Depolarizing shift in the GABA-induced current reversal potential by lidocaine hydrochloride
Depolarizing shift in the GABA-induced current reversal potential by lidocaine hydrochloride
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DOI：
10.1016/j.brainres.2010.05.052
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发表时间：
2010-07-23
期刊：
影响因子：
2.9
通讯作者：
Ishibashi, Hitoshi
中科院分区：
文献类型：
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作者：
Nakahata, Yoshihisa;Miyamoto, Akiko;Ishibashi, Hitoshi
盐酸利多卡因（LC-HCl）被广泛用作局部麻醉剂，同时也有各种不良反应的报道，如癫痫发作。据报道，利多卡因可抑制多种通道和受体，包括GABA（A）受体。虽然GABA（A）受体介导的反应依赖于Cl-平衡电位（E-Cl），但关于LC-HCl对E-Cl的影响知之甚少。在本研究中，我们研究了LC-HCl对GABA诱导的电流在培养的大鼠海马神经元短杆菌肽穿孔膜片钳记录，这是已知的保持细胞内的Cl-浓度完整的影响。LC-HCl抑制GABA诱导的外向电流，并使GABA逆转电位（E-GABA）去极化移位。用传统的全细胞膜片钳方法不能保持细胞内Cl-浓度的完整性，不能观察到LC-HCl诱导的E-GABA正向位移。LC-HCl对E-GABA的作用可被Na ~+-K ~+-Cl ~-协同转运体（NKCC）和K ~+-Cl ~-协同转运体（K-CC）的阻断剂呋塞米或细胞外K ~+浓度的增加所抑制。无论是布美他尼，NKCC的特异性抑制剂，也没有Na+的外部解决方案有任何LC-HCl诱导的E-GABA移位的影响。QX-314是一种不透膜的利多卡因衍生物，不能使E-GABA转变为正电位。此外，LC-HCl引起培养的表达KCC 2的GT 1 -7细胞中的E-GABA的去极化移位，但不能改变不表达KCC 2的GT 1 -7细胞中的E-GABA。这些结果表明，LC-HCl诱导的正E-GABA移位是由于KCC 2的阻断。与LC-HCl对GABA（A）受体的直接作用一起，LC-HCl诱导的正E-GABA移位减少了中枢神经系统中的GABA能抑制。(C)2010 Elsevier BV保留所有权利。
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 (K-CC), 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. (C) 2010 Elsevier B.V. All rights reserved.