Oral Administration of the Antioxidant, N-Acetylcysteine, Abrogates Diabetes-Induced Endothelial Dysfunction

Abstract

Oxidative stress is believed to play an important role in the development of vascular complications associated with diabetes mellitus. In this study, we examined the efficacy of long-term treatment with the antioxidant, N-acetylcysteine, in preventing the development of defective endothelium-dependent relaxation in streptozotocin-induced, Sprague-Dawley diabetic rats. At 48 h after injection of streptozotocin, a portion of diabetic rats received 250 mg/L N-acetylcysteine in drinking water for a total duration of 8 weeks. Oral administration did not alter the increase in blood glucose or the reduction in serum insulin but did modestly reduce total glycosylated hemoglobin. In precontracted thoracic aortic rings suspended in isolated tissue baths, endothelium-dependent relaxation to acetylcholine was impaired in diabetic rings compared with control rings. Endothelium-independent relaxation to nitroglycerin was unaltered. Long-term oral administration of N-acetylcysteine did not alter responses to nitroglycerin but completely prevented the defective relaxation to acetylcholine. These studies indicate a dissociation between glycemic control and correction of endothelial dysfunction and suggest that long-term exposure to reactive oxygen subsequent to diabetes rather than hyperglycemia per se is responsible for the development of endothelial dysfunction in diabetes mellitus.

NADPH Oxidase-Derived Overproduction of Reactive Oxygen Species Impairs Postischemic Neovascularization in Mice with Type 1 Diabetes

“…30 The chronic treatment of diabetic animals with NAC improved or normalized endothelium-dependent responses. 31 Alternatively, increased superoxide production by NADPH oxidase likely reduces NO bioactivity by scavenging or through uncoupling of endothelial nitric oxide synthase and may also lead to the formation of other signaling species such as peroxynitrite. 16,18 In keeping with this, we found increased 3-nitrotyrosine staining in ischemic muscles, consistent with increased levels of nitrating species.…”

Endothelial dysfunction in diabetes

“…Acute administration of scavengers of superoxide anion, including superoxide dismutase (Hattori et al, 1991;Tesfamariam & Cohen, 1992;Pieper et al, 1996;Bohlen & Lash, 1993) and the combination of superoxide dismutase with catalase (Pieper et al, 1997) improved or normalized the abnormal endothelium-dependent responses in di erent models of diabetes and during high glucose exposure. Similarly, chronic treatment with probucol (Tesfamariam & Cohen, 1992), N-acetylcysteine (Pieper & Siebeneich, 1998b), vitamin E (Keegan et al, 1995;RoÈ sen et al, 1996) and vitamin C (Ting et al, 1996) prevented the development of endothelial dysfunction in clinical and experimental diabetes. In an in vivo study of high glucose exposure of the mesenteric circulation, superoxide dismutase and catalase were equally or more e ective than cyclo-oxygenase inhibition in restoring the impaired ACh-induced vasodilatation, suggesting that the oxygen-derived radicals produced during prostanoid synthesis, rather than the prostanoids themselves, were responsible for the endothelial dysfunction (Bohlen & Lash, 1993).…”

The impaired renal vasodilator response attributed to endothelium-derived hyperpolarizing factor in streptozotocin - induced diabetic rats is restored by 5-methyltetrahydrofolate

“…The existence of such an action of vasoconstrictor prostanoids in the kidney is not supported by our study, inasmuch as cyclooxygenase-inhibition did not restore the blunted relaxations observed in the diabetic animals. Other investigations showed an impaired acetylcholine-induced cyclic GMP generation [7,8] or a restoration of the relaxation with l-arginine [9] or with free radical scavengers [10,11], suggesting a reduced availability or an increased destruction of endotheliumderived NO. Another study specifically found no evidence for an impaired EDHF release in diabetes [34].…”