Effect of chronic insulin treatment on NO production and endothelium-dependent relaxation in aortae from established STZ-induced diabetic rats.

The hypothesis that the impaired endothelial function seen in streptozotocin (STZ)-induced diabetic rats may result from an increased nitric oxide (NO) metabolism was tested. Acetylcholine (ACh) increased the nitrite NO(2-) and nitrate (NO(3-)) levels in the perfusates from both control and diabetic aortic strips, although the level of NO(2-) was significantly lower in diabetic rats while the NO(3-) level was significantly higher. Both effects (decrease in NO(2-) and increase in NO(3-)) were ameliorated by chronic administration of insulin to diabetic rats but NOx (NO(2-) plus NO(3-)) was increased. The expression of endothelial nitric oxide synthase (eNOS) was significantly increased by chronic administration of insulin to diabetic rats. A decrease in NO(2-) and an increase in NO(3-) occurred following treatment of control aortae with hypoxanthine/xanthine oxidase. Incubating diabetic aortic strips with superoxide dismutase (SOD) normalized the production of both NO(2-) and NO(3-). Both the basal and the ACh-stimulated production of O(2)(-) were significantly higher in diabetic rats than in controls. These results demonstrate that the ACh-induced relaxation of aortic strips was significantly impaired in diabetic rats and that this impairment may be due to an abnormal oxidative metabolism of NO, rather than to a decrease in NOS mRNA and NO production.