Atrial natriuretic peptide is a potent diuretic and vasorelaxant peptide secreted from the cardiac atria of adult mammals in response to increased intravascular volume. In sheep, fetal plasma levels of atrial natriuretic peptide are significantly greater than maternal levels, but the factors that control fetal release of atrial natriuretic peptide have not been defined. The present studies were conducted to determine whether the fetus responds to increased intravascular volume by atrial natriuretic peptide secretion. The mean (+/- standard error of the mean) atrial natriuretic peptide of basal fetal plasma (115 +/- 24 pg/ml) in chronically catheterized ovine fetuses (131 +/- 1 days' gestation) was significantly greater than atrial natriuretic peptide levels of basal maternal plasma (56 +/- 12 pg/ml). In response to successive 30-minute intravenous infusions of 0.9% saline solution at 0.5 and 1.0 ml/kg/min, fetal plasma atrial natriuretic peptide significantly increased to a maximum of 409 +/- 72 pg/ml during the high-dose saline infusion and returned to 234 +/- 83 pg/ml during a 30-minute recovery period. The increase in fetal plasma atrial natriuretic peptide was significantly correlated with the volume of saline solution infused (r = 0.68). During the saline infusion, a significant increase in fetal blood volume and heart rate was noted. Fetal blood pressure, maternal plasma levels of atrial natriuretic peptide, and fetal and maternal plasma osmolality remained unchanged. Despite elevated basal levels of plasma atrial natriuretic peptide, the third-trimester ovine fetus responds to increases in intravascular volume with a further increase in atrial natriuretic peptide secretion.