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

Diabetologia. 2017 Mar;60(3):568-573. doi: 10.1007/s00125-016-4134-x. Epub 2016 Oct 17.

Abstract

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.

Keywords: Calcium; Cardiac death; Diabetes; Glucose; Heart failure; Sodium.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Benzhydryl Compounds / therapeutic use*
  • Calcium / metabolism
  • Cytoplasm / drug effects
  • Cytoplasm / metabolism
  • Diabetes Mellitus, Type 2 / drug therapy
  • Diabetes Mellitus, Type 2 / metabolism
  • Glucosides / therapeutic use*
  • Hypoglycemic Agents / therapeutic use*
  • Myocardium / metabolism*
  • Myocytes, Cardiac / drug effects
  • Myocytes, Cardiac / metabolism*
  • Rabbits
  • Rats
  • Sodium / metabolism*
  • Sodium-Hydrogen Exchangers / antagonists & inhibitors*
  • Sodium-Hydrogen Exchangers / metabolism*

Substances

  • Benzhydryl Compounds
  • Glucosides
  • Hypoglycemic Agents
  • Sodium-Hydrogen Exchangers
  • Sodium
  • empagliflozin
  • Calcium