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 endothelia-1 level is related to endothelial dysfunction in cardiovascular diseases. In this study, we tested whether prolonged treatment of aortas with endothelia-1 induces endothelial dysfunction. When isolated aortas from control rats were cultured with endothelia-1, at levels above the plasma concentration, the acetylcholine-induced endothelium-dependent relaxation was significantly decreased (as compared with endothelia-1-nontreatment). This endothelia-1-induced endothelial dysfunction was more marked in aortas obtained from rats with streptozotocin-induced diabetes than in those from the controls. The endothelia-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 endothelia-1 can induce endothelial dysfunction, and that this may be related to superoxide generation and to P13-kinase activity.