Class effects of SGLT2 inhibitors in mouse cardiomyocytes and hearts: inhibition of Na+/H+ exchanger, lowering of cytosolic Na+ and vasodilation

• Published in: Diabetologia Vol. 61; no. 3; pp. 722 - 726
• Main Authors: Uthman, Laween, Baartscheer, Antonius, Bleijlevens, Boris, Schumacher, Cees A., Fiolet, Jan W. T., Koeman, Anneke, Jancev, Milena, Hollmann, Markus W., Weber, Nina C., Coronel, Ruben, Zuurbier, Coert J.
• Format: Journal Article
• Language: English
• Published: Berlin/Heidelberg Springer Berlin Heidelberg 01.03.2018; Springer Nature B.V
• Subjects: Aminopyridines - pharmacology; Animals; Benzhydryl Compounds - pharmacology; Binding sites; Calcium; Canagliflozin - pharmacology; Cardiomyocytes; Cytosol - metabolism; Diabetes; Diabetes mellitus; Glucosides - pharmacology; Heart diseases; Heart failure; Human Physiology; Hydrogen; Internal Medicine; Kidneys; Male; Medicine; Medicine & Public Health; Metabolic Diseases; Mice; Myocytes, Cardiac - drug effects; Myocytes, Cardiac - metabolism; Na+/glucose cotransporter; Na+/H+-exchanging ATPase; pH effects; Phosphocreatine; Short Communication; Sodium; Sodium - metabolism; Sodium-Glucose Transporter 2 - metabolism; Sodium-Glucose Transporter 2 Inhibitors; Sodium-Hydrogen Exchangers - drug effects; Sodium-Hydrogen Exchangers - metabolism; Sulfonamides - pharmacology; Vasodilation; Heart failure; Na; Sodium; Cardiac; exchanger; H; Diabetes; SGLT2i; Vasodilation; Na+/H+ exchanger
• ISSN: 0012-186X; 1432-0428
• DOI: 10.1007/s00125-017-4509-7

Aims/hypothesis Sodium–glucose cotransporter 2 (SGLT2) inhibitors (SGLT2i) constitute a novel class of glucose-lowering (type 2) kidney-targeted agents. We recently reported that the SGLT2i empagliflozin (EMPA) reduced cardiac cytosolic Na + ([Na + ] c ) and cytosolic Ca 2+ ([Ca 2+ ] c ) concentrations through inhibition of Na + /H + exchanger (NHE). Here, we examine (1) whether the SGLT2i dapagliflozin (DAPA) and canagliflozin (CANA) also inhibit NHE and reduce [Na + ] c ; (2) a structural model for the interaction of SGLT2i to NHE; (3) to what extent SGLT2i affect the haemodynamic and metabolic performance of isolated hearts of healthy mice. Methods Cardiac NHE activity and [Na + ] c in mouse cardiomyocytes were measured in the presence of clinically relevant concentrations of EMPA (1 μmol/l), DAPA (1 μmol/l), CANA (3 μmol/l) or vehicle. NHE docking simulation studies were applied to explore potential binding sites for SGTL2i. Constant-flow Langendorff-perfused mouse hearts were subjected to SGLT2i for 30 min, and cardiovascular function, O 2 consumption and energetics (phosphocreatine (PCr)/ATP) were determined. Results EMPA, DAPA and CANA inhibited NHE activity (measured through low pH recovery after NH 4 + pulse: EMPA 6.69 ± 0.09, DAPA 6.77 ± 0.12 and CANA 6.80 ± 0.18 vs vehicle 7.09 ± 0.09; p  < 0.001 for all three comparisons) and reduced [Na + ] c (in mmol/l: EMPA 10.0 ± 0.5, DAPA 10.7 ± 0.7 and CANA 11.0 ± 0.9 vs vehicle 12.7 ± 0.7; p  < 0.001). Docking studies provided high binding affinity of all three SGLT2i with the extracellular Na + -binding site of NHE. EMPA and CANA, but not DAPA, induced coronary vasodilation of the intact heart. PCr/ATP remained unaffected. Conclusions/interpretation EMPA, DAPA and CANA directly inhibit cardiac NHE flux and reduce [Na + ] c , possibly by binding with the Na + -binding site of NHE-1. Furthermore, EMPA and CANA affect the healthy heart by inducing vasodilation. The [Na + ] c -lowering class effect of SGLT2i is a potential approach to combat elevated [Na + ] c that is known to occur in heart failure and diabetes.