Abnormal regulation of local vascular tone occurs early in human and experimental atherosclerosis. Impaired endothelium-dependent vascular relaxations mediated by endothelium-derived relaxing factor are an important contributor to these abnormalities. Endothelium-derived relaxing factor is nitric oxide released as such or attached to a carrier molecule. Oxidized lipoproteins impede endothelium-derived relaxing factor-mediated responses in vitro. We designed in vivo experiments to determine whether hypercholesterolemia with and without deficiency of two endogenous lipid antioxidants, vitamin E and selenium, would result in endothelial dysfunction. Vitamin E and selenium deficiencies were induced in a group of hypertension-prone Dahl salt-sensitive rats fed a diet high in cholesterol (4%) but low in NaCl (0.5%) for 18 weeks. Two other groups of Dahl salt-sensitive rats received diets sufficient in vitamin E and selenium but containing either high or normal cholesterol levels (control group). Serum cholesterol levels increased approximately 10-fold in the two groups of rats fed high-cholesterol diets. Systolic blood pressure was 143 +/- 3 mm Hg in high-cholesterol/vitamin E- and selenium-sufficient rats and 142 +/- 5 mm Hg in high-cholesterol/vitamin E- and selenium-deficient rats (P = NS). Mild intimal thickening and occasional mononuclear cell infiltration were observed in both of these groups. Serum vitamin E levels were decreased, whereas serum thiobarbituric acid-reactive substances and exhaled pentane (two indicators of endogenous lipid oxidation) were significantly increased in high-cholesterol/vitamin E- and selenium-deficient rats compared with high-cholesterol/vitamin E- and selenium-sufficient rats.(ABSTRACT TRUNCATED AT 250 WORDS)