Abstract
An accumulating body of evidence indicates that an increased endothelin-1 level is related to endothelial dysfunction in cardiovascular diseases. In this study, we tested whether prolonged treatment of aortas with endothelin-1 induces endothelial dysfunction. When isolated aortas from control rats were cultured with endothelin-1, at levels above the plasma concentration, the acetylcholine-induced endothelium-dependent relaxation was significantly decreased (as compared with endothelin-1-nontreatment). This endothelin-1-induced endothelial dysfunction was more marked in aortas obtained from rats with streptozotocin-induced diabetes than in those from the controls. The endothelin-1- induced attenuation was very strongly suppressed by co-incubation with J-104132, endothelin receptor A/B antagonist, or polyethylene-glycolated superoxide dismutase, a cell-permeant superoxide anion scavenger or LY294002, phosphoinositide 3-kinase inhibitor. These results indicate that endothelin-1 can induce endothelial dysfunction, and that this may be related to superoxide generation and to PI3-kinase activity.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Acetylcholine / pharmacology
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Animals
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Aorta / metabolism
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Aorta / physiopathology
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Chromones / pharmacology
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Diabetes Mellitus, Experimental / metabolism*
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Diabetes Mellitus, Experimental / physiopathology
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Dose-Response Relationship, Drug
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Endothelin Receptor Antagonists
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Endothelin-1 / metabolism*
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Endothelium, Vascular / drug effects
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Endothelium, Vascular / metabolism*
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Endothelium, Vascular / physiopathology
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Free Radical Scavengers / pharmacology
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Male
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Morpholines / pharmacology
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Nitroprusside / pharmacology
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Phosphatidylinositol 3-Kinases / metabolism
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Phosphoinositide-3 Kinase Inhibitors
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Polyethylene Glycols / pharmacology
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Protein Kinase Inhibitors / pharmacology
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Pyridines / pharmacology
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Rats
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Rats, Wistar
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Receptors, Endothelin / metabolism
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Superoxide Dismutase / pharmacology
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Superoxides / metabolism
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Tissue Culture Techniques
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Vasodilation* / drug effects
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Vasodilator Agents / pharmacology
Substances
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Chromones
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Endothelin Receptor Antagonists
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Endothelin-1
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Free Radical Scavengers
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Morpholines
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Phosphoinositide-3 Kinase Inhibitors
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Protein Kinase Inhibitors
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Pyridines
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Receptors, Endothelin
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Vasodilator Agents
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Superoxides
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Nitroprusside
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2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one
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Polyethylene Glycols
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Superoxide Dismutase
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polyethylene glycol-superoxide dismutase
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J 104132
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Acetylcholine