Two components of use-dependent block of sodium current by lidocaine in voltage clamped cardiac Purkinje cells.

Lidocaine is an effective antiarrhythmic and local anesthetic agent, and it has also been a useful tool for characterizing drug interactions with the Na channel. We studied the block of sodium current (INa) caused by lidocaine (20 microM to 2 mM) in canine cardiac Purkinje cells at reduced Na (45 mM outside, 0 mM inside) and temperature (14-17 degrees C). Lidocaine block of INa developed in response to strains of depolarizations, was greater with increasing drug concentration, faster pulsing frequency, longer depolarization duration, and less negative holding potential. The time course of the fall in peak INa was best fitted by two exponentials. In contrast, block of peak INa in pulse trains by the permanently charged lidocaine analogue QX-314 was always best fitted by a single, slow exponential. When the pH was lowered from 7.4 to 6.8 to increase the proportion of the charged form of lidocaine, the contribution of the slow component increased both absolutely and relative to the fast component. The time course of the development of lidocaine block was characterized with a two pulse protocol, and it showed that block developed in a biexponential manner with initial rapid binding to a transiently available state (such as the open state) and with slower binding to a long-lived state (such as the inactivated state). We conclude that the complex binding and unbinding of lidocaine to different conformations of the cardiac Na channel is related to different affinities for the charged and uncharged forms of lidocaine.(ABSTRACT TRUNCATED AT 250 WORDS)