Animal studies have indicated that increased nitric oxide (NO) synthesis plays a significant role in the renal adaptation to increased sodium intake. To investigate the role of NO during increased sodium intake in humans, we studied the effect of acute, systemic injection of N^G-monomethyl-l-arginine (l-NMMA) on renal hemodynamics [glomerular filtration rate and renal plasma flow (GFR and RPF, respectively)], urinary sodium excretion (FE_Na), systemic hemodynamics [mean arterial blood pressure and heart rate (MAP and HR)], and plasma levels of several vasoactive hormones in 12 healthy subjects during high (250 mmol/day) and low (77 mmol/day) sodium intake in a crossover design. The sodium diets were administered for 5 days before the l-NMMA treatments, in randomized order, with a washout period of 9 days between each diet and l-NMMA treatment. GFR and RPF were measured using the renal clearance of⁵¹Cr-labeled EDTA and¹²⁵I-labeled hippuran by the constant infusion technique in clearance periods of 30-min duration. Two baseline periods were obtained, after whichl-NMMA was given (3 mg/kg over 10 min), and the effect of treatment was followed over the next five clearance periods. During high sodium intake,l-NMMA induced a more pronounced relative decrease in RPF ( P = 0.0417, ANOVA), a more pronounced relative decrease in FE_Na( P = 0.0032, ANOVA), and a more pronounced relative increase in MAP ( P= 0.0231, ANOVA). During low sodium intake, the effect ofl-NMMA on FE_Nawas abolished. During low sodium intake, l-NMMA induced a sustained drop in plasma renin (31 ± 5 vs. 25 ± 5 μU/ml, P < 0.001), which was not seen during high sodium intake. The data indicate that increased production of NO is an important part of the adaptation to increased dietary sodium intake in healthy humans, with respect to renal hemodynamics, sodium excretion, and the secretion of renin.