The online version of this article (doi:10.1007/s00125-016-4134-x) contains peer-reviewed but unedited supplementary material, which is available to authorised users.
Antonius Baartscheer and Cees A. Schumacher contributed equally to this study and are joint first authors.
Ruben Coronel and Coert J. Zuurbier contributed equally to this study and are joint senior authors.
Empagliflozin (EMPA), an inhibitor of the renal sodium–glucose cotransporter (SGLT) 2, reduces the risk of cardiovascular death in patients with type 2 diabetes. The underlying mechanism of this effect is unknown. Elevated cardiac cytoplasmic Na+ ([Na+]c) and Ca2+ ([Ca2+]c) concentrations and decreased mitochondrial Ca2+ concentration ([Ca2+]m) are drivers of heart failure and cardiac death. We therefore hypothesised that EMPA would directly modify [Na+]c, [Ca2+]c and [Ca2+]m in cardiomyocytes.
[Na+]c, [Ca2+]c, [Ca 2+]m and Na+/H+ exchanger (NHE) activity were measured fluorometrically in isolated ventricular myocytes from rabbits and rats.
An increase in extracellular glucose, from 5.5 mmol/l to 11 mmol/l, resulted in increased [Na+]c and [Ca2+]c levels. EMPA treatment directly inhibited NHE flux, caused a reduction in [Na+]c and [Ca2+]c and increased [Ca2+]m. After pretreatment with the NHE inhibitor, Cariporide, these effects of EMPA were strongly reduced. EMPA also affected [Na+]c and NHE flux in the absence of extracellular glucose.
The glucose lowering kidney-targeted agent, EMPA, demonstrates direct cardiac effects by lowering myocardial [Na+]c and [Ca2+]c and enhancing [Ca2+]m, through impairment of myocardial NHE flux, independent of SGLT2 activity.
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Baartscheer A, Schumacher CA, Borren MM, Belterman CN, Coronel R, Fiolet JW (2003) Increased Na +/H +-exchange activity is the cause of increased [Na +]i and underlies disturbed calcium handling in the rabbit pressure and volume overload heart failure model. Cardiovasc Res 57:1015–1024 CrossRefPubMed
Van Steenbergen A, Balteau M, Scholasse J et al (2015) Identification of a glucose sensor in the heart. Eur Heart J 36 (Suppl 1):381(abstract)
- Empagliflozin decreases myocardial cytoplasmic Na+ through inhibition of the cardiac Na+/H+ exchanger in rats and rabbits
Cees A. Schumacher
Rob C. I. Wüst
Jan W. T. Fiolet
Ger J. M. Stienen
Coert J. Zuurbier
- Springer Berlin Heidelberg
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