Atrial-selective inhibition of sodium-channel current by Wenxin Keli is effective in suppressing atrial fibrillation

Abstract

Background: Wenxin Keli is a Chinese herb extract reported to be of benefit in the treatment of cardiac arrhythmias, cardiac inflammation, and heart failure.

Methods and results: We evaluated the electrophysiologic effects of Wenxin Keli in isolated canine arterially perfused right atrial preparations with a rim of right ventricular tissue (n = 11). Transmembrane action potentials and a pseudoelectrocardiogram were simultaneously recorded. Acetylcholine (1 μM) was used to induce atrial fibrillation (AF) and to test the anti-AF potential of Wenxin Keli (5 g/L). Wenxin Keli produced preferential abbreviation of action potential duration measured at 90% repolarization (APD(90)) in atria, but caused atrial-selective prolongation of the effective refractory period, due to the development of postrepolarization refractoriness. The maximum rate of rise of the action potential upstroke was preferentially reduced in atria. The diastolic threshold of excitation increased in both atria and ventricles, but much more in atria. The duration of the "P wave" (index of atrial conduction time) was prolonged to a much greater extent than the duration of the "QRS complex" (index of ventricular conduction time). Wenxin Keli significantly reduced I(Na) and shifted steady-state inactivation to more negative potentials in HEK293 cells stably expressing SCN5A. Wenxin Keli prevented the induction of persistent AF in 100% atria (6/6) and, in another experimental series, was found to terminate persistent acetylcholine-mediated AF in 100% of atria (3/3).

Conclusion: Wenxin Keli produces atrial-selective depression of I(Na)-dependent parameters in canine isolated coronary-perfused preparations via a unique mechanism and is effective in suppressing AF and preventing its induction, with minimal effects on the ventricular electrophysiology.

Figure 1

Wenxin Keli causes a greater abbreviation of action potential duration (APD₉₀) in atria than in ventricles. Upper panels: superimposed action potentials recorded from atrial and ventricular muscle under control conditions (C) and after addition of 5 g/L Wenxin Keli (W) to the coronary perfusate. Pacing cycle length (CL) = 500 ms. Bottom panels: Plots depict the average APD₉₀ data recorded at pacing CLs of 500 and 300 ms. * - p<0.05 vs. control. ** - p<0.001 vs. control.

Figure 2

Wenxin Keli prolongs effective refractory period (ERP) selectively in atria due to induction of post-repolarization refractoriness (PRR) in atria but not in the ventricles. Upper panels: Shown are typical action potentials recorded from atrial and ventricular parts of the coronary-perfused preparation in control and after Wenxin Keli. Each tracing shows a basic beat following by the premature beat with the shortest coupling interval producing an active propagating response, thus depicting the ERP. Bottom panels: Plots show average action potential duration (APD) and ERP data at a cycle length (CL) of 500 and 300 ms. Dashed lines depict the duration of PRR. PRR was approximated by the difference between ERP and APD₇₀ in atria and between ERP and APD₉₀ in ventricles; note that ERP corresponds to APD_70-75 in atria and to APD₉₀ in ventricles. * - p<0.05 vs. control. ** - <0.001 vs. control. † - p <0.001 vs. APD₇₀ Despite a significant abbreviation of APD in atria, Wenxin Keli significantly prolonged ERP in atria. In contrast, Wenxin Keli abbreviated both APD and ERP in ventricles.

Figure 3

Wenxin Keli (5 g/L) produced a much greater reduction of the maximum rate of rise of the action potential upstroke (V_max) in atria vs. ventricles. Upper panel: Transmembrane action potentials and respective V_max values recorded upon abbreviation of cycle length (CL) from 500 to 300 ms and following return to 500 ms Bottom panels: Summary data of the effects of Wenxin Keli on V_max in atrial and ventricular preparations. All data are normalized to control V_max the value recorded at a CL of 500 ms. *- p<0.05 vs. control; ** - p<0.001 vs. control.

Figure 4

Wenxin Keli (5 g/L) increases diastolic threshold of excitation (DTE) and conduction time (CT) preferentially in atria. These atrioventricular differences in response to Wenxin Keli are greater at a cycle length (CL) of 300 vs. 500 ms. * - p<0.01 vs. control. ** - p<0.001 vs. control.

Figure 5

Wenxin Keli (5 g/L) increases the shortest S₁ – S₁ permitting 1:1 activation in atria but not in the ventricles (measured at a DTEx2at a cycle length (CL) = 500 ms). Upper panel: typical examples of action potential tracings showing failure of 1:1 activation at a CL of 300 ms in an atria but 1:1 capture in the ventricle. Lower panel: summary data. * - p<0.001 vs. control.

Figure 6

Wenxin Keli (5 g/L) effectively terminates persistent acetylcholine (ACh)-mediated atrial fibrillation and prevents its induction. Shown are ECG and action potential tracings recorded 1) during persistent atrial fibrillation (AF) induced in the presence of ACh alone (upper panel); at the moment of termination of persistent ACh-mediated AF by Wenxin Keli (bottom left panel); and 3) during a failed attempt to induce AF by rapid pacing in the presence of both ACh and Wenxin Keli.

Figure 7

Wenxin Keli (5 g/L) prolongs atrial action potential duration in the presence of acetylcholine (1.0 μM). Shown are superimposed action potentials recorded from pectinate muscle under baseline conditions (control), in the presence of acetylcholine (ACh) and following addition of Wenxin Keli in the continuous presence of ACh. Cycle length = 500 ms.

Figure 8

The effects of Wenxin Keli on peak I_Na measured in HEK293 cells stably expressing SCN5A. A: Representative currents recorded at −20 mV following a preconditioning pulse to −140 mV, −90 mV and −60 mV (inset) at 0.1 Hz before and after 5g/L Wenxin Keli. B: Steady-state inactivation (availability) relationship in control and after 5 and 10g/L Wenxin Keli. C: Rate-dependence of I_Na before and after exposure to 5g/L or 10g/L Wenxin Keli. A train of 40 pulses (to −20 mV for 20 ms) was applied at 10 Hz from a holding potential of −120 mV. Numbers indicate the 1^st and 40^th pulse of the 10-Hz train. D: Use-dependent block (UDB) of I_Na following acceleration from 1 to 10 Hz in control and after exposure to 5 and 10g/L Wenxin Keli.