INCREASED SUPEROXIDE CONTRIBUTES TO ENHANCEMENT OF VASCULAR CONTRACTION IN INS2AKITA DIABETIC MICE, AN AUTOSOMAL DOMINANT MUTANT MODEL.

1. Superoxide has been reported to be involved in vascular dysfunction in diabetes. The Ins2Akita mouse is an autosomal dominant mutant diabetic model that can serve as an excellent substitute for the Type 1 diabetic mouse model induced by chemical diabetogens. The purpose of the present study was to investigate the role of superoxide on vascular dysfunction using this new diabetic model. 2. Compared with age-matched normal C57BL/6 mice, in Ins2Akita diabetic mice arterial superoxide, lipid peroxidation production (1.2 ± 0.1 vs 17.4 ± 1.9 mmol/mg tissue, respectively; P < 0.01) and plasma lipid peroxidation production (0.08 ± 0.02 vs 0.40 ± 0.03 mmol/L, respectively; P < 0.01) were increased. Meanwhile, expression of vascular adhesion molecule-1, E-selectin and monocyte chemoattractant protein-1 in the aorta and/or plasma was elevated. 3. The contraction of carotid arteries to U46619 in Ins2Akita diabetic mice was significantly enhanced compared with control mice ( P < 0.05). Tempol (a scavenger of superoxide), apocynin (an inhibitor of NADPH oxidase) and allopurinol (an inhibitor of xanthine oxidase) all not only decreased superoxide in carotid arteries, but also suppressed arterial contractions to U46619 in Ins2Akita diabetic mice. Indomethacin, an inhibitor of cyclo-oxygenase, and chelerythrine, an inhibitor of protein kinase C, also suppressed the enhanced vascular contraction. 4. These results suggest that increased arterial superoxide generated from diverse sources may potentiate the contractions of carotid arteries in Ins2Akita diabetic mice. [ABSTRACT FROM AUTHOR]