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.
[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.
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.
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.