title: Cardiac Calcium Release Channel (Ryanodine Receptor 2) Regulation by Halogenated Anesthetics.
abstract: BACKGROUND
  Halogenated anesthetics activate cardiac ryanodine receptor 2-mediated sarcoplasmic reticulum Ca release, leading to sarcoplasmic reticulum Ca depletion, reduced cardiac function, and providing cell protection against ischemia-reperfusion injury. Anesthetic activation of ryanodine receptor 2 is poorly defined, leaving aspects of the protective mechanism uncertain.
  
  
  METHODS
  Ryanodine receptor 2 from the sheep heart was incorporated into artificial lipid bilayers, and their gating properties were measured in response to five halogenated anesthetics.
  
  
  RESULTS
  Each anesthetic rapidly and reversibly activated ryanodine receptor 2, but only from the cytoplasmic side. Relative activation levels were as follows: halothane (approximately 4-fold; n = 8), desflurane and enflurane (approximately 3-fold,n = 9), and isoflurane and sevoflurane (approximately 1.5-fold, n = 7, 10). Half-activating concentrations (Ka) were in the range 1.3 to 2.1 mM (1.4 to 2.6 minimum alveolar concentration [MAC]) with the exception of isoflurane (5.3 mM, 6.6 minimum alveolar concentration). Dantrolene (10 μM with 100 nM calmodulin) inhibited ryanodine receptor 2 by 40% but did not alter the Ka for halothane activation. Halothane potentiated luminal and cytoplasmic Ca activation of ryanodine receptor 2 but had no effect on Mg inhibition. Halothane activated ryanodine receptor 2 in the absence and presence (2 mM) of adenosine triphosphate (ATP). Adenosine, a competitive antagonist to ATP activation of ryanodine receptor 2, did not antagonize halothane activation in the absence of ATP.
  
  
  CONCLUSIONS
  At clinical concentrations (1 MAC), halothane desflurane and enflurane activated ryanodine receptor 2, whereas isoflurane and sevoflurane were ineffective. Dantrolene inhibition of ryanodine receptor 2 substantially negated the activating effects of anesthetics. Halothane acted independently of the adenine nucleotide-binding site on ryanodine receptor 2. The previously observed adenosine antagonism of halothane activation of sarcoplasmic reticulum Ca release was due to competition between adenosine and ATP, rather than between halothane and ATP.
authors.affiliation: From the School of Biomedical Sciences and Pharmacy, University of Newcastle and Hunter Medical Research Institute, Newcastle, New South Wales, Australia (D.R.L., A.W.Q.) and the School of Medicine and Public Health, University of Newcastle and Hunter Medical Research Institute, Newcastle, New South Wales, Australia (J.A., C.O., A.W.Q.).
authors.forename: Derek R
authors.initials: DR
authors.lastname: Laver
authors.forename: John
authors.initials: J
authors.lastname: Attia
authors.forename: Christopher
authors.initials: C
authors.lastname: Oldmeadow
authors.forename: Anthony W
authors.initials: AW
authors.lastname: Quail
mesh_terms: D018685:Anesthetics, Inhalation / Q000494:pharmacology; D000818:Animals; D018929:Cell Culture Techniques; D000077335:Desflurane; D004737:Enflurane / Q000494:pharmacology*; D006221:Halothane / Q000494:pharmacology*; D006321:Heart; D007530:Isoflurane / Q000031:analogs & derivatives* / Q000494:pharmacology*; D008738:Methyl Ethers / Q000494:pharmacology*; D019837:Ryanodine Receptor Calcium Release Channel / Q000187:drug effects*; D000077149:Sevoflurane; D012756:Sheep
chemical_list: D018685:Anesthetics, Inhalation; D008738:Methyl Ethers; D019837:Ryanodine Receptor Calcium Release Channel; D000077149:Sevoflurane; D004737:Enflurane; D000077335:Desflurane; D007530:Isoflurane; D006221:Halothane