There is evidence in animals and in humans for accelerated natriuresis after oral compared with intravenous sodium loading. To assess the role of atrial natriuretic peptide (ANP) as a contributory mechanism, we compared the hormonal responses to an intravenous sodium load and to the same sodium load taken orally in three separate groups of healthy subjects in balance on low, normal, or high sodium intake. On each diet, there was a trend for an early delay in sodium excretion, followed by increased natriuresis after the oral compared with intravenous sodium load. On all levels of dietary sodium intake, there was a significant (~2-fold) increase in plasma ANP levels after intravenous saline infusion. There was a significant suppression of the renin system both after oral and intravenous sodium loading. However, there was no acute increase in plasma ANP levels after the oral sodium load, except on the very low sodium intake. This striking and unexpected observation suggests that changes in plasma ANP levels appear to play little role in the early response to an acute oral sodium load in subjects with sodium intake in the range of 150-350 mmol/day. Endocrine mechanisms for the accelerated increase in sodium excretion after oral compared with intravenous sodium loading remain to be elucidated.