Cl<SUP>-</SUP> induces endothelium-dependent mesenteric arteriolar vasorelaxation through the NKCC1/TRPV4/NCX axis

作者全名："Lu, Cheng; Zhang, Luyun; Chen, Xiongying; Wan, Hanxing; Dong, Hui"

作者地址："[Lu, Cheng; Dong, Hui] Qingdao Univ Med Coll, Sch Pharm, Dept Pharmacol, 1 Ningde Rd, Qingdao 266073, Peoples R China; [Lu, Cheng; Wan, Hanxing; Dong, Hui] Army Med Univ, Xinqiao Hosp, Dept Gastroenterol, Chongqing 400037, Peoples R China; [Zhang, Luyun; Chen, Xiongying] Chongqing Med Univ, Dept Pediat Intens Care Unit, Childrens Hosp, Chongqing 400014, Peoples R China"

通信作者："Dong, H (通讯作者)，Qingdao Univ Med Coll, Sch Pharm, Dept Pharmacol, 1 Ningde Rd, Qingdao 266073, Peoples R China.; Wan, HX; Dong, H (通讯作者)，Army Med Univ, Xinqiao Hosp, Dept Gastroenterol, Chongqing 400037, Peoples R China."

来源：LIFE SCIENCES

ESI学科分类：BIOLOGY & BIOCHEMISTRY

WOS号：WOS:001053431700001

JCR分区：Q1

影响因子：5.2

年份：2023

卷号：330

期号：　

开始页：　

结束页：　

文献类型：Article

关键词：Chloride ions; Endothelial-dependent hyperpolarization; NKCC1; TRPV4 channels; NCX; Vasorelaxation

摘要："Aims: Although absorbed NaCl increases intestinal blood flow to facilitate absorption and transportation, it is unclear if it can directly mediate mesenteric arterial relaxation. We aimed to investigate and test our hypothesis that Cl- induces mesenteric arterial vasorelaxation via endothelium-dependent hyperpolarization (EDH). Main methods: We used wire myograph to study NaCl-induced vasorelaxation of mesenteric arteries isolated from mice. Cl-, Ca2+ and K+ imaging was performed in human vascular endothelial cells pre-treated with pharmacological agents. Key findings: The Cl- concentration-dependently induced vasorelaxation of mesenteric arteries likely through EDH. The Cl--induced vasorelaxation was attenuated in TRPV4 KO mice and inhibited by selective blockers of Na+-K+-2Cl(-) cotransporter 1 (NKCC1) (bumetanide, 10 mu M), transient receptor potential vanilloid 4 (TRPV4) (RN-1734, 40 mu M), and small conductance Ca2+-activated K+ channels (SKCa) (apamin, 3 mu M)/ intermediate conductance Ca2+-activated K+ channels (IKCa) (TRAM-34, 10 mu M) and myoendothelial gap junction (18a-glycyrrhetinic acid, 10 mu M), but enhanced by a selective activator of IKCa/SKCa (SKA-31, 0.3 mu M). Cl- decreased intracellular K+ concentrations in endothelial cells, which was reversed by apamin (200 nM) plus TRAM-34 (500 nM). Extracellular Cl- raised intracellular Cl- concentrations in endothelial cells, which was attenuated by bumetanide (10 mu M). Finally, Cl- induced a transient Ca2+ signaling via TRPV4 in endothelial cells, which became sustained when the Ca2+ exit mode of Na+-Ca2+ exchanger (NCX) was blocked. Significance: Cl- induces a pure EDH-mediated vasorelaxation of mesenteric arteries through activation of endothelial NKCC1/TRPV4/NCX axis. We have provided a novel insight into the role of Cl--induced vasorelaxation via EDH mechanism."

基金机构：National Natural Science Foundation of China [82273115]; [81972328]

基金资助正文：<BOLD>Funding</BOLD> This work was supported by the National Natural Science Foundation of China (No. 81972328 to HW and 82273115 to HD) .