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Xenon preconditioning: the role of prosurvival signaling, mitochondrial permeability transition and bioenergetics in rats.

 Yasushi Mio  ;  Yon Hee shim  ;  Ebony Richards  ;  Zeljko J. Bosnjak  ;  Paul S. Pagel  ;  Martin Bienengraeber 
 ANESTHESIA AND ANALGESIA, Vol.108(3) : 858-866, 2009 
Journal Title
Issue Date
Anesthetics, Inhalation/pharmacology* ; Animals ; Blood Pressure/drug effects ; Blotting, Western ; Calcium/pharmacology ; Cardiotonic Agents* ; Energy Metabolism/drug effects* ; Glycogen Synthase Kinase 3/metabolism ; Glycogen Synthase Kinase 3 beta ; Heart Rate/drug effects ; Ischemic Preconditioning, Myocardial* ; Male ; Mitochondria, Heart/drug effects* ; Mitochondria, Heart/pathology ; Myocardial Infarction/pathology ; Myocardial Infarction/prevention & control ; Myocardial Reperfusion Injury/pathology ; Myocardial Reperfusion Injury/prevention & control* ; Oxygen Consumption/drug effects ; Permeability/drug effects ; Phosphorylation ; Proto-Oncogene Proteins c-akt/metabolism ; Rats ; Rats, Wistar ; Xenon/pharmacology*
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
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1. College of Medicine (의과대학) > Dept. of Anesthesiology and Pain Medicine (마취통증의학교실) > 1. Journal Papers
Yonsei Authors
Shim, Yon Hee(심연희) ORCID logo https://orcid.org/0000-0003-1921-3391
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