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内源性促肾上腺皮质激素释放因子通过激活其1型受体增强自发性高血压大鼠室旁核前交感神经元兴奋性

马宏宇¹, 郭鑫淇¹, 赵绮悦¹, 杨沛芸¹, 朱怀冰¹, 关玥^1,2, 张翼¹, 马会杰^1,2,3,*

¹河北医科大学生理学教研室，石家庄 050017；²河北省神经生理学重点实验室，石家庄 050017；³河北医科大学神经与血管生物学教育部重点实验室，石家庄 050017

摘要

在高血压期间，下丘脑室旁核(paraventricular nucleus, PVN)前交感神经元兴奋性增强导致交感传出活动增加、血压升高。然而，PVN前交感神经元兴奋性增强的机制尚不清楚。本研究应用Western blot、动脉血压与肾交感神经活动记录、CRISPR/Cas9技术与脑片膜片钳技术，旨在探讨下丘脑内源性促肾上腺皮质激素释放因子(corticotropin-releasing factor, CRF)对PVN前交感神经元兴奋性的影响。结果显示，相比于Wistar-Kyoto (WKY)大鼠，自发性高血压大鼠(spontaneously hypertensive rats, SHRs) PVN CRF蛋白表达水平明显升高。此外，PVN局部给予外源性CRF可显著增强WKY大鼠肾交感神经活动，升高心率与动脉血压。相反，敲低SHRs室旁核高表达的CRF可抑制内源性CRF表达，并导致PVN前交感神经元膜电位超极化，降低电流诱发的动作电位频率，而给予外源性CRF可逆转这一效应。用含CRF受体1 (CRF receptor 1, CRFR1)阻断剂NBI-35965与CRF受体2 (CRF receptor 2, CRFR2)阻断剂Antisauvagine-30的人工脑脊液灌流大鼠脑片后发现，阻断CRFR1而非CRFR2能够使SHRs PVN前交感神经元膜电位超极化，并抑制电流诱发的动作电位，但阻断CRFR1或CRFR2对WKY大鼠PVN前交感神经元膜电位和电流诱发的动作电位均无影响。本研究结果表明，SHRs下丘脑PVN CRF神经元CRF释放增加，通过激活CRFR1导致前交感神经元兴奋性增高。

关键词： 高血压; 促肾上腺皮质激素释放因子; 室旁核前交感神经元; 促肾上腺皮质激素释放因子受体

Endogenous corticotropin-releasing factor potentiates the excitability of presympathetic neurons in paraventricular nucleus via activation of its receptor 1 in spontaneously hypertensive rats

MA Hong-Yu¹, GUO Xin-Qi¹, ZHAO Qi-Yue¹, YANG Pei-Yun¹, ZHU Huai-Bing¹, GUAN Yue^1,2, ZHANG Yi¹, MA Hui-Jie^1,2,3,*

¹Department of Physiology, Hebei Medical University, Shijiazhuang 050017, China；²Key Laboratory of Neurophysiology of Hebei Province, Shijiazhuang 050017, China；³The Key Laboratory of Neural and Vascular Biology, Ministry of Education, Hebei Medical University, Shijiazhuang 050017, China

Abstract

It is well established that increased excitability of the presympathetic neurons in the hypothalamic paraventricular nucleus (PVN) during hypertension leads to heightened sympathetic outflow and hypertension. However, the mechanism underlying the overactivation of PVN presympathetic neurons remains unclear. This study aimed to investigate the role of endogenous corticotropin- releasing factor (CRF) on the excitability of presympathetic neurons in PVN using Western blot, arterial blood pressure (ABP) and renal sympathetic nerve activity (RSNA) recording, CRISPR/Cas9 technique and patch-clamp technique. The results showed that CRF protein expression in PVN was significantly upregulated in spontaneously hypertensive rats (SHRs) compared with normotensive Wistar-Kyoto (WKY) rats. Besides, PVN administration of exogenous CRF significantly increased RSNA, heart rate and ABP in WKY rats. In contrast, knockdown of upregulated CRF in PVN of SHRs inhibited CRF expression, led to membrane potential hyperpolarization, and decreased the frequency of current-evoked firings of PVN presympathetic neurons, which were reversed by incubation of exogenous CRF. Perfusion of rat brain slices with artificial cerebrospinal fluid containing CRF receptor 1 (CRFR1) blocker, NBI-35965, or CRF receptor 2 (CRFR2) blocker, Antisauvagine-30, showed that blocking CRFR1, but not CRFR2, hyperpolarized the membrane potential and inhibited the current-evoked firing of PVN presympathetic neurons in SHRs. However, blocking CRFR1 or CRFR2 did not affect the membrane potential and current-evoked firing of presympathetic neurons in WKY rats. Overall, these findings indicate that increased endogenous CRF release from PVN CRF neurons enhances the excitability of presympathetic neurons via activation of CRFR1 in SHRs. 

Key words: Hypertension; corticotropin-releasing factor; PVN presympathetic neuron; CRF receptor

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通讯作者：马会杰　　E-mail: huijiema@hebmu.edu.cn

引用本文：

马宏宇, 郭鑫淇, 赵绮悦, 杨沛芸, 朱怀冰, 关玥, 张翼, 马会杰. 内源性促肾上腺皮质激素释放因子通过激活其1型受体增强自发性高血压大鼠室旁核前交感神经元兴奋性[J]. 生理学报 2023; 75 (4): 487-496.

MA Hong-Yu, GUO Xin-Qi, ZHAO Qi-Yue, YANG Pei-Yun, ZHU Huai-Bing, GUAN Yue, ZHANG Yi, MA Hui-Jie. Endogenous corticotropin-releasing factor potentiates the excitability of presympathetic neurons in paraventricular nucleus via activation of its receptor 1 in spontaneously hypertensive rats. Acta Physiol Sin 2023; 75 (4): 487-496