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Empagliflozin and Dapagliflozin Increase Na+ and Inward Rectifier K+ Current Densities in Human Cardiomyocytes Derived from Induced Pluripotent Stem Cells (hiPSC-CMs).

Published version
Peer-reviewed

Type

Article

Change log

Authors

Dago, María 
Crespo-García, Teresa  ORCID logo  https://orcid.org/0000-0003-3635-1446
Cámara-Checa, Anabel  ORCID logo  https://orcid.org/0000-0002-6124-2236
Rubio-Alarcón, Marcos  ORCID logo  https://orcid.org/0000-0002-3005-2149

Abstract

Dapagliflozin (dapa) and empagliflozin (empa) are sodium-glucose cotransporter-2 inhibitors (SGLT2is) that reduce morbidity and mortality in heart failure (HF) patients. Sodium and inward rectifier K+ currents (INa and IK1), carried by Nav1.5 and Kir2.1 channels, respectively, are responsible for cardiac excitability, conduction velocity, and refractoriness. In HF patients, Nav1.5 and Kir2.1 expression are reduced, enhancing risk of arrhythmia. Incubation with dapa or empa (24-h,1 µM) significantly increased INa and IK1 densities recorded in human-induced pluripotent stem cell-cardiomyocytes (hiPSC-CMs) using patch-clamp techniques. Dapa and empa, respectively, shifted to more hyperpolarized potentials the INa activation and inactivation curves. Identical effects were observed in Chinese hamster ovary (CHO) cells that were incubated with dapa or empa and transiently expressed human Nav1.5 channels. Conversely, empa but not dapa significantly increased human Kir2.1 currents in CHO cells. Dapa and empa effects on INa and IK1 were also apparent in Ca-calmodulin kinase II-silenced CHO cells. Cariporide, a Na+/H+ exchanger type 1 (NHE1) inhibitor, did not increase INa or IK1 in hiPSC-CMs. Dapa and empa at therapeutic concentrations increased INa and IK1 in healthy human cardiomyocytes. These SGLT2is could represent a new class of drugs with a novel and long-pursued antiarrhythmic mechanism of action.

Description

Keywords

dapagliflozin, empagliflozin, human cardiomyocytes, inward rectifier current, sodium current, Animals, Cricetinae, Humans, CHO Cells, Cricetulus, Induced Pluripotent Stem Cells, Sodium-Glucose Transporter 2 Inhibitors

Journal Title

Cells

Conference Name

Journal ISSN

2073-4409
2073-4409

Volume Title

11

Publisher

MDPI AG