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 NO2− and nitrate (NO3−) levels in the perfusates from both control and diabetic aortic strips, although the level of NO2− was significantly lower in diabetic rats while the NO3− level was significantly higher. Both effects (decrease in NO2− and increase in NO3−) were ameliorated by chronic administration of insulin to diabetic rats but NOx (NO2− plus NO3−) was increased. The expression of endothelial nitric oxide synthase (eNOS) was significantly increased by chronic administration of insulin to diabetic rats. A decrease in NO2− and an increase in NO3− occurred following treatment of control aortae with hypoxanthine/xanthine oxidase. Incubating diabetic aortic strips with superoxide dismutase (SOD) normalized the production of both NO2− and NO3−. Both the basal and the ACh-stimulated production of O2− 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.