• Anesthesiology · Sep 2013

    Sevoflurane protects ventricular myocytes against oxidative stress-induced cellular Ca(2+) overload and hypercontracture.

    • Akiko Kojima, Hirotoshi Kitagawa, Mariko Omatsu-Kanbe, Hiroshi Matsuura, and Shuichi Nosaka.
    • Department of Anesthesiology, Shiga University of Medical Science, Seta Tsukinowa-cho, Otsu, Shiga 520–2192, Japan. akiko77@belle.shiga-med.ac.jp
    • Anesthesiology. 2013 Sep 1;119(3):606-20.

    BackgroundOxidative stress is implicated in pathogenesis of cardiac reperfusion injury, characterized by cellular Ca2+ overload and hypercontracture. Volatile anesthetics protect the heart against reperfusion injury primarily by attenuating Ca2+ overload. This study investigated electrophysiological mechanisms underlying cardioprotective effects of sevoflurane against oxidative stress-induced cellular injury.MethodsThe cytosolic Ca2+ levels and cell morphology were assessed in mouse ventricular myocytes, using confocal fluo-3 fluorescence imaging, whereas membrane potentials and L-type Ca2+ current (ICa,L) were recorded using wholecell patch-clamp techniques. Phosphorylation of Ca2+/calmodulin-dependent protein kinase II was examined by Western blotting.ResultsExposure to H2O2 (100 μm) for 15 min evoked cytosolic Ca2+ elevation and hypercontracture in 56.8% of ventricular myocytes in 11 experiments, which was partly but significantly reduced by nifedipine, tetracaine, or SEA0400. Sevoflurane prevented H2O2-induced cellular Ca2+ overload in a concentration-dependent way (IC50 = 1.35%). Isoflurane (2%) and desflurane (10%) also protected ventricular myocytes by a degree similar to sevoflurane (3%). Sevoflurane suppressed H2O2-induced electrophysiological disturbances, including early afterdepolarizations, voltage fluctuations in resting potential, and abnormal automaticities. H2O2 significantly enhanced ICa,L by activating Ca2+/calmodulin-dependent protein kinase II, and subsequent addition of sevoflurane, isoflurane, or desflurane similarly reduced ICa,L to below baseline levels. Phosphorylated Ca2+/calmodulin-dependent protein kinase II increased after 10-min incubation with H2O2, which was significantly prevented by concomitant administration of sevoflurane.ConclusionsSevoflurane protected ventricular myocytes against H2O2-induced Ca2+ overload and hypercontracture, presumably by affecting multiple Ca2+ transport pathways, including ICa,L, Na+/Ca2+ exchanger and ryanodine receptor. These actions appear to mediate cardioprotection against reperfusion injury associated with oxidative stress.

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