斜方体后核参与高血压大鼠交感神经过度激活的机制研究

Essential hypertension is a common cardiovascular disease and its cause remains unknown. It is established that sympathetic nerve activity increased proportionally as hypertension develops but it is unclear what triggers heightened sympathetic traffic. Several lines of evidence demonstrated that respiratory-sympathetic coupling dysfunction contributes likely to this sympathetic overactivation. The retrotrapezoid nucleus (RTN) is able to control breathing through sensing interstitial H+ as well as increase sympathetic outflows. Thereby using electrophysiological and molecular approaches, the aim of this project is to investigate how the RTN triggers the overactivation of sympathetic nerve in spontaneously hypertensive rats (SHRs) through respiratory-sympathetic coupling. Attempts will be made to determine if an enhancement of respiratory central chemoreflex and sympathetic activity occurs synchronously in SHRs, and to determine if activation of RTN neurons significantly enhances sympathetic activity in SHRs, and to determine if the chemosensitivity of RTN neurons is enhanced in SHRs, and to determine what mechanism is responsible for the alterations of RTN neuronal chemosensitivity. The data to be obtained will reveal the mechanism of RTN-stimulated sympathetic overactivation and will provide important clues to basic investigation and to clinical treatment of essential hypertension.

原发性高血压是最常见的心血管疾病之一，其关键发病机制涉及交感神经系统的过度激活，而这种过度激活现象可能与呼吸-交感神经耦联的可塑性有关。斜方体后核（retrotrapezoid nucleus，RTN）神经元能感受周围组织液中H+浓度变化而发挥调控呼吸作用，此外RTN还参与紧张性调节交感神经的活动。因此本课题将应用电生理学和分子生物学技术，观察自发高血压大鼠的RTN如何通过呼吸-交感神经耦联参与交感神经的过度激活。此研究将观察：高血压大鼠呼吸性中枢化学感受器反射和交感神经活动是否同步增强及二者活动的相关性；激活高血压大鼠的RTN神经元是否能显著增强交感神经传出活动；高血压大鼠的RTN神经元的化学敏感性是否升高及其分子机制。研究结果将揭示RTN在交感神经过度激活中的作用模式和机制，为原发性高血压的基础研究和临床治疗提供有益的思路和启示。

高血压病是最常见的心血管疾病之一，其关键发病机制涉及交感神经系统的过度激活，而放大的呼吸-心血管耦联效应可能参与了交感的过渡激活。近期研究表明，呼吸性血压调节与呼吸化学感受器的功能密切相关，而斜方体后核（RTN）作为重要的中枢呼吸化学感受器，很可能参与了呼吸-心血管耦联效应。因此，本课题致力于观察RTN是否参与自发高血压大鼠（SHR）的呼吸-心血管耦联效应并揭示可能的分子机制。应用电生理学、动脉血压遥测、清醒动物肺功能测量、遗传学以及免疫组织化学等多学科技术，我们发现：（1）麻醉的成年SHR表现为增强的呼吸-交感神经耦联；（2）清醒成年SHR大鼠表现高碳酸性通气反应增强，同时，CO2刺激引起SHR更加明显的动脉血压升高和心率增加；（3）幼年SHR（高血压前期）已经表现为更强的高碳酸性通气反应、高碳酸性心血管效应；（4）损毁RTN神经元，可减弱成年SHR增强的高碳酸性通气反应和心血管效应；（5）应用氯非铵通过抑制RTN神经元的TASK-2通道，进而抑制成年SHR增强的高碳酸性通气反应和心血管效应；（6）成年SHR的RTN神经元ASIC3、Kv12.1和TASK-2通道的蛋白水平上调。这些发现表明，SHR的RTN区的pH敏感性离子通道蛋白的高表达，增加了RTN神经元的化学敏感性，进而促进了增强的高碳酸性通气反应和心血管效应。这些结果提示RTN介导的呼吸-心血管耦联的放大效应可能参与了SHR高血压的发生发展。我们研究结果拓展了了心血管神经调控理论，而且为揭示神经源性高血压的发生机制提供了新的思路和见解。..

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