The temporal changes in the plasma concentration of immunoreactive atrial natriuretic factor (iANF) were studied in six conscious dogs with an arteriovenous (AV) fistula, a model of chronic high-output heart failure. Following the creation of the AV fistula, the dogs retained sodium avidly for 5 days, and plasma renin activity, plasma aldosterone concentration, and right atrial pressure increased significantly from controls. During this initial stage, iANF increased only modestly. From day 6 to 14, the dogs increased their daily sodium excretion and approached sodium balance. This natriuretic response was associated with a significant rise in iANF, with the return of renin and aldosterone levels to base line, and with a progressive significant elevation in right atrial pressure. Thus, in dogs with an AV fistula and cardiac volume overload, chronic increases in atrial pressure appear to be a sustained stimulus for the release of ANF. It is suggested that following the initial period of sodium retention in this experimental mental model of heart failure, chronic endocrine adjustments for the reestablishment of sodium balance involve an increase in ANF which subsequently can exert a tonic inhibitory action on the renin-aldosterone axis. It is concluded that the ANF endocrine system might function as an effective chronic compensatory mechanism to help promote sodium and water excretion in dogs with an AV fistula through the suppression of the renin-aldosterone system and possibly through its direct renal actions.