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. 2023 Sep 8;24(18):13842.
doi: 10.3390/ijms241813842.

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

Ann-Kathrin Rahm  1   2   3 , Juline Hackbarth  1   2 , Mara E Müller  1   2   3 , Julia Pfeiffer  1   2 , Heike Gampp  1   2 , Finn Petersenn  1   2 , Rasmus Rivinius  1   2 , Norbert Frey  1   2   3 , Patrick Lugenbiel  1   2   3 , Dierk Thomas  1   2   3
Affiliations

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

Ann-Kathrin Rahm et al. Int J Mol Sci. .

Abstract

Cardiac Kv4.3 channels contribute to the transient outward K+ current, Ito, during early repolarization of the cardiac action potential. Two different isoforms of Kv4.3 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 Kv4.3 isoforms to explore their potential for isoform-specific therapy. Kv4.3 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 Kv4.3 isoforms and analyzed with Western blots. Carvedilol (100 µM) blocked Kv4.3 L by 77 ± 2% and Kv4.3 S by 67 ± 6%, respectively. Metoprolol (100 µM) was less effective with inhibition of 37 ± 3% (Kv4.3 L) and 35 ± 4% (Kv4.3 S). Bisoprolol showed no inhibitory effect. Current reduction was not caused by changes in Kv4.3 protein expression. Carvedilol inhibited Kv4.3 channels at physiologically relevant concentrations, affecting both isoforms. Metoprolol showed a weaker blocking effect and bisoprolol did not exert an effect on Kv4.3. Blockade of repolarizing Kv4.3 channels by carvedilol and metoprolol extend their pharmacological mechanism of action, potentially contributing beneficial antiarrhythmic effects in normal and failing hearts.

Keywords: Ito; Kv4.3; antiarrhythmic effects; betablocker; heart failure.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
Effects of carvedilol (100 µM) on currents produced by the Kv4.3 isoform. (A,B) Representative current traces of Kv4.3 L (A) and Kv4.3 S (B) prior to (gray) and after (black) carvedilol application (50 min). (C,D) Relative peak current of Kv4.3 L (n = 8) (C) and Kv4.3 S (n = 8) (D) before, during and after the application 100 µM carvedilol. (E,F) Concentration-response curves for Kv4.3 L (n = 8–12) (IC50 = 57.1 ± 12.6 µM) (E) and Kv4.3 S (n = 8–13) (IC50 = 58.2 ± 6.2 µM) (F).
Figure 2
Figure 2
Effects of carvedilol (100 µM) on activation and inactivation of the Kv4.3 isoforms. (A,B) Representative current traces of Kv4.3 L (A) and S (B) evoked by the indicated voltage protocol prior to (gray) and after (black) carvedilol application (50 min). (C,D) I-V-plots for activation of Kv4.3 L (C) and Kv4.3 S (D) (n = 11). (E,F) I-V-plots for inactivation of Kv4.3 L (E) and Kv4.3 S (F) (n = 11). * p < 0.05, ** p < 0.01, *** p < 0.001.
Figure 3
Figure 3
Effects of carvedilol (100 µM) on the activation and inactivation of the two Kv4.3 isoforms with short depolarizing steps. (A,B) Representative current traces of Kv4.3 L (A) and S (B) induced by the indicated voltage protocol prior to (gray) and after (black) carvedilol application (50 min). (C,D) I-V plots for activation of Kv4.3 L (C) and Kv4.3 S (D) (n = 11). (E,F) I-V-plots for inactivation of Kv4.3 L (E) and Kv4.3 S (F) (n = 11). * p < 0.05, ** p < 0.01, *** p < 0.001.
Figure 4
Figure 4
Effects of carvedilol (100 µM) on the recovery from inactivation of the two Kv4.3 isoforms. (A,B) Representative Kv4.3 L (A) and Kv4.3 S (B) current traces of induced by the indicated voltage protocol prior to (gray) and after (black) carvedilol application (50 min). (C,D) Recovery from inactivation curves were calculated by plotting peak current amplitudes against the duration of the preceding repolarizing step for Kv4.3 L (C) and Kv4.3 S (D) (n = 10). * p < 0.05, ** p < 0.01.
Figure 5
Figure 5
Effects of carvedilol (100 µM) on deactivation of Kv4.3 isoforms. (A,B) Representative current traces of Kv4.3 L (A) and Kv4.3 S (B) induced by indicated voltage protocol prior to (gray) and after (black carvedilol application (50 min)). (C,D) Deactivation time constants for Kv4.3 L (C) and Kv4.3 S (D) (n = 11). *** p < 0.001.
Figure 6
Figure 6
Effects of bisoprolol (100 µM) on Kv4.3 isoforms. (A,B) Representative Kv4.3 L (A) and Kv4.3 S (B) current traces of prior to (gray) and after (black) bisoprolol application (50 min). (C,D) Relative peak current carried by Kv4.3 L (n = 11) (C) or Kv4.3 S (n = 9) (D) during application of 100 µM bisoprolol.
Figure 7
Figure 7
Effects of metoprolol (100 µM) on Kv4.3 currents. (A,B) Representative Kv4.3 L (A) and Kv4.3 S (B) current traces of prior to (gray) and after (black) metoprolol application (50 min). (C,D) Relative peak currents of Kv4.3 L (n = 9) (C) and Kv4.3 S (n = 9) (D) before, during and after application of 100 µM metoprolol. (E,F) Concentration-response curves for Kv4.3 L (n = 9–11) (IC50 = 47.3 ± 34.2 µM) (E) and Kv4.3 S (n = 9–11) (IC50 = 49.8 ± 0.7 µM) (F).
Figure 8
Figure 8
Effects of betablockers on Kv4.3 isoform expression in HEK-293T cells. (A) Representative Western blots after transfection with Kv4.3 L (A) or Kv4.3 S (B) before and after incubation with respective betablockers (100 µM) for 24 h (n = 6 each). (C,D) Protein quantification of Kv4.3 L (C) and Kv4.3 S (D) protein relative to respective controls and normalized to GAPDH.
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