Zinc pyrithione induces endothelium-dependent hyperpolarization-mediated mesenteric vasorelaxation in healthy and colitic mice

作者全名："Sun, Chensijin; Zhang, Luyun; Zhang, Mengting; Wang, Jianxin; Rong, Shaoya; Lu, Wei; Dong, Hui"

作者地址："[Sun, Chensijin; Zhang, Luyun; Zhang, Mengting; Wang, Jianxin; Rong, Shaoya; Lu, Wei; Dong, Hui] Qingdao Univ, Med Coll, Sch Pharm, Dept Pharmacol, 1 Ningde Rd, Qingdao 266073, Peoples R China; [Zhang, Luyun] Chongqing Med Univ, Childrens Hosp, Dept Pediat, Intens Care Unit, Chongqing 400014, Peoples R China"

通信作者："Lu, W; Dong, H (通讯作者)，Qingdao Univ, Med Coll, Sch Pharm, Dept Pharmacol, 1 Ningde Rd, Qingdao 266073, Peoples R China."

来源：BIOCHEMICAL PHARMACOLOGY

ESI学科分类：PHARMACOLOGY & TOXICOLOGY

WOS号：WOS:001095886900001

JCR分区：Q1

影响因子：5.3

年份：2023

卷号：217

期号：　

开始页：　

结束页：　

文献类型：Article

关键词：ZPT; Endothelium-dependent hyperpolarization; TRPV1; TRPV4; TRPA1; Ulcerative colitis

摘要："Background: Although Zinc pyrithione (ZPT) could lower blood pressure by inducing vasorelaxation, it is unclear if it is able to induce vasorelaxation of mesenteric arterioles in health and ulcerative colitis (UC) to exert anti-colitic action.Methods: The vasorelaxation of the second-order branch of the mesenteric artery from wide type (WT) mice, TRPV1-/-(KO) mice, and TRPV4- /- (KO)mice was determined using a Mulvany-style wire myograph. Calcium imaging and patch clamp were applied to analyze the actions of ZPT in human vascular endothelial cells. Mouse model of UC was used to evaluate the anti-colitic action of ZPT.Results: ZPT dose-dependently induced mesenteric vasorelaxation predominately through endothelium dependent hyperpolarization (EDH), which could be attenuated by intracellular Zn2+ and Ca2+ chelators TPEN and BAPTA-AM. The ZPT/EDH-mediated vasorelaxation via TRPV1, TRPV4 and TRPA1 channels was verified by a combination of selective pharmacological inhibitors and TRPV1-KO and TRPV4-KO mice. Moreover. ZPT induced Ca2+ entry via vascular endothelial TRPV1/4 and TRPA1 channels and enhanced membrane nonselective currents through these channels. Notably, ZPT exerted anti-colitic effects by rescuing the impaired acetylcholine (ACh)-induced mesenteric vasorelaxation in colitic mice.Conclusions: ZPT/Zn2+ induces EDH-mediated mesenteric vasorelaxation through activating endothelial multiple TRPV1/4 and TPPA1 channels in health, and rescues the impaired ACh-induced vasorelaxation to exert anti-colitic action. Our study may open a new avenue of potential vessel-specific targeted therapy for UC."

基金机构："National Nat-ural Science Foundation of China [82273115, 82200601]"

基金资助正文："This work was supported by research grants from the National Nat-ural Science Foundation of China (No. 82273115 to HD, No. 82200601 to WL) ."