LIDOCAINE ACTION ON NA+ CURRENTS IN VENTRICULAR MYOCYTES FROM THE EPICARDIAL BORDER ZONE OF THE INFARCTED HEART

Myocytes overlying a zone of infarction form the primary substrate for serious reentrant ventricular arrhythmias. In vitro and in vivo studi es suggest that antiarrhythmic agents affect Na+ channels of cells fro m the epicardial border zone (EBZ) of the 5-day infarcted heart differ ently than they affect those of normal muscle. However, the mechanisms responsible for this difference remain unclear. Previous studies have revealed differences in Na+ current (I-Na) density and inactivation g ating kinetics in myocytes dispersed from the EBZ (IZs), Since changes in inactivation gating could influence lidocaine action, we examined the effects of lidocaine on I-Na of IZs (n=38) and epicardial myocytes from the noninfarcted heart (NZs) (n=50) using the whole-cell variati on of the patch-clamp technique. In drug-free conditions, the voltage dependence of steady-state inactivation of IZs was shifted negative to that of NZs, causing greater inactivation of IZ channels at depolariz ed (greater than or equal to-100-mV) holding potentials. Consistent wi th a high affinity for the inactivated channel conformation, lidocaine produced more tonic block in IZs than NZs at depolarized holding pote ntials. Additionally, in drug-free conditions, IZ I-Na exhibited an en hanced rate of inactivation from closed states, a delay in recovery fr om inactivation, and increased use-dependent reduction in amplitude du ring rapid (1- to 3-Hz) pulse trains. In both IZs and NZs, lidocaine ( 20 to 120 mu mol/L) accelerated The rate of time-dependent loss of ava ilability and markedly delayed recovery from availability, inducing si gnificant use-dependent reduction of I-Na. However, at drug concentrat ions greater than or equal to 60 mu mol/L, the difference in use-depen dent current reduction between IZs and NZs was minimized. The action o f lidocaine to render Na+ channel inactivation in NZs more similar to that of IZs may be central to its (pro)antiarrhythmic effects.