Mitochondrial uncoupler carbonyl cyanide m-chlorophenylhydrazone induces vasorelaxation without involving KATP channel activation in smooth muscle cells of arteries

作者：Zhang, Yan-Qiu; Shen, Xin; Xiao, Xiao-Lin; Liu, Ming-Yu; Li, Shan-Liang; Yan, Jie; Jin, Jing; Gao, Jin-Lai; Zhen, Chang-Lin; Hu, Nan; Zhang, Xin-Zi; Tai, Yu; Zhang, Liang-Shuan; Bai, Yun-Long; Dong, De-Li^*

来源：British Journal of Pharmacology, 2016, 173(21): 3145-3158.

DOI：10.1111/bph.13578

• PROTEIN-KINASE
• ENDOTHELIAL-CELLS
• CONCISE GUIDE
• CARDIAC-HYPERTROPHY
• INSULIN-RESISTANCE
• CEREBRAL-ARTERIES
• PHARMACOLOGY
• SUPEROXIDE
• INHIBITION
• EXPRESSION

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 amultiwire 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 alpha 1 knockout (-/-) mice. SERCA inhibitors thapsigargin and cyclopiazonic acid (CPA) but not the K-ATP channel 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. @@@ CONCLUSIONS AND IMPLICATIONS @@@ CCCP induces vasorelaxation by a mechanism that does not involve K-ATP channel activation in smooth muscle cells of arteries.

• 出版日期2016-11
• 单位哈尔滨医科大学