Differential Effects of the Betablockers Carvedilol, Metoprolol and Bisoprolol on Cardiac K_v4.3 (I_to) Channel Isoforms

Cardiac K_v4.3 channels contribute to the transient outward K⁺ current, I_to, during early repolarization of the cardiac action potential. Two different isoforms of K_v4.3 are present in the human ventricle and exhibit differential remodeling in heart failure (HF). Cardioselective betablockers are a cornerstone of HF with reduced ejection fraction therapy as well as ventricular arrhythmia treatment. In this study we examined pharmacological effects of betablockers on both K_v4.3 isoforms to explore their potential for isoform-specific therapy. K_v4.3 isoforms were expressed in Xenopus laevis oocytes and incubated with the respective betablockers. Dose-dependency and biophysical characteristics were examined. HEK 293T-cells were transfected with the two K_v4.3 isoforms and analyzed with Western blots. Carvedilol (100 µM) blocked K_v4.3 L by 77 ± 2% and K_v4.3 S by 67 ± 6%, respectively. Metoprolol (100 µM) was less effective with inhibition of 37 ± 3% (K_v4.3 L) and 35 ± 4% (K_v4.3 S). Bisoprolol showed no inhibitory effect. Current reduction was not caused by changes in K_v4.3 protein expression. Carvedilol inhibited K_v4.3 channels at physiologically relevant concentrations, affecting both isoforms. Metoprolol showed a weaker blocking effect and bisoprolol did not exert an effect on K_v4.3. Blockade of repolarizing K_v4.3 channels by carvedilol and metoprolol extend their pharmacological mechanism of action, potentially contributing beneficial antiarrhythmic effects in normal and failing hearts.