Differential Effects of the Betablockers Carvedilol, Metoprolol and Bisoprolol on Cardiac Kv4.3 (Ito) Channel Isoforms

Cardiac K(v)4.3 channels contribute to the transient outward K+ current, I-to, during early repolarization of the cardiac action potential. Two different isoforms of K(v)4.3 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(v)4.3 isoforms to explore their potential for isoform-specific therapy. K(v)4.3 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(v)4.3 isoforms and analyzed with Western blots. Carvedilol (100 mu M) blocked K(v)4.3 L by 77 +/- 2% and K(v)4.3 S by 67 +/- 6%, respectively. Metoprolol (100 mu M) was less effective with inhibition of 37 +/- 3% (K(v)4.3 L) and 35 +/- 4% (K(v)4.3 S). Bisoprolol showed no inhibitory effect. Current reduction was not caused by changes in K(v)4.3 protein expression. Carvedilol inhibited K(v)4.3 channels at physiologically relevant concentrations, affecting both isoforms. Metoprolol showed a weaker blocking effect and bisoprolol did not exert an effect on K(v)4.3. Blockade of repolarizing K(v)4.3 channels by carvedilol and metoprolol extend their pharmacological mechanism of action, potentially contributing beneficial antiarrhythmic effects in normal and failing hearts.

Automated summary

Cardiac K(v)4.3 channels contribute to the transient outward K+ current, I-to, during early repolarization of the cardiac action potential. Different isoforms of K(v)4.3 in the human ventricle exhibit differential remodeling in heart failure. This study explores the pharmacological effects of betablockers on the two K(v)4.3 isoforms to potentially develop isoform-specific therapy.