Tacrolimus restores the high- and low-pressure baroreflex control of renal sympathetic nerve activity in cisplatin-induced renal injury rats.

Abstract

What is the central question of this study? Does immunosuppression restore the baroreflex control of renal sympathetic nerve activity (RSNA) in an animal model of kidney injury? What is the main finding and its importance? Tacrolimus, a calcineurin inhibitor, restored the high- and low-pressure baroreflex control of RSNA following cisplatin-induced renal injury. Cisplatin administration causes depression of renal haemodynamic and excretory function and is associated with renal sympatho-excitation and loss of baroreflex regulation of renal sympathetic nerve activity (RSNA). This study investigated whether administration of the immunosuppressant tacrolimus in this cisplatin-mediated renal injury model could restore, or the acute intra-renal infusion of tumour necrosis factor α (TNF-α) could blunt, the high- or low-pressure baroreflex control of RSNA. Groups of control and cisplatin-treated (5mgkg-1 , i.p. on day 0) rats received either saline or tacrolimus (0.25mgkg-1 day-1 , i.p.) for 7days prior to study. Rats were anaesthetised and prepared for measurement of mean arterial pressure (MAP), heart rate (HR) and RSNA. Baroreflex gain curves were generated and the degree of renal sympatho-inhibition determined (area under the curve (AUC) reported as %RSNAmin) during acute volume expansion. Intrarenal TNF-α infusion (0.3µgkg-1 h-1 ) in control rats decreased baroreflex gain by 32% (P<0.05) compared to intra-renal saline infusion. In the cisplatin group (MAP: 98±14mmHg; HR: 391±24beatsmin-1 ), the baroreflex gain for RSNA was 39% (P<0.05) lower than that for the control group (MAP: 91±7mmHg; HR: 382±29beatsmin-1 ). In cisplatin-treated rats given daily tacrolimus (MAP: 84±12mmHg; HR: 357±30beatsmin-1 ), the baroreflex gain and renal sympatho-inhibition (AUC, 2440±1071vs. 635±498%min) were restored to normal values. These findings provide evidence for the view that cisplatin administration initiates an injury involving inflammation which may contribute to the deranged baroreflex regulation of RSNA. This phenomenon appears mediated in part via the renal innervation.