title: Sevoflurane protects ventricular myocytes against oxidative stress-induced cellular Ca2+ overload and hypercontracture.
abstract: BACKGROUND
  Oxidative stress is implicated in pathogenesis of cardiac reperfusion injury, characterized by cellular Ca overload and hypercontracture. Volatile anesthetics protect the heart against reperfusion injury primarily by attenuating Ca overload. This study investigated electrophysiological mechanisms underlying cardioprotective effects of sevoflurane against oxidative stress-induced cellular injury.
  
  
  METHODS
  The cytosolic Ca levels and cell morphology were assessed in mouse ventricular myocytes, using confocal fluo-3 fluorescence imaging, whereas membrane potentials and L-type Ca current (ICa,L) were recorded using whole-cell patch-clamp techniques. Phosphorylation of Ca/calmodulin-dependent protein kinase II was examined by Western blotting.
  
  
  RESULTS
  Exposure to H2O2 (100 μM) for 15 min evoked cytosolic Ca 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 Ca 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 Ca/calmodulin-dependent protein kinase II, and subsequent addition of sevoflurane, isoflurane, or desflurane similarly reduced ICa,L to below baseline levels. Phosphorylated Ca/calmodulin-dependent protein kinase II increased after 10-min incubation with H2O2, which was significantly prevented by concomitant administration of sevoflurane.
  
  
  CONCLUSIONS
  Sevoflurane protected ventricular myocytes against H2O2-induced Ca overload and hypercontracture, presumably by affecting multiple Ca transport pathways, including ICa,L, Na/Ca exchanger and ryanodine receptor. These actions appear to mediate cardioprotection against reperfusion injury associated with oxidative stress.
authors.affiliation: Department of Physiology, Shiga University of Medical Science, Otsu, Shiga 520-2192, Japan. akiko77@belle.shiga-med.ac.jp
authors.forename: Akiko
authors.initials: A
authors.lastname: Kojima
authors.forename: Hirotoshi
authors.initials: H
authors.lastname: Kitagawa
authors.forename: Mariko
authors.initials: M
authors.lastname: Omatsu-Kanbe
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Matsuura
authors.forename: Shuichi
authors.initials: S
authors.lastname: Nosaka
mesh_terms: D000200:Action Potentials / Q000187:drug effects; D018685:Anesthetics, Inhalation / Q000494:pharmacology*; D000818:Animals; D002118:Calcium / Q000378:metabolism*; D020746:Calcium Channels, L-Type / Q000502:physiology; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2 / Q000502:physiology; D006352:Heart Ventricles; D006861:Hydrogen Peroxide / Q000494:pharmacology; D008297:Male; D008738:Methyl Ethers / Q000494:pharmacology*; D051379:Mice; D008810:Mice, Inbred C57BL; D009200:Myocardial Contraction / Q000187:drug effects*; D032383:Myocytes, Cardiac / Q000187:drug effects* / Q000502:physiology; D009543:Nifedipine / Q000494:pharmacology; D018384:Oxidative Stress; D043562:Receptors, G-Protein-Coupled / Q000502:physiology; D019837:Ryanodine Receptor Calcium Release Channel / Q000502:physiology; D000077149:Sevoflurane; D019831:Sodium-Calcium Exchanger / Q000502:physiology
chemical_list: D018685:Anesthetics, Inhalation; D020746:Calcium Channels, L-Type; D008738:Methyl Ethers; D043562:Receptors, G-Protein-Coupled; D019837:Ryanodine Receptor Calcium Release Channel; D019831:Sodium-Calcium Exchanger; D000077149:Sevoflurane; D006861:Hydrogen Peroxide; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2; D009543:Nifedipine; D002118:Calcium