The neonate conserves sodium avidly, and sodium intake is normally limited to that present in maternal milk. To evaluate the role of atrial natriuretic peptide (ANP) in this adaptation, preweaned rat pups were artificially reared and fed a formula with either normal sodium (25 mEq/L) or high sodium (145 mEq/L) for 7-8 d. To determine whether increased dietary sodium decreases ANP clearance receptor activity, animals were anesthetized, and the plasma ANP concentration (ANPp), urine flow (V), urinary sodium (UNa V), and cGMP excretion (UcGMP V) were measured before and after infusion of ANF(4-23), an ANP clearance receptor inhibitor (C-ANF), at 50 micrograms/kg/ min. Infusion of C-ANF increased ANPp 10-fold in both normal and high sodium groups, but V, UNa V, and UcGMP V increased only in animals receiving the high sodium diet (p < 0.05). Incubation of isolated glomeruli with 0.1 microM ANP increased extracellular cGMP more in high sodium than normal sodium groups (p < 0.05). We conclude that ANP clearance receptors in the neonate are highly activated regardless of sodium intake. Increased dietary sodium increases the renal diuretic and natriuretic response to circulating ANP through enhanced generation of cGMP.