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

Autor: Baartscheer A; Department of Clinical and Experimental Cardiology, Academic Medical Center, University of Amsterdam, Amsterdam, the Netherlands., Schumacher CA; Department of Clinical and Experimental Cardiology, Academic Medical Center, University of Amsterdam, Amsterdam, the Netherlands., Wüst RC; 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., Fiolet JW; Department of Clinical and Experimental Cardiology, Academic Medical Center, University of Amsterdam, Amsterdam, the Netherlands., Stienen GJ; 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., Coronel R; 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., Zuurbier CJ; 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.
Jazyk: angličtina
Zdroj: Diabetologia [Diabetologia] 2017 Mar; Vol. 60 (3), pp. 568-573. Date of Electronic Publication: 2016 Oct 17.
DOI: 10.1007/s00125-016-4134-x
Abstrakt: 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 Ca 2+ ([Ca 2+ ] c ) concentrations and decreased mitochondrial Ca 2+ concentration ([Ca 2+ ] m ) are drivers of heart failure and cardiac death. We therefore hypothesised that EMPA would directly modify [Na + ] c , [Ca 2+ ] c and [Ca 2+ ] m in cardiomyocytes.
Methods: [Na + ] c, [Ca 2+ ] 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 [Ca 2+ ] c levels. EMPA treatment directly inhibited NHE flux, caused a reduction in [Na + ] c and [Ca 2+ ] c and increased [Ca 2+ ] 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 [Ca 2+ ] c and enhancing [Ca 2+ ] m , through impairment of myocardial NHE flux, independent of SGLT2 activity.
Databáze: MEDLINE
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