To explore factors that modulate the magnitude of vasorelaxation and natriuretic/diuretic responses to exogenous ANP, clearance studies were performed in unilateral hydronephrotic rats with renal vasoconstriction complications. An increase in renal plasma flow associated with a decrease in calculated renal vascular resistance in response to ANP (2 micrograms.min-1.kg-1, i.v.) was obtained only in the hydronephrotic kidney. In contrast, the control kidney of the unilateral hydronephrotic rat had a decrease in glomerular filtration rate and an abolished natriuretic response following ANP administration. A prior renal denervation in the control kidney restored the natriuretic effect of ANP and abolished the lowering of glomerular filtration rate. These data suggest that the vasodilatory effect of ANP may depend on the vascular tone itself, and that renal responses to ANP are significantly modified by renal nerve activity.