室旁核促炎性细胞因子调控自发性高血压大鼠交感神经系统亢进的作用及机制研究

The excessive sympathetic activation plays a vital role in the pathogenesis and progression of hypertension. Studies confirmed that the paraventricular nucleus(PVN) activities were involved significantly in the enhanced sympathetic activation in hypertension. Our previous study has shown that pro-inflammatory cytokines (PICs) in the PVN in normotensive rats contributes to the enhanced sympathetic nerve activity and pressor effects. However, the roles of PICs in the PVN in modulating the sympathetic activity in hypertensive rats are unknown. Accordingly, this research project will have a comprehensive study of the role of PICs in PVN in sympathetic hyperactivity in the hypertensive rats at the integrative, organizational, and cellular and molecular level. The role of NMDAergic synaptic mechanism in sympathetic hyperactivity induced by PICs in PVN will be investigated therewith. Furthermore, the therapeutic effect of chronic block the PICs in PVN on hypertension will be further explored. The research results will not only help to clarify one serious theoretical issue such as the relationship between PICs in PVN and the pathogenesis of hypertension but provide the basis for the development of new methods of prevention and treatment of hypertension.

高血压时交感神经活动亢进在高血压发病和并发症形成中起重要作用。研究证实高血压时下丘脑室旁核（PVN）神经细胞活动改变显著影响交感神经活动。我们过去的研究表明PVN的促炎性细胞因子（PICs）调控正常血压大鼠的交感神经活动增强和血压升高，但其是否参与高血压大鼠交感活动亢进及其具体机制尚不清楚。本课题以此为基础，从整体、组织和细胞分子水平综合研究PVN中PICs在高血压大鼠交感神经活动亢进中的作用；探讨PVN中NMDA能突触机制在PICs促进交感神经活动亢进中的作用，并进一步探讨阻断PVN中PICs的作用对高血压的治疗作用。研究结果不仅有助于阐明PVN中PICs与高血压发病机制的关系等重大理论问题，而且为开发防治高血压的新方法提供依据。

高血压时交感神经活动亢进在高血压发病和并发症形成中起重要作用。研究证实高血压时下丘脑室旁核（PVN）神经细胞活动改变显著影响交感神经活动。我们过去的研究表明PVN的促炎性细胞因子（PICs）调控正常血压大鼠的交感神经活动增强和血压升高，但其是否参与高血压大鼠交感活动亢进及其具体机制尚不清楚。本课题以此为基础，从整体、组织和细胞分子水平综合研究PVN中PICs在高血压大鼠交感神经活动亢进中的作用；探讨PVN中NMDA能突触机制在PICs促进交感神经活动亢进中的作用，并进一步探讨阻断PVN中PICs的作用对高血压的治疗作用。主要研究结果表明：自发性高血压大鼠(SHR)PVN内应用TNF-α或IL-1β具有比在正常血压WKY大鼠更显著的升高基础血压和增强基础肾交感神经活动以及增强心交感传入反射的作用；急性药物（entanercept或IL-1ra）阻断PVN内PIC效应均降低SHR交感神经活动和血压； APV或MK-801预处理阻断PVN内NMDA受体均减弱PIC增强SHR交感神经活动和升高血压的效应；慢性阻断PVN内PIC（RNA干涉抑制PVN内IL-1RI受体蛋白表达）有显著的降低SHR血压和改善心血管重构的效应。研究结果不仅有助于阐明PVN中PICs与高血压发病机制的关系等重大理论问题，而且为开发防治高血压的新方法提供依据。