Inhibition of presynaptic sodium channels by halothane

Anesthesiology. 1998 Apr;88(4):1043-54. doi: 10.1097/00000542-199804000-00025.


Background: Recent electrophysiologic studies indicate that clinical concentrations of volatile general anesthetic agents inhibit central nervous system sodium (Na+) channels. In this study, the biochemical effects of halothane on Na+ channel function were determined using rat brain synaptosomes (pinched-off nerve terminals) to assess the role of presynaptic Na+ channels in anesthetic effects.

Methods: Synaptosomes from adult rat cerebral cortex were used to determine the effects of halothane on veratridine-evoked Na+ channel-dependent Na+ influx (using 22Na+), changes in intrasynaptosomal [Na+] (using ion-specific spectrofluorometry), and neurotoxin interactions with specific receptor sites of the Na+ channel (by radioligand binding). The potential physiologic and functional significance of these effects was determined by measuring the effects of halothane on veratridine-evoked Na+ channel-dependent glutamate release (using enzyme-coupled spectrofluorometry).

Results: Halothane inhibited veratridine-evoked 22Na+ influx (IC50 = 1.1 mM) and changes in intrasynaptosomal [Na+] (concentration for 50% inhibition [IC50] = 0.97 mM), and it specifically antagonized [3H]batrachotoxinin-A 20-alpha-benzoate binding to receptor site two of the Na+ channel (IC50 = 0.53 mM). Scatchard and kinetic analysis revealed an allosteric competitive mechanism for inhibition of toxin binding. Halothane inhibited veratridine-evoked glutamate release from synaptosomes with comparable potency (IC50 = 0.67 mM).

Conclusions: Halothane significantly inhibited Na+ channel-mediated Na influx, increases in intrasynaptosomal [Na+] and glutamate release, and competed with neurotoxin binding to site two of the Na+ channel in synaptosomes at concentrations within its clinical range (minimum alveolar concentration, 1-2). These findings support a role for presynaptic Na+ channels as a molecular target for general anesthetic effects.

Publication types

  • Comparative Study
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Anesthetics, Inhalation / pharmacology*
  • Animals
  • Batrachotoxins / metabolism
  • Brain / drug effects
  • Brain / metabolism
  • Excitatory Postsynaptic Potentials / drug effects
  • Exocytosis / drug effects
  • Glutamic Acid / metabolism
  • Halothane / pharmacology*
  • Male
  • Neurotoxins / metabolism
  • Presynaptic Terminals / drug effects*
  • Presynaptic Terminals / physiology
  • Rats
  • Rats, Sprague-Dawley
  • Sodium / metabolism
  • Sodium Channels / drug effects*
  • Sodium Channels / metabolism
  • Synaptosomes / drug effects*
  • Synaptosomes / metabolism
  • Veratridine / pharmacology


  • Anesthetics, Inhalation
  • Batrachotoxins
  • Neurotoxins
  • Sodium Channels
  • Glutamic Acid
  • Veratridine
  • batrachotoxinin A 20-alpha-benzoate
  • Sodium
  • Halothane