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

K. Purtell, K. J. Gingrich, W. Ouyang, K. F. Herold, H. C. Hemmings

Research output: Contribution to journalArticle

12 Citations (Scopus)

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<inf>v</inf>) have been implicated as a target for anaesthetic inhibition of neurotransmitter release. We hypothesize that state-dependent interactions of isoflurane with Na<inf>v</inf> lead to increased inhibition of Na<sup>+</sup> current (I<inf>Na</inf>) 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<inf>v</inf>1.2 expressed in ND7/23 neuroblastoma cells and on endogenous Na<inf>v</inf> in isolated rat neurohypophysial nerve terminals. Rate constants determined from experiments on the recombinant channel were used in a simple model of Na<inf>v</inf> gating. Results At resting membrane potentials, isoflurane depressed peak I<inf>Na</inf> and shifted steady-state inactivation in a hyperpolarizing direction. After membrane depolarization, isoflurane accelerated entry (τ<inf>control</inf>=0.36 [0.03] ms compared with τ<inf>isoflurane</inf>=0.33 [0.05] ms, P<0.05) and slowed recovery (τ<inf>control</inf>=6.9 [1.1] ms compared with τ<inf>isoflurane</inf>=9.0 [1.9] ms, P<0.005) from apparent fast inactivation, resulting in enhanced depression of I<inf>Na</inf>, during high-frequency stimulation of both recombinant and endogenous nerve terminal Na<inf>v</inf>. A simple model of Na<inf>v</inf> 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<inf>v</inf> leading to greater depression of I<inf>Na</inf> during high-frequency stimulation, consistent with enhanced inhibition of fast firing neurones.

Original languageEnglish (US)
Pages (from-to)112-121
Number of pages10
JournalBritish Journal of Anaesthesia
Volume115
Issue number1
DOIs
StatePublished - Jul 1 2015

Fingerprint

General Anesthetics
Sodium Channels
Isoflurane
Anesthetics
Voltage-Gated Sodium Channels
Neuroblastoma
Membrane Potentials
Neurotransmitter Agents
Neurons
Membranes
Brain

Keywords

  • anaesthetics
  • general
  • isoflurane
  • presynaptic terminals
  • voltage-gated sodium channels

ASJC Scopus subject areas

  • Anesthesiology and Pain Medicine

Cite this

Activity-dependent depression of neuronal sodium channels by the general anaesthetic isoflurane. / Purtell, K.; Gingrich, K. J.; Ouyang, W.; Herold, K. F.; Hemmings, H. C.

In: British Journal of Anaesthesia, Vol. 115, No. 1, 01.07.2015, p. 112-121.

Research output: Contribution to journalArticle

Purtell, K. ; Gingrich, K. J. ; Ouyang, W. ; Herold, K. F. ; Hemmings, H. C. / Activity-dependent depression of neuronal sodium channels by the general anaesthetic isoflurane. In: British Journal of Anaesthesia. 2015 ; Vol. 115, No. 1. pp. 112-121.
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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 (Nav) have been implicated as a target for anaesthetic inhibition of neurotransmitter release. We hypothesize that state-dependent interactions of isoflurane with Nav lead to increased inhibition of Na+ current (INa) 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 Nav1.2 expressed in ND7/23 neuroblastoma cells and on endogenous Nav in isolated rat neurohypophysial nerve terminals. Rate constants determined from experiments on the recombinant channel were used in a simple model of Nav gating. Results At resting membrane potentials, isoflurane depressed peak INa and shifted steady-state inactivation in a hyperpolarizing direction. After membrane depolarization, isoflurane accelerated entry (τcontrol=0.36 [0.03] ms compared with τisoflurane=0.33 [0.05] ms, P<0.05) and slowed recovery (τcontrol=6.9 [1.1] ms compared with τisoflurane=9.0 [1.9] ms, P<0.005) from apparent fast inactivation, resulting in enhanced depression of INa, during high-frequency stimulation of both recombinant and endogenous nerve terminal Nav. A simple model of Nav gating involving stabilisation of fast inactivation, accounts for this novel form of activity-dependent block. Conclusions Isoflurane stabilises the fast-inactivated state of neuronal Nav leading to greater depression of INa during high-frequency stimulation, consistent with enhanced inhibition of fast firing neurones.",
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AU - Gingrich, K. J.

AU - Ouyang, W.

AU - Herold, K. F.

AU - Hemmings, H. C.

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N2 - 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 (Nav) have been implicated as a target for anaesthetic inhibition of neurotransmitter release. We hypothesize that state-dependent interactions of isoflurane with Nav lead to increased inhibition of Na+ current (INa) 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 Nav1.2 expressed in ND7/23 neuroblastoma cells and on endogenous Nav in isolated rat neurohypophysial nerve terminals. Rate constants determined from experiments on the recombinant channel were used in a simple model of Nav gating. Results At resting membrane potentials, isoflurane depressed peak INa and shifted steady-state inactivation in a hyperpolarizing direction. After membrane depolarization, isoflurane accelerated entry (τcontrol=0.36 [0.03] ms compared with τisoflurane=0.33 [0.05] ms, P<0.05) and slowed recovery (τcontrol=6.9 [1.1] ms compared with τisoflurane=9.0 [1.9] ms, P<0.005) from apparent fast inactivation, resulting in enhanced depression of INa, during high-frequency stimulation of both recombinant and endogenous nerve terminal Nav. A simple model of Nav gating involving stabilisation of fast inactivation, accounts for this novel form of activity-dependent block. Conclusions Isoflurane stabilises the fast-inactivated state of neuronal Nav leading to greater depression of INa during high-frequency stimulation, consistent with enhanced inhibition of fast firing neurones.

AB - 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 (Nav) have been implicated as a target for anaesthetic inhibition of neurotransmitter release. We hypothesize that state-dependent interactions of isoflurane with Nav lead to increased inhibition of Na+ current (INa) 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 Nav1.2 expressed in ND7/23 neuroblastoma cells and on endogenous Nav in isolated rat neurohypophysial nerve terminals. Rate constants determined from experiments on the recombinant channel were used in a simple model of Nav gating. Results At resting membrane potentials, isoflurane depressed peak INa and shifted steady-state inactivation in a hyperpolarizing direction. After membrane depolarization, isoflurane accelerated entry (τcontrol=0.36 [0.03] ms compared with τisoflurane=0.33 [0.05] ms, P<0.05) and slowed recovery (τcontrol=6.9 [1.1] ms compared with τisoflurane=9.0 [1.9] ms, P<0.005) from apparent fast inactivation, resulting in enhanced depression of INa, during high-frequency stimulation of both recombinant and endogenous nerve terminal Nav. A simple model of Nav gating involving stabilisation of fast inactivation, accounts for this novel form of activity-dependent block. Conclusions Isoflurane stabilises the fast-inactivated state of neuronal Nav leading to greater depression of INa during high-frequency stimulation, consistent with enhanced inhibition of fast firing neurones.

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