The obese Zucker rat, a popular model of insulin resistance allied with oxidant stress, is associated with either normal or paradoxically enhanced endothelial vasodilator function compared with its lean litter mate. We have investigated hindquarter endothelium-dependent vasodilation in the obese Zucker rat in-situ and have examined its relationship with oxidant stress. In perfused hindquarter preparations equivalently preconstricted with phenylephrine, vasodilator responses to the endothelium-dependent agent acetylcholine (0.03-1000 pmol) were greater in obese (pD2 = 11.03+/-0.19) compared with lean (pD2 = 10.53+/-0.13) animals (P < 0.01, two-way analysis of variance). In contrast, maximal vasodilation to the nitric oxide (NO) donor sodium nitroprusside (100 nmol) was similar in obese (59.6+/-19.8%) and lean (51.9+/-2.6%) preparations (P > 0.05). However, this exaggerated vasodilator reactivity to acetylcholine in obese animals was abolished following four-week dietary supplementation with the lipophilic antioxidant vitamin E (obese pD2 = 10.74+/-0.18; lean pD2 = 10.74+/-0.08). This antioxidant-mediated effect was associated with a reduction (P < 0.02, two-way analysis of variance) and an enhancement (P < 0.01, two-way analysis of variance) in endothelium-dependent vasodilator responses in obese and lean hindlimb preparations, respectively. Our data therefore now point to a differential modulation of hindquarter endothelium-dependent vasodilation in the obese and lean Zucker rat by the prevailing oxidant tone, resulting in an agonist-stimulated endothelial vasodilator hyperreactivity in obese animals.