Renal failure is associated with increased sympathetic nerve activity and hypertension. High levels of inflammatory cytokines are found in the diseased kidney including tumour necrosis factor-α (TNF-α). This study investigated the effect of the immunosuppressive agent tacrolimus, a macrolide antibiotic, that can block the transcription of TNF-α, on the high-pressure baroreflex control of renal sympathetic nerve activity (RSNA) in rats with renal failure. Male Wistar rats (275-350g, n=30) were divided into renal failure and control groups. Renal failure was induced using cisplatin (5mg/kg, I.P.) while the control group received a similar volume of saline (0.9% NaCl) 7 days prior to the acute experiment. Renal failure or control rats received tacrolimus (0.25mg/kg/day, I.P.) for 7 days starting on the day of cisplatin or saline administration. A further group of control rats (n=6) received an intra-renal infusion of TNF-α (2µg/kg/h) during the acute study. Following anaesthesia (1ml 16.5:250mg/ml chloralose/urethane I.P.), cannulae were inserted into the right femoral artery, to measure mean arterial pressure (MAP) and heart rate (HR), and vein for saline (50µl/min) and supplementary anaesthetic infusion. Flank incisions were used to expose the right kidney, to allow cannula insertion 4.5 mm into the cortex for intra-renal infusions, and left kidney, to permit placing the renal sympathetic nerves onto recording electrodes. High-pressure RSNA baroreflex gain curves were generated using I.V. injections of phenyelphrine and sodium nitroprusside (50µg/kg/min) to increase and decrease blood pressure, respectively. RSNA was calculated as a percentage of baseline values. Data are expressed as means ± s.e.m. and compared using student’s t-test or ANOVA where relevant. P<0.05 indicated significance. In the renal failure group (MAP: 98±6 mmHg; HR: 391±10 beats/min; RSNA: 1.95±0.52 µV.s), the maximum baroreflex gain (sensitivity) was lower by 57% (P<0.05) compared to the control (MAP: 91±3 mmHg; HR: 382±12 beats/min; RSNA: 2.28±0.56 µV.s). Treatment with tacrolimus restored the maximum gain to near normal levels in the renal failure group but had no effect on the maximum gain in controls. Intra-renal infusion of TNF-α in control rats decreased maximum baroreflex gain by 34% (P<0.05) compared to the intra-renal vehicle controls. These findings demonstrate that blockade of the inflammatory process with tacrolimus in renal failure normalises the high pressure baroreflex regulation of RSNA. Moreover, intra-renal TNF-α, blunts the high-pressure baroreflex of RSNA in normal rats. The dysregulation of the RSNA baroreflex control in renal failure is dependent on an intact renal innervation and suggests that proinflammatory cytokines can importantly modulate afferent renal nerve activity.