Mice harboring a functional deletion of the pro-atrial natriuretic peptide (ANP) gene (/) develop salt-sensitive hypertension relative to their wild-type (+/+) counterparts after prolonged (>1 wk) maintenance on high-salt (HS, 8% NaCl) diet. We reported recently that the sensitization of arterial blood pressure (ABP) to dietary salt in the / mice is associated with failure to downregulate plasma renin activity. To further characterize the role and mechanism of ANG II in the sensitization of ABP to salt in the ANP "knockout" mice, we measured ABP, heart rate (HR), and plasma catecholamine and aldosterone concentrations in / and +/+ mice maintained on HS for 4 wk and treated with daily injections of AT₁ receptor antagonist DuP-753 (losartan) or distilled water (control). Daily food and water intake and fluid and electrolyte excretion were also measured during the first and last weeks of the dietary regimen. Cumulative urinary excretion of fluid and electrolytes did not differ significantly between genotypes and was not altered by chronic treatment with losartan. Basal ABP and HR were significantly elevated in control / mice compared with control +/+ mice. Losartan did not affect ABP or HR in +/+ mice, but reduced ABP and HR in the / mice to the levels in the +/+ mice. Total plasma catecholamine was elevated by approximately ten-fold in control / mice compared with control +/+ mice. Losartan reduced plasma catecholamine concentration significantly in / mice and abrogated the difference in plasma catecholamine between / and +/+ mice on HS diet. Plasma aldosterone did not differ significantly between genotypes and was not altered by losartan. We conclude that salt sensitivity of ABP in ANP knockout mice is mediated, at least in part, by a synergistic interaction between ANG II and sympathetic nerve activity.