhalation
Blood Pressure
Blotting, Western
Cardiotonic Agents
Energy Metabolism
Glycogen Synthase Kinase 3
Glycogen Synthase Kinase 3 beta
Heart Rate
Ischemic Preconditioning, Myocardial
Mitochondria, Heart
Myocardial Infarction
Myocardial Reperfusion Injury
Oxygen Consumption
Proto-Oncogene Proteins c-akt
Rats, Wistar
jenkins-FCD Prod-387 b0ced2662056320369de4e5cd5f21c218c03feb3