Effects of Sodium Channel Block with Mexiletine to Reverse Action Potential Prolongation in In Vitro Models of the Long QT Syndrome


  • Supported by Grant HL47678 from the National Institutes of Health, and grants from the Sixth and Seventh Manhattan Masonic Districts and Masons of New York State and Florida.

Charles Antzelevitch, Ph.D., Director Masonic Medical Research Laboratory, 2150 Bleecker St., Utica, NY 13501. Fax: 315-735-5648; E-mail: ca@mmrl.edu


Sodium Channel Block in In Vitro Models of LQTS. Introduction: Recent clinical studies have reported a greater effectiveness of sodium channel block with mexiletine to abbreviate the QT interval in patients with the chromosome 3 variant (SCN5A, LQT3) of the long QT syndrome (LQTS) than those with the chromosome 7 form of the disease (HERG, LQT2), suggesting the possibility of gene-specific therapy for the two distinct forms of the congenital LQTS. Experimental studies using the arterially perfused left ventricular wedge preparation have confirmed these clinical observations on the QT interval but have gone on to further demonstrate a potent effect of mexiletine to reduce dispersion of repolarization and prevent torsades de pointes (TdP) in both LQT2 and LQT3 models. A differential action of sodium channel block on the three ventricular cell types is thought to mediate these actions of mexiletine. This study provides a test of this hypothesis by examining the effects of mexiletine in isolated canine ventricular epicardial, endocardial, and M region tissues under conditions that mimic the SCN5A and HERG gene defects.

Methods and Results: We used standard microelectrode techniques to record transmembrane activity from endocardial, epicardial, mid-myocardial, and transmural strips isolated from the canine left ventricle, d-Sotalol, an Ikr blocker, was used to mimic the HERG defect (LQT2), and ATX-II, which increases late Na channel current, was used to mimic the SCN5A defect (LQT3). d-Sotalol (100 μM) preferentially prolonged the action potential of the mid-myocardial M cell (APD90, increased from 340 ± 65 to 623 ± 203 msec) as did ATX-II (10 to 20 nM; APD90, increased from 325 ± 51 to 580 ± 178 msec; basic cycle length = 2000 msec), thus causing a marked increase in transmural dispersion of repolarization (TDR). Mexiletine (2 to 20 μM) dose-dependently reversed the ATX-II-induced prolongation of APD90, in all three cell types. Mexiletine also reversed the d-sotalol-induced prolongation of the M cell action potential duration (APD), but bad little effect on the action potential of epicardium and endocardium. Due to its preferential effect to abbreviate the action potential of M cells, mexiletine reduced the dispersion of repolarization in both models. Low concentrations of mexiletine (5 to 10 μM) totally suppressed early afterdepolarization (EAD) and KAD-induced triggered activity in both models.

Conclusions: Our results indicate that the actions of mexiletine are both cell and model specific, but that sodium channel block with mexiletine is effective in reducing transmural differences in APD and in abolishing triggered activity induced by d-sotalol and ATX-II. The data suggest that mexiletine's actions to reduce TDR and prevent the induction of spontaneous and programmed stimulation-induced TdP in these models are due to a preferential effect of the drug to abbreviate the APD of the M cell and to suppress the development of EADs. The data provide further support for the hypothesis that block of the late sodium current may be of value in the treatment of LQT2 as well as LQT3 and perhaps other congenital and acquired (drug-induced) forms of LQTS.