Vol. 298, Issue 1, 201-208, July 2001

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

Department of Anaesthesiology, Klinikum rechts der Isar, Technische Universität München, Munich, Germany (G.H., R.H., M.B., E.K.); and Max-Planck-Institute of Psychiatry, Munich, Germany (W.Z.)

Clinically relevant concentrations of isoflurane (ISO) and nitrous oxide (N₂O) enhance chloride currents induced by activating -aminobutyric acid_A receptors (GABA_AR). 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 _122L GABA_AR 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 GABA_AR.