title: Sevoflurane protects ventricular myocytes from Ca2+ paradox-mediated Ca2+ overload by blocking the activation of transient receptor potential canonical channels.
abstract: BACKGROUND
  Volatile anesthetics produce cardioprotective action by attenuating cellular Ca2+ overload. The Ca2+ paradox is an important model for studying the mechanisms associated with Ca2+ overload-mediated myocardial injury, and was recently found to be mediated by Ca2+ entry through the transient receptor potential canonical channels upon Ca2+ repletion. This study investigated the effect of sevoflurane on cellular mechanisms underlying the Ca2+ paradox.
  
  
  METHODS
  The Ca2+ paradox was examined in fluo-3 or mag-fluo-4-loaded mouse ventricular myocytes using confocal laser scanning microscope, upon Ca2+ repletion after 15 min of Ca2+ depletion in the absence and presence of sevoflurane.
  
  
  RESULTS
  The Ca2+ paradox was evoked in approximately 65% of myocytes upon Ca2+ repletion, as determined by an abrupt elevation of cytosolic Ca2+ accompanied by hypercontracture. The Ca2+ paradox was significantly suppressed by sevoflurane administered for 3 min before and during Ca2+ repletion (Post) or during Ca2+ depletion and repletion (Postlong), and Postlong was more beneficial than Post application. The sarcoplasmic reticulum Ca2+ levels gradually decreased during Ca2+ depletion, and the Ca2+ paradox was readily evoked in myocytes with reduced sarcoplasmic reticulum Ca2+ levels. Postlong but not Post application of sevoflurane prevented decrease in sarcoplasmic reticulum Ca2+ levels by blocking Ca2+ leak through ryanodine receptors. Whole cell patch-clamp recordings revealed that sevoflurane rapidly blocked thapsigargin-induced transient receptor potential canonical currents.
  
  
  CONCLUSIONS
  Sevoflurane protects ventricular myocytes from Ca2+ paradox-mediated Ca2+ overload by blocking transient receptor potential canonical channels and by preventing the decrease in sarcoplasmic reticulum Ca2+ levels, which is associated with less activation of transient receptor potential canonical channels.
authors.affiliation: Department of Anesthesiology, Shiga University of Medical Science, Otsu, Shiga, Japan.
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: D018685:Anesthetics, Inhalation / Q000494:pharmacology*; D000814:Aniline Compounds; D000818:Animals; D002118:Calcium / Q000378:metabolism / Q000502:physiology*; D002316:Cardiotonic Agents; D055724:Electrophysiological Phenomena; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005456:Fluorescent Dyes; D006352:Heart Ventricles; D066298:In Vitro Techniques; D008297:Male; D008738:Methyl Ethers / Q000494:pharmacology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018613:Microscopy, Confocal; D032383:Myocytes, Cardiac / Q000187:drug effects*; D018408:Patch-Clamp Techniques; D012519:Sarcoplasmic Reticulum / Q000187:drug effects / Q000378:metabolism; D000077149:Sevoflurane; D019284:Thapsigargin / Q000494:pharmacology; D050051:Transient Receptor Potential Channels / Q000037:antagonists & inhibitors*; D014966:Xanthenes
chemical_list: D018685:Anesthetics, Inhalation; D000814:Aniline Compounds; D002316:Cardiotonic Agents; D004791:Enzyme Inhibitors; C409648:Fluo 4; D005456:Fluorescent Dyes; D008738:Methyl Ethers; D050051:Transient Receptor Potential Channels; D014966:Xanthenes; C059715:Fluo-3; D000077149:Sevoflurane; D019284:Thapsigargin; D002118:Calcium