Effect of WenxinKeli and quinidine tosuppress arrhythmogenesis in an experimental model of Brugada syndrome

Yoshino Minoura,MD,PhD,BrianK.Panama,PhD,VIadisIavV.Nesterenko,PhD,
Matthew Betzenhauser,PhD,HectorBarajas-Martinez,PhD,DanHu,MD,PhD,JoseM.DiDiego;MD;
Charles Antzelevitch,PhD,FHRS
(From the Masonic Medical Research Laboratory, Utica, New York.)

Background: Wenxin Keli(WK),a Chinese herb extract,is reported to be effective in the treatment of atrial and ventricular cardiac arrhythmias. Recent studies suggest that WK inhibits the transient potassium out ward current (Ito).

Objeot:  To examine the effectiveness of WK, alone and in combination with quinidine, to suppress arrhyth mogenesis in an experimental model of Brugada syndrome (BrS).

Methods:  Action potential and electroca rdiographic recordings were obtained from epicardia land endocardia Isites of coronary- perfused caninerightv entricular wedge preparations.The Ito agonist NS5806(10-15 NM) was used to pharmacologically mimic a genetic predisposition to BrS.

Results: The Ito agonist induced Phase2 reentry (P2R) in 139 preparations and polymorphic ventricular tachycardia (pVT) in 11/19 wedge preparations.WK(lOg/L)suppressed P2R and pVT in 100%(3/3) of preparations.A lower concentration of WK(5g/L) suppressed P2R in 60% (3/5) and pVT in 50%(2/4),but in combination with a low concentration of quinidine(5 NM), was 100% effective in suppressing P2R and pVT Quinidine alone suppressed P2R and pVT in 60%(3/5) and 50%(2/4), respectively, and incombination with WK(5g/L) suppressed P2R and pVT by 80% (4/5) and 75%(3/4), respectively. WK reduced Ito, the L-type calcium current,and contractility in single cardio myocytes,but dose-dependently increased contractility in intact wedge prepara一tions, an effect mimicked by tyramine. Conclusions Our data provide support. for the hypothesis that WK, particularly in combination with quinidine, effectively suppresses arrhythmogenesis in an experimental model of Br5 via
inhibition of Ito and indirect adrenergic sympathomimetic effects.

Keywords:  Transient outward potassium channel current; Positive inotropic effect; Cardiac arrhythmias; Suddendeath;wenxin keli

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

XIAOLIN XUE, M.D.,* DONGLIN GUQ M.D., PH.D.,t HONGMEI SUN, M.S.,*
DAN WANG, M.S.,* JIANA LI, M.S.,* TENGXIAN LIU, B.S.,t LIN YANG, M.D.,*
JUAN SHU, M.D., PH.D.,* and GAN-XIN YAN, M.D., PH.D.*,t,$
(*Department of Cardiology, the First Affiliated Hospital, Xi’ an Jiaotong University,Xi’ an, China;
tlankenau Institute for Medical Research and Main Line Health Heart Center, Wynnewood, Pennsylvania;
and #Jefferson Medical College, Thomas Jefferson University, Philadelphia, Pennsylvania〕

Background:  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.

Methods and results: 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 1 0.4 mg/mL, which was significantly lower than the IC50 of 10.6士0.9 mg/mL (n二6, 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-a interval at concentrations >_1 mg/mL. Wenxin Keli increased QRS duration by 10.1% from 34.8土1.0 ms to 38.3土1.1 ms (n二6, 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-a 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 afterdepolarization (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). Conclusions: Wenxin Keli suppressed EADs, DADS, and triggered ventricular arrhythmia via selective inhibition of late INa. (PACE 2013; 36:732-740)

Keywords: Wenxin Keli, late sodium current, early afterdepolarization, delayed afterdepolarization,
triggered activities

Wenxin Keli attenuates ischemia一induced ventricular arrhythmias in rats

XI WANG, XIN WANG,YONGWEI GU, TENG WANG and CONGXIN HUANG
( Department of Cardiology Renmin Hospital of Wuhan University, Wuhan, PR. China

Abstract: Wenxin Keli is the first state一sanctioned traditional Chinese medicine (TCM)一based
antiarrhythmic drug. The present study aimed to examine whether long-term treatment with Wenxin
Keli reduces ischemia-induced ventricular arrhythmias in rats in vivo, and if so, which mechanisms are
involved. Male rats were treated with either saline (control group) or Wenxin Keli for 3 weeks and were
subjected to myocardial ischemia for 30 min with assessment of the resulting ventricular arrhythmias.
The L-type calcium current  and transient outward potassium current were measured by the patch clamp technique in normal rat cardiac ventricular myocytes. During the 30-min ischemia, Wenxin
Keli significantly reduced the incidence of ventricular fibrillation(VF) (P<0.05). The number of ventricular
tachycardia (VT)+VF episodes and the severity of arrhythmias were significantly reduced by Wenxin Keli
administration compared to the control group (P<0.05). In addition, Wenxin Keli inhibited I(cal) and I(to) in a
concentration-dependent manner. These results suggest that Tong-term treatment with Wenxin Keli may
attenuate ischemia-induced ventricular arrhythmias in rats and that I(cal) and I(to)  may be involved in this
attenuation.

Keywords: wenxin keli,ventricular arrhythmias, L-type calcium current, transient outward potassium current, patch clamp techniques, traditional Chinese medicines