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In normotensive rats fed high salt, arteriolar responsiveness to endothelium-dependent dilators is reduced due to suppression of local nitric oxide (NO) bioavailability. In the first study we evaluated the possibility that an increase in microvascular reactive oxygen species (ROS) may account for this decrease in NO activity. Arcade arterioles in the spinotrapezius muscle of Sprague-Dawley rats fed either a low (0.45%, LS) or high (7%, HS) salt diet for 4–5 weeks were examined. Arteriolar responses to acetylcholine (ACh) were significantly reduced in the HS rats but could be returned to normal in the presence of the ROS scavengers superoxide dismutase (SOD) + catalase or 2,2,6,6-Tetamethylpiperidine-N-oxyl (TEMPO) + catalase. Oxidant activity, as assessed by the tetranitroblue tetrazolium reduction, was significantly higher in the HS arterioles and venules and could also be returned to levels observed in LS rats after exposure to TEMPO + catalase. These data suggest that an increase in microvascular ROS is responsible for the decreased NO bioavailability and endothelium-dependent responses observed in HS rats. The second and third study investigated possible mechanisms responsible for the increased oxidative stress in HS vessels. The expression and in vivo activity of SOD, catalase, NAD(P)H oxidase and xanthine oxidase (XO) in the arterioles and venules was determined. Western analysis showed no difference between LS and HS rats in the expression of any of these enzymes. Inhibition of catalase increased oxidative stress by the same amount in LS and HS rats, whereas SOD inhibition increased the oxidant activity to a greater degree in LS vessels than HS. Inhibition of NAD(P)H oxidase and/or XO decreased the oxidant activity in the HS rats but had to effect on LS rats. Arteriolar responsiveness to ACh was significantly reduced in LS, but not HS rats, after SOD inhibition. Catalase, NAD(P)H oxidase or XO inhibition did not effect arteriolar responsiveness to ACh in either group. These results suggest that a reduction of SOD activity and an increase in NAD(P)H oxidase and XO activity contribute to the increased oxidative stress observed in HS rats, and that oxidants from another source also contribute to reduced NO activity in rats fed high salt.