Department of Physiology, Western Gateway Building, University College Cork, College Road, Cork, Ireland.
Exp Physiol. 2019 Nov;104(11):1726-1736. doi: 10.1113/EP087829. Epub 2019 Oct 9.
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 (5 mg kg , i.p. on day 0) rats received either saline or tacrolimus (0.25 mg kg day , i.p.) for 7 days 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 %RSNA min) during acute volume expansion. Intrarenal TNF-α infusion (0.3 µg kg h ) in control rats decreased baroreflex gain by 32% (P < 0.05) compared to intra-renal saline infusion. In the cisplatin group (MAP: 98 ± 14 mmHg; HR: 391 ± 24beats min ), the baroreflex gain for RSNA was 39% (P < 0.05) lower than that for the control group (MAP: 91 ± 7 mmHg; HR: 382 ± 29 beats min ). In cisplatin-treated rats given daily tacrolimus (MAP: 84 ± 12 mmHg; HR: 357 ± 30 beats min ), the baroreflex gain and renal sympatho-inhibition (AUC, 2440 ± 1071 vs. 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.
本研究的核心问题是什么？免疫抑制是否能恢复顺铂诱导的肾损伤动物模型中肾交感神经活动（RSNA）的压力反射控制？主要发现及其重要性是什么？钙调神经磷酸酶抑制剂他克莫司可恢复顺铂诱导肾损伤后 RSNA 的高、低血压压力反射控制。
顺铂给药会导致肾脏血流动力学和排泄功能下降，并与肾脏交感神经兴奋和 RSNA 的压力反射调节丧失有关。本研究旨在探讨在顺铂介导的肾损伤模型中，免疫抑制剂他克莫司的给药是否可以恢复，或急性肾内注射肿瘤坏死因子-α（TNF-α）是否可以减弱 RSNA 的高、低血压压力反射控制。对照组和顺铂处理组（5mg/kg，腹腔注射，第 0 天）的大鼠在研究前 7 天分别接受生理盐水或他克莫司（0.25mg/kg/天，腹腔注射）治疗。大鼠麻醉并准备测量平均动脉压（MAP）、心率（HR）和 RSNA。生成压力反射增益曲线，并报告（作为%RSNA min的曲线下面积（AUC））急性容量扩张期间肾交感神经抑制的程度。在对照组大鼠中，肾内 TNF-α输注（0.3μg/kg/h）使压力反射增益降低 32%（P<0.05），与肾内生理盐水输注相比。在顺铂组（MAP：98±14mmHg；HR：391±24 次/min）中，RSNA 的压力反射增益降低 39%（P<0.05），低于对照组（MAP：91±7mmHg；HR：382±29 次/min）。在接受每日他克莫司治疗的顺铂处理大鼠中（MAP：84±12mmHg；HR：357±30 次/min），压力反射增益和肾交感神经抑制（AUC，2440±1071 与 635±498% min）恢复正常。这些发现为顺铂给药引发的炎症损伤可能导致 RSNA 的压力反射调节紊乱的观点提供了证据。这种现象似乎部分通过肾神经支配介导。
