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  2. 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

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

  • Cardiovasc Res. 2021 Dec 17;117(14):2794-2806. doi: 10.1093/cvr/cvaa323.
Yu Jin Chung 1 Kyung Chan Park 2 Sergiy Tokar 1 Thomas R Eykyn 1 3 William Fuller 4 Davor Pavlovic 5 Pawel Swietach 2 Michael J Shattock 1
Affiliations

Affiliations

  • 1 British Heart Foundation Centre of Research Excellence, King's College London, The Rayne Institute, St Thomas' Hospital, Lambeth Palace Road, London SE1 7EH, UK.
  • 2 Department of Physiology, Anatomy and Genetics, Parks Road, Oxford, OX1 3PT, UK.
  • 3 School of Biomedical Engineering and Imaging Sciences, King's College London, The Rayne Institute, St Thomas' Hospital, Lambeth Palace Road, London SE1 7EH, UK.
  • 4 Institute of Cardiovascular & Medical Sciences, Sir James Black Building, University of Glasgow, University Avenue, Glasgow G12 8QQ, UK.
  • 5 Institute for Cardiovascular Sciences, University of Birmingham, Wolfson Drive, Birmingham B15 2TT, UK.
Abstract

Aims: Emipagliflozin (EMPA) is a potent inhibitor of the renal sodium-glucose co-transporter 2 (SGLT2) and an effective treatment for type-2 diabetes. 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.

Methods and results: 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 µM cariporide produced near-complete inhibition, there was no evidence for NHE1 inhibition with EMPA treatment (1, 3, 10, or 30 µM). 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 µM) 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.

Conclusions: Our findings indicate that cardiac NHE1 activity is not inhibited by EMPA (or other SGLT2i's) and EMPA has no effect on [Na+]i over a wide range of concentrations, including the therapeutic dose. Thus, the beneficial effects of SGLT2i's in failing hearts should not be interpreted in terms of actions on myocardial NHE1 or intracellular [Na+].

Keywords

Heart failure; Intracellular Na; NMR spectroscopy; Na/H exchanger-1; SGLT2 inhibitor.

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