Lidocaine block of cardiac sodium channels

Abstract

Lidocaine block of cardiac sodium channels was studied in voltageclamped rabbit Purkinje fibers at drug concentrations ranging from 1 mM down to effective antiarrhythmic doses (5-20 µM). Dose-response curves indicated that lidocaine blocks the channel by binding one-to-one, with a voltagedependent Kd. The half-blocking concentration varied from >300 µM, at a negative holding potential where inactivation was completely removed, to ~10 µM, 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 displayed two exponential components, a normally recovering component (τ <0.2 S), and a lidocaine-induced, slowly recovering fraction (~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 one-half at ~10 µM lidocaine, just as expected if it corresponded to drug-bound, inactivated channels. At ≤ 20 µM 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. This argues that use dependence at therapeutic levels reflects block of inactivated channels, rather than block of open channels. Overall, these results provide direct evidence for the "modulated-receptor hypothesis" of Hille (1977) and Hondeghem and Katzung (1977). Unlike tetrodotoxin, lidocaine shows similar interactions with Na channels of heart, nerve, and skeletal muscle. © 1983, Rockefeller University Press., All rights reserved.