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 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. Methods: [Na⁺]_c, [Ca²⁺]_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 [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. Conclusions/interpretation: 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.