Induction of oxidative stress by glutathione depletion causes severe hypertension in normal rats

Several recent studies have shown that certain forms of genetic or acquired hypertension are associated with oxidative stress and that animals with th ose types of hypertension respond favorably to antioxidant therapy. We hypo thesize that oxidative stress may cause hypertension via (among other mecha nisms) enhanced oxidation and inactivation of nitric oxide (NO). To test th is hypothesis, Sprague-Dawley rats were subjected to oxidative stress by gl utathione (GSH) depletion by means of the GSH synthase inhibitor buthionine sulfoxinline (BSO, 30 mmol/L in drinking water) for 2 weeks. The control g roup was given drug-free drinking water. In parallel experiments, subgroups of animals were provided vitamin E-fortified chow and vitamin C-supplement ed drinking water. The BSO-treated group showed a 3-fold decrease in tissue GSH content, a marked elevation in blood pressure, and a significant reduc tion in the urinary excretion of the NO metabolite nitrate plus nitrite, wh ich suggests depressed NO availability. These characteristics were associat ed with a significant accumulation in various tissues of nitrotyrosine, whi ch is the footprint of NO inactivation by reactive oxygen species. Administ ration of vitamin E plus vitamin C ameliorated hypertension, improved urina ry nitrate-plus-nitrite excretion, and mitigated nitrotyrosine accumulation (despite GSH depletion) in the BSO-treated animals but had no effect in th e control group. In conclusion, GSH depletion resulted in perturbation of t he NO system and severe hypertension in normal animals. The effects of BSO were mitigated by concomitant antioxidant therapy despite GSH depletion, wh ich supports the notion that oxidative stress was involved in the pathogene sis of hypertension in this model.