Mechanism of Action of Some Inhibitors of Endothelium-Derived Relaxing Factor

The mechanism of the inhibitory action of phenidone, 3-amino-1-[m-(trifluoromethyl)phenyl]-2-pyrazoline (BW 755C), dithiothreitol, hydroquinone, and pyrogallol on the vascular relaxation induced by endothelium-derived relaxing factor (EDRF) was investigated. EDRF was related from porcine aortic endo...

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Bibliographic Details
Published in:Proceedings of the National Academy of Sciences - PNAS 1986-12, Vol.83 (23), p.9164-9168
Main Authors: Moncada, Salvador, Richard M. J. Palmer, Gryglewski, Ryszard J.
Format: Article
Language:English
Subjects:
4,5-Dihydro-1-(3-(trifluoromethyl)phenyl)-1H-pyrazol-3-amine
Animals
Bioassay
Biological and medical sciences
Cardiovascular system
Cultured cells
Cytochrome c Group - metabolism
Cytochromes
Dithiothreitol - pharmacology
Endothelial cells
Endothelium - physiology
Enzymes
Hydroquinones
Hydroquinones - pharmacology
In Vitro Techniques
Ions
Medical sciences
Muscle, Smooth, Vascular - drug effects
Nitric Oxide
Oxidation-Reduction
Pharmacology. Drug treatments
Pyrazoles - pharmacology
Pyrogallol - pharmacology
Superoxide Dismutase - metabolism
Superoxides
Swine
Transcriptional regulatory elements
Vascular wall
Vasodilator Agents - antagonists & inhibitors
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Summary:The mechanism of the inhibitory action of phenidone, 3-amino-1-[m-(trifluoromethyl)phenyl]-2-pyrazoline (BW 755C), dithiothreitol, hydroquinone, and pyrogallol on the vascular relaxation induced by endothelium-derived relaxing factor (EDRF) was investigated. EDRF was related from porcine aortic endothelial cells in culture and bioassayed on a cascade of superfused rabbit aortic strips. These compounds inhibited EDRF-induced relaxation of vascular strips, without affecting the relaxation induced by glyceryl trinitrate, and their inhibitory potency was markedly attenuated (by more than 1 order of magnitude) by the addition of superoxide dismutase (5-15 units/ml) or oxidized cytochrome c (20-40 μ M) but not by catalase (30 units/ml) or heat-inactivated superoxide dismutase. These data indicate that the above five inhibitors inactivate EDRF through the formation of superoxide ions, which have recently been shown to destroy EDRF. The inhibition of EDRF by these compounds is therefore attributable to their redox properties rather than to any specific biological action.
ISSN:0027-8424
1091-6490
DOI:10.1073/pnas.83.23.9164