title: Mitochondrial uncoupler carbonyl cyanide m-chlorophenylhydrazone induces vasorelaxation without involving KATPchannel activation in smooth muscle cells of arteries.
abstract: 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.
  
  
  
  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.
  
  
  
  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 mesenteric arteries. CCCP increased cytosolic [Ca2+]i, mitoROS production and depolarized mitochondrial membrane potential in A10 cells. FCCP, the analogue of CCCP, had similar vasoactivity as CCCP in rat mesenteric arteries.
  
  
  
  CCCP induces vasorelaxation by a mechanism that does not involve KATPchannel activation in smooth muscle cells of arteries.
authors.affiliation: Department of Pharmacology (the State-Province Key Laboratories of Biomedicine-Pharmaceutics of China, Key Laboratory of Cardiovascular Research, Ministry of Education), College of Pharmacy; Translational Medicine Research and Cooperation Center of Northern China, Heilongjiang Academy of Medical Sciences, Harbin Medical University, Harbin, PR China.
authors.forename: Yan-Qiu
authors.initials: YQ
authors.lastname: Zhang
authors.affiliation: Department of Pharmacology (the State-Province Key Laboratories of Biomedicine-Pharmaceutics of China, Key Laboratory of Cardiovascular Research, Ministry of Education), College of Pharmacy; Translational Medicine Research and Cooperation Center of Northern China, Heilongjiang Academy of Medical Sciences, Harbin Medical University, Harbin, PR China.
authors.forename: Xin
authors.initials: X
authors.lastname: Shen
authors.affiliation: Department of Pharmacology (the State-Province Key Laboratories of Biomedicine-Pharmaceutics of China, Key Laboratory of Cardiovascular Research, Ministry of Education), College of Pharmacy; Translational Medicine Research and Cooperation Center of Northern China, Heilongjiang Academy of Medical Sciences, Harbin Medical University, Harbin, PR China.
authors.forename: Xiao-Lin
authors.initials: XL
authors.lastname: Xiao
authors.affiliation: Department of Pharmacology (the State-Province Key Laboratories of Biomedicine-Pharmaceutics of China, Key Laboratory of Cardiovascular Research, Ministry of Education), College of Pharmacy; Translational Medicine Research and Cooperation Center of Northern China, Heilongjiang Academy of Medical Sciences, Harbin Medical University, Harbin, PR China.
authors.forename: Ming-Yu
authors.initials: MY
authors.lastname: Liu
authors.affiliation: Department of Pharmacology (the State-Province Key Laboratories of Biomedicine-Pharmaceutics of China, Key Laboratory of Cardiovascular Research, Ministry of Education), College of Pharmacy; Translational Medicine Research and Cooperation Center of Northern China, Heilongjiang Academy of Medical Sciences, Harbin Medical University, Harbin, PR China.
authors.forename: Shan-Liang
authors.initials: SL
authors.lastname: Li
authors.affiliation: Department of Pharmacology (the State-Province Key Laboratories of Biomedicine-Pharmaceutics of China, Key Laboratory of Cardiovascular Research, Ministry of Education), College of Pharmacy; Translational Medicine Research and Cooperation Center of Northern China, Heilongjiang Academy of Medical Sciences, Harbin Medical University, Harbin, PR China.
authors.forename: Jie
authors.initials: J
authors.lastname: Yan
authors.affiliation: Department of Pharmacology (the State-Province Key Laboratories of Biomedicine-Pharmaceutics of China, Key Laboratory of Cardiovascular Research, Ministry of Education), College of Pharmacy; Translational Medicine Research and Cooperation Center of Northern China, Heilongjiang Academy of Medical Sciences, Harbin Medical University, Harbin, PR China.
authors.forename: Jing
authors.initials: J
authors.lastname: Jin
authors.affiliation: Department of Pharmacology (the State-Province Key Laboratories of Biomedicine-Pharmaceutics of China, Key Laboratory of Cardiovascular Research, Ministry of Education), College of Pharmacy; Translational Medicine Research and Cooperation Center of Northern China, Heilongjiang Academy of Medical Sciences, Harbin Medical University, Harbin, PR China.
authors.forename: Jin-Lai
authors.initials: JL
authors.lastname: Gao
authors.affiliation: Department of Pharmacology (the State-Province Key Laboratories of Biomedicine-Pharmaceutics of China, Key Laboratory of Cardiovascular Research, Ministry of Education), College of Pharmacy; Translational Medicine Research and Cooperation Center of Northern China, Heilongjiang Academy of Medical Sciences, Harbin Medical University, Harbin, PR China.
authors.forename: Chang-Lin
authors.initials: CL
authors.lastname: Zhen
authors.affiliation: Department of Pharmacology (the State-Province Key Laboratories of Biomedicine-Pharmaceutics of China, Key Laboratory of Cardiovascular Research, Ministry of Education), College of Pharmacy; Translational Medicine Research and Cooperation Center of Northern China, Heilongjiang Academy of Medical Sciences, Harbin Medical University, Harbin, PR China.
authors.forename: Nan
authors.initials: N
authors.lastname: Hu
authors.affiliation: Department of Pharmacology (the State-Province Key Laboratories of Biomedicine-Pharmaceutics of China, Key Laboratory of Cardiovascular Research, Ministry of Education), College of Pharmacy; Translational Medicine Research and Cooperation Center of Northern China, Heilongjiang Academy of Medical Sciences, Harbin Medical University, Harbin, PR China.
authors.forename: Xin-Zi
authors.initials: XZ
authors.lastname: Zhang
authors.affiliation: Department of Pharmacology (the State-Province Key Laboratories of Biomedicine-Pharmaceutics of China, Key Laboratory of Cardiovascular Research, Ministry of Education), College of Pharmacy; Translational Medicine Research and Cooperation Center of Northern China, Heilongjiang Academy of Medical Sciences, Harbin Medical University, Harbin, PR China.
authors.forename: Yu
authors.initials: Y
authors.lastname: Tai
authors.affiliation: Department of Pharmacology (the State-Province Key Laboratories of Biomedicine-Pharmaceutics of China, Key Laboratory of Cardiovascular Research, Ministry of Education), College of Pharmacy; Translational Medicine Research and Cooperation Center of Northern China, Heilongjiang Academy of Medical Sciences, Harbin Medical University, Harbin, PR China.
authors.forename: Liang-Shuan
authors.initials: LS
authors.lastname: Zhang
authors.affiliation: Department of Pharmacology (the State-Province Key Laboratories of Biomedicine-Pharmaceutics of China, Key Laboratory of Cardiovascular Research, Ministry of Education), College of Pharmacy; Translational Medicine Research and Cooperation Center of Northern China, Heilongjiang Academy of Medical Sciences, Harbin Medical University, Harbin, PR China.
authors.forename: Yun-Long
authors.initials: YL
authors.lastname: Bai
authors.affiliation: Department of Pharmacology (the State-Province Key Laboratories of Biomedicine-Pharmaceutics of China, Key Laboratory of Cardiovascular Research, Ministry of Education), College of Pharmacy; Translational Medicine Research and Cooperation Center of Northern China, Heilongjiang Academy of Medical Sciences, Harbin Medical University, Harbin, PR China. dongdeli@ems.hrbmu.edu.cn.
authors.forename: De-Li
authors.initials: DL
authors.lastname: Dong
mesh_terms: D000818:Animals; D001158:Arteries / Q000166:cytology* / Q000187:drug effects; D002258:Carbonyl Cyanide m-Chlorophenyl Hydrazone / Q000737:chemistry / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D054086:KATP Channels / Q000378:metabolism; D008297:Male; D008928:Mitochondria / Q000378:metabolism*; D032389:Myocytes, Smooth Muscle / Q000187:drug effects*; D051381:Rats; D017207:Rats, Sprague-Dawley; D013329:Structure-Activity Relationship; D014475:Uncoupling Agents / Q000737:chemistry / Q000494:pharmacology*; D014664:Vasodilation / Q000187:drug effects*
chemical_list: D054086:KATP Channels; D014475:Uncoupling Agents; D002258:Carbonyl Cyanide m-Chlorophenyl Hydrazone