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 studies suggest that antiarrhythmic agents affect Na+ channels of cells from the epicardial border zone (EBZ) of the 5-day infarcted heart differently 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 gating 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 variation 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 depolarized (greater than or equal to-100-mV) holding potentials. Consistent with a high affinity for the inactivated channel conformation, lidocaine produced more tonic block in IZs than NZs at depolarized holding potentials. Additionally, in drug-free conditions, IZ I-Na exhibited an enhanced rate of inactivation from closed states, a delay in recovery from inactivation, and increased use-dependent reduction in amplitude during 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 availability and markedly delayed recovery from availability, inducing significant use-dependent reduction of I-Na. However, at drug concentrations greater than or equal to 60 mu mol/L, the difference in use-dependent current reduction between IZs and NZs was minimized. The action of lidocaine to render Na+ channel inactivation in NZs more similar to that of IZs may be central to its (pro)antiarrhythmic effects.