慢性肾脏去神经支配增加大鼠肾小管对 P2X 受体激动剂的反应：对肾交感神经消融的影响。

Chronic renal denervation increases renal tubular response to P2X receptor agonists in rats: implication for renal sympathetic nerve ablation.

机构信息

Department of Therapy Monitoring and Pharmacogenetics, Medical University of Gdańsk, Gdańsk, Poland.

出版信息

Nephrol Dial Transplant. 2012 Sep;27(9):3443-8. doi: 10.1093/ndt/gfs087. Epub 2012 Apr 19.

DOI:10.1093/ndt/gfs087

PMID:22516625

Abstract

BACKGROUND

Kidney noradrenergic innervation regulates tubular function. Adenosine triphosphate (ATP)-a co-transmitter of norepinephrine-acts on purinoceptors, including ion channel receptor, P2X. P2X receptor agonists, α,β-methylene ATP (α,β-meATP) and β,γ-methylene ATP (β,γ-meATP), induce natriuresis. Regarding the functional co-localization of adrenoceptors and P2X receptors, we evaluated rat renal tubular system sensitivity to natriuretic action of P2X receptor agonists in chronically denervated kidney.

METHODS

Clearance studies with α,β-meATP and β,γ-meATP (intravenous infusion rate, 2 µmol/kg + 20 nmol/kg/min) were performed after bilateral surgical kidney denervation (DNx) and sham-operation (Sham). Na/K-ATPase activity was measured in isolated rat renal proximal tubules.

RESULTS

In DNx compared with Sham, saline infusion significantly increased renal sodium and urine excretion and P2X receptor agonist infusion was significantly more natriuretic and diuretic. In DNx and Sham, respectively, α,β-meATP increased fractional excretion of sodium (FE(Na)) by 2 ± 0.3 and 0.6 ± 0.1% and urine (FE(V)) by 1.6 ± 0.3 and 0.9 ± 0.2%; β,γ-meATP had similar effects. In both groups of rats, natriuretic and diuretic actions were abolished by P2 receptor blocker (pyridoxal-phosphate-6-azophenyl-2',4'-disulphonate, PPADS), mean arterial blood pressure and glomerular filtration rate remained unchanged during infusion of P2X receptor agonists and antagonist and basal Na/K-ATPase activities in isolated proximal tubules were similar. Both α,β-meATP and β,γ-me-ATP decreased the Na/K-ATPase activity, with 20% inhibition (P < 0.05) in denervated and innervated rats; these inhibitory effects were abolished in the presence of PPADS.

CONCLUSIONS

Decreased renal sympathetic activity enhances the natriuretic effect of P2X receptor stimulation. This effect is probably not related to altered Na/K-ATPase activity in renal proximal tubules.

摘要

背景

肾脏去甲肾上腺素能神经支配调节肾小管功能。三磷酸腺苷 (ATP) - 去甲肾上腺素的共递质 - 作用于嘌呤能受体，包括离子通道受体 P2X。P2X 受体激动剂，α，β-亚甲基 ATP（α，β-meATP）和β，γ-亚甲基 ATP（β，γ-meATP），诱导钠排泄。关于肾上腺素能受体和 P2X 受体的功能共定位，我们评估了慢性去神经支配肾脏中 P2X 受体激动剂对钠排泄作用的大鼠肾小管系统敏感性。

方法

在双侧手术肾去神经支配（DNx）和假手术（Sham）后，进行 α，β-meATP 和 β，γ-meATP（静脉输注率，2µmol/kg+20nmol/kg/min）的清除研究。在分离的大鼠肾近端小管中测量 Na/K-ATP 酶活性。

结果

与 Sham 相比，DNx 中的盐水输注显着增加了肾脏钠排泄和尿液排泄，并且 P2X 受体激动剂输注的利尿作用更强。在分别的 DNx 和 Sham 中，α，β-meATP 分别增加了钠的分数排泄（FE（Na））2±0.3%和 0.6±0.1%和尿液（FE（V））1.6±0.3%和 0.9±0.2%；β，γ-meATP 具有相似的作用。在两组大鼠中，P2 受体阻滞剂（吡哆醛-6-偶氮苯-2'，4'-二磺酸盐，PPADS）消除了利尿和利尿作用，在输注 P2X 受体激动剂和拮抗剂期间平均动脉血压和肾小球滤过率保持不变，并且分离的近端小管中的基础 Na/K-ATP 酶活性相似。α，β-meATP 和β，γ-me-ATP 均降低了 Na/K-ATP 酶活性，在去神经和神经支配的大鼠中抑制率分别为 20%（P<0.05）; 在存在 PPADS 的情况下，这些抑制作用被消除。