Lidocaine blockade of continuously and transiently accessible sites in cardiac sodium channels.

Lidocaine binds to sodium channels in a voltage dependent manner where depolarization enhances block and hyperpolarization relieves block. Voltage--clamp studies demonstrate that there are two components of block: one involving interaction with a binding site that is accessible for the duration of a depolarizing clamp (continuous access or availability) and one involving interaction with a site that is transiently available or accessible during transitions between polarized and depolarized potentials. Here we report results demonstrating two distinct voltage dependencies of blockade. The voltage dependence of block of the transiently accessible site is similar to that of channel activation and exhibits a maximal binding rate of 1.37 x 10(6)/M/S and an unbinding rate of 39.5/s at -30 mV. Blockade of the sustained site exhibits a voltage dependence similar to inactivation with a maximal binding rate of 3.59 x 10(4)/M/S and an unbinding rate of 0.678/s at -30 mV. Recovery from blockade acquired by either process is voltage dependent and proportional to exp(-0.037 Vm). Drug induced shifts in channel availability and transient site block are accurately predicted from kinetic rates estimated from frequency dependent protocols.