Lidocaine Action on Na⁺ Currents in Ventricular Myocytes From the Epicardial Border Zone of the Infarcted Heart

From the Department of Pharmacology, Columbia University (J.P., P.A.B.), New York, NY, and the Department of Anesthesiology and Critical Care Medicine, Johns Hopkins University School of Medicine (J.R.B.), Baltimore, Md.

Correspondence to Penelope A. Boyden, PhD, Department of Pharmacology, Columbia College of Physicians and Surgeons, 630 West 168th St, New York, NY 10032. E-mail pab4{at}columbia.edu

Abstract—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 (-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 µmol/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 60 µmol/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.

Key Words: Na⁺ current • ion channel • ventricular myocyte • myocardial infarction • epicardial border zone • lidocaine

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