高盐和应激致室旁核神经激素兴奋引发血管功能异常和高血压的机制

High-salt diet and chronic stress are important risk factors of hypertension. Imbalance of vascular homeostasis and vascular remodeling contribute to the pathogenesis of hypertension. This study will explore whether high-salt diet and chronic stress-induced imbalance of vascular homeostasis and vascular remodeling are mediated by the neurohormonal excitation (NHE) in the hypothalamic paraventricular nucleus (PVN). Stress-induced hypertensive rats and spontaneously hypertensive rats (SHR) will be treated for 4 weeks with bilateral PVN infusion of corticotrophin releasing hormone (CRH) blocker, and Dahl salt sensitive rats will be treated for 4 weeks with bilateral PVN infusion of the blockers of renin-angiotensin system (RAS) components, proinflammatory cytokines (PIC) or reactive oxygen species (ROS), the antagonist of glutamate (Glu) or norepinephrine (NE) receptor, the agonist of gamma-aminobutyric acid (GABA) receptor, or vehicle. The mean arterial pressure, renal sympathetic nerve activity, the levels of vasoactive substancesin blood, and vascular function will be measured. The levels of the neurotransmitters, RAS, PIC, CRH and ROS in the PVN of these rats will also be measured. This study will determine whether high salt- and stress-induced imbalance of vascular homeostasis, vascular remodeling and hypertension are mediated by the neurohormonal excitation in the PVN. This study will explore the central mechanism of imbalance of vascular homeostasis, vascular remodeling and hypertension. The successful completion of this study will expand our knowledge about the PVN mechanisms contributing to the pathogenesis of imbalance of vascular homeostasis, vascular remodeling and hypertension. This study will ultimately lead to new and effective strategies to treat hypertension and so have important clinical implications.

高盐饮食和应激是高血压的重要危险因素。血管稳态失衡与重构是高血压的主要病理基础。本课题拟研究高盐饮食和应激是否引起下丘脑室旁核神经激素兴奋，进而引发血管稳态失衡与重构和高血压并探讨其机制。经双侧室旁核给予应激性高血压和自发性高血压大鼠促肾上腺皮质激素释放激素(CRH)阻断剂4周，经双侧室旁核给予盐敏感性高血压大鼠肾素-血管紧张素系统(RAS)组分、炎性细胞因子(PIC)、活性氧簇(ROS)、去甲肾上腺素受体、谷氨酸受体阻断剂或γ-氨基丁酸受体激动剂4周，植入式无线遥测系统记录血压和肾交感神经活动，检测室旁核RAS、PIC、CRH、ROS和神经递质的变化，观察血管活性物质及血管稳态与重构的指标变化，探讨高盐和应激引起室旁核神经激素兴奋，进而导致交感神经活动增强、血管稳态失衡与血压升高的机制。本课题探讨血管稳态失衡与重构和高血压的中枢机制，为血管稳态失衡与重构及高血压的防治寻求早期干预的靶点。

高盐饮食和应激是高血压的重要危险因素。血管稳态失衡与重构是高血压的主要病理基础。本项目主要研究高盐饮食和应激是否引起下丘脑室旁核神经激素兴奋(NHE)，进而引发血管稳态失衡与重构和高血压并探讨其机制。本项目主要取得以下重要研究结果：(1)高盐饮食可引起大鼠下丘脑室旁核(PVN)中NAD(P)H氧化酶依赖的活性氧簇(ROS)产生增多、兴奋性神经递质和抑制性神经递质失平衡以及炎性细胞因子与抗炎性细胞因子失平衡、肾素-血管紧张素系统(RAS)激活；经PVN给予ROS清除剂后，发现PVN中ROS产生明显减少，兴奋性和抑制性神经递质失平衡以及炎性与抗炎性细胞因子失平衡得以改善，RAS组分血管紧张素转化酶和血管紧张素II 1型受体(AT1-R)表达降低。以上结果表明PVN活性氧簇可能通过与神经递质、炎性细胞因子和RAS的相互作用参与高盐诱导的高血压的发生发展。(2) 替米沙坦(TEL)是一种AT1-R阻断剂。经双侧PVN连续4周慢性给予TEL后，发现室旁核炎性细胞因子和诱导型一氧化氮合酶水平降低，室旁核PPAR-γ受体表达增加，而室旁核TLR4、MyD88蛋白和mRNA水平降低，室旁核NF-κB活性降低，血浆去甲肾上腺素减少和血压降低，表明抑制RAS可通过抑制TLR4/MyD88/NF-κB信号通路和激活PPAR-γ受体，降低室旁核炎性反应，减弱交感神经活动和改善高血压。(3) 应激可引起大鼠下丘脑-垂体-肾上腺皮质轴(HPA轴)和室旁核RAS激活，交感神经活动增强和血压升高。阻断PVN中促肾上腺皮质激素释放激素受体1(CRH-R1)可抑制HPA轴和室旁核RAS的激活，减弱交感神经活动和改善高血压。本项目阐明了高盐和应激可引起室旁核神经激素兴奋，进而引起血管功能异常和血压升高的中枢机制，发现PVN是盐敏感性高血压、应激性高血压和交感神经活动增强的关键中枢核团，抑制PVN的神经激素兴奋可减弱交感神经活动和改善高血压，为血管稳态失衡与重构和高血压的研究和治疗提供新思路。本项目的研究已经达到预期目标，相关研究成果发表31篇SCI收录期刊论文，研究期间指导博士后6名、培养博士生10名和硕士生12名，课题研究期间已毕业博士生6名和硕士生5名。