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

• DOI: 10.1007/s00125-016-4134-x
• Publication Date: 2016-10-17T08:12:15Z
• Authors: Antonius Baartscheer; Cees A. Schumacher; Rob C. I. Wüst; Jan W. T. Fiolet; Ger J. M. Stienen; Ruben Coronel; Coert J. Zuurbier
• Keywords: Cytoplasm; Sodium-Hydrogen Exchangers; Endocrinology, Diabetes and Metabolism; Short Communication; Heart failure; 03 medical and health sciences; 0302 clinical medicine; SDG 3 - Good Health and Well-being; Glucosides; Internal Medicine; Animals; Hypoglycemic Agents; Myocytes, Cardiac; Benzhydryl Compounds; Cardiac death; Myocardium; Diabetes; Sodium; Rats; 3. Good health; Glucose; Diabetes Mellitus, Type 2; Calcium; 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.[Na+]c, [Ca2+]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 [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.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.