Background: Atrial fibrillation (AF) is the most common sustained cardiac arrhythmia in the Western population. However, the use of current antiarrhythmic drugs is limited by poor tolerability, adverse effects and unfavourable pharmacokinetics, highlighting the need for novel therapeutic options for AF in addition to catheter ablation. Sulcardine is a novel antiarrhythmic multichannel modulator which has been shown to suppress ventricular tachycardia and AF in preclinical models. Its primary mechanism of action involves inhibition of Nav1.5 and Kv11.1, key ion channels in atrial and ventricular action potential (AP) formation. However, a detailed characterization of its atrial ion channel inhibition profile is required to better understand its therapeutic potential in AF treatment.
Purpose: This study aimed to identify atrial ion channels that are modulated by sulcardine to evaluate its potential for treatment of AF.
Methods: Atrial ion channel subunits were heterologously expressed in Xenopus laevis oocytes. The two-electrode voltage clamp (TEVC) method was used to record the respective ionic currents before and after superfusion with sulcardine. Additionally, whole-cell patch clamp measurements of human atrial cardiomyocytes obtained from patients in sinus rhythm were used to characterize the effects of sulcardine on the atrial AP.
Results: At a screening concentration of 1 mM, sulcardine significantly inhibited Kv11.1 (48%, p=0.0001, n=5), Nav1.5 (38%, p=0.0215, n=6) and K2P3.1 (29%, p=0.0001, n=5). Non-significant inhibition was shown for Kv1.5, Kir2.1 and K2P9.1. For the three hit channels, concentration-dependent effects were detected. For K2P3.1, no significant difference in inhibition was observed between stimulation rates of 0.1 Hz and 1 Hz (15% vs. 21% inhibition, p=0.8371, n=5), nor in the time course of inhibition.
Patch-clamp recordings of human atrial cardiomyocytes revealed a significant, dose-dependent reduction in atrial AP amplitude upon sulcardine administration: -29 mV at 100 µM (p=0.0004), -50 mV at 200 µM (p=0.0015) and -55 mV at 500 µM (p=0.0005; n=7 cells from N=3 individual patients each). The AP duration at 50% repolarization (APD50) was significantly prolonged by 16 ms at 200 µM (p=0.0054) and by 19 ms at 500 µM (p=0.0025) sulcardine (n/N=7/3 each). In contrast, the APD90 showed only a small, non-significant trend towards prolongation (baseline: 131.6 ms; +5 ms at 100 µM sulcardine, p=0.8395; +15 ms at 200 µM sulcardine, p=0.1612; and +12 ms at 500 µM sulcardine, p=0.4296; n/N=7/3 each).
Conclusion: In addition to Nav1.5 and Kv11.1, this study identified K2P3.1, an atrial specific ion channel known to be upregulated in AF, as a molecular target of sulcardine. Patch clamp recordings in isolated human atrial cardiomyocytes demonstrated significant reduction in AP amplitude and prolongation of APD50. These findings are consistent with inhibition of Nav1.5 and potassium channel, suggesting that sulcardine may exert class I and III antiarrhythmic effects in the atria.
