Activity-dependent depression of neuronal sodium channels by the general anaesthetic isoflurane

K. Purtell, K. J. Gingrich, W. Ouyang, K. F. Herold, H. C. Hemmings

Research output: Contribution to journalArticle

12 Scopus citations

Abstract

Background The mechanisms by which volatile anaesthetics such as isoflurane alter neuronal function are poorly understood, in particular their presynaptic mechanisms. Presynaptic voltage-gated sodium channels (Na<inf>v</inf>) have been implicated as a target for anaesthetic inhibition of neurotransmitter release. We hypothesize that state-dependent interactions of isoflurane with Na<inf>v</inf> lead to increased inhibition of Na<sup>+</sup> current (I<inf>Na</inf>) during periods of high-frequency neuronal activity. Methods The electrophysiological effects of isoflurane, at concentrations equivalent to those used clinically, were measured on recombinant brain-type Na<inf>v</inf>1.2 expressed in ND7/23 neuroblastoma cells and on endogenous Na<inf>v</inf> in isolated rat neurohypophysial nerve terminals. Rate constants determined from experiments on the recombinant channel were used in a simple model of Na<inf>v</inf> gating. Results At resting membrane potentials, isoflurane depressed peak I<inf>Na</inf> and shifted steady-state inactivation in a hyperpolarizing direction. After membrane depolarization, isoflurane accelerated entry (τ<inf>control</inf>=0.36 [0.03] ms compared with τ<inf>isoflurane</inf>=0.33 [0.05] ms, P<0.05) and slowed recovery (τ<inf>control</inf>=6.9 [1.1] ms compared with τ<inf>isoflurane</inf>=9.0 [1.9] ms, P<0.005) from apparent fast inactivation, resulting in enhanced depression of I<inf>Na</inf>, during high-frequency stimulation of both recombinant and endogenous nerve terminal Na<inf>v</inf>. A simple model of Na<inf>v</inf> gating involving stabilisation of fast inactivation, accounts for this novel form of activity-dependent block. Conclusions Isoflurane stabilises the fast-inactivated state of neuronal Na<inf>v</inf> leading to greater depression of I<inf>Na</inf> during high-frequency stimulation, consistent with enhanced inhibition of fast firing neurones.

Original languageEnglish (US)
Pages (from-to)112-121
Number of pages10
JournalBritish Journal of Anaesthesia
Volume115
Issue number1
DOIs
StatePublished - Jul 1 2015

Keywords

  • anaesthetics
  • general
  • isoflurane
  • presynaptic terminals
  • voltage-gated sodium channels

ASJC Scopus subject areas

  • Anesthesiology and Pain Medicine

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