Nuss H B, Tomaselli G F, Marbán E
Department of Medicine, Johns Hopkins University, Baltimore, Maryland 21205, USA.
J Gen Physiol. 1995 Dec;106(6):1193-209. doi: 10.1085/jgp.106.6.1193.
When lidocaine is given systemically, cardiac Na channels are blocked preferentially over those in skeletal muscle and nerve. This apparent increased affinity is commonly assumed to arise solely from the fact that cardiac Na channels spend a large fraction of their time in the inactivated state, which exhibits a high affinity for local anesthetics. The oocyte expression system was used to compare systematically the sensitivities of skeletal (mu 1-beta 1) and cardiac (hH1-beta 1) Na channels to block by lidocaine, under conditions in which the only difference was the choice of alpha subunit. To check for differences in tonic block, Na currents were elicited after 3 min of exposure to various lidocaine concentrations at -100 mV, a potential at which both hH1-beta 1 and mu 1-beta 1 channels were fully reprimed. Surprisingly, hH1-beta 1 Na channels were threefold more sensitive to rested-state block by lidocaine (402 +/- 36 microM, n = 4-22) than were mu 1-beta 1 Na channels (1,168 +/- 34 microM, n = 7-19). In contrast, the inactivated state binding affinities determined at partially depolarized holding potentials (h infinity approximately 0.2) were similar (Kd = 16 +/- 1 microM, n = 3-9 for hH1-beta 1 and 12 +/- 2 microM, n = 4-11 for mu 1-beta 1). Lidocaine produced more use-dependent block of peak hH1-beta 1 Na current elicited by trains of short-(10 ms) or long- (1 s) duration step depolarizations (0.5 Hz, -20 mV) than of mu 1-beta 1 Na current. During exposure to lidocaine, hH1-beta 1 channels recover from inactivation at -100 mV after a prolonged delay (20 ms), while mu 1-beta 1 channels begin repriming immediately. The overall time course of recovery from inactivation in the presence of lidocaine is much slower in hH1-beta 1 than in mu 1-beta 1 channels. These unexpected findings suggest that structural differences in the alpha subunits impart intrinsically different lidocaine sensitivities to the two isoforms. The differences in steady state affinities and in repriming kinetics are both in the correct direction to help explain the increased potency of cardiac Na channel block by local anesthetics.
当利多卡因经全身给药时，与骨骼肌和神经中的钠通道相比，心脏钠通道被优先阻断。通常认为这种明显增加的亲和力仅仅源于心脏钠通道大部分时间处于失活状态，而失活状态对局部麻醉药表现出高亲和力。卵母细胞表达系统用于在仅α亚基选择不同的条件下，系统比较骨骼肌（mu 1-β1）和心脏（hH1-β1）钠通道对利多卡因阻断的敏感性。为检查强直阻断的差异，在暴露于不同利多卡因浓度3分钟后，于-100 mV引出钠电流，在该电位下hH1-β1和mu 1-β1通道均完全恢复。令人惊讶的是，hH1-β1钠通道对利多卡因静息状态阻断的敏感性（402±36 microM，n = 4 - 22）是mu 1-β1钠通道（1,168±34 microM，n = 7 - 19）的三倍。相反，在部分去极化钳制电位（h无穷大约为0.2）下测定的失活状态结合亲和力相似（hH1-β1的Kd = 16±1 microM，n = 3 - 9；mu 1-β1的Kd = 12±2 microM，n = 4 - 11）。利多卡因对短（10 ms）或长（1 s）持续时间的阶跃去极化（0.5 Hz，-20 mV）串刺激诱发的hH1-β1钠电流峰值的使用依赖性阻断比对mu 1-β1钠电流更强。在暴露于利多卡因期间，hH1-β1通道在-100 mV从失活状态恢复存在长时间延迟（20 ms），而mu 1-β1通道立即开始恢复。在利多卡因存在下，hH1-β1通道从失活状态恢复的总体时间进程比mu 1-β1通道慢得多。这些意外发现表明α亚基的结构差异赋予这两种异构体本质上不同的利多卡因敏感性。稳态亲和力和恢复动力学的差异都朝着有助于解释局部麻醉药对心脏钠通道阻断效力增加的正确方向。
