In order to evaluate the effect of atrial natriuretic peptide (ANP) infusion on plasma and urinary digitalis-like substance (DLS) levels, 18 essential hypertensive males (mean age 45.6 +/- 3.8 y) were studied. After 1 week on a normal NaCl intake (120 mmol/24h), patients were randomly double-blindly assigned to receive either ANP (99-126) (0.3 microgram/kg/min) (number of patients = 10) or its vehicle (50 ml isotonic saline) (8 patients) over a period of 60 min, in supine position. Plasma and urinary DLS levels were measured at time -60, 0, 30, 60, 120, 180, and 240 min (infusion time from 0-60 min). During ANP infusion, plasma DLS levels decreased significantly (from 25.2 +/- 6.8 pg/ml at time 0 to 12.5 +/- 5.6 pg/ml at 60 min, p < 0.01), while urinary DLS excretion increased (from 60.5 +/- 26.1 pg/ml at time 0 to 246.3 +/- 34.2 pg/ml at 30 min, p < 0.0001). and 402.3 +/- 44.1 pg/ml at 60 min, p < 0.0001). After 3 h from the end of ANP infusion, both plasma and urinary DLS returned to baseline levels (20.5 +/- 14.4 pg/ml and 84.5 +/- 34.2 pg/ml, respectively). Taken together, our data show that ANP infusion significantly increases urinary DLS excretion, while decreasing its circulating levels. This phenomenon could explain the different response of ANP and DLS to some stimuli, such as acute volume expansion. In fact, the rapid increment of plasma ANP due to an acute increase of extracellular fluid volume might simultaneously inhibit the increase in circulating DLS levels by promoting the urinary excretion of this substance.