The hypothesis that renal sodium handling is controlled by changes in plasma sodium concentration was tested in seated volunteers. A standard salt load (3.08 mmol/kg body wt over 120 min) was administered as 0.9% saline (Isot) or as 5% saline (Hypr) after 4 days of constant sodium intake of 75 (LoNa+) or 300 mmol/day (HiNa+). Hypr increased plasma sodium by approximately 4 mmol/l but increased plasma volume and central venous pressure significantly less than Isot irrespective of diet. After LoNa+, Hypr induced a smaller increase in sodium excretion than Isot (48 +/- 8 vs. 110 +/- 17 micromol/min). However, after HiNa+ the corresponding natriureses were identical (135 +/- 33 vs. 139 +/- 39 micromol/min), despite significant difference between the increases in central venous pressure. Decreases in plasma ANG II concentrations of 23-52% were inversely related to sodium excretion. Mean arterial pressure, plasma oxytocin and atrial natriuretic peptide concentrations, and urinary excretion rates of endothelin-1 and urodilatin remained unchanged. The results indicate that an increase in plasma sodium may contribute to the natriuresis of salt loading when salt intake is high, supporting the hypothesis that osmostimulated natriuresis is dependent on sodium balance in normal seated humans.