Mitochondrial uncoupler carbonyl cyanide m‐chlorophenylhydrazone induces vasorelaxation without involving KATPchannel activation in smooth muscle cells of arteries

作者：Yan‐Qiu Zhang, Xin Shen, Xiao‐Lin Xiao, Mingyu Liu, Shanliang Li, Jie Yan, Jing Jin, Jin‐Lai Gao, Changlin Zhen, Nan Hu, Xinzi Zhang, Yu Tai, Liang‐Shuan Zhang, Yunlong Bai, De‐Li Dong · 发表于：British Journal of Pharmacology · 年份：2016 · DOI：10.1111/bph.13578 · 被引用次数：55 · 研究领域：Mitochondrial Function and Pathology、Adipose Tissue and Metabolism、Cardiac Ischemia and Reperfusion

Background and Purpose The effects and mechanisms of chemical mitochondrial uncouplers on vascular function have never been identified. Here, we characterized the effects of the typical mitochondrial uncoupler carbonyl cyanide m‐chlorophenylhydrazone (CCCP) on vascular function in rat mesenteric arteries and aorta and elucidated the potential mechanisms. Experimental Approach Isometric tension of mesenteric artery and thoracic aorta was recorded by using a multiwire myograph system. Protein levels were measured by western blot analyses. Cytosolic [Ca2+]i, mitochondrial ROS (mitoROS) and mitochondrial membrane potential of smooth muscle cells (A10) were measured by laser scanning confocal microscopy. Key Results Acute treatment with CCCP relaxed phenylephrine (PE)‐ and high K+(KPSS)‐induced constriction of rat mesenteric arteries with intact and denuded endothelium. Pretreatment with CCCP prevented PE‐ and KPSS‐induced constriction of rat mesenteric arteries with intact and denuded endothelium. Similarly, CCCP prevented PE‐ and KPSS‐induced constriction of rat thoracic aorta. CCCP increased the cellular ADP/ATP ratio in vascular smooth muscle cells (A10) and activated AMPK in A10 cells and rat thoracic aorta tissues. CCCP‐induced aorta relaxation was attenuated in AMPK α1 knockout (−/−) mice. SERCA inhibitors thapsigargin and cyclopiazonic acid (CPA) but not the KATPchannel blocker glibenclamide partially inhibited CCCP‐induced vasorelaxation in endothelium‐denuded rat mesente...