Reactive oxygen species (ROS) in the brain are thought to contribute to the neuropathogenesis of hypertension by enhancing sympathetic nervous system activity. The nicotinamide-adenine dinucleotide phosphate (NADPH) oxidase and its regulatory subunit Rac1 (a small GTPase) play important roles in ROS production in the brain. Resent evidences reported that resveratrol activates AMP-activated protein kinase (AMPK) to suppress oxidative stress. Therefore, we examined whether promotion of AMPK in the brain decreases Rac1-derived ROS generation, thereby reducing blood pressure in fructose-induced hypertensive rats (F rats). In this study we elucidated the ROS level in the nucleus tractus solitarii (NTS) and rostral ventrolateral medulla (RVLM) were greater in F rats than in Wistar-Kyoto rats (WKY). Inhibitions of ROS, oral resveratrol for one week decrease blood pressure and increase NO production in F rats but not in WKY. Diminutions of Rac1 through resveratrol also reduce NADPH oxidase subunit expression (p22-phox and p67-phox) and induce SOD2 production. In addition, inhibition of AMPK by an AMPK inhibitor (compound C) abolished resveratrol-induced decreases in Rac1 and NADPH oxidase activities and resveratrol-induced increases in SOD2 expression, suggesting that AMPK is an important mediator of the resveratrol-induced regulation of these enzymes. Interestingly, abolish Rac1 by overexpression of AMPK that decrease blood pressure through reduced extracellular signal-regulated kinases 1/2 (ERK1/2), ribosomal protein S6 kinase (RSK), and nNOS phosphorylation in in F rats. These results indicate that the activation of Rac1 in the brain generates ROS via induced NADPH oxidase, which cause dysfunction of ERK1/2-RSK-nNOS signal pathway in F rats, and this mechanism might be important for the neuropathogenesis of hypertension in fructose-induced hypertension.