Although maneuvers augmenting atrial volume and/or stretch also augment plasma levels of atrial natriuretic factor (ANF), the role of ANF in modulating renal sodium and water handling has not been defined. Water immersion to the neck (NI) was employed to assess the ANF response to acute volume expansion in 13 seated sodium-replete normal subjects. ANF increased promptly and markedly from 7.8 +/- 1.8 to 19.4 +/- 3.8 fmol/ml, then declined to 6.3 +/- 1.4 fmol/ml after 60 min recovery. Concomitantly, NI increased urine flow rate (V) (2.0 +/- 0.6 to 7.0 +/- 0.9 ml/min; P less than 0.001) and sodium excretion (UNaV) (92 +/- 12 to 191 +/- 15 mu eq/min; P less than 0.001), and decreased PRA (-66 +/- 3%) and plasma aldosterone (-57 +/- 6%). Increases of plasma ANF ranged from less than 20% to over 12-fold. Similarly, the natriuretic response to NI varied markedly from none to 500%. There was a strong correlation between peak ANF and peak UNaV (r = 0.67; P less than 0.025), but none between peak V and peak plasma ANF (r = -0.10; P greater than 0.5). These findings suggest that an increase in plasma ANF contributes to the natriuretic response to NI, implying a physiological role for ANF in modulating volume homeostasis in humans.