FREE-RADICALS IN DIABETIC ENDOTHELIAL-CELL DYSFUNCTION

Several studies have shown impairment of endothelium-dependent relaxat ions as well as increased release of vasoconstrictor prostanoids in ar teries from diabetic animals and humans. This impairment is restored t owards normal by prostaglandin (PG) H-2/thromboxane A(2) receptor bloc kade or superoxide dismutase, indicating that the PGH(2) and/or supero xide anion (0(2)(.-)) generated contributes to the abnormality. Of par ticular note is that PGH(2) impairs endothelium-dependent relaxations and causs contractions by a mechanism that involves generation of O-2( .-) in the endothelium. The effects of elevated glucose are exacerbate d by increased aldose reductase activity leading to depletion of NADPH and generation of reactive oxidants. Because NADPH is required for ge neration of nitric oxide from L-arginine, the depletion of NADPH leads to reduced nitric oxide formation. In a manner similar to that observ ed with elevated glucose, oxygen-derived free radicals or activation o f protein kinase C also cause impairment of endothelium-dependent rela xations, smooth muscle contractions, and release constricter prostanoi ds, indicating that a common mechanism for the impairment of endotheli al cell function may be operative in diabetes. In this review the cumu lative effects of oxidative stress on diabetic endothelial cell dysfun ction, together with the complex interrelationship of cyclooxygenase c atalysis, protein kinase C activity, and flux through the polyol pathw ay, are considered.