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

Abstract

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.