Bischoff Ulrike, Bräu Michael E, Vogel Werner, Hempelmann Gunter, Olschewski Andrea
Department of Physiology, Justus-Liebig-University, 35392 Giessen, Germany.
Br J Pharmacol. 2003 Aug;139(7):1273-80. doi: 10.1038/sj.bjp.0705363.
(1) Hyperpolarizing voltage steps evoke slowly activating inward currents in a variety of neurones and in cardiac cells. This hyperpolarization-activated inward current (I(h)) is thought to play a significant role in cell excitability, firing frequency, or in setting of the resting membrane potential in these cells. We studied the effects of lidocaine, mepivacaine, QX-314 and bupivacaine as well as its enantiomers on I(h) in the membrane of dorsal root ganglion neurones (DRG). (2) The patch-clamp technique was applied to small dorsal root ganglion neurones identified in 200 micro M thin slices of young rat DRGs. Under voltage-clamp conditions, the whole-cell I(h) current was recorded in the presence of different concentrations of the local anaesthetics. In current-clamp mode the resting membrane potential and the voltage response of DRG neurones to injected current pulses were investigated. (3) I(h) was reversibly blocked by bupivacaine, lidocaine and mepivacaine applied externally in clinically relevant concentrations. Concentration-response curves gave half-maximum inhibiting concentrations of 55, 99 and 190 micro M, respectively. Bupivacaine block of the I(h) current was not stereoselective. No significant effect was observed when QX-314 was applied to the external surface of the membrane. (4) In current-clamp experiments 60 micro M bupivacaine slightly hyperpolarized the membrane. The membrane stimulation by low-amplitude current pulses in the presence of bupivacaine showed an increase of the hyperpolarizing responses. (5) Our findings suggest an important role of the I(h)-block by local anaesthetics in the complex mechanism of drug action during epidural and spinal anaesthesia.
(1) 超极化电压阶跃可在多种神经元和心肌细胞中诱发缓慢激活的内向电流。这种超极化激活的内向电流（I(h)）被认为在这些细胞的兴奋性、放电频率或静息膜电位的设定中起重要作用。我们研究了利多卡因、甲哌卡因、QX-314和布比卡因及其对映体对背根神经节神经元（DRG）膜中I(h)的影响。(2) 膜片钳技术应用于从幼鼠DRG的200微摩尔薄片中鉴定出的小型背根神经节神经元。在电压钳制条件下，在不同浓度的局部麻醉剂存在下记录全细胞I(h)电流。在电流钳模式下，研究了DRG神经元的静息膜电位和对注入电流脉冲的电压响应。(3) 临床相关浓度的布比卡因、利多卡因和甲哌卡因从外部施加时可使I(h)可逆性阻断。浓度-反应曲线给出的半数最大抑制浓度分别为55、99和190微摩尔。布比卡因对I(h)电流的阻断无立体选择性。将QX-314应用于膜外表面时未观察到显著影响。(4) 在电流钳实验中，60微摩尔布比卡因使膜轻度超极化。在布比卡因存在下，低幅度电流脉冲对膜的刺激显示超极化反应增强。(5) 我们的研究结果表明，局部麻醉剂对I(h)的阻断在硬膜外和脊髓麻醉期间药物作用的复杂机制中起重要作用。
