title: Depolarizing shift in the GABA-induced current reversal potential by lidocaine hydrochloride.
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.
authors.affiliation: Department of Developmental Physiology, National Institute for Physiological Sciences, Okazaki, Japan.
authors.forename: Yoshihisa
authors.initials: Y
authors.lastname: Nakahata
authors.forename: Akiko
authors.initials: A
authors.lastname: Miyamoto
authors.forename: Miho
authors.initials: M
authors.lastname: Watanabe
authors.forename: Andrew J
authors.initials: AJ
authors.lastname: Moorhouse
authors.forename: Junichi
authors.initials: J
authors.lastname: Nabekura
authors.forename: Hitoshi
authors.initials: H
authors.lastname: Ishibashi
mesh_terms: D000779:Anesthetics, Local / Q000494:pharmacology*; D000818:Animals; D002460:Cell Line; D002478:Cells, Cultured; D002712:Chlorides / Q000378:metabolism; D006624:Hippocampus / Q000187:drug effects / Q000502:physiology; D008012:Lidocaine / Q000494:pharmacology*; D008564:Membrane Potentials / Q000187:drug effects* / Q000502:physiology; D009474:Neurons / Q000187:drug effects* / Q000502:physiology; D018408:Patch-Clamp Techniques / Q000379:methods; D011188:Potassium / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D012964:Sodium / Q000378:metabolism; D028021:Sodium-Potassium-Chloride Symporters / Q000378:metabolism; D027981:Symporters / Q000037:antagonists & inhibitors / Q000172:deficiency / Q000378:metabolism; D005680:gamma-Aminobutyric Acid / Q000378:metabolism*; D000096922:K Cl- Cotransporters
chemical_list: D000779:Anesthetics, Local; D002712:Chlorides; D008012:Lidocaine; D011188:Potassium; D012964:Sodium; D028021:Sodium-Potassium-Chloride Symporters; D027981:Symporters; D005680:gamma-Aminobutyric Acid; D000096922:K Cl- Cotransporters