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Wu J, Harata N, Akaike N: Potentiation by sevoflurane of the gamma-aminobutyric acid-induced chloride current in acutely dissociated CA1 pyramidal neurones from rat hippocampus. Br J Pharmacol. 1996 Nov;119(5):1013-21.
1. The effects of a new kind of volatile anaesthetic, sevoflurane (Sev), on gamma-aminobutyric acid (GABA)-gated chloride current (Icl) in single neurones dissociated from the rat hippocampal CA1 area were examined using the nystatin perforated patch recording configuration under the voltage-clamp condition. All drugs were applied with a rapid perfusion system, termed the "Y-tube' method. 2. When the concentrations were higher than 3 x 10 (-4) M, Sev, itself, induced an inward current (ISev) at a holding potential (VH) of -40 mV. The concentration-response curve of ISev was bell-shaped, with a suppressed peak and plateau currents at high concentrations (above 2 x 10 (-3) M). The reversal potential of ISev (ESev) was close to the theoretical Cl- equilibrium potential, indicating that ISev was carried mainly by Cl-. 3. ISev was reversibly blocked by bicuculline (Bic), an antagonist of the GABAA receptor, in a concentration-dependent manner with a half-inhibitory concentration (IC50) of 7.2 x 10 (-7) M. But ISev was insensitive to strychnine (Str), an antagonist of the glycine receptor. 4. At low concentrations (between 3 x 10 (-4) and 10 (-3) M), Sev markedly enhanced the 10 (-6) M GABA induced current (IGABA) but reduced the IGABA with accelerating desensitization accompanied by a "hump' current after washout at high concentrations (higher than 2 x 10 (-3) M). 5. Sev, 10 (-3) M potentiated the current induced by low concentrations of GABA (between 10 (-7) and 3 x 10 (-6) M) but reduced the current induced by high concentrations (higher than 10 (-5) M) of GABA with a clear acceleration of IGABA desensitization. 6. Sev, like pentobarbitone (PB), pregnanolone (PGN) or diazepam (DZP), potentiated the 10 (-6) M GABA-induced response without shifting the reversal potential of IGABA. 7. ISev was augmented by PB, PGN, or DZP at concentrations that maximally potentiated IGABA, suggesting that Sev enhanced IGABA at a binding site distinct from that for PB, PGN, or DZP. 8. It is concluded that Sev acts on the GABAA receptor complex mimicking the GABA-induced chloride current at high concentrations. At low concentrations, Sev enhances GABA-gated chloride current at a binding site independent of the allosteric modulator sites of barbiturates, benzodiazepines or neurosteroids. The reversible potentiation of the inhibitory GABAA receptor-mediated Cl- current may result in the depressing of postsynaptic excitability and may, at least in part, underlie the anaesthetic action of Sev. |
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