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Cardiovascular Drugs and Therapy
Published in: Cardiovascular Drugs and Therapy 3/2023

04-01-2022 | Empagliflozin | Original Article

Empagliflozin Ameliorates Ouabain-Induced Na+ and Ca2+ Dysregulations in Ventricular Myocytes in an Na+-Dependent Manner

Authors: Xiaodong Peng, Linling Li, Rong Lin, Xuesi Wang, Xinmeng Liu, Yukun Li, Changsheng Ma, Yanfei Ruan, Nian Liu

Published in: Cardiovascular Drugs and Therapy | Issue 3/2023

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Abstract

Purpose

Sodium-glucose cotransporter 2 (SGLT2) inhibitors are a novel class of glucose-lowering agents that have improved clinical outcomes in patients with heart failure; however, their therapeutic mechanisms remain elusive. Although contradictory results have been reported, it has been proposed that improving Na+ homeostasis may be the underlying mechanism of action of SGLT2 inhibitors in heart failure treatment. This study explored whether empagliflozin ameliorates Na+ and Ca2+ handling disorders induced by ouabain in an Na+-dependent manner.

Methods

Isolated ventricular myocytes of mice were incubated with ouabain to establish a cellular model of Na+ overload. Effects of empagliflozin on Na+ and Ca2+ handling were evaluated using an ionOptix system and a confocal microscope. Distinct cytosolic Na+ levels were established by incubating different ouabain concentrations (10, 50, and 100 μmol/L).

Results

In the absence of ouabain, 1 μmol/L empagliflozin had a negligible impact on Na+ and Ca2+ handling in ventricular myocytes. Ouabain (50 μmol/L) significantly enhanced cytosolic Na+ levels and dysregulated Ca2+ handling, including an increased Ca2+ transient amplitude, elevated Ca2+ content in the sarcoplasmic reticulum, and enhanced spontaneous Ca2+ release normalized by treatment with 1 μmol/L empagliflozin within 10 min. All Na+ and Ca2+ handling abnormalities induced by ouabain were reversed by 1 μmol/L empagliflozin. The efficacy of empagliflozin was more potent at higher cytosolic Na+ levels. Pretreatment with the Na+/H+ exchanger (NHE) inhibitor (1 μmol/L cariporide) abolished the effects of empagliflozin.

Conclusion

Empagliflozin ameliorates ouabain-induced Na+ and Ca2+ handling disorders in a cytosolic Na+-dependent manner, potentially by inhibiting the NHE.
Appendix
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Metadata
Title
Empagliflozin Ameliorates Ouabain-Induced Na+ and Ca2+ Dysregulations in Ventricular Myocytes in an Na+-Dependent Manner
Authors
Xiaodong Peng
Linling Li
Rong Lin
Xuesi Wang
Xinmeng Liu
Yukun Li
Changsheng Ma
Yanfei Ruan
Nian Liu
Publication date
04-01-2022
Publisher
Springer US
Published in
Cardiovascular Drugs and Therapy / Issue 3/2023
Print ISSN: 0920-3206
Electronic ISSN: 1573-7241
DOI
https://doi.org/10.1007/s10557-021-07311-x

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