British Heart Foundation Centre of Research Excellence, King's College London, The Rayne Institute, St Thomas' Hospital, Lambeth Palace Road, London SE1 7EH, UK.
Department of Physiology, Anatomy and Genetics, Parks Road, Oxford, OX1 3PT, UK.
Cardiovasc Res. 2021 Dec 17;117(14):2794-2806. doi: 10.1093/cvr/cvaa323.
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.
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.
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+].
依帕格列净（EMPA）是一种有效的钠-葡萄糖共转运蛋白 2（SGLT2）抑制剂，可有效治疗 2 型糖尿病。在患有糖尿病和心力衰竭的患者中，尽管 SGLT2 不在心脏中表达，但 EMPA 具有独立于改善血糖控制的心脏保护作用。已经提出了许多非典型机制来解释这些心脏作用，最值得注意的是对心脏钠-氢交换器 1（NHE1）的抑制作用，导致细胞内[Na+]（[Na+]i）减少。然而，在静息细胞内 pH（pHi）下，NHE1 活性非常低，其药理学抑制作用预计不会显著改变稳态[Na+]i。我们通过测量心脏 NHE1 活性重新评估了这个假定的 EMPA 靶点。
使用 cSNARF1 荧光成像，通过测量铵预脉冲操作后 pHi 恢复，测试 EMPA 对分离的大鼠心室心肌细胞中 NHE1 活性的影响。虽然 10μM 卡立泊来德几乎完全抑制，但 EMPA 处理没有证据表明 NHE1 抑制（1、3、10 或 30μM）。用乙酸超灌注引起的细胞内酸化引发 NHE1 活性并升高[Na+]i，由苯并呋喃异邻苯二甲酸（SBFI）荧光报告，但 EMPA 并没有消除这种升高。EMPA（10μM）对用含钠缓冲液灌注去钠细胞时细胞质[Na+]i 上升率也没有显著影响。在 Langendorff 灌注的小鼠、大鼠和豚鼠心脏中，EMPA 既不影响基线[Na+]i，也不影响急性酸中毒后 pHi 恢复，分别通过 23Na 三重量子过滤 NMR 和 31P NMR 测量。
我们的研究结果表明，心脏 NHE1 活性不受 EMPA（或其他 SGLT2i）抑制，EMPA 在广泛的浓度范围内（包括治疗剂量）对[Na+]i 没有影响。因此，SGLT2i 在心力衰竭中的有益作用不应从心肌 NHE1 或细胞内[Na+]的作用来解释。
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