LIDOCAINE BLOCK OF CARDIAC SODIUM-CHANNELS
LIDOCAINE BLOCK OF CARDIAC SODIUM-CHANNELS
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DOI：
10.1085/jgp.81.5.613
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发表时间：
1983-01-01
影响因子：
3.8
通讯作者：
TSIEN, RW
中科院分区：
文献类型：
--
作者：
BEAN, BP;COHEN, CJ;TSIEN, RW
在电压钳位的兔浦肯野纤维中研究利多卡因对心脏Na通道的阻断，药物浓度范围从1 mM低至有效抗心律失常剂量（5-20 μ M）。剂量-反应曲线表明利多卡因通过一对一结合阻断通道，具有电压依赖性Kd。半阻断浓度从> 300 μ M（失活被完全去除的负保持电位）到约10 μ M，在去极化保持电位下，其中灭活几乎完全。利多卡因阻滞表现出明显的使用依赖性，具有负保持电位的去极化脉冲序列。在脉冲之间的间隔期间，INa [内向Na电流]的再引发显示2个指数分量，一个正常恢复分量（τ）。<0.2s）和利多卡因诱导的缓慢恢复级分（τ）。. apprx. 1-2 s（pH 7.0）。提高利多卡因浓度放大了缓慢恢复的部分，而不改变其时间过程;在长去极化后，该部分在λ时为1/2。10 μ M利多卡因，正如所预期的，如果它对应于药物结合的失活通道。在.ltoreq. 20 μ M利多卡因时，随着前一去极化的延长，缓慢恢复的级分呈指数增长至稳定水平;强或弱去极化的时程相同，即，有或没有INa的显著活化。显然，在治疗水平上的使用依赖反映了失活通道的阻断，而不是开放通道的阻断。这些结果为受体调节假说提供了直接证据。与河豚毒素不同，利多卡因与心脏、神经和骨骼肌的Na通道具有相似的相互作用。
Lidocaine block of cardiac Na channels was studied in voltage-clamped rabbit Purkinje fibers at drug concentrations ranging from 1 mM down to effective antiarrhythmic doses (5-20 .mu.M). Dose-response curves indicated that lidocaine blocks the channel by binding one-to-one, with a voltage-dependent Kd. The half-blocking concentration varied from > 300 .mu.M, at a negative holding potential where inactivation was completely removed, to .apprx. 10 .mu.M, at a depolarized holding potential where inactivation was nearly complete. Lidocaine block showed prominent use dependence with trains of depolarizing pulses from a negative holding potential. During the interval between pulses, repriming of INa [inward Na current] displayed 2 exponential components, a normally recovering component (.tau. < 0.2 s), and a lidocaine-induced, slowly recovering fraction (.tau. .apprx. 1-2 s at pH 7.0). Raising the lidocaine concentration magnified the slowly recovering fraction without changing its time course; after a long depolarization, this fraction was 1/2 at .apprx. 10 .mu.M lidocaine, just as expected if it corresponded to drug-bound, inactivated channels. At .ltoreq. 20 .mu.M lidocaine, the slowly recovering fraction grew exponentially to a steady level as the preceding depolarization was prolonged; the time course was the same for strong or weak depolarizations, that is, with or without significant activation of INa. Apparently use dependence at therapeutic levels reflects block of inactivated channels, rather than block of open channels. These results provide direct evidence for the modulated-receptor hypothesis. Unlike tetrodotoxin, lidocaine shows similar interactions with Na channels of heart, nerve and skeletal muscle.