Wenxin Keli Suppresses Ventricular Triggered Arrhythmias via Selective Inhibition of Late Sodium Current

Abstract

Wenxin Keli is a popular Chinese herb extract that approximately five million Asians are currently taking for the treatment of a variety of ventricular arrhythmias. However, its electrophysiological mechanisms remain poorly understood. The concentration-dependent electrophysiological effects of Wenxin Keli were evaluated in the isolated rabbit left ventricular myocytes and wedge preparation. Wenxin Keli selectively inhibited late sodium current (INa) with an IC50 of 3.8 ± 0.4 mg/mL, which was significantly lower than the IC50 of 10.6 ± 0.9 mg/mL (n = 6, P < 0.05) for the fast INa. Wenxin Keli produced a small but statistically significant QT prolongation at 0.3 mg/mL, but shortened the QT and Tp-e interval at concentrations ≥ 1 mg/mL. Wenxin Keli increased QRS duration by 10.1% from 34.8 ± 1.0 ms to 38.3 ± 1.1 ms (n = 6, P < 0.01) at 3 mg/mL at a basic cycle length of 2,000 ms. However, its effect on the QRS duration exhibited weak use-dependency, that is, QRS remained less changed at increased pacing rates than other classic sodium channel blockers, such as flecainide, quinidine, and lidocaine. On the other hand, Wenxin Keli at 1-3 mg/mL markedly reduced dofetilide-induced QT and Tp-e prolongation by attenuation of its reverse use-dependence and abolished dofetilide-induced early afterdepolarization (EAD) in four of four left ventricular wedge preparations. It also suppressed digoxin-induced delayed after depolarization (DAD) and ventricular tachycardias without changing the positive staircase pattern in contractility at 1-3 mg/mL in a separate experimental series (four of four). Wenxin Keli suppressed EADs, DADs, and triggered ventricular arrhythmias via selective inhibition of late INa.