The relative importance of systemic volume, concentration, and pressure signals in sodium homeostasis was investigated by intravenous infusion of isotonic (IsoLoad) or hypertonic (HyperLoad) saline at a rate (1 micromol Na(+) x kg(-1) x s(-1)), similar to the rate of postprandial sodium absorption. IsoLoad decreased plasma vasopressin (-35%) and plasma ANG II (-77%) and increased renal sodium excretion (95-fold), arterial blood pressure (DeltaBP; +6 mmHg), and heart rate (HR; +36%). HyperLoad caused similar changes in plasma ANG II and sodium excretion, but augmented vasopressin (12-fold) and doubled DeltaBP (+12 mm Hg) without changing HR. IsoLoad during vasopressin clamping (constant vasopressin infusion) caused comparable natriuresis at augmented DeltaBP (+14 mm Hg), but constant HR. Thus vasopressin abolished the Bainbridge reflex. IsoLoad during normotensive angiotensin clamping (enalaprilate plus constant angiotensin infusion) caused marginal natriuresis (9% of unclamped response) despite augmented DeltaBP (+14 mm Hg). Cessation of angiotensin infusion during IsoLoad immediately decreased BP (-13 mm Hg) and increased glomerular filtration rate by 20% and sodium excretion by 45-fold. The results suggest that fading of ANG II is the cause of acute "volume-expansion" natriuresis, that physiological ANG II deviations override the effects of modest systemic blood pressure changes, and that endocrine rather than hemodynamic mechanisms are the pivot of normal sodium homeostasis.