We studied the role of altered pituitary function in the reflex natriuresis that occurs after acute unilateral nephrectomy (AUN). In normal rats, AUN increased both sodium (UNaV) and potassium excretion within 90 min. In hypophysectomized rats, no increase in cation excretion after AUN occurred, results which were duplicated in rats in which pituitary function was altered by prior treatment with dexamethasone (2 mg/kg ip for 3 days). In adrenalectomized rats, AUN led to increases in cation excretion similar to those seen in normal rats, indicating that intact adrenal function was not necessary for this excretory response following AUN. These changes in cation excretion were correlated with measurements in peripheral plasma of two peptides derived from the pituitary precursor molecule pro-opiomelanocortin (POMC). Radioimmunoassayable plasma beta-endorphin failed to change after AUN in any of the conditions studied. However, a sensitive radioimmunoassay for the N-terminal fragment (NTF) of POMC indicated that plasma NTF rose significantly after AUN in normal and adrenalectomized rats but did not change in hypophysectomized, steroid-pretreated, or shamoperated rats. The increase in NTF concentration correlated with the increase in UNaV after AUN. These results demonstrate that the reflex increase in cation excretion after AUN is dependent on an intact pituitary gland and is associated with an increase in peripheral plasma concentration of NTF. NTF, or some other peptide residing in the N-terminal portion of POMC, could promote the natriuresis after AUN; the importance of the pituitary gland in this response could be the secretion of this peptide.