| Title |
Class effects of SGLT2 inhibitors in mouse cardiomyocytes and hearts: inhibition of Na+/H+ exchanger, lowering of cytosolic Na+ and vasodilation
|
|---|---|
| Published in |
Diabetologia, December 2017
|
| DOI | 10.1007/s00125-017-4509-7 |
| Pubmed ID | |
| Authors |
Laween Uthman, Antonius Baartscheer, Boris Bleijlevens, Cees A. Schumacher, Jan W. T. Fiolet, Anneke Koeman, Milena Jancev, Markus W. Hollmann, Nina C. Weber, Ruben Coronel, Coert J. Zuurbier |
| Abstract |
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. 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. 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. 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. |
X Demographics
The data shown below were collected from the profiles of 74 X users who shared this research output. Click here to find out more about how the information was compiled.
Geographical breakdown
| Country | Count | As % |
|---|---|---|
| Spain | 15 | 20% |
| United Kingdom | 9 | 12% |
| United States | 4 | 5% |
| India | 3 | 4% |
| Canada | 2 | 3% |
| Germany | 2 | 3% |
| Australia | 1 | 1% |
| Venezuela, Bolivarian Republic of | 1 | 1% |
| Mexico | 1 | 1% |
| Other | 6 | 8% |
| Unknown | 30 | 41% |
Demographic breakdown
| Type | Count | As % |
|---|---|---|
| Members of the public | 55 | 74% |
| Practitioners (doctors, other healthcare professionals) | 9 | 12% |
| Scientists | 9 | 12% |
| Science communicators (journalists, bloggers, editors) | 1 | 1% |
Mendeley readers
The data shown below were compiled from readership statistics for 259 Mendeley readers of this research output. Click here to see the associated Mendeley record.
Geographical breakdown
| Country | Count | As % |
|---|---|---|
| Unknown | 259 | 100% |
Demographic breakdown
| Readers by professional status | Count | As % |
|---|---|---|
| Researcher | 28 | 11% |
| Student > Ph. D. Student | 25 | 10% |
| Student > Master | 21 | 8% |
| Student > Bachelor | 21 | 8% |
| Student > Doctoral Student | 20 | 8% |
| Other | 40 | 15% |
| Unknown | 104 | 40% |
| Readers by discipline | Count | As % |
|---|---|---|
| Medicine and Dentistry | 79 | 31% |
| Biochemistry, Genetics and Molecular Biology | 22 | 8% |
| Pharmacology, Toxicology and Pharmaceutical Science | 13 | 5% |
| Agricultural and Biological Sciences | 9 | 3% |
| Nursing and Health Professions | 6 | 2% |
| Other | 21 | 8% |
| Unknown | 109 | 42% |
Attention Score in Context
This research output has an Altmetric Attention Score of 47. This is our high-level measure of the quality and quantity of online attention that it has received. This Attention Score, as well as the ranking and number of research outputs shown below, was calculated when the research output was last mentioned on 07 July 2022.
All research outputs
#908,719
of 25,732,188 outputs
Outputs from Diabetologia
#461
of 5,376 outputs
Outputs of similar age
#20,213
of 447,169 outputs
Outputs of similar age from Diabetologia
#15
of 70 outputs
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