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We investigated the effect of apocynin, an NADPH oxidase inhibitor, in the impairment of vascular responses in Otsuka Long-Evans Tokushima Fatty (OLETF) rats (type 2 diabetic rat model) with or without (w/wo) N-nitro-l-arginine methyl ester treatment. Male OLETF and littermate Long-Evans Tokushima Otsuka (LETO) (28 weeks old) rats were separated as follows: LETO w/wo apocynin (Gp C, Gp C-apo), OLETF w/wo apocynin (Gp DM, Gp DM-apo) and OLETF plusl-nitro arginine acetate ester w/wo apocynin (Gp DMLN, Gp DMLN-apo). Five days after, peritoneal macrophages were stimulated with thioglycolate. Two days after, they were evaluated. Plasma glucose and lipid levels remained unchanged. Acetylcholine-induced nitric oxide-dependent (NO-dependent) relaxation and nitroglycerin-induced NO-independent relaxation were improved in the Gp DMLN-apo, compared with that in Gp DMLN. Tone-related basal NO release and plasma NO2− and NO3− tended to be lower in Gp DM and Gp DMLN groups. The increased amount of superoxide anion released from macrophages in Gp DM and Gp DMLN was restored by apocynin. Intimal thickening was observed in aortae of Gp DM and Gp DMLN animals; however, there was little in aortae of Gp DM-apo and Gp DMLN– apo rats. Increased tumour necrosis factor-α (TNF-α) in the Gp DM and Gp DMLN was also restored by apocynin treatment. Apocynin restores the impairment of endothelial and non-endothelial function in diabetic angiopathy in OLETF without changing plasma glucose and lipid levels. NO and O2− may play a role in this process by decreasing TNF-α levels. [ABSTRACT FROM AUTHOR]