The renin-angiotensin-aldosterone system (RAAS) has been implicated in the pathophysiology of salt-induced hypertension. Angiotensin converting enzyme inhibitors, angiotensin II-type 1 receptor blockers, and aldosterone receptor blockers are used to treat hypertension and congestive heart disease. In addition to their blood pressure lowering effects, they appear to protect against myocardial, renal, and vascular damage. In various models of hypertension, generation of reactive oxygen species is increased in the vasculature and that treatment with antioxidants or superoxide dismutase mimetics (e.g., tempol) improves vascular function and structure and reduces blood pressure. The purpose of this study was to examine the effects of enalapril, an angiotensin II converting enzyme inhibitor; eplerenone, a selective aldosterone receptor antagonist; and tempol, a superoxide dismutase mimetic, on salt-induced hypertension in Dahl Salt-Sensitive rats. The rats were placed on a high salt (HS; 8%) diet for 3 weeks prior to switching to a normal salt (0.3%) diet for an additional 3 weeks. While on the normal salt (NS) diet, rats were treated with enalapril (30 mg/kg/day in the drinking water), eplerenone (100 mg/kg/day by gavage), tempol (1 mM/day in the drinking water), eplerenone + enalapril, eplerenone + enalapril + tempol, or without drug treatment (control). After 3 weeks on HS diet, systolic blood pressure rose from 127 +/- 7 to 206 +/- 11 mm Hg and remained elevated when switched to NS diet. Subsequently, treatment with eplerenone alone or in combination with enalapril and tempol produced a stepwise reduction in systolic blood pressure reaching -80 mm Hg; however, enalapril and tempol alone produced more modest pressure reduction (approximately -35 mmHg). Plasma levels of prostacyclin and nitric oxide were elevated in rats treated with enalapril and eplerenone alone or in combination. Enalapril and eplerenone alone and in combination reduced heart and kidney levels of angiotensin II and aldosterone when compared with control. Renal and heart levels of reduced glutathione were diminished by eplerenone alone; however, enalapril tended to attenuate the effect of eplerenone on reduced glutathione levels in the heart. The findings from this study suggest that eplerenone reduces salt-induced hypertension by increasing endothelium-derived relaxing factors, inhibiting RAAS components and oxidative stress. (353words).