Free radical production in endothelial cells as a pathogenetic factor for vascular dysfunction in the insulin resistance state

Impairment of nitric oxide-dependent vascular relaxation is a characteristic feature of the insulin-resistant state. To understand those mechanisms, we examined imbalance of O-2(-)/NO production in aortic endothelial cells obtained from high fructose-fed, exogenous hyperinsulinemic, and control rats. Aortic segments from both high fructose-fed and insulin-treated rats produced a 4-fold more O-2(-) than control rats evaluated by a chemiluminescence method. The O-2(-) production in the aortas of both high fructose-fed and insulin-treated rats was mediated through activation of NADH/NADPH oxidase. In isometric tension studies, high fructose Vessels with endothelium elicited impaired relaxation in response to acetylcholine or a calcium ionophore A23187 when compared with control rats, whereas these impaired vascular responses were not found in insulin-treated rats. Furthermore, endothelial constitutive NO synthase activity was increased in Vessels from insulin-treated rats, but decreased in vessels from high fructose-fed rats. These results indicate that relative excess of O-2(-) production through activation of NADH/NADPH oxidase over NO generation in endothelial cells may contribute to impaired endothelial-dependent relaxation in insulin-resistant state. (C) 1999 Elsevier Science Ireland Ltd. All rights reserved.