Recent clinical and experimental studies have shown that renal injury or inflammation elevates sympathetic nerve activity. The present investigation explored the hypothesis that inflammatory cytokines contributed to the blunted renal sympatho-inhibition resulting from an acute volume expansion (VE) in a model of renal injury/failure. Male Wistar rats (275-350g, n=36) were divided into a control (C) and a renal failure (RF) groups. Renal failure was induced using cisplatin (5mg/kg, I.P.) given seven days prior to surgery. Tacrolimus, was administered daily to C and RF rats for 7 days prior to the acute studies to supress the inflammatory response. On the day of experiment, rats were anaesthetised (1ml 16.5:250mg/ml chloralose/urethane i.p.) and the right femoral artery and vein were cannulated to allow measurement of mean arterial pressure (MAP) and infusion of saline (50µl/min) and supplemental anaesthetic. Flank incisions allowed exposure of the right kidney, for insertion of a cannula into the cortex to a depth of 4.5mm for intra-renal (I.R.) infusions, and left kidney, to facilitate sealing the renal sympathetic nerves onto recording electrodes. Baseline values of MAP and RSNA were recorded for 5min after which the saline VE was begun (0.25% body weight/min I.V.) for 30min. Thereafter, a 30min recovery period was allowed. RSNA was calculated as a percentage of baseline values and both the maximal degree on RSNA inhibition and area under the curve (AUC) were determined. A separate control group received intra-renal TNF-a (2µg/kg/h) and the renal sympatho-inhibitory response to VE was examined. Data were expressed as means ± s.e.m. and compared using Student’s t-test or ANOVA where relevant. P<0.05 indicated significance. In RF, the MAP, HR and RSNA values were not different from their respective values in C (93±4mmHg, 376±10bpm, 2.06±0.41µV.s, respectively). VE in C, caused a significant renal sympatho-inhibition, which was blunted in RF (AUC, RF vs. C, 6±2 vs. 25±5 AU, P<0.05), but in tacrolimus treated RF, this response was restored (24±4 AU, P<0.05). In C rats given intra-renal TNF-α, there was a blunted sympatho-inhibitory response to VE compared to C (AUC, TNF-α vs. C, 5±1 vs 17±4 AU, P<0.05). These findings demonstrate that the depressed renal sympatho-inhibitory responses to VE in renal failure are normalised following suppression of inflammatory processes by tacrolimus. Moreover, the pro-inflammatory cytokine, TNF-a prevents the reduction in RSNA due to VE. Because renal denervation in this model of renal failure restores the renal sympatho-inhibition to VE, these findings are consistent with the view that inflammatory cascades within the kidney initiate afferent nerve activity which causes a dysregulation of the low pressure baroreceptor control of RSNA.