Niclosamide ethanolamine inhibits artery constriction

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• 作者：Shan-Liang Li^a ; Jie Yan^a ; Yan-Qiu Zhang^a ; Chang-Lin Zhen^a ; Ming-Yu Liu^a ; Jing Jin^a ; Jin-Lai Gao^a ; Xiao-Lin Xiao^a ; Xin Shen^a ; Yu Tai^a ; Nan Hu^a ; Xin-Zi Zhang^a ; Zhi-Jie Sun^b ; De-Li Dong^a ; ^{dongdeli@ems.hrbmu.edu.cn}
• 关键词：Acetylcholine chloride (PubChem CID ; 6060) ; Carbonyl cyanide m-chlorophenylhydrazone (PubChem CID ; 2603) ; Cyclopiazonic acid (PubChem CID ; 54682463) ; Glibenclamide (PubChem CID ; 3488) ; Paxilline (PubChem CID ; 105008) ; Phenylephrine hydrochloride (PubChem CID ; 5284443) ; Niclosamide ethanolamine (PubChem CID ; 14992)
• 刊名：Pharmacological Research
• 出版年：2017
• 出版时间：January 2017
• 年：2017
• 卷：115
• 期：Complete
• 页码：78-86
• 全文大小：2760 K
• 卷排序：115

文摘

We previously demonstrated that the typical mitochondrial uncoupler carbonyl cyanide m-chlorophenylhydrazone (CCCP) inhibited artery constriction, but CCCP was used only as a pharmacological tool. Niclosamide is an anthelmintic drug approved by FDA. Niclosamide ethanolamine (NEN) is a salt form of niclosamide and has been demonstrated to uncouple mitochondrial oxidative phosphorylation. The aim of the present study was to elucidate the vasoactivity of NEN and the potential mechanisms. Isometric tension of rat mesenteric artery and thoracic aorta was recorded by using multi-wire myograph system. The protein levels were measured by using western blot techniques. Niclosamide ethanolamine (NEN) treatment relaxed phenylephrine (PE)- and high K+ (KPSS)-induced constriction, and pre-treatment with NEN inhibited PE- and KPSS-induced constriction of rat mesenteric arteries. In rat thoracic aorta, NEN also showed antagonism against PE- and KPSS-induced constriction. NEN induced increase of cellular ADP/ATP ratio in vascular smooth muscle cells (A10) and activated AMP-activated protein kinase (AMPK) in A10 cells and rat thoracic aorta. NEN-induced aorta relaxation was attenuated in AMPKα1 knockout (-/-) mice. SERCA inhibitors cyclopiazonic acid and thapsigargin, but not KATP channel blockers glibenclamide and 5-hydroxydecanoic acid, attenuated NEN-induced vasorelaxation in rat mesenteric arteries. NEN treatment increased cytosolic [Ca2+]i and depolarized mitochondrial membrane potential in vascular smooth muscle cells (A10). Niclosamide in non-salt form showed the similar vasoactivity as NEN in rat mesenteric arteries. Niclosamide ethanolamine inhibits artery constriction, indicating that it would be promising to be developed as an anti-hypertensive drug or it would induce vasodilation-related side effects when absorbed in vivo.