Lidocaine block of cardiac sodium channels.

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Abstract
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.