FAST LIDOCAINE BLOCK OF CARDIAC AND SKELETAL-MUSCLE SODIUM-CHANNELS -ONE-SITE WITH 2 ROUTES OF ACCESS

We have studied the block by lidocaine and its quaternary derivative, QX-314, of single, batrachotoxin (BTX)-activated cardiac and skeletal muscle sodium channels incorporated into planar lipid bilayers. Lidoca ine and QX-314, applied to the intracellular side, appear to induce in completely resolved, rapid transitions between the open and the blocke d state of BTX-activated sodium channels from both heart and skeletal muscle. We used amplitude distribution analysis (Yellen, G. 1984. J. G en. Physiol. 84:157-186.) to estimate the rate constants for block and unblock. Block by lidocaine and QX-314 from the cytoplasmic side exhi bits rate constants with similar voltage dependence. The blocking rate increases with depolarization, and the unblocking rate increases with hyperpolarization. Fast lidocaine block was virtually identical for s odium channels from skeletal (rat, sheep) and cardiac (beef, sheep) mu scle. Lidocaine block from the extracellular side occurred at similar concentrations. However, for externally applied lidocaine, the blockin g rate was voltage-independent, and was proportional to concentration of the uncharged, rather than the charged, form of the drug. In contra st, unblocking rates for internally and externally applied lidocaine w ere identical in magnitude and voltage dependence. Our kinetic data su ggest that lidocaine, coming from the acqueous phase on the cytoplasmi c side in the charged form, associates and dissociates freely with the fast block effector site, whereas external lidocaine, in the uncharge d form, approaches the same site via a direct, hydrophobic path.