The sodium-glucose co-transporter-2 (SGLT2) inhibitor dapagliflozin is increasingly used in the treatment of diabetes and heart failure. Dapagliflozin has been associated with reduced incidence of atrial fibrillation (AF) in clinical trials. We hypothesized that the favorable antiarrhythmic outcome of dapagliflozin use may be caused in part by previously unrecognized effects on atrial repolarizing potassium (K⁺) channels. This study was designed to assess direct pharmacological effects of dapagliflozin on cloned ion channels K_v11.1, K_v1.5, K_v4.3, K_ir2.1, K_2P2.1, K_2P3.1, and K_2P17.1, contributing to I_Kur, I_to, I_Kr, I_K1, and I_K2P K⁺ currents. Human channels coded by KCNH2, KCNA5, KCND3, KCNJ2, KCNK2, KCNK3, and KCNK17 were heterologously expressed in Xenopus laevis oocytes, and currents were recorded using the voltage clamp technique. Dapagliflozin (100 µM) reduced K_v11.1 and K_v1.5 currents, whereas K_ir2.1, K_2P2.1, and K_2P17.1 currents were enhanced. The drug did not significantly affect peak current amplitudes of K_v4.3 or K_2P3.1 K⁺ channels. Biophysical characterization did not reveal significant effects of dapagliflozin on current–voltage relationships of study channels. In conclusion, dapagliflozin exhibits direct functional interactions with human atrial K⁺ channels underlying I_Kur, I_Kr, I_K1, and I_K2P currents. Substantial activation of K_2P2.1 and K_2P17.1 currents could contribute to the beneficial antiarrhythmic outcome associated with the drug. Indirect or chronic effects remain to be investigated in vivo.

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.