-To evaluate whether ACE inhibition and angiotensin II type 1 blockade exert beneficial effects on NO availability independent of their blood pressure-lowering effect, we used a double-blind crossover design to study vascular function in 18 patients with hypertensive renovascular disease during 6 weeks of therapy with enalapril (Ena) and valsartan (Val) compared with non-renin-angiotensin system-mediated treatment with the alpha(1)-blocker doxazosin (Dox). Control measurements were performed in 13 age-matched volunteers. Forearm blood flow was assessed with venous occlusion plethysmography, and serotonin and nitroprusside were used as endothelium-dependent and -independent vasodilators, respectively. Blood pressure was similar during all treatment periods. Serotonin-induced vasodilation was decreased in patients during Dox treatment (n=12) compared with control subjects (n=13) (increase 42+/-20% versus 107+/-65%, P:<0.05). Crossover from Dox to Val (n=6) had no effect on serotonin response (increase 50+/-14%), but crossover to Ena (n=6) caused a significant improvement (increase 79+/-39%, P:<0.05 versus Dox). In an assessment of all patients, serotonin-induced vasodilation during Ena (n=12, increase 75+/-31%) was increased compared with both Val and Dox (43+/-14% and 42+/-20%, respectively; both P:<0.05 versus Ena). The nitroprusside response remained unaltered during all treatment periods. In conclusion, ACE inhibition improves the impaired endothelium-dependent vascular function in patients with hypertensive renovascular disease. This effect is unrelated to blood pressure-lowering or angiotensin II-mediated effects.