To study the hemodynamic and metabolic effects of chronic inhibition of endothelium-derived nitric oxide, we treated conscious rats with an oral solution of N omega-nitro-L-arginine (LNA), an inhibitor of nitric oxide production by endothelial cells. After 3 days of treatment with 2.74 mM LNA, rats had higher blood pressures (136 +/- 5 versus 113 +/- 3 mm Hg, p < 0.0005) than did the control animals. This effect was maintained through 7 days of treatment (142 +/- 6 versus 109 +/- 4 mm Hg, p < 0.0005) and in three animals for 35 days (167 +/- 7 mm Hg). The blood pressure rise was dose dependent. The hypertensive effect of oral LNA was not enhanced by the administration of 20 mg intraperitoneal LNA and was prevented by pretreatment with L-arginine, although L-arginine also caused a transient but significant increase in urinary sodium excretion. When LNA treatment was discontinued, blood pressure fell gradually, with an effective biological half-life of 4.2 days. Metabolic balance studies did not identify differences in sodium or potassium balance between treated and control animals. Plasma renin activity was lower in LNA-treated animals, and aldosterone concentrations tended to be lower. In contrast, atrial natriuretic factor levels and serum electrolyte concentrations were unchanged after 7 days of treatment with LNA. These data support the premise that endothelium-derived nitric oxide plays an important role in basal hemodynamic homeostasis. Oral administration of LNA may serve as a model of chronic nitric oxide-deficient hypertension and allow for the future study of endothelium dependence in hypertension.