Empagliflozin decreases myocardial cytoplasmic Na(+) through inhibition of the cardiac Na(+)/H(+) exchanger in rats and rabbits

AIMS/HYPOTHESIS: 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 Ca(2+) ([Ca(2+)](c)) concentrations and decreased mitochondrial Ca(2+) concentration ([Ca(2+)](m)) are drivers of heart failure and cardiac death. We therefore hypothesised that EMPA would directly modify [Na(+)](c), [Ca(2+)](c) and [Ca(2+)](m) in cardiomyocytes. METHODS: [Na(+)](c,) [Ca(2+)](c), [Ca (2+)](m) and Na(+)/H(+) exchanger (NHE) activity were measured fluorometrically in isolated ventricular myocytes from rabbits and rats. RESULTS: An increase in extracellular glucose, from 5.5 mmol/l to 11 mmol/l, resulted in increased [Na(+)](c) and [Ca(2+)](c) levels. EMPA treatment directly inhibited NHE flux, caused a reduction in [Na(+)](c) and [Ca(2+)](c) and increased [Ca(2+)](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. CONCLUSIONS/INTERPRETATION: The glucose lowering kidney-targeted agent, EMPA, demonstrates direct cardiac effects by lowering myocardial [Na(+)](c) and [Ca(2+)](c) and enhancing [Ca(2+)](m), through impairment of myocardial NHE flux, independent of SGLT2 activity. ELECTRONIC SUPPLEMENTARY MATERIAL: 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.