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  • Title: Depolarizing shift in the GABA-induced current reversal potential by lidocaine hydrochloride.
    Author: Nakahata Y, Miyamoto A, Watanabe M, Moorhouse AJ, Nabekura J, Ishibashi H.
    Journal: Brain Res; 2010 Jul 23; 1345():19-27. PubMed ID: 20580693.
    Abstract:
    Lidocaine hydrochloride (LC-HCl) is widely used as a local anesthetic, while various adverse effects of LC-HCl, such as seizures have also been reported. Lidocaine is reported to inhibit various channels and receptors including GABA(A) receptors. Although the GABA(A) receptor-mediated response depends on Cl(-) equilibrium potential (E(Cl)), little is known about the effect of LC-HCl on E(Cl). In the present study, we investigated the effect of LC-HCl on GABA-induced currents in cultured rat hippocampal neurons with gramicidin-perforated patch-clamp recording which is known to keep the intracellular Cl(-) concentration intact. LC-HCl inhibited outward GABA-induced currents with depolarizing shift of the GABA reversal potential (E(GABA)). The LC-HCl-induced positive E(GABA) shift was not observed with conventional whole-cell patch-clamp method which cannot retain intact intracellular Cl(-) concentration. The LC-HCl action on E(GABA) was inhibited by either furosemide, a blocker of both Na(+)-K(+)-Cl(-) cotransporter (NKCC) and K(+)-Cl(-) cotransporter (KCC), or an increase in extracellular K(+) concentrations. Neither bumetanide, a specific inhibitor of NKCC, nor Na(+)-free external solution had any effect on the LC-HCl-induced E(GABA) shift. QX-314, a membrane impermeable lidocaine derivative, failed to shift E(GABA) to positive potential. Furthermore, LC-HCl caused a depolarizing shift of E(GABA) in cultured GT1-7 cells expressing KCC2 but failed to change E(GABA) in GT1-7 cells without expression of KCC2. These results suggest that the LC-HCl-induced positive E(GABA) shift is due to a blockade of KCC2. Together with the direct LC-HCl action to GABA(A) receptors, the positive E(GABA) shift induced by LC-HCl reduces the GABAergic inhibition in the central nervous system.
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