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

Br J Anaesth. 2015 Jul;115(1):112-21. doi: 10.1093/bja/aev203.


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(v)) have been implicated as a target for anaesthetic inhibition of neurotransmitter release. We hypothesize that state-dependent interactions of isoflurane with Na(v) lead to increased inhibition of Na(+) current (I(Na)) 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(v)1.2 expressed in ND7/23 neuroblastoma cells and on endogenous Na(v) in isolated rat neurohypophysial nerve terminals. Rate constants determined from experiments on the recombinant channel were used in a simple model of Na(v) gating.

Results: At resting membrane potentials, isoflurane depressed peak I(Na) and shifted steady-state inactivation in a hyperpolarizing direction. After membrane depolarization, isoflurane accelerated entry (τ(control)=0.36 [0.03] ms compared with τ(isoflurane)=0.33 [0.05] ms, P<0.05) and slowed recovery (τ(control)=6.9 [1.1] ms compared with τ(isoflurane)=9.0 [1.9] ms, P<0.005) from apparent fast inactivation, resulting in enhanced depression of I(Na), during high-frequency stimulation of both recombinant and endogenous nerve terminal Na(v). A simple model of Na(v) 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(v) leading to greater depression of I(Na) during high-frequency stimulation, consistent with enhanced inhibition of fast firing neurones.

Keywords: anaesthetics, general; isoflurane; presynaptic terminals; voltage-gated sodium channels.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Anesthesia, General*
  • Anesthetics, Inhalation / pharmacology*
  • Animals
  • Cells, Cultured
  • Isoflurane / pharmacology*
  • Membrane Potentials / drug effects
  • Neurons / drug effects*
  • Rats
  • Sodium Channels / drug effects*


  • Anesthetics, Inhalation
  • Sodium Channels
  • Isoflurane