SGLT2 Inhibitor Empagliflozin Modulates Ion Channels in Adult Zebrafish Heart

Abstract

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 (INa, ICaL, ICaT, IKr, IKs) 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 IKr step current density in the range of testing potentials from 0 to +30 mV, IKr tail current density in the range of testing potentials from +10 to +70 mV, and IKs 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 (INa) and L- and T-type calcium currents (ICaL and ICaT) in zebrafish ventricular cardiomyocytes. Thus, we conclude that empagliflozin increases the rapid and slow components of delayed rectifier K+ current (IKr and IKs). This mechanism could be favorable for cardiac protection.

Empagliflozin reduces arrhythmogenic effects in rat neonatal and human iPSC-derived cardiomyocytes and improves cytosolic calcium handling at least partially independent of NHE1

“…Nevertheless, since EMPA also reduces APD50 and APD90, another potential target of this gliflozin might be the delayed K + current, which is the primary outward current responsible for phase 3 of cardiac repolarization 43 , 44 . This hypothesis is strengthened by the recent report of Karpushev and colleagues in which EMPA upregulated rapid and slow components of the delayed rectifier K + current in zebrafish ventricular cardiomyocytes 45 . However, as those hypotheses were not directly tested in this study, future studies are necessary to explore whether Na v 1.5 and/or delayed rectifier K + channel impact the observed SGLT2 inhibitor effect on rat and human cardiomyocyte action potential shortening.…”

Empagliflozin reduces arrhythmogenic effects in rat neonatal and human iPSC-derived cardiomyocytes and improves cytosolic calcium handling at least partially independent of NHE1

“…Nevertheless, since EMPA also reduces APD50 and APD90, another potential target of this gli ozin might be the delayed K + current, which is the primary outward current responsible for phase 3 of cardiac repolarization (38,39). This hypothesis is strengthened by the recent report of Karpushev and colleagues in which EMPA upregulated rapid and slow components of the delayed recti er K + current in zebra sh ventricular cardiomyocytes (40). However, as those hypotheses were not directly tested in this study, future studies are necessary to explore whether Na v 1.5 and/or delayed recti er K + channel impact the observed SGLT2 inhibitor effect on rat and human cardiomyocyte action potential shortening.…”

Empagliflozin suppressed cardiac fibrogenesis through sodium-hydrogen exchanger inhibition and modulation of the calcium homeostasis

“…Isoproterenol activates Ca 2+ /calmodulin-dependent protein kinase II (CaMKII) signaling and induces aberrant Ca 2+ spark frequency, thereby inducing arrhythmogenesis in failing heart [ 56 , 57 ]. Empagliflozin modulates various ion channels including Ca 2+ channels [ 52 ], Na + channels [ 44 ], and K + channels [ 58 ], suggesting that empagliflozin may modulate cardiac electrical activity. Empagliflozin has been shown to reduce ventricular arrhythmia induced by isoproterenol in diabetic heart [ 59 ].…”