title: Activity-dependent depression of neuronal sodium channels by the general anaesthetic isoflurane.
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.
authors.affiliation: Department of Pharmacology, Weill Cornell Medical College, New York, NY 10065, USA.
authors.forename: K
authors.initials: K
authors.lastname: Purtell
authors.affiliation: Department of Anesthesiology, University of Texas Southwestern Medical Center, Dallas, TX 75235, USA.
authors.forename: K J
authors.initials: KJ
authors.lastname: Gingrich
authors.affiliation: Department of Anesthesiology, Weill Cornell Medical College, New York, NY 10065, USA Present address: College of Physical Education and Health Sciences, Zhejiang Normal University, Jinhua, Zhejiang, China.
authors.forename: W
authors.initials: W
authors.lastname: Ouyang
authors.affiliation: Department of Anesthesiology, Weill Cornell Medical College, New York, NY 10065, USA kah2016@med.cornell.edu hchemmi@med.cornell.edu.
authors.forename: K F
authors.initials: KF
authors.lastname: Herold
authors.affiliation: Department of Pharmacology, Weill Cornell Medical College, New York, NY 10065, USA Department of Anesthesiology, Weill Cornell Medical College, New York, NY 10065, USA kah2016@med.cornell.edu hchemmi@med.cornell.edu.
authors.forename: H C
authors.initials: HC
authors.lastname: Hemmings
mesh_terms: D000768:Anesthesia, General; D018685:Anesthetics, Inhalation / Q000494:pharmacology*; D000818:Animals; D002478:Cells, Cultured; D007530:Isoflurane / Q000494:pharmacology*; D008564:Membrane Potentials / Q000187:drug effects; D009474:Neurons / Q000187:drug effects*; D051381:Rats; D015222:Sodium Channels / Q000187:drug effects*
chemical_list: D018685:Anesthetics, Inhalation; D015222:Sodium Channels; D007530:Isoflurane
keywords: anaesthetics, general; isoflurane; presynaptic terminals; voltage-gated sodium channels