Mechanisms of oxidative stress in the Dahl hypertensive rat

Reactive oxygen species play a critical role in the pathogenesis of various diseases. In hypertension, superoxide radicals have been postulated to affect vascular resistance as well as cause vascular injury. The objective of this dissertation was to investigate mechanisms by which oxygen free radicals contribute to the development of salt-induced hypertension. Dahl salt-sensitive (Dahl-S) and salt-resistant (Dahl-R) rats were fed either a low salt or high salt diet for four weeks. The high salt diet elevated the blood pressure of Dahl-S rats and had no effect on Dahl-R rats. Reduction of a tetranitroblue tetrazolium (TNBT) dye was used to detect superoxide radicals in vivo. Light absorption of formazan crystals revealed enhanced staining along the endothelium of mesenteric arterioles and venules in hypertensive Dahl-S rats. In addition, a Clark electrochemical electrode was used to measure hydrogen peroxide production levels in plasma. Hypertensive Dahl-S rats had a higher plasma hydrogen peroxide concentration compared to normotensive counterparts. To determine if xanthine oxidase was a potential source for excess oxygen free radical production, Dahl-S and Dahl-R rats were fed either a low salt, high salt or high salt + tungsten diet for four weeks. Compared to high salt treated Dahl-S rats, the tungsten diet lowered the blood pressure of Dahl-S rats and had no effect on Dahl-R rats. Tungsten treated Dahl-S rats also had reduced TNBT staining along the endothelium of mesenteric microvessels and reduced plasma hydrogen peroxide levels compared to hypertensive, high salt treated Dahl-S rats. To determine if renal cytochrome P450 monooxygenase was involved in the development of salt induced hypertension, Dahl-S rats were fed either a low or high salt diet and injected with either tin or plasmalyte for two weeks. The tin treatment elevated blood pressure, in vivo superoxide and plasma hydrogen peroxide levels in Dahl-S rats maintained on the high salt diet and had no effect on Dahl-S rats maintained on the low salt diet. Thus, hypertension in the Dahl rat is associated with an enhanced production of oxygen free radicals, possibly through increased xanthine oxidase activity, and decreased arachidonic acid metabolite activity.