title: Empagliflozin decreases myocardial cytoplasmic Na+through inhibition of the cardiac Na+/H+exchanger in rats and rabbits.
abstract: 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+]cand [Ca2+]min cardiomyocytes.
  
  
  
  [Na+]c,[Ca2+]c, [Ca2+]mand 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+]cand [Ca2+]clevels. EMPA treatment directly inhibited NHE flux, caused a reduction in [Na+]cand [Ca2+]cand increased [Ca2+]m. After pretreatment with the NHE inhibitor, Cariporide, these effects of EMPA were strongly reduced. EMPA also affected [Na+]cand NHE flux in the absence of extracellular glucose.
  
  
  
  The glucose lowering kidney-targeted agent, EMPA, demonstrates direct cardiac effects by lowering myocardial [Na+]cand [Ca2+]cand enhancing [Ca2+]m, through impairment of myocardial NHE flux, independent of SGLT2 activity.
authors.affiliation: Department of Clinical and Experimental Cardiology, Academic Medical Center, University of Amsterdam, Amsterdam, the Netherlands.
authors.forename: Antonius
authors.initials: A
authors.lastname: Baartscheer
authors.affiliation: Department of Clinical and Experimental Cardiology, Academic Medical Center, University of Amsterdam, Amsterdam, the Netherlands.
authors.forename: Cees A
authors.initials: CA
authors.lastname: Schumacher
authors.affiliation: Department of Physiology, Institute for Cardiovascular Research, VU University Medical Centre, Amsterdam, the Netherlands.|Laboratory Genetic Metabolic Diseases, Academic Medical Center, University of Amsterdam, Amsterdam, the Netherlands.
authors.forename: Rob C I
authors.initials: RC
authors.lastname: Wüst
authors.affiliation: Department of Clinical and Experimental Cardiology, Academic Medical Center, University of Amsterdam, Amsterdam, the Netherlands.
authors.forename: Jan W T
authors.initials: JW
authors.lastname: Fiolet
authors.affiliation: Department of Physiology, Institute for Cardiovascular Research, VU University Medical Centre, Amsterdam, the Netherlands.|Department of Physics and Astronomy, Faculty of Science, VU University, Amsterdam, the Netherlands.
authors.forename: Ger J M
authors.initials: GJ
authors.lastname: Stienen
authors.affiliation: Department of Clinical and Experimental Cardiology, Academic Medical Center, University of Amsterdam, Amsterdam, the Netherlands.|University of Bordeaux, L'Institut du Rythmologie et Modélisation Cardiaque (LIRYC), Bordeaux, France.
authors.forename: Ruben
authors.initials: R
authors.lastname: Coronel
authors.affiliation: Department of Anesthesiology, Laboratory of Experimental Intensive Care and Anesthesiology, Academic Medical Center, University of Amsterdam, Meibergdreef 9, 1105 AZ, Amsterdam, the Netherlands. c.j.zuurbier@amc.uva.nl.
authors.forename: Coert J
authors.initials: CJ
authors.lastname: Zuurbier
mesh_terms: D000818:Animals; D001559:Benzhydryl Compounds / Q000627:therapeutic use*; D002118:Calcium / Q000378:metabolism; D003593:Cytoplasm / Q000187:drug effects / Q000378:metabolism; D003924:Diabetes Mellitus, Type 2 / Q000188:drug therapy / Q000378:metabolism; D005960:Glucosides / Q000627:therapeutic use*; D007004:Hypoglycemic Agents / Q000627:therapeutic use*; D009206:Myocardium / Q000378:metabolism*; D032383:Myocytes, Cardiac / Q000187:drug effects / Q000378:metabolism*; D011817:Rabbits; D051381:Rats; D012964:Sodium / Q000378:metabolism*; D017923:Sodium-Hydrogen Exchangers / Q000037:antagonists & inhibitors* / Q000378:metabolism*
chemical_list: D001559:Benzhydryl Compounds; D005960:Glucosides; D007004:Hypoglycemic Agents; D017923:Sodium-Hydrogen Exchangers; D012964:Sodium; C570240:empagliflozin; D002118:Calcium
keywords: Calcium; Cardiac death; Diabetes; Glucose; Heart failure; Sodium