Differential Effects of the Betablockers Carvedilol, Metoprolol and Bisoprolol on Cardiac K4.3 (I) Channel Isoforms.

Cardiac K4.3 channels contribute to the transient outward K current, I, during early repolarization of the cardiac action potential. Two different isoforms of K4.3 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 K4.3 isoforms to explore their potential for isoform-specific therapy. K4.3 isoforms were expressed in Xenopus oocytes and incubated with the respective betablockers. Dose-dependency and biophysical characteristics were examined. HEK 293T-cells were transfected with the two K4.3 isoforms and analyzed with Western blots. Carvedilol (100 µM) blocked K4.3 L by 77 ± 2% and K4.3 S by 67 ± 6%, respectively. Metoprolol (100 µM) was less effective with inhibition of 37 ± 3% (K4.3 L) and 35 ± 4% (K4.3 S). Bisoprolol showed no inhibitory effect. Current reduction was not caused by changes in K4.3 protein expression. Carvedilol inhibited K4.3 channels at physiologically relevant concentrations, affecting both isoforms. Metoprolol showed a weaker blocking effect and bisoprolol did not exert an effect on K4.3. Blockade of repolarizing K4.3 channels by carvedilol and metoprolol extend their pharmacological mechanism of action, potentially contributing beneficial antiarrhythmic effects in normal and failing hearts.