Investigation of oxidant stress and vasodepression to glyceryl trinitrate in the obese Zucker rat in vivo

1 We examined the relationship between oxidant stress and the vasodepressor activity of glyceryl trinitrate (GTN) in vivo , including rapid GTN tolerance development, in 13‐week old obese and age‐matched lean Zucker rats which had been maintained for 4 weeks on either control diet or diets enriched with the lipophilic, chain‐breaking antioxidants vitamin E (0.5% w w −1 ) or probucol (0.5% w w −1 ) or the superoxide anion scavenger tiron (1% w v −1 in drinking water). 2 The basal plasma level of the isoprostane 8‐epi‐PGF 2α , an in vivo marker of lipid peroxidation, was elevated by approximately 5 fold in the obese Zucker rat and markedly reduced by dietary lipophilic antioxidants and depressed by dietary tiron. 3 Vasodepression to bolus does GTN (0.1–100 μg kg −1 i.v.), but not endothelium‐dependent vasodepression to bolus dose acetylcholine (ACh, 0.02–2.0 μg kg −1 i.v.), was impaired in obese animals and completely restored by dietary antioxidants. 4 Nitrate tolerance developed in vivo during a 1 h infusion of GTN (40 μg kg −1  min −1 i.v.) appeared more severe in obese animals. However, rapid nitrate tolerance was not affected by dietary antioxidants in either the obese or lean Zucker rat. 5 We therefore provide evidence that elevated oxidant stress in the obese Zucker rat is associated with an impairment in nitrate vasodepressor activity. However, our data are not consistent with either a role for oxidant stress in rapid nitrate tolerance development in the anaesthetized Zucker rat or the aggravation of this tolerance by pre‐existing oxidant stress.British Journal of Pharmacology (1998) 125 , 895–901; doi: 10.1038/sj.bjp.0702132