Mammalian atria contain peptides that have depressor and natriuretic activities. Four peptides, atriopeptin I to III (AP I to III) and alpha-human atrial natriuretic factor (alpha-hANP), were synthesized and assayed in the urethane-anesthetized rat for cardiovascular changes and natriuretic activities. All four peptides produced depressor responses and natriuresis. The relative activities were: alpha-hANP = AP III greater than AP II greater than AP I. The disappearance of iodinated AP III from plasma was rapid, with an estimated half-life of 2.5 min. Atriopeptin III was degraded by tissue homogenates, the relative activities being: kidney greater than liver greater than lung greater than plasma greater than heart. The HPLC profile of AP III suggested that smaller peptide fragments were formed after incubation with kidney homogenates. The degradation of AP III was inhibited by bestatin, an aminopeptidase inhibitor, and SQ 20881, a carboxypeptidase inhibitor.