Sevoflurane potentiates and blocks GABA-induced currents through recombinant α[sub 1]β[sub 2]γ[sub 2] GABA[sub A] receptorsimplications for an enhanced GABAergic transmission.

Summary Background and objective The gamma-aminobutyric acid[sub A] receptor (GABA[sub A]R) is a target for anaesthetic agents. We investigated the interactions of sevoflurane with a recombinant GABA[sub A]R. Emphasis was on the mechanism of block, as relevant open-channel block by a volatile anaesthetic would possibly explain prolonged GABAergic postsynaptic currents. Methods The effect of sevoflurane on GABA-induced currents through recombinant alpha[sub 1]beta[sub 2]gamma[sub 2] GABA[sub A]R channels was studied (patch clamp; HEK293 cells). GABA 0.01 mM or 1 mM was applied alone or together with sevoflurane (0.05 mM to 5 mM). Results Currents elicited by GABA 0.01 mM were increased by low sevoflurane concentrations to 183% and decreased by high sevoflurane concentrations (>1 mM) to 34% (P<0.05). Ten- to 90%-rise times of the currents were reduced by sevoflurane concentration dependently. At GABA (1 mM), peak currents and 10-90%-rise times decreased with increasing sevoflurane concentrations. A transient current increase was induced by discontinuation of GABA and sevoflurane. Such rebound currents indicate a reversal of an open-channel block by sevoflurane. Conclusions Sevoflurane (a) increases the apparent affinity of GABA to the GABA[sub A]R, as suggested by the decreased current rise times. This explains the enhancement of the currents induced by low GABA concentrations (0.01mM). Additionally, sevoflurane (b) induces a picrotoxin-like open-channel block at the GABA[sub A]R. The reversal of the open-channel block elicits a delayed GABA response. These findings indicate at least two different sites of action of sevoflurane at this receptor that are both important for an enhanced GABAergic synaptic transmission. [ABSTRACT FROM AUTHOR]