Cardiac calcium release channel (ryanodine receptor 2) regulation by halogenated anesthetics

Laver, Derek R.; Attia, John; Oldmeadow, Christopher; Quail, Anthony W.

Title: Cardiac calcium release channel (ryanodine receptor 2) regulation by halogenated anesthetics
Creator: Laver, Derek R.; Attia, John; Oldmeadow, Christopher; Quail, Anthony W.
Relation: Funding BodyNHMRCGrant Number1082204 http://purl.org/au-research/grants/nhmrc/1082204
Relation: Anesthesiology Vol. 126, Issue 3, p. 495-506
Publisher Link: http://dx.doi.org/10.1097/ALN.0000000000001519
Publisher: Lippincott Williams & Wilkins
Resource Type: journal article
Date: 2017
Description: 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.
Subject: cardiac function; calcium release channel; ryanodine receptor; cell protection; ischemia-reperfusion injury
Identifier: http://hdl.handle.net/1959.13/1391674
Identifier: uon:33273
Identifier: ISSN:0003-3022
Language: eng
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