To study the mechanism of atrial natriuretic factor (ANF) release in heart failure, we measured plasma ANF concentrations, cardiac volumes and filling pressures at rest and during three graded exercise levels (E1, E2, E3) in six male patients with congestive heart failure (CHF) and compared them with 13 normal male subjects. At rest, ANF concentrations were sixfold higher in patients with CHF than in normal subjects (at rest: 53 +/- 12 vs 8 +/- 1 pmol.l-1; P less than 0.02). End-systolic ventricular volumes were increased threefold in patients with CHF (P less than 0.02) despite normal mean central venous pressure, pulmonary artery pressure (PAP) and pulmonary wedge pressure (PWP). A positive correlation was found between end-systolic ventricular volumes and plasma ANF (r = 0.93, P less than 0.001). During exercise, ANF rose by 120% over basal values both in patients with CHF and in normal subjects (P less than 0.01). Volumes higher than normal in patients with CHF increased further at E2 (P less than 0.05) in contrast to a decrease of systolic volumes recorded in normal subjects (P less than 0.05). Filling pressures rising abnormally in patients with CHF correlated with plasma ANF during exercise (r = 0.53, P less than 0.02 for PAP; r = 0.51, P less than 0.05 for PWP). In conclusion, our data suggest that ANF release in CHF is regulated at rest by cardiac volumes when filling pressures are still normal. During exercise, ANF release is not impaired in CHF with normal rest filling pressures and is regulated during exercise by left filling pressures.