Endothelin-1-induced impairment of endothelium-dependent relaxation in aortas isolated from controls and diabetic rats.
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.
Kamata
Katsuo
K
Department of Physiology and Morphology, Institute of Medicinal Chemistry, Hoshi University, Shinagawa-ku, Japan. kamata@hoshi.ac.jp
Kanie
Noriyasu
N
Matsumoto
Takayuki
T
Kobayashi
Tsuneo
T
D000109:Acetylcholine / Q000494:pharmacology; D000818:Animals; D001011:Aorta / Q000378:metabolism / Q000503:physiopathology; D002867:Chromones / Q000494:pharmacology; D003921:Diabetes Mellitus, Experimental / Q000378:metabolism* / Q000503:physiopathology; D004305:Dose-Response Relationship, Drug; D065128:Endothelin Receptor Antagonists; D019332:Endothelin-1 / Q000378:metabolism*; D004730:Endothelium, Vascular / Q000187:drug effects / Q000378:metabolism* / Q000503:physiopathology; D016166:Free Radical Scavengers / Q000494:pharmacology; D008297:Male; D009025:Morpholines / Q000494:pharmacology; D009599:Nitroprusside / Q000494:pharmacology; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D000081082:Phosphoinositide-3 Kinase Inhibitors; D011092:Polyethylene Glycols / Q000494:pharmacology; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D011725:Pyridines / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D017466:Receptors, Endothelin / Q000378:metabolism; D013482:Superoxide Dismutase / Q000494:pharmacology; D013481:Superoxides / Q000378:metabolism; D046509:Tissue Culture Techniques; D014664:Vasodilation / Q000187:drug effects; D014665:Vasodilator Agents / Q000494:pharmacology
D000109:Acetylcholine; D002867:Chromones; D065128:Endothelin Receptor Antagonists; D019332:Endothelin-1; D016166:Free Radical Scavengers; D009025:Morpholines; D009599:Nitroprusside; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D011092:Polyethylene Glycols; D047428:Protein Kinase Inhibitors; D011725:Pyridines; D017466:Receptors, Endothelin; D013482:Superoxide Dismutase; D013481:Superoxides; D014665:Vasodilator Agents; C085911:2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one; C063471:polyethylene glycol-superoxide dismutase; C119319:J 104132