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.