Urinary kallikrein excretion during acute water or saline loading was studied in normal and hypertensive humans after chronic Na+depletion and Na+loading to answer the following questions. 1. Is urinary kallikrein a natriuretic or diuretic substance? 2. During acute water or saline loading, does the underlying Na+balance influence (a) the urinary kallikrein response? or (b) the relationship between urinary kallikrein and renal Na+or water handling? 1) Urinary kallikrein did not change during a 1.2 liter water load given to nine white hypertensive and five white normal men. Urinary kallikrein was significantly decreased, however, in five white hypertensive and five white normal subjects during and after 1 hour of isotonic saline infusion (30 ml/kg). In sodiumdepleted hypertensive patients kallikrein excretion was decreased from 19.8 to 9.5 mEU/min, and in Na+-depleted normal subjects it was decreased from 15.7 to 12.6 mEU/min (p = 0.003). The response in hypertensive patients was not different from normal subjects. In all Na+-loaded subjects, kallikrein excretion was also significantly decreased during isotonic saline infusion (p = 0.01). Urinary kallikrein did not change in three other subjects given hypertonic saline. 2(a) The underlying state of Na+balance influenced the baseline level of kallikrein excretion, but not the directional decline in kallikrein during isotonic saline, (b) In Na+-restricted hypertensives given isotonic saline, urinary kallikrein was inversely related to the fractional excretion of Na+(r = -0.54,p< 0.01) and the tubular reabsorption of H2O (TcH2O/GFR; r = - 0.50,p< 0.01). In Na+-loaded hypertensives given isotonic saline, urinary kallikrein was directly related to TcH2O/GFR (r = 0.38,p< 0.05). Prior to infusion, the hypertensives who received isotonic saline showed subnormal renin and aldosterone after dietary Na+restriction, but normal kallikrein excretion. Factors in addition to mineralocorticoids appear to regulate kallikrein excretion. Urinary kallikrein was not a natriuretic or diuretic factor in normal and hypertensive subjects who received acute water or saline loads. In Na+-restricted and -loaded hypertensive and normal subjects, urinary kallikrein was clearly decreased by isotonic saline loading. The state of Na+balance influenced the relationship between urinary kallikrein and renal handling of Na+and H2O.