Kindler C H, Yost C S, Gray A T
Department of Anesthesia, University of California, San Francisco 94143-0542, USA.
Anesthesiology. 1999 Apr;90(4):1092-102. doi: 10.1097/00000542-199904000-00024.
Recently, a new structural family of potassium channels characterized by two pore domains in tandem within their primary amino acid sequence was identified. These tandem pore domain potassium channels are not gated by voltage and appear to be involved in the control of baseline membrane conductances. The goal of this study was to identify mechanisms of local anesthetic action on these channels.
Oocytes of Xenopus laevis were injected with cRNA from five cloned tandem pore domain baseline potassium channels (TASK, TREK-1, TOK1, ORK1, and TWIK-1), and the effects of several local anesthetics on the heterologously expressed channels were assayed using two-electrode voltage-clamp and current-clamp techniques.
Bupivacaine (1 mM) inhibited all studied tandem pore potassium channels, with TASK inhibited most potently. The potency of inhibition was directly correlated with the octanol: buffer distribution coefficient of the local anesthetic, with the exception of tetracaine, to which TASK is relatively insensitive. The approximate 50% inhibitory concentrations of TASK were 709 microM mepivacaine, 222 microM lidocaine, 51 microM R(+)-ropivacaine, 53 microM S(-)-ropivacaine, 668 microM tetracaine, 41 microM bupivacaine, and 39 microM etidocaine. Local anesthetics (1 mM) significantly depolarized the resting membrane potential of TASK cRNA-injected oocytes compared with saline-injected control oocytes (tetracaine 22+/-6 mV rs. 7+/-1 mV, respectively, and bupivacaine 31+/-7 mV vs. 6+/-4 mV).
Local anesthetics inhibit tandem pore domain baseline potassium channels, and they could depolarize the resting membrane potential of cells expressing these channels. Whether inhibition of these channels contributes to conduction blockade or to the adverse effects of local anesthetics remains to be determined.
最近，在其一级氨基酸序列中发现了一个新的钾通道结构家族，其特征是有两个串联的孔结构域。这些串联孔结构域钾通道不受电压门控，似乎参与了基线膜电导的控制。本研究的目的是确定局部麻醉药对这些通道的作用机制。
将来自五个克隆的串联孔结构域基线钾通道（TASK、TREK-1、TOK1、ORK1和TWIK-1）的cRNA注射到非洲爪蟾卵母细胞中，使用双电极电压钳和电流钳技术检测几种局部麻醉药对异源表达通道的影响。
布比卡因（1 mM）抑制了所有研究的串联孔钾通道，其中TASK受抑制作用最强。抑制效力与局部麻醉药的辛醇：缓冲液分配系数直接相关，但丁卡因除外，TASK对其相对不敏感。TASK的大约50%抑制浓度分别为：甲哌卡因709 microM、利多卡因222 microM、R(+)-罗哌卡因51 microM、S(-)-罗哌卡因53 microM、丁卡因668 microM、布比卡因41 microM和依替卡因39 microM。与注射生理盐水的对照卵母细胞相比，局部麻醉药（1 mM）使注射TASK cRNA的卵母细胞的静息膜电位显著去极化（丁卡因分别为22±6 mV对7±1 mV，布比卡因为31±7 mV对6±4 mV）。
局部麻醉药抑制串联孔结构域基线钾通道，并可使表达这些通道的细胞的静息膜电位去极化。这些通道的抑制是否导致传导阻滞或局部麻醉药的不良反应仍有待确定。
