Chronic salt depletion was used as a model to study the mechanism of renal resistance to the natriuretic effect of atrial natriuretic factor (ANF). Rats were pretreated with furosemide and placed on a low-salt diet (<0.008% NaCl) for 1 wk before a clearance experiment. Compared with animals on a normal salt diet (0.4% NaCl), the natriuretic reponse to ANF administration was reduced by one order of magnitude and was quantitatively trivial. To assess the influence of the sympathoadrenergic system, different groups of rats were either subjected to acute unilateral renal denervation, to chronic adrenal enucleation to reduce circulating catecholamines, or to pretreatment with 6-hydroxydopamine (OHDA) to destroy sympathetic postganglionic nerve endings. None of these treatments was able to fully or even partially restore ANF natriuresis. To determine whether an effect of angiotensin on the kidney prevented the response, the specific receptor antagonist losartan (DuP-753) was administered during the week prior to the experiment. This treatment also did not influence ANF resistance. Similarly, bilateral adrenalectomy 2 wk before the experiment did not affect the renal ANF resistance in salt-depleted rats. The depressed excretory response could not be explained on the basis of reduced renal perfusion pressure or glomerular filtration rate. We conclude that undetermined compensatory mechanism(s) ensures renal salt conservation in this model in the face of even supraphysiological levels of ANF.