Aims Sodium/glucose transporter 2 (SGLT2 or SLC5A2) inhibitors lower blood glucose and are also approved treatments for heart failure independent of raised glucose. Various studies have showed that SGLT2 inhibitors relax arteries, but the underlying mechanisms are poorly understood and responses variable across arterial beds. We speculated that SGLT2 inhibitor-mediated arterial relaxation is dependent upon calcitonin gene-related peptide (CGRP) released from sensory nerves independent of glucose transport. Methods and results The functional effects of SGLT1 and 2 inhibitors (mizagliflozin, dapagliflozin, and empagliflozin) and the sodium/hydrogen exchanger 1 (NHE1) blocker cariporide were determined on pre-contracted resistance arteries (mesenteric and cardiac septal arteries) as well as main renal conduit arteries from male Wistar rats using wire myography. SGLT2, CGRP, TRPV1, and NHE1 expression was determined by western blot and immunohistochemistry. Kv7.4/5/KCNE4 and TRPV1 currents were measured in the presence and absence of dapagliflozin and empagliflozin. All SGLT inhibitors (1–100 µM) and cariporide (30 µM) relaxed mesenteric arteries but had negligible effect on renal or septal arteries. Immunohistochemistry with TRPV1 and CGRP antibodies revealed a dense innervation of sensory nerves in mesenteric arteries that were absent in renal and septal arteries. Consistent with a greater sensory nerve component, the TRPV1 agonist capsaicin relaxed mesenteric arteries more effectively than renal or septal arteries. In mesenteric arteries, relaxations to dapagliflozin, empagliflozin, and cariporide were attenuated by the CGRP receptor antagonist BIBN-4096, depletion of sensory nerves with capsaicin, and blockade of TRPV1 or Kv7 channels. Neither dapagliflozin nor empagliflozin activated heterologously expressed TRPV1 channels or Kv7 channels directly. Sensory nerves also expressed NHE1 but not SGLT2 and cariporide pre-application as well as knockdown of NHE1 by translation stop morpholinos prevented the relaxant response to SGLT2 inhibitors. Conclusion SGLT2 inhibitors relax mesenteric arteries by promoting the release of CGRP from sensory nerves in a NHE1-dependent manner.

中文翻译：

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感觉神经和 Na/H 交换蛋白抑制在达格列净和恩格列净诱导的动脉舒张中起关键作用


目的钠/葡萄糖转运蛋白 2 （SGLT2 或 SLC5A2） 抑制剂可降低血糖，也是独立于血糖升高而获批的心力衰竭治疗方法。各种研究表明，SGLT2 抑制剂可松弛动脉，但其潜在机制知之甚少，并且不同动脉床的反应各不相同。我们推测 SGLT2 抑制剂介导的动脉舒张依赖于降钙素基因相关肽 （CGRP） 从感觉神经释放，与葡萄糖转运无关。方法和结果 SGLT1 和 2 抑制剂 （mizagliflozin、dapagliflozin 和 empagliflozin） 和钠/氢交换器 1 （NHE1） 阻滞剂卡立泊利对雄性 Wistar 大鼠的预收缩阻力动脉 （肠系膜和心脏间隔动脉） 以及主要肾导管动脉的功能影响使用线肌图。通过蛋白质印迹和免疫组织化学测定 SGLT2 、 CGRP 、 TRPV1 和 NHE1 的表达。在存在和不存在达格列净和恩格列净的情况下测量 Kv7.4/5/KCNE4 和 TRPV1 电流。所有 SGLT 抑制剂 （1-100 μM） 和卡泊利 （30 μM） 均可松弛肠系膜动脉，但对肾动脉或间隔动脉的影响可以忽略不计。TRPV1 和 CGRP 抗体的免疫组织化学显示肠系膜动脉中感觉神经的密集神经支配，而肾动脉和间隔动脉中不存在。与更大的感觉神经成分一致，TRPV1 激动剂辣椒素比肾动脉或间隔动脉更有效地松弛肠系膜动脉。在肠系膜动脉中，CGRP 受体拮抗剂 BIBN-4096 减弱了对达格列净、恩格列净和卡列净的松弛，辣椒素耗竭了感觉神经，并阻断了 TRPV1 或 Kv7 通道。 达格列净和恩格列净均未直接异源表达 TRPV1 通道或 Kv7 通道。感觉神经也表达 NHE1 但不表达 SGLT2，卡利泊利在应用前以及通过翻译终止吗啉代敲低 NHE1 阻止了对 SGLT2 抑制剂的松弛反应。结论 SGLT2 抑制剂以 NHE1 依赖性方式促进感觉神经释放 CGRP，从而松弛肠系膜动脉。