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Research ArticleNEUROPHARMACOLOGY

Coadministered Nitrous Oxide Enhances the Effect of Isoflurane on GABAergic Transmission by an Increase in Open-Channel Block

Gerhard Hapfelmeier, Rainer Haseneder, Eberhard Kochs, Michaela Beyerle and Walter Zieglgänsberger
Journal of Pharmacology and Experimental Therapeutics July 2001, 298 (1) 201-208;
Gerhard Hapfelmeier
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Rainer Haseneder
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Eberhard Kochs
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Michaela Beyerle
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Walter Zieglgänsberger
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Abstract

Clinically relevant concentrations of isoflurane (ISO) and nitrous oxide (N2O) enhance chloride currents induced by activating γ-aminobutyric acidA receptors (GABAAR). Channel blocking by ISO overcomes the enhancing effect at higher concentrations. In this study, the effect of coadministered ISO and N2O on responses evoked by GABA in transfected human embryonic kidney 293 cells carrying α1β2γ2L GABAAR was investigated. Patch-clamp recordings from these cells were performed in the whole cell mode. A piezo-driven “liquid filament” drug application system was used to apply solutions of GABA, ISO, and N2O. Increasing the concentration of ISO in steps from 0.15 to 1.2 mM resulted in a bell-shaped concentration-response curve for GABA-induced currents. The maximum increase in current (1.51 ± 0.14-fold) was seen at 0.45 mM ISO (about 1 minimum alveolar concentration, EC50). N2O (29.2 mM) increased GABA-evoked currents 1.54 ± 0.10-fold. The enhancing effects of ISO and N2O on the GABAergic response were not additive. However, a transient current, associated with the rapid withdrawal of ISO from the receptor, was markedly increased by N2O. Such rebound currents probably reflect the transition from a “channel-blocked” to a “reopened” state. An open-channel block at ligand-gated receptors can prolong postsynaptic currents. Thus, we conclude that coadministered N2O could increase the enhancing effect of ISO on the GABAergic transmission by an increase in open-channel block at the GABAAR.

Footnotes

  • This work was supported by the Deutsche Forschungsgemeinschaft (Grant Schn-514/2-2), and by the Dr.-Ing. Leonhard Lorenz-Stiftung, München, Az. 376/97. The results were partly presented at the 1999 ASA meeting, Dallas, TX, Abstract no. A795.

  • Abbreviations:
    MAC
    minimum alveolar concentration
    ISO
    isoflurane
    GABAAR
    A-type receptor for γ-aminobutyric acid
    GABA
    γ-aminobutyric acid
    IPSC
    inhibitory postsynaptic current
    HEK
    human embryonic kidney
    • Received December 27, 2000.
    • Accepted March 22, 2001.
  • The American Society for Pharmacology and Experimental Therapeutics
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Journal of Pharmacology and Experimental Therapeutics: 298 (1)
Journal of Pharmacology and Experimental Therapeutics
Vol. 298, Issue 1
1 Jul 2001
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Research ArticleNEUROPHARMACOLOGY

Coadministered Nitrous Oxide Enhances the Effect of Isoflurane on GABAergic Transmission by an Increase in Open-Channel Block

Gerhard Hapfelmeier, Rainer Haseneder, Eberhard Kochs, Michaela Beyerle and Walter Zieglgänsberger
Journal of Pharmacology and Experimental Therapeutics July 1, 2001, 298 (1) 201-208;

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Research ArticleNEUROPHARMACOLOGY

Coadministered Nitrous Oxide Enhances the Effect of Isoflurane on GABAergic Transmission by an Increase in Open-Channel Block

Gerhard Hapfelmeier, Rainer Haseneder, Eberhard Kochs, Michaela Beyerle and Walter Zieglgänsberger
Journal of Pharmacology and Experimental Therapeutics July 1, 2001, 298 (1) 201-208;
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