Tubular sodium handling in humans undergoing hypotonic expansion due to the administration of antidiuretic hormone was studied using the clearance of lithium as an index of distal filtrate and sodium delivery. Clearance studies were performed in the morning in eight normal subjects before and on the fourth day of intranasal I-desamino-8-D-arginine vasopressin (dDAVP) administration. Fluid intake was kept constant at 25 ml/kg body weight. After dDAVP body weight increased (2.5 +/- 0.4 kg), plasma sodium fell (from 143 +/- 1 to 128 +/- 5 mmol/liter) and a progressive natriuresis developed. Sodium balance remained negative up to the second clearance study, when the cumulative sodium loss amounted to 148 +/- 96 mmol. Plasma renin activity fell significantly, but plasma aldosterone did not. Inulin clearance rose from 110 +/- 14 to 135 +/- 23 ml/min and lithium clearance from 30.9 +/- 7.6 to 48.9 +/- 15.1 ml/min. Fractional reabsorption of uric acid, phosphate and calcium decreased. Together these changes suggest that the negative sodium balance in hypotonic expansion with dDAVP results from increased filtered sodium load, decreased fractional reabsorption in the proximal tubules, and increased distal delivery. Estimated fractional reabsorption in the distal nephron remained unaltered. The plasma concentration of lithium, of which 10.8 mmol was ingested on the eve of the clearance studies, was not lower during the dDAVP-clearance study. This indicates that the tubular adaptations mentioned are present intermittently, in particular during daytime.