title: The mechanism of sevoflurane-induced cardioprotection is independent of the applied ischaemic stimulus in rat trabeculae.
abstract: BACKGROUND
  Sevoflurane protects the myocardium against ischaemic injury through protein kinase C (PKC) activation, mitochondrial K+ATP-channel (mitoK+ATP) opening and production of reactive oxygen species (ROS). However, it is unclear whether the type of ischaemia determines the involvement of these signalling molecules. We therefore investigated whether hypoxia (HYP) or metabolic inhibition (MI), which differentially inhibit the mitochondrial electron transport chain (ETC), are comparable concerning the relative contribution of PKC, mitoK+ATP and ROS in sevoflurane-induced cardioprotection.
  
  
  METHODS
  Rat right ventricular trabeculae were isolated and isometric contractile force (Fdev) was measured. Trabeculae were subjected to HYP (hypoxic glucose-free buffer; 40 min) or MI (glucose-free buffer, 2 mM cyanide; 30 min), followed by 60 min recovery (60 min). Contractile recovery (Fdev,rec) was determined at the end of the recovery period and expressed as a percentage of Fdev before hypoxia or MI, respectively. Chelerythrine (CHEL; 6 microM), 5-hydroxydecanoic acid sodium (100 microM) and n-(2-mercaptopropionyl)-glycine (MGP; 300 microM) were used to inhibit PKC, mitoK+ATP and ROS, respectively.
  
  
  RESULTS
  Fdev,rec after HYP was reduced to 47 (3)% (P<0.001 vs control; n=5) whereas MI reduced Fdev,rec to 28 (5)% (P<0.001 vs control; n=5). A 15 min period of preconditioning with sevoflurane (3.8%) equally increased contractile recovery after HYP [76 (9)%; P<0.05 vs HYP] and MI [67 (8)%; P<0.01 vs MI]. Chelerythrine, 5-hydroxydecanoate and n-(2-mercaptopropionyl)-glycine abolished the protective effect of sevoflurane in both ischaemic models. Trabeculae subjected to HYP or MI did not demonstrate any increased apoptotic or necrotic markers.
  
  
  CONCLUSIONS
  PKC, mitoK+ATP and ROS are involved in sevoflurane-induced cardioprotection after HYP or MI, suggesting that the means of mitochondrial ETC inhibition does not determine the signal transduction pathway for cardioprotection by anaesthetics.
authors.affiliation: Department of Anesthesiology, VU University Medical Center -Institute for Cardiovascular Research Vrije Universiteit De Boelelaan 1117, 1081 HV Amsterdam, The Netherlands. a.bouwman@vumc.nl
authors.forename: R A
authors.initials: RA
authors.lastname: Bouwman
authors.forename: F N G
authors.initials: FN
authors.lastname: van't Hof
authors.forename: W
authors.initials: W
authors.lastname: de Ruijter
authors.forename: B J
authors.initials: BJ
authors.lastname: van Beek-Harmsen
authors.forename: R J P
authors.initials: RJ
authors.lastname: Musters
authors.forename: J J
authors.initials: JJ
authors.lastname: de Lange
authors.forename: C
authors.initials: C
authors.lastname: Boer
mesh_terms: D018685:Anesthetics, Inhalation / Q000494:pharmacology*; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D004789:Enzyme Activation / Q000187:drug effects; D006352:Heart Ventricles / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D000860:Hypoxia / Q000150:complications; D019157:Ischemic Preconditioning, Myocardial / Q000379:methods*; D008297:Male; D008738:Methyl Ethers / Q000494:pharmacology*; D009200:Myocardial Contraction / Q000187:drug effects; D017202:Myocardial Ischemia / Q000209:etiology* / Q000378:metabolism / Q000503:physiopathology; D015428:Myocardial Reperfusion Injury / Q000517:prevention & control; D009336:Necrosis; D015221:Potassium Channels / Q000502:physiology; D011493:Protein Kinase C / Q000502:physiology; D051381:Rats; D017208:Rats, Wistar; D017382:Reactive Oxygen Species / Q000378:metabolism; D000077149:Sevoflurane; D015398:Signal Transduction / Q000187:drug effects; D012966:Sodium Cyanide; D046509:Tissue Culture Techniques
chemical_list: D018685:Anesthetics, Inhalation; D008738:Methyl Ethers; D015221:Potassium Channels; D017382:Reactive Oxygen Species; C117780:mitochondrial K(ATP) channel; D000077149:Sevoflurane; D011493:Protein Kinase C; D012966:Sodium Cyanide