Empagliflozin, an inhibitor of sodium-glucose co-transporter 2 (iSGLT2), improves cardiovascular outcomes in patients with and without diabetes and possesses an antiarrhythmic activity. However, the mechanisms of these protective effects have not been fully elucidated. This study aimed to explore the impact of empagliflozin on ion channel activity and electrophysiological characteristics in the ventricular myocardium. The main cardiac ionic currents (I_Na, I_CaL, I_CaT, I_Kr, I_Ks) and action potentials (APs) were studied in zebrafish. Whole-cell currents were measured using the patch clamp method in the isolated ventricular cardiomyocytes. The conventional sharp glass microelectrode technique was applied for the recording of APs from the ventricular myocardium of the excised heart. Empagliflozin pretreatment compared to the control group enhanced potassium I_Kr step current density in the range of testing potentials from 0 to +30 mV, I_Kr tail current density in the range of testing potentials from +10 to +70 mV, and I_Ks current density in the range of testing potentials from −10 to +20 mV. Moreover, in the ventricular myocardium, empagliflozin pretreatment shortened AP duration APD as shown by reduced APD50 and APD90. Empagliflozin had no influence on sodium (I_Na) and L- and T-type calcium currents (I_CaL and I_CaT) in zebrafish ventricular cardiomyocytes. Thus, we conclude that empagliflozin increases the rapid and slow components of delayed rectifier K⁺ current (I_Kr and I_Ks). This mechanism could be favorable for cardiac protection.

Background: Brugada syndrome (BrS) is a rare inherited cardiac arrhythmia with increased risk of sudden cardiac death. Mutations in gene SCN5A, which encodes the α-subunit of cardiac voltage-gated sodium channel NaV1.5, have been identified in over 20% of patients with BrS. However, only a small fraction of NaV1.5 variants, which are associated with BrS, are characterized in electrophysiological experiments. Results: Here we explored variants V281A and L1582P, which were found in our patients with BrS, and variants F543L and K1419E, which are reportedly associated with BrS. Heterologous expression of the variants in CHO-K1 cells and the Western blot analysis demonstrated that each variant appeared at the cell surface. We further measured sodium current in the whole-cell voltage clamp configuration. Variant F543L produced robust sodium current with a hyperpolarizing shift in the voltage dependence of steady-state fast inactivation. Other variants did not produce detectable sodium currents, indicating a complete loss of function. In a recent cryoEM structure of the hNaV1.5 channel, residues V281, K1419, and L1582 are in close contacts with residues whose mutations are reportedly associated with BrS, indicating functional importance of respective contacts. Conclusions: Our results support the notion that loss of function of NaV1.5 or decrease of the channel activity is involved in the pathogenesis of BrS.

Introduction. The development of heart failure is closely associated with the appearance of life threatening arrhythmias, which are often a terminal event for these patients. An analysis of randomized clinical trials of inhibitors of sodium-glucose cotransporter type 2 indicates the clinically significant potential of these drugs as agents with antiarrhythmic properties. However, at the moment the full mechanism by which this effect can be realized is still not fully understood.Aim. To evaluate the effect of empagliflozin on the transmembrane calcium currents and the intracellular calcium transients on isolated ventricular cardiomyocytes of mice under conditions of normoglycemia.Materials and methods. In the experiment, ventricular cardiomyocytes were isolated from 12 outbred male mice. 2 groups were formed: group № 1 – control ventricular cardiomyocytes; group № 2 – ventricular cardiomyocytes after two hours incubation with 5 µmol/L empagliflozin solution. Transmembrane calcium currents were recorded and intracellular calcium transients were assessed.Results and discussion. Incubation of ventricular cardiomyocytes with empagliflozin significantly increased I_Ca current density and accelerated Ca²⁺ temporal dynamics. The amplitude of the Ca²⁺ wave and the rate of rise and decay were increased and the duration of the Ca²⁺ wave was shortened.Conclusion. The result of the experiment indicates that empagliflozin is able to modulate Ca²⁺-dependent mechanism of the excitation-contraction-coupling, enhancing and accelerating Ca²⁺ release into cytoplasm and reuptake. This presumably can optimize, namely reduce the time of systole and enhance it, which may be one of the important elements in the manifestation of empagliflozin antiarrhythmic properties.

It has been previously demonstrated that melatonin exerts antiarrhythmic effects under conditions of ischemia and reperfusion in vivo by maintaining a relatively high conduction velocity in the myocardium. However, mechanistical details of this effect remain unclear, specifically whether melatonin affects myocardium directly or via systemic mediating signaling. The aim of the present study was to assess the impact of melatonin on the expression of genes encoding proteins potentially responsible for maintaining myocardial conduction in cultured cardiomyocytes. Ventricular cardiomyocytes isolated from neonatal rats were incubated with melatonin (100 µM) for 24 hours. Melatonin at a concentration of 100 µM enhanced the mRNA expression level of Scn5a gene and increased the amplitude of INa sodium current in cultured neonatal rat cardiomyocytes, but did not affect the parameters of steady-state activation and inactivation of INa. Thus, the present study demonstrated the direct effect of melatonin on sodium current in cardiomyocytes.