Background

Cardiac K_v4.3 channels contribute to the transient outward K⁺ current, I_to, which plays an important role in the early repolarization of the cardiac action potential. Two different K_v4.3 isoforms (K_v4.3 L and K_v4.3 S) are expressed in the human ventricle. These isoforms are differently remodelled in heart failure. In heart failure therapy, betablockers such as carvedilol, metoprolol and bisoprolol are essential drugs. In addition, they are used in the context of ventricular arrhythmia. In this study we examined pharmacological effects of betablockers on the two K_v4.3 isoforms.

 

Methods

K_v4.3 isoforms were heterologously expressed in Xenopus laevis oocytes. Using the two-electrode voltage-clamp technique, pharmacological effects of betablockers on K_v4.3 channel function were analysed. Furthermore, biophysical effects of carvedilol on K_v4.3 current were examined. Additionally, potential effects of betablockers on protein trafficking were assessed in HEK cells expressing the K_v4.3 isoforms. 

 

Results

Carvedilol (100 µM) and metoprolol (100 µM) inhibited both K_v4.3 isoforms. Carvedilol blocked K_v4.3 L by 77 ± 2% and K_v4.3 S by 67 ± 6%. Metoprolol reduced K_v4.3 L and K_v4.3 S currents by 37 ± 3% and by 35 ± 4%, respectively. No relevant inhibitory effect was observed for bisoprolol. Carvedilol exerted significant biophysical effects on activation, inactivation, recovery from inactivation, and deactivation of K_v4.3 S and L currents. Expression of K_v4.3 isoform protein was not modified by betablockers. 

 

Conclusion

Betablockers carvedilol and metoprolol inhibited K_v4.3 channels at physiological relevant concentrations. The drugs similarly affected both cardiac channel isoforms. Blockade of repolarizing K_v4.3 channels by carvedilol and metoprolol extend their pharmacological mechanism of action, potentially exerting beneficial antiarrhythmic effects in normal and failing hearts.