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

Diabetologia. 2018 Mar;61(3):722-726. doi: 10.1007/s00125-017-4509-7. Epub 2017 Dec 2.

Abstract

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 Ca2+ ([Ca2+]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, O2 consumption and energetics (phosphocreatine (PCr)/ATP) were determined.

Results: EMPA, DAPA and CANA inhibited NHE activity (measured through low pH recovery after NH4+ 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.

Keywords: Cardiac; Diabetes; Heart failure; Na+/H+ exchanger; SGLT2i; Sodium; Vasodilation.

MeSH terms

  • Aminopyridines / pharmacology
  • Animals
  • Benzhydryl Compounds / pharmacology
  • Canagliflozin / pharmacology
  • Cytosol / metabolism*
  • Glucosides / pharmacology
  • Male
  • Mice
  • Myocytes, Cardiac / drug effects*
  • Myocytes, Cardiac / metabolism*
  • Sodium / metabolism*
  • Sodium-Glucose Transporter 2 / metabolism*
  • Sodium-Glucose Transporter 2 Inhibitors*
  • Sodium-Hydrogen Exchangers / drug effects*
  • Sodium-Hydrogen Exchangers / metabolism*
  • Sulfonamides / pharmacology

Substances

  • Aminopyridines
  • Benzhydryl Compounds
  • Glucosides
  • N-ethyl-2-((6-methoxy-pyridin-3-yl)-(toluene-2-sulphonyl)amino)-N-pyridin-3-ylmethyl-acetamide
  • Sodium-Glucose Transporter 2
  • Sodium-Glucose Transporter 2 Inhibitors
  • Sodium-Hydrogen Exchangers
  • Sulfonamides
  • Canagliflozin
  • dapagliflozin
  • Sodium
  • empagliflozin