We are seeing patients in-person and through Video Visits. Learn more about how we’re keeping you safe and please review our updated visitor policy. Please also consider supporting Weill Cornell Medicine’s efforts to support our front-line workers.
Department of Anesthesiology

You are here

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

TitleActivity-dependent depression of neuronal sodium channels by the general anaesthetic isoflurane.
Publication TypeJournal Article
Year of Publication2015
AuthorsPurtell K, Gingrich KJ, OuYang W, Herold KF, Hemmings HC
JournalBr J Anaesth
Volume115
Issue1
Pagination112-21
Date Published2015 Jul
ISSN1471-6771
KeywordsAnesthesia, General, Anesthetics, Inhalation, Animals, Cells, Cultured, Isoflurane, Membrane Potentials, Neurons, Rats, Sodium Channels
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(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.

DOI10.1093/bja/aev203
Alternate JournalBr J Anaesth
PubMed ID26089447
PubMed Central IDPMC4471819
Grant ListGM58055 / GM / NIGMS NIH HHS / United States
GM58055S1 / GM / NIGMS NIH HHS / United States