Comparative study of carvedilol and quinidine for inhibiting hKv4.3 channel stably expressed in HEK 293 cells

• Published in: European journal of pharmacology 2019-06, Vol.853, p.74-83
• Main Authors: Zhang, Rui, Jie, Ling-Jun, Wu, Wei-Yin, Wang, Zhi-Quan, Sun, Hai-Ying, Xiao, Guo-Sheng, Wang, Yan, Li, Yi-Gang, Li, Gui-Rong
• Format: Article
• Language: English
• Subjects: Brugada syndrome; Carvedilol; Kv4.3; Quinidine; Transient outward K+ current
• ISSN: 0014-2999; 1879-0712
• DOI: 10.1016/j.ejphar.2019.03.029

The inhibition of transient outward potassium current (Ito) is the major ionic mechanism for quinidine to treat Brugada syndrome; however, quinidine is inaccessible in many countries. The present study compared the inhibitory effect of the nonselective β-adrenergic blocker carvedilol with quinidine on human Kv4.3 (hKv4.3, encoding for Ito) channel and action potential notch using a whole-cell patch technique in HEK 293 cell line expressing KCND3 as well as in ventricular epicardial myocytes of rabbit hearts. It was found that carvedilol and quinidine inhibited hKv4.3 current in a concentration-dependent manner. The IC50 of carvedilol was 1.2 μM for inhibiting hKv4.3 charge area, while the IC50 of quinidine was 2.9 μM (0.2 Hz). Both carvedilol and quinidine showed typical open channel blocking properties (i.e. decreasing the time to peak of activation and increasing the inactivation of hKv4.3), negatively shifted the V1/2 of activation and inactivation, and slowed the recovery from inactivation of the channel. Although carvedilol had weaker in use- and rate-dependent inhibition of hKv4.3 peak current than quinidine, its reduction of the charge area was more than quinidine at all frequencies (0.2–3.3 Hz). Moreover, the inhibitory effect of carvedilol on action potential notch was greater than quinidine. These results provide the novel information that carvedilol, like quinidine, significantly inhibits hKv4.3 and action potential notch, suggesting that carvedilol is likely an alternative drug for preventing malignant ventricular arrhythmias in patients with Brugada syndrome in countries where quinidine is unavailable.