Previous studies have shown that acute unilateral nephrectomy stimulates sodium (UNaV) and potassium (UKV) excretion by the remaining kidney through reflex pathways requiring an intact pituitary gland, and the natriuresis is accompanied by an increase in the plasma concentration of a peptide or peptides derived from the adrenocorticotropic hormone-beta-endorphin precursor molecule pro-opiomelanocortin. We tested the hypothesis that gamma-melanocyte stimulating hormone (gamma-MSH) was such a peptide involved in the postnephrectomy natriuresis. In six rats undergoing sham nephrectomy, no change in UNaV or UKV occurred and plasma immunoreactive gamma-MSH-like material was 40 +/- 18 (SD) fmol/ml 2 hours after the sham procedure. In 10 rats undergoing acute unilateral nephrectomy, UNaV and UKV from the remaining kidney increased significantly, and immunoreactive gamma-MSH was 81 +/- 36 fmol/ml (p less than 0.02). In individual studies, the increase in UNaV after nephrectomy correlated with the postnephrectomy concentration of immunoreactive gamma-MSH (r = 0.75, p less than 0.001). In 17 rats injected with serum or globulin from control rabbits, unilateral nephrectomy led to the expected increases in UNaV and UKV. In 23 rats injected with serum or globulin from rabbits immunized against gamma-MSH, no postnephrectomy natriuresis occurred and the kaliuresis was blunted. In hydropenic, mineralocorticoid-treated rats, intravenous infusion of synthetic gamma-MSH led to natriuresis and kaliuresis with no change in inulin clearance; pretreatment with rabbit anti-gamma-MSH antiserum blocked this effect of peptide infusion.(ABSTRACT TRUNCATED AT 250 WORDS)