Department of Anesthesiology

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Comparative effects of halogenated inhaled anesthetics on voltage-gated Na+ channel function.

TitleComparative effects of halogenated inhaled anesthetics on voltage-gated Na+ channel function.
Publication TypeJournal Article
Year of Publication2009
AuthorsOuyang W, Herold KF, Hemmings HC
JournalAnesthesiology
Volume110
Issue3
Pagination582-90
Date Published2009 Mar
ISSN1528-1175
KeywordsAnesthetics, Inhalation, Animals, CHO Cells, Cricetinae, Cricetulus, Dose-Response Relationship, Drug, Halogenation, Muscle Proteins, Sodium Channels
Abstract

BACKGROUND: Inhibition of voltage-gated Na channels (Na(v)) is implicated in the synaptic actions of volatile anesthetics. We studied the effects of the major halogenated inhaled anesthetics (halothane, isoflurane, sevoflurane, enflurane, and desflurane) on Na(v)1.4, a well-characterized pharmacological model for Na(v) effects.

METHODS: Na currents (I(Na)) from rat Na(v)1.4 alpha-subunits heterologously expressed in Chinese hamster ovary cells were analyzed by whole cell voltage-clamp electrophysiological recording.

RESULTS: Halogenated inhaled anesthetics reversibly inhibited Na(v)1.4 in a concentration- and voltage-dependent manner at clinical concentrations. At equianesthetic concentrations, peak I(Na) was inhibited with a rank order of desflurane > halothane approximately enflurane > isoflurane approximately sevoflurane from a physiologic holding potential (-80 mV). This suggests that the contribution of Na channel block to anesthesia might vary in an agent-specific manner. From a hyperpolarized holding potential that minimizes inactivation (-120 mV), peak I(Na) was inhibited with a rank order of potency for tonic inhibition of peak I(Na) of halothane > isoflurane approximately sevoflurane > enflurane > desflurane. Desflurane produced the largest negative shift in voltage-dependence of fast inactivation consistent with its more prominent voltage-dependent effects. A comparison between isoflurane and halothane showed that halothane produced greater facilitation of current decay, slowing of recovery from fast inactivation, and use-dependent block than isoflurane.

CONCLUSIONS: Five halogenated inhaled anesthetics all inhibit a voltage-gated Na channel by voltage- and use-dependent mechanisms. Agent-specific differences in efficacy for Na channel inhibition due to differential state-dependent mechanisms creates pharmacologic diversity that could underlie subtle differences in anesthetic and nonanesthetic actions.

DOI10.1097/ALN.0b013e318197941e
Alternate JournalAnesthesiology
PubMed ID19225394
PubMed Central IDPMC2699670
Grant ListGM 58055 / GM / NIGMS NIH HHS / United States
R01 GM058055-11 / GM / NIGMS NIH HHS / United States