Department of Anesthesiology

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Inhibition of presynaptic sodium channels by halothane.

TitleInhibition of presynaptic sodium channels by halothane.
Publication TypeJournal Article
Year of Publication1998
AuthorsRatnakumari L, Hemmings HC
JournalAnesthesiology
Volume88
Issue4
Pagination1043-54
Date Published1998 Apr
ISSN0003-3022
KeywordsAnesthetics, Inhalation, Animals, Batrachotoxins, Brain, Excitatory Postsynaptic Potentials, Exocytosis, Glutamic Acid, Halothane, Male, Neurotoxins, Presynaptic Terminals, Rats, Rats, Sprague-Dawley, Sodium, Sodium Channels, Synaptosomes, Veratridine
Abstract

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.

Alternate JournalAnesthesiology
PubMed ID9579514
Grant ListGM 52441 / GM / NIGMS NIH HHS / United States