Atrial natriuretic factor (ANF) causes plasma fluid to shift out of the circulation and enhances the escape of radiolabeled albumin. Examination of the mechanisms by which ANF alters microcirculatory fluid and protein transfer will likely require studies in localized vascular regions. This study was aimed at determining the specific organs in which ANF increases the escape of albumin. Anesthetized, splenectomized rats that had both kidneys removed were infused with vehicle alone or rat ANF-(99-126) at 0.025, 0.05, 0.1, or 0.5 micrograms.min-1.kg-1 for 2 hours (n = 8 per group). Total red cell and plasma volumes were measured with chromium-51-labeled erythrocytes and iodine-125-labeled albumin, respectively. At the end of 2 hours, the rats were frozen in liquid nitrogen, and organ blood volumes and tissue 125I-albumin were determined. ANF decreased plasma volume at infusion rates of 0.1 and 0.5 micrograms.min-1.kg-1. ANF increased the rate at which 125I-albumin escaped from the overall circulation at infusion rates of 0.1 and 0.5 micrograms.min-1.kg-1. At an ANF infusion rate of 0.1 micrograms.min-1.kg-1, the albumin escape rate increased in the gastrointestinal tract, skeletal muscle, heart, and lungs. At an infusion rate of 0.5 micrograms.min-1.kg-1, the albumin escape rate increased in the gastrointestinal tract, muscle, and skin, but not the lungs. These findings suggest that at pathophysiological levels, ANF shifts protein out of the circulation in peripheral vascular beds and the lungs and may contribute to pulmonary edema in states such as congestive heart failure. At pharmacological levels, ANF may be protective of the lungs by preventing increased pulmonary albumin escape.