Inhibition of presynaptic sodium channels by halothane.

TitleInhibition of presynaptic sodium channels by halothane.
Publication TypeJournal Article
Year of Publication1998
AuthorsRatnakumari L, Hemmings HC
Date Published1998 Apr
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

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