We examined the question of whether escape from the sodium-retaining effect of mineralocorticoid involves an increased natriuretic effect of atrial natriuretic factor (ANF). Seven healthy volunteers taking a 170 mmol Na/100 mmol K diet received an intravenous bolus (25 micrograms) followed by a 1-hour infusion (0.02 micrograms/kg/min) of ANF (human ANF-[99-126]) before and after 10 days of 9-fludrocortisone acetate, 0.5 mg b.i.d. Escape was accompanied by an increase in body weight (from 72.2 +/- 12.9 to 74.0 +/- 12.6 kg; p less than 0.05), mean arterial pressure (from 95 +/- 4 to 109 +/- 3 mm Hg; p less than 0.01), plasma ANF (from 9 +/- 2 to 24 +/- 4 pmol/L; p less than 0.01), and inulin clearance (from 124 +/- 9 to 137 +/- 7 ml/min; p less than 0.05). Indexes for renal sodium handling (lithium and free water clearance) were compatible with a decreased "proximal" and an increased "distal" tubular reabsorption fraction. ANF infusion raised inulin clearance comparably before and after escape to 138 +/- 10 and 152 +/- 7 ml/min, respectively, but the natriuretic effect was much larger (p less than 0.05) after escape (from 366 +/- 34 to 1294 +/- 278 mumol/min) than before (from 248 +/- 48 to 630 +/- 124 mumol/min). Indexes for tubular reabsorption were consistent with greater suppression of both "proximal" and "distal" tubular sodium reabsorption by ANF after versus before mineralocorticoid expansion. These results indicate that escape is accompanied not only by a rise in plasma ANF but also by potentiation of the natriuretic effect of ANF.(ABSTRACT TRUNCATED AT 250 WORDS)