New Findings What is the central question of this study? Knockout mice lacking both α2A- and α2C-adrenergic receptors (α2A/α2C-ARKO) provide a model for understanding the mechanisms underlying the deleterious effects of sympathetic hyperactivity on the cardiovascular system. The purpose of this study was to compare the effects of sympathetic hyperactivity on the vascular reactivity of large and small arteries from α2A/α2C-ARKO mice and to evaluate the role of nitric oxide and oxidative stress., What is the main finding and its importance? We show that sympathetic hyperactivity alters vascular reactivity only in small arteries. Uncoupling endothelial nitric oxide synthase may be a significant source of superoxide anion and reduced NO bioavailability in small arteries from α2A/α2C-ARKO mice, increasing the contractile tone., Knockout mice lacking both α2A- and α2C-adrenergic receptors (α2A/α2C-ARKO) provide a model for understanding the mechanisms underlying the deleterious effects of sympathetic hyperactivity on the cardiovascular system. Thus, in the present study we investigated the vascular reactivity of large and small arteries of α2A/α2C-ARKO mice. Aorta and mesenteric small arteries (MSAs) from 7-month-old male α2A/α2C-ARKO mice and congenic C57BL6/J mice (wild-type, WT) were studied. In the aorta, noradrenaline- and serotonin-induced contraction was similar between groups, but in MSAs there was an increase in agonist-induced contraction in α2A/α2C-ARKO compared with WT. The l-NAME effect was reduced in MSAs of α2A/α2C-ARKO mice compared with WT mice, as was basal NO evaluated by a 4,5-diaminofluorescein diacetate probe. Increased total endothelial nitric oxide synthase (eNOS) protein expression was observed in MSAs from α2A/α2C-ARKO mice, while the dimer/monomer ratio of eNOS was decreased. Mesenteric small arteries from α2A/α2C-ARKO mice showed an increase in ethidium bromide-positive nuclei, indicating oxidative stress, which was attenuated by incubation with l-NAME. The sympathetic hyperactivity present in α2A/α2C-ARKO mice alters vascular reactivity only in certain types of arteries. Moreover, after chronic sympathetic hyperactivity, uncoupling eNOS may be a significant source of superoxide anion and reduced NO bioavailability in small vessels, increasing the contractile tone. [ABSTRACT FROM AUTHOR]