Baroreflex sensitivity (BRS) is often reduced in elderly populations and patients with chronic cardiovascular diseases leading to a concomitant rise in blood pressure variability (BPV) that is associated with increased cardiovascular related morbidity and mortality. Thus, there is a need to better understand the mechanisms by which BPV causes cardiovascular end-organ damage. Animal studies using sinoaortic denervation (SAD) to increase BPV have demonstrated pathologic changes in the structure of the heart and blood vessels; however, there is a paucity of data investigating changes in functional measures of the heart and smaller, resistance type arteries. Furthermore, the pathogenic mechanisms involved in BPV-induced cardiovascular end-organ damage remain unknown. Baroreceptor denervation results in multiple cardiac stressors, many of which are associated with production of reactive oxygen species. Oxidative stress is known to promote cardiovascular end-organ damage but it is unclear if it plays a role in models of increased BPV. Thus, this study was designed to investigate the functional responses of smaller resistance type arteries and the heart to chronic exposure to enhanced BPV. In addition, the role of oxidative stress on these functional responses in a normotensive rat model of increased BPV was also investigated. Rats were subjected to either SAD surgery or a sham procedure and were observed for six weeks. To determine the role of oxidative stress, SAD rats were either treated with the superoxide dismutase mimetic tempol or left untreated. During the observation period, mean blood pressure remained normotensive, whereas baroreflex sensitivity was reduced and BPV increased two to three fold. Weekly in vivo assessment of vascular function of the long posterior ciliary artery (LPCA) demonstrated a significant reduction in endothelial-dependent dilation starting three weeks after SAD surgery compared to the sham group. Endothelial-independent dilation was not affected by SAD. Structural changes were not evident in the LPCA following SAD. However, structural (wall thickness, wall area, and wall area/lumen area ratio) and functional (strain and distensibility) changes were observed in the aorta. Cardiac structural (hypertrophy) and functional (diastolic dysfunction) effects were also evident following six weeks of increased BPV. Antioxidant treatment with tempol did not have any effect on the SAD-induced increase in BPV or decrease in BRS. Nevertheless, chronic tempol treatment prevented or reduced the cardiovascular end-organ damage (endothelial-dependent vascular dysfunction, decreased aortic distensibility, cardiac and vascular hypertrophy, and cardiac dysfunction) observed in the untreated SAD group. These findings suggest that the pathology observed following SAD is at least partly mediated by oxidative stress. Antioxidant treatment in patients with increased BPV (e.g., hypertension, diabetes, heart failure) may prevent or ameliorate cardiovascular end-organ damage and reduce the overall risk for cardiovascular disease events.