An investigation was undertaken into the potential role of nitric oxide (NO) and its interaction with renal sympathetic nerves in mediating renal responses to acute saline volume expansion (VE). Groups of anaesthetized Wistar rats with innervated and denervated kidneys were subjected to VE, 0.25% body wt min(-1) for 40 min, in the presence and absence of nitric oxide synthase (NOS) inhibitors, NC-nitro-L-arginine-methylester (L-NAME, non-selective), aminoguanidine (AG, relatively selective for inducible NOS (iNOS)), and 7-nitroindazole (7-NI, relatively selective for neuronal NOS (nNOS)). Pretreatment with L-NAME or AG enhanced the cumulative sodium excretion (CuUNaV) after 40 min VE in the innervated kidneys by 27 and 23% (both P <0.001), respectively, compared to the untreated control group, whereas they were without effect in the denervated kidneys. Cumulative urine now (CuUV) after VE in L-NAME- and AG-treated groups was enhanced in both kidneys, by some 17-21% in the denervated (P <0.01) and 37-39% in the innervated kidneys (P <0.001) by comparison with the corresponding untreated controls. 7-NI had no effect on CuUV, but reduced CuUNaV in the denervated kidneys by 25% (P <0.01) when compared to the control group. The results suggested that NO, possibly generated by endothelial NOS (eNOS) and iNOS, was a contributory factor in mediating the renal response to VE. There appeared to be a tonic inhibitory action of NO on water excretion which was renal nerve independent, whereas its impact on sodium handling appeared to be dependent upon a background level of renal nerve activity.