+1 Recommend
0 collections
      • Record: found
      • Abstract: found
      • Article: not found

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

      Read this article at

          There is no author summary for this article yet. Authors can add summaries to their articles on ScienceOpen to make them more accessible to a non-specialist audience.



          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.


          [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.


          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.


          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.

          Electronic supplementary material

          The online version of this article (doi:10.1007/s00125-016-4134-x) contains peer-reviewed but unedited supplementary material, which is available to authorised users.

          Related collections

          Most cited references 14

          • Record: found
          • Abstract: found
          • Article: not found

          Empagliflozin, a novel selective sodium glucose cotransporter-2 (SGLT-2) inhibitor: characterisation and comparison with other SGLT-2 inhibitors.

          Empagliflozin is a selective sodium glucose cotransporter-2 (SGLT-2) inhibitor in clinical development for the treatment of type 2 diabetes mellitus. This study assessed pharmacological properties of empagliflozin in vitro and pharmacokinetic properties in vivo and compared its potency and selectivity with other SGLT-2 inhibitors. [(14)C]-alpha-methyl glucopyranoside (AMG) uptake experiments were performed with stable cell lines over-expressing human (h) SGLT-1, 2 and 4. Two new cell lines over-expressing hSGLT-5 and hSGLT-6 were established and [(14)C]-mannose and [(14)C]-myo-inositol uptake assays developed. Binding kinetics were analysed using a radioligand binding assay with [(3)H]-labelled empagliflozin and HEK293-hSGLT-2 cell membranes. Acute in vivo assessment of pharmacokinetics was performed with normoglycaemic beagle dogs and Zucker diabetic fatty (ZDF) rats. Empagliflozin has an IC(50) of 3.1 nM for hSGLT-2. Its binding to SGLT-2 is competitive with glucose (half-life approximately 1 h). Compared with other SGLT-2 inhibitors, empagliflozin has a high degree of selectivity over SGLT-1, 4, 5 and 6. Species differences in SGLT-1 selectivity were identified. Empagliflozin pharmacokinetics in ZDF rats were characterised by moderate total plasma clearance (CL) and bioavailability (BA), while in beagle dogs CL was low and BA was high. Empagliflozin is a potent and competitive SGLT-2 inhibitor with an excellent selectivity profile and the highest selectivity window of the tested SGLT-2 inhibitors over hSGLT-1. Empagliflozin represents an innovative therapeutic approach to treat diabetes. © 2011 Blackwell Publishing Ltd.
            • Record: found
            • Abstract: found
            • Article: not found

            Elevated cytosolic Na+ increases mitochondrial formation of reactive oxygen species in failing cardiac myocytes.

            Oxidative stress is causally linked to the progression of heart failure, and mitochondria are critical sources of reactive oxygen species in failing myocardium. We previously observed that in heart failure, elevated cytosolic Na(+) ([Na(+)](i)) reduces mitochondrial Ca(2+) ([Ca(2+)](m)) by accelerating Ca(2+) efflux via the mitochondrial Na(+)/Ca(2+) exchanger. Because the regeneration of antioxidative enzymes requires NADPH, which is indirectly regenerated by the Krebs cycle, and Krebs cycle dehydrogenases are activated by [Ca(2+)](m), we speculated that in failing myocytes, elevated [Na(+)](i) promotes oxidative stress. We used a patch-clamp-based approach to simultaneously monitor cytosolic and mitochondrial Ca(2+) and, alternatively, mitochondrial H(2)O(2) together with NAD(P)H in guinea pig cardiac myocytes. Cells were depolarized in a voltage-clamp mode (3 Hz), and a transition of workload was induced by beta-adrenergic stimulation. During this transition, NAD(P)H initially oxidized but recovered when [Ca(2+)](m) increased. The transient oxidation of NAD(P)H was closely associated with an increase in mitochondrial H(2)O(2) formation. This reactive oxygen species formation was potentiated when mitochondrial Ca(2+) uptake was blocked (by Ru360) or Ca(2+) efflux was accelerated (by elevation of [Na(+)](i)). In failing myocytes, H(2)O(2) formation was increased, which was prevented by reducing mitochondrial Ca(2+) efflux via the mitochondrial Na(+)/Ca(2+) exchanger. Besides matching energy supply and demand, mitochondrial Ca(2+) uptake critically regulates mitochondrial reactive oxygen species production. In heart failure, elevated [Na(+)](i) promotes reactive oxygen species formation by reducing mitochondrial Ca(2+) uptake. This novel mechanism, by which defects in ion homeostasis induce oxidative stress, represents a potential drug target to reduce reactive oxygen species production in the failing heart.
              • Record: found
              • Abstract: found
              • Article: not found

              Intracellular Na(+) concentration is elevated in heart failure but Na/K pump function is unchanged.

              Intracellular sodium concentration ([Na(+)](i)) modulates cardiac contractile and electrical activity through Na/Ca exchange (NCX). Upregulation of NCX in heart failure (HF) may magnify the functional impact of altered [Na(+)](i). We measured [Na(+)](i) by using sodium binding benzofuran isophthalate in control and HF rabbit ventricular myocytes (HF induced by aortic insufficiency and constriction). Resting [Na(+)](i) was 9.7+/-0.7 versus 6.6+/-0.5 mmol/L in HF versus control. In both cases, [Na(+)](i) increased by approximately 2 mmol/L when myocytes were stimulated (0.5 to 3 Hz). To identify the mechanisms responsible for [Na(+)](i) elevation in HF, we measured the [Na(+)](i) dependence of Na/K pump-mediated Na(+) extrusion. There was no difference in V(max) (8.3+/-0.7 versus 8.0+/-0.8 mmol/L/min) or K(m) (9.2+/-1.0 versus 9.9+/-0.8 mmol/L in HF and control, respectively). Therefore, at measured [Na(+)](i) levels, the Na/K pump rate is actually higher in HF. However, resting Na(+) influx was twice as high in HF versus control (2.3+/-0.3 versus 1.1+/-0.2 mmol/L/min), primarily the result of a tetrodotoxin-sensitive pathway. Myocyte [Na(+)](i) is elevated in HF as a result of higher diastolic Na(+) influx (with unaltered Na/K-ATPase characteristics). In HF, the combined increased [Na(+)](i), decreased Ca(2+) transient, and prolonged action potential all profoundly affect cellular Ca(2+) regulation, promoting greater Ca(2+) influx through NCX during action potentials. Notably, the elevated [Na(+)](i) may be critical in limiting the contractile dysfunction observed in HF.

                Author and article information

                Springer Berlin Heidelberg (Berlin/Heidelberg )
                17 October 2016
                17 October 2016
                : 60
                : 3
                : 568-573
                [1 ]GRID grid.7177.6, ISNI 0000000084992262, Department of Clinical and Experimental Cardiology, Academic Medical Center, , University of Amsterdam, ; Amsterdam, the Netherlands
                [2 ]GRID grid.16872.3a, ISNI 000000040435165X, Department of Physiology, Institute for Cardiovascular Research, , VU University Medical Centre, ; Amsterdam, the Netherlands
                [3 ]GRID grid.7177.6, ISNI 0000000084992262, Laboratory Genetic Metabolic Diseases, Academic Medical Center, , University of Amsterdam, ; Amsterdam, the Netherlands
                [4 ]GRID grid.12380.38, ISNI 0000000417549227, Department of Physics and Astronomy, Faculty of Science, , VU University, ; Amsterdam, the Netherlands
                [5 ]GRID grid.412041.2, ISNI 000000012106639X, University of Bordeaux, L’Institut du Rythmologie et Modélisation Cardiaque (LIRYC), ; Bordeaux, France
                [6 ]GRID grid.7177.6, ISNI 0000000084992262, Department of Anesthesiology, Laboratory of Experimental Intensive Care and Anesthesiology, Academic Medical Center, , University of Amsterdam, ; Meibergdreef 9, 1105 AZ Amsterdam, the Netherlands
                © The Author(s) 2016

                Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (, which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made.

                Funded by: Netherlands CardioVascular Research Initiative
                Award ID: CVON2011-11 ARENA
                Short Communication
                Custom metadata
                © Springer-Verlag Berlin Heidelberg 2017

                Endocrinology & Diabetes

                calcium, cardiac death, diabetes, glucose, heart failure, sodium


                Comment on this article