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 O2-/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 O2- than control rats evaluated by a chemiluminescence method. The O2- 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 O2- production through activation of NADH/NADPH oxidase over NO generation in endothelial cells may contribute to impaired endothelial-dependent relaxation in insulin-resistant state.
Kashiwagi
A
A
Third Department of Medicine, Shiga University of Medical Science, Otsu, Japan. kasiwagi@belle.shiga-med.ac.jp
Shinozaki
K
K
Nishio
Y
Y
Okamura
T
T
Toda
N
N
Kikkawa
R
R
D000109:Acetylcholine / Q000494:pharmacology; D000818:Animals; D000001:Calcimycin / Q000494:pharmacology; D004730:Endothelium, Vascular / Q000187:drug effects / Q000502:physiology* / Q000503:physiopathology; D005609:Free Radicals / Q000378:metabolism; D005632:Fructose / Q000494:pharmacology; D006946:Hyperinsulinism / Q000503:physiopathology*; D066298:In Vitro Techniques; D007213:Indomethacin / Q000494:pharmacology; D007328:Insulin / Q000494:pharmacology*; D007333:Insulin Resistance / Q000502:physiology*; D008163:Luminescent Measurements; D008297:Male; D008955:Models, Cardiovascular; D009131:Muscle, Smooth, Vascular / Q000187:drug effects / Q000502:physiology* / Q000503:physiopathology; D009569:Nitric Oxide / Q000378:metabolism; D010656:Phenylephrine / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D013481:Superoxides / Q000378:metabolism; D014664:Vasodilation / Q000187:drug effects / Q000502:physiology
D005609:Free Radicals; D007328:Insulin; D013481:Superoxides; D010656:Phenylephrine; D005632:Fructose; D009569:Nitric Oxide; D000001:Calcimycin; D000109:Acetylcholine; D007213:Indomethacin