The effects of myocardial extracts on renal function were studied in the rat. Infusion of rat atrial extract but not of ventricular extract resulted in a significant natriuresis in both pentobarbitone anaesthetized and unanaesthetized rats that were either deprived of food and water (for 18 h before the experiment) or were expanded with isotonic sodium chloride solution (1.5% body weight/h) during the experiment. The increase in sodium excretion was three to four times greater in both groups of volume-expanded rats than in the two groups of food- and water-deprived rats. Glomerular filtration rate and renal blood flow were not affected by atrial extract, indicating that the atrial natriuretic factor (ANF) directly inhibited sodium reabsorption at the tubular level. Distal tubular blockade with a combination of frusemide and amiloride was employed to differentiate between proximal and distal tubular sites of action of ANF. Infusion of atrial extract into saline-expanded, distally blocked rats resulted in a transient increase in both the glomerular filtration rate and sodium excretion; fractional sodium excretion was unaffected by atrial extract in these experiments. We conclude that (a) the renal response to ANF is not affected by pentobarbitone anaesthesia, (b) the renal response to ANF is dependent on the state of the extracellular fluid volume of the animal and (c) that ANF inhibits sodium reabsorption in the distal nephron.