BACKGROUND AND OBJECTIVE: The gamma-aminobutyric acidA receptor (GABAAR) is a target for anaesthetic agents. We investigated the interactions of sevoflurane with a recombinant GABAAR. 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 alpha1beta2gamma2 GABAAR 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 GABAAR, as suggested by the decreased current rise times. This explains the enhancement of the currents induced by low GABA concentrations (0.01 mM). Additionally, sevoflurane (b) induces a picrotoxin-like open-channel block at the GABAAR. 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.
BACKGROUND AND OBJECTIVE: The gamma-aminobutyric acidA receptor (GABAAR) is a target for anaesthetic agents. We investigated the interactions of sevoflurane with a recombinant GABAAR. 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 alpha1beta2gamma2 GABAAR 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 GABAAR, as suggested by the decreased current rise times. This explains the enhancement of the currents induced by low GABA concentrations (0.01 mM). Additionally, sevoflurane (b) induces a picrotoxin-like open-channel block at the GABAAR. 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.
Authors: Jill Singsank-Coats; Reza Seddighi; Barton W Rohrbach; Sherry K Cox; Christine M Egger; Thomas J Doherty Journal: Can J Vet Res Date: 2015-04 Impact factor: 1.310
Authors: Andreas Ranft; Daniel Golkowski; Tobias Kiel; Valentin Riedl; Philipp Kohl; Guido Rohrer; Joachim Pientka; Sebastian Berger; Alexander Thul; Max Maurer; Christine Preibisch; Claus Zimmer; George A Mashour; Eberhard F Kochs; Denis Jordan; Rüdiger Ilg Journal: Anesthesiology Date: 2016-11 Impact factor: 7.892