Kidney failure is associated with renal inflammation and there is evidence that pro-inflammatory cytokines can activate the renal sensory innervation causing a dysregulation of baroreflex regulation of sympathetic outflow. This study investigated the effect of tacrolimus, an anti-inflammatory agent, on the baroreflex-mediated control of heart rate (HR) in cisplatin-induced renal failure rats. Wistar rats (275-350g, n=30) were randomly assigned into renal failure (RF) and control (C) groups and received either I.P. cisplatin (5mg/kg) or saline (5ml/kg) respectively, 7 days prior to the acute study. RF and C rats received either I.P. tacrolimus (0.25mg/kg/day) or saline (0.75ml/kg/day) for 7 days after the injection of cisplatin or saline. In another group of rats, during the acute experiment TNF-α was infused intra-renally (2µg/kg/h) and the HR baroreflex gain curve (DHR vs. DMAP) was examined. Anaesthesia was induced with chloralose/urethane (1ml 16.5:250 mg/ml, I.P.) and the right femoral artery and vein were cannulated to allow measurement of mean arterial pressure (MAP) and HR, and infusion of sustaining saline and supplemental anaesthetic. The right kidney was exposed via a flank incision and a cannula was inserted 4.5mm into renal cortex to allow infusion of saline or TNF-α at 17µl/min. Animals were allowed to stabilise for 60-90min. High-pressure baroreflex gain curves for HR were generated using I.V. injections of phenyelphrine and sodium nitroprusside (50µg/kg/min) to increase and decrease blood pressure, respectively. 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 RF group (MAP: 98±6 mmHg; HR: 391±10 beats/min), the HR baroreflex gain curve sensitivity was 61% (P<0.05) lower than C group (MAP: 91±3 mmHg; HR: 382±12 beats/min) but in rats receiving tacrolimus the baroreflex sensitivity was restored to normal values. The HR baroreflex sensitivity in the group of C rats which received intrarenal TNF-α was similar to the vehicle (saline). However, the mid-point of the baroreflex curve was shifted by 15% (P<0.05) to a higher MAP value. In the renal failure model, blockade of the inflammatory response with tacrolimus restored the high pressure baroreflex control of HR to normal levels while TNF-α depressed the gain sensitivity in control rats. Previous studies have shown that in this renal failure model that renal denervation restores HR baroreflex to normal levels. The present findings suggest that pro-inflammatory mediators could be important in increasing renal afferent nerve activity to the central nervous system causing a dysregulation of the high pressure baroreflex.