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

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 froAims/hypothesism 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/interprelation 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.