Vascular Biology Section, Molecular & Clinical Sciences Research Institute, St George's University, Cranmer Terrace, London SW17 ORE, UK.
I Instituto de Fisiología Celular, Universidad Nacional Autónoma de México, Mexico City, Mexico.
Cardiovasc Res. 2024 Nov 25;120(14):1811-1824. doi: 10.1093/cvr/cvae156.
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.
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.
SGLT2 inhibitors relax mesenteric arteries by promoting the release of CGRP from sensory nerves in a NHE1-dependent manner.
钠/葡萄糖协同转运蛋白 2（SGLT2 或 SLC5A2）抑制剂可降低血糖，并且独立于葡萄糖升高也被批准用于心力衰竭的治疗。各种研究表明，SGLT2 抑制剂可舒张动脉，但潜在机制尚不清楚，并且对不同动脉床的反应也不同。我们推测，SGLT2 抑制剂介导的动脉舒张依赖于感觉神经释放的降钙素基因相关肽（CGRP），而与葡萄糖转运无关。
使用线描肌动描记法，从雄性 Wistar 大鼠的预收缩阻力动脉（肠系膜和心隔动脉）以及主要肾导管动脉中确定 SGLT1 和 2 抑制剂（米格列净、达格列净和恩格列净）以及钠/氢交换器 1（NHE1）阻滞剂卡立泊来的功能效应。通过 Western blot 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）和卡立泊来（30 μM）均舒张肠系膜动脉，但对肾或心隔动脉几乎没有作用。用 TRPV1 和 CGRP 抗体进行免疫组织化学显示，肠系膜动脉中有密集的感觉神经支配，而在肾和心隔动脉中则不存在。与感觉神经成分更大一致的是，TRPV1 激动剂辣椒素比肾或心隔动脉更有效地舒张肠系膜动脉。在肠系膜动脉中，达格列净、恩格列净和卡立泊来的舒张作用被 CGRP 受体拮抗剂 BIBN-4096、用辣椒素耗竭感觉神经和阻断 TRPV1 或 Kv7 通道减弱。达格列净和恩格列净既不直接激活异源表达的 TRPV1 通道，也不直接激活 Kv7 通道。感觉神经也表达 NHE1，但不表达 SGLT2，卡立泊来预应用以及翻译终止型 MOR 对 NHE1 的敲低可阻止 SGLT2 抑制剂的舒张反应。
SGLT2 抑制剂通过以 NHE1 依赖性方式促进感觉神经释放 CGRP 来舒张肠系膜动脉。
