Sah R L, Tsushima R G, Backx P H
Department of Medicine, University of Toronto, Toronto, Ontario, Canada M5G 1L7.
Am J Physiol. 1998 Aug;275(2):C389-400. doi: 10.1152/ajpcell.1998.275.2.C389.
We examined the ability of local anesthetics to correct altered inactivation properties of rat skeletal muscle Na+ channels containing the equine hyperkalemic periodic paralysis (eqHPP) mutation when expressed in Xenopus oocytes. Increased time constants of current decay in eqHPP channels compared with wild-type channels were restored by 1 mM benzocaine but were not altered by lidocaine or mexiletine. Inactivation curves, which were determined by measuring the dependence of the relative peak current amplitude after depolarization to -10 mV on conditioning prepulse voltages, could be shifted in eqHPP channels back toward that observed for wild-type (WT) channels using selected concentrations of benzocaine, lidocaine, and mexiletine. Recovery from inactivation at -80 mV (50-ms conditioning pulse) in eqHPP channels followed a monoexponential time course and was markedly accelerated compared with wild-type channels (tauWT = 10.8 +/- 0.9 ms; taueqHPP = 2.9 +/- 0.4 ms). Benzocaine slowed the time course of recovery (taueqHPP,ben = 9.6 +/- 0.4 ms at 1 mM) in a concentration-dependent manner. In contrast, the recovery from inactivation with lidocaine and mexiletine had a fast component (taufast,lid = 3.2 +/- 0.2 ms; taufast,mex = 3.1 +/- 0.2 ms), which was identical to the recovery in eqHPP channels without drug, and a slow component (tauslow,lid = 1,688 +/- 180 ms; tauslow,mex = 2,323 +/- 328 ms). The time constant of the slow component of the recovery from inactivation was independent of the drug concentration, whereas the fraction of current recovering slowly depended on drug concentrations and conditioning pulse durations. Our results show that local anesthetics are generally incapable of fully restoring normal WT behavior in inactivation-deficient eqHPP channels.
我们研究了局部麻醉药对在非洲爪蟾卵母细胞中表达的、含有马高钾性周期性麻痹（eqHPP）突变的大鼠骨骼肌钠通道改变的失活特性的纠正能力。与野生型通道相比，eqHPP通道中电流衰减的时间常数增加，1 mM苯佐卡因可使其恢复，但利多卡因或美西律不能改变。通过测量去极化至 -10 mV后相对峰值电流幅度对预处理脉冲电压的依赖性来确定的失活曲线，使用选定浓度的苯佐卡因、利多卡因和美西律可使eqHPP通道中的失活曲线向野生型（WT）通道的方向移动。eqHPP通道在 -80 mV（50 ms预处理脉冲）下从失活状态恢复遵循单指数时间进程，与野生型通道相比明显加速（tauWT = 10.8 ± 0.9 ms；taueqHPP = 2.9 ± 0.4 ms）。苯佐卡因以浓度依赖性方式减慢恢复的时间进程（1 mM时taueqHPP,ben = 9.6 ± 0.4 ms）。相比之下，利多卡因和美西律引起的从失活状态恢复有一个快速成分（taufast,lid = 3.2 ± 0.2 ms；taufast,mex = 3.1 ± 0.2 ms），这与无药物时eqHPP通道中的恢复相同，还有一个缓慢成分（tauslow,lid = 1,688 ± 180 ms；tauslow,mex = 2,323 ± 328 ms）。从失活状态恢复的缓慢成分的时间常数与药物浓度无关，而缓慢恢复的电流分数取决于药物浓度和预处理脉冲持续时间。我们的结果表明，局部麻醉药通常无法在失活缺陷的eqHPP通道中完全恢复正常的WT行为。
