Mitochondrial uncoupler carbonyl cyanide m‐chlorophenylhydrazone induces vasorelaxation without involving KATPchannel activation in smooth muscle cells of arteries
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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 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 KATPchannel activation in smooth muscle cells of arteries.
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FCCP and CCCP increase O2•− production in rat vascular smooth muscle cells.
“For instance, while both FCCP and CCCP increase O2•− production in rat vascular smooth muscle cells [145], BAM15, a mitochondria-specific uncoupler, does not change ROS production in this cell type despite efficient induction of mitochondrial uncoupling [45].”
From Mitochondrial Uncoupling: A Key Controller of Biological Processes in Physiology and Diseases (2019) · cites this paper as [145]
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Mitochondrial Uncoupling: A Key Controller of Biological Processes in Physiology and Diseases
Demine, S., Renard, P., & Arnould, T. (2019) · Cells · doi:10.3390/cells8080795 · Cited by 476 · see citing works
“For instance, while both FCCP and CCCP increase O2•− production in rat vascular smooth muscle cells [145], BAM15, a mitochondria-specific uncoupler, does not change ROS production in this cell type despite efficient induction of mitochondrial uncoupling [45].”
BackgroundAntidiabetic and cardiovascular beneficial effects of a liver-localized mitochondrial uncoupler
Kanemoto, N., Okamoto, T., Tanabe, K., Shimada, T., Minoshima, H., Hidoh, Y., Aoyama, M., Ban, T., Kobayashi, Y., Ando, H., et al. (2019) · Nature Communications · doi:10.1038/s41467-019-09911-6 · Cited by 55 · see citing works
- Authors
- Zhang, Y., Shen, X., Xiao, X., Liu, M., Li, S., Yan, J., Jin, J., Gao, J., Zhen, C., Hu, N., Zhang, X., Tai, Y., Zhang, L., Bai, Y., & Dong, D.
- Affiliations
- Harbin Medical University (CN)
- 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
- Corresponding author
- Dong, De‐Li
- Venue
- British Journal of Pharmacology
- Publisher
- Wiley
- Published
- 2016-09-09
- Volume
- 173
- Issue
- 21
- Pages
- 3145-3158
- ISSN
- 0007-1188 (ISSN-L)
- 1476-5381
- PMC
- PMC5056225
- OpenAlex
- W2520622153
- Cited by
- 55
- References
- 63
- Citations by year
- 2026: 5 · 2025: 6 · 2024: 9 · 2023: 8 · 2022: 1 · 2021: 9 · 2020: 3 · 2019: 5 · 2018: 4 · 2017: 4 · 2016: 1
- FWCI
- 2.43
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- British Journal of Pharmacology (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Natural Science Foundation of China (81421063, 81373406)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Mitochondrial Function and Pathology
- Health Sciences › Medicine › Physiology › Nitric Oxide and Endothelin Effects
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Ion channel regulation and function
- Keywords
- CCCP, mitochondrial uncouplers, vasorelaxation, vascular smooth muscle cells, AMPK, ATP/ADP ratio, SERCA, intracellular calcium, mitochondrial reactive oxygen species, mitochondrial membrane potential, phenylephrine-induced contraction, mesenteric arteries, thoracic aorta, A10 cells
- MeSH terms
- Animals, Arteries, Carbonyl Cyanide m-Chlorophenyl Hydrazone, Dose-Response Relationship, Drug, Male, Mitochondria, Structure-Activity Relationship, Uncoupling Agents, Vasodilation, Rats, Sprague-Dawley, Myocytes, Smooth Muscle, Rats, KATP Channels
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