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In patients with diabetes and heart failure, EMPA has cardioprotective effects independent of improved glycaemic control, despite SGLT2 not being expressed in the heart. A number of non-canonical mechanisms have been proposed to explain these cardiac effects, most notably an inhibitory action on cardiac Na+\/H+ exchanger 1 (NHE1), causing a reduction in intracellular [Na+] ([Na+]i). However, at resting intracellular pH (pHi), NHE1 activity is very low and its pharmacological inhibition is not expected to meaningfully alter steady-state [Na+]i. We re-evaluate this putative EMPA target by measuring cardiac NHE1 activity.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Methods and results\u2003<\/jats:title>\n                  <jats:p>The effect of EMPA on NHE1 activity was tested in isolated rat ventricular cardiomyocytes from measurements of pHi recovery following an ammonium pre-pulse manoeuvre, using cSNARF1 fluorescence imaging. Whereas 10\u2009\u00b5M cariporide produced near-complete inhibition, there was no evidence for NHE1 inhibition with EMPA treatment (1, 3, 10, or 30\u2009\u00b5M). Intracellular acidification by acetate-superfusion evoked NHE1 activity and raised [Na+]i, reported by sodium binding benzofuran isophthalate (SBFI) fluorescence, but EMPA did not ablate this rise. EMPA (10\u2009\u00b5M) also had no significant effect on the rate of cytoplasmic [Na+]i rise upon superfusion of Na+-depleted cells with Na+-containing buffers. In Langendorff-perfused mouse, rat and guinea pig hearts, EMPA did not affect [Na+]i at baseline nor pHi recovery following acute acidosis, as measured by 23Na triple quantum filtered NMR and 31P NMR, respectively.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Conclusions\u2003<\/jats:title>\n                  <jats:p>Our findings indicate that cardiac NHE1 activity is not inhibited by EMPA (or other SGLT2i\u2019s) and EMPA has no effect on [Na+]i over a wide range of concentrations, including the therapeutic dose. Thus, the beneficial effects of SGLT2i\u2019s in failing hearts should not be interpreted in terms of actions on myocardial NHE1 or intracellular [Na+].<\/jats:p>\n               <\/jats:sec>","DOI":"10.1093\/cvr\/cvaa323","type":"journal-article","created":{"date-parts":[[2020,10,23]],"date-time":"2020-10-23T03:26:23Z","timestamp":1603423583000},"page":"2794-2806","source":"Crossref","is-referenced-by-count":127,"title":["Off-target effects of sodium-glucose co-transporter 2 blockers: empagliflozin does not inhibit Na+\/H+ exchanger-1 or lower [Na+]i in the heart"],"prefix":"10.1093","volume":"117","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-7262-7705","authenticated-orcid":false,"given":"Yu Jin","family":"Chung","sequence":"first","affiliation":[{"name":"British Heart Foundation Centre of Research Excellence, King\u2019s College London, The Rayne Institute, St Thomas\u2019 Hospital, Lambeth Palace Road, London SE1 7EH, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7203-0127","authenticated-orcid":false,"given":"Kyung Chan","family":"Park","sequence":"additional","affiliation":[{"name":"Department of Physiology, Anatomy and Genetics, Parks Road, Oxford, OX1 3PT,\u00a0UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sergiy","family":"Tokar","sequence":"additional","affiliation":[{"name":"British Heart Foundation Centre of Research Excellence, King\u2019s College London, The Rayne Institute, St Thomas\u2019 Hospital, Lambeth Palace Road, London SE1 7EH, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1768-3808","authenticated-orcid":false,"given":"Thomas R","family":"Eykyn","sequence":"additional","affiliation":[{"name":"British Heart Foundation Centre of Research Excellence, King\u2019s College London, The Rayne Institute, St Thomas\u2019 Hospital, Lambeth Palace Road, London SE1 7EH, UK"},{"name":"School of Biomedical Engineering and Imaging Sciences, King\u2019s College London, The Rayne Institute, St Thomas' Hospital, Lambeth Palace Road, London SE1 7EH, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5883-4433","authenticated-orcid":false,"given":"William","family":"Fuller","sequence":"additional","affiliation":[{"name":"Institute of Cardiovascular & Medical Sciences, Sir James Black Building, University of Glasgow, University Avenue, Glasgow G12 8QQ, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3171-3551","authenticated-orcid":false,"given":"Davor","family":"Pavlovic","sequence":"additional","affiliation":[{"name":"Institute for Cardiovascular Sciences, University of Birmingham, Wolfson Drive, Birmingham B15 2TT, 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