The discovery that atrial extracts have potent diuretic and natriuretic properties revealed a possible endocrine function of the heart in the regulation of extracellular fluid volume. Since that first report intense research activity has been directed towards determining the mechanism of action of the active atrial natriuretic polypeptides (ANP) found in these extracts. Despite these efforts it remains controversial whether the renal actions of ANP are exerted solely on the process of glomerular filtration or involve additional direct actions on tubular transport. We have investigated the possibility that atrial natriuretic polypeptides may induce natriuresis by suppression of proximal tubular sodium and water reabsorption. Using shrinking split-drop micropuncture combined with simultaneous capillary perfusion in anaesthetized rats we report that 20 nanomolar alpha-rANP (the main component of ANP in rat plasma) added to the peritubular fluid had no direct effect on proximal fluid uptake whereas picomolar angiotensin II had a marked stimulatory action as reported. The stimulatory effect of angiotensin II on fluid reabsorption was inhibited by peritubular ANP at physiological concentrations and abolished by higher concentrations of ANP. Thus at physiological concentrations ANP acts within the kidney to decrease proximal reabsorption by inhibition of angiotensin-stimulated sodium and water transport.