Perioperative Medicine  |   March 2017
Cardiac Calcium Release Channel (Ryanodine Receptor 2) Regulation by Halogenated Anesthetics
Author Notes
  • 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.).
  • Corresponding article on page 373.
    Corresponding article on page 373.×
  • Submitted for publication February 1, 2016. Accepted for publication December 12, 2016.
    Submitted for publication February 1, 2016. Accepted for publication December 12, 2016.×
  • Address correspondence to Dr. Laver: School of Biomedical Sciences and Pharmacy, University of Newcastle and Hunter Medical Research Institute, Callaghan, New South Wales 2308 Australia. Derek.Laver@newcastle.edu.au. Information on purchasing reprints may be found at www.anesthesiology.org or on the masthead page at the beginning of this issue. Anesthesiology’s articles are made freely accessible to all readers, for personal use only, 6 months from the cover date of the issue.
Article Information
Perioperative Medicine / Basic Science
Perioperative Medicine   |   March 2017
Cardiac Calcium Release Channel (Ryanodine Receptor 2) Regulation by Halogenated Anesthetics
Anesthesiology 3 2017, Vol.126, 495-506. doi:10.1097/ALN.0000000000001519
Anesthesiology 3 2017, Vol.126, 495-506. doi:10.1097/ALN.0000000000001519
Abstract

Background: Halogenated anesthetics activate cardiac ryanodine receptor 2–mediated sarcoplasmic reticulum Ca2+ release, leading to sarcoplasmic reticulum Ca2+ 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 Ca2+ activation of ryanodine receptor 2 but had no effect on Mg2+ 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 Ca2+ release was due to competition between adenosine and ATP, rather than between halothane and ATP.