AngII-Salt Hypertension Increases Respiratory-Vasomotor Neuron Coupling in RVLM

描述（由申请人提供）：本项目将研究交感神经活动（SNA）升高的神经机制，SNA目前被广泛认为在多种形式的人类高血压（HTN）中起关键作用。我们将使用我们的血管紧张素ii依赖性盐敏感HTN模型（AngII-salt HTN）在这个项目中探索一些创新，其中第一个是概念性的。我们假设血管盐HTN的神经源性阶段是由髓质吻侧腹外侧（RVLM）的血管运动神经元响应中枢呼吸网络的兴奋性输入而过度放电支持的。因此，过度的呼吸-血管舒缩神经元耦合被认为支持血管盐HTN中SNA和ABP升高。具体来说，我们认为内脏SNA （SSNA）的吸气后爆发幅度特别重要。这一概念与SSNA受到强烈的呼吸调节这一事实相一致，也与已发表的数据相一致，数据显示，腹腔神经节切除术中断SSNA可阻止血管盐HTN的神经源性阶段。第二个主要创新是通过[1]激活RVLM中的AngII AT1受体和[2]前列腺素E2 (PGE2) EP3受体介导的呼吸- ssna偶联。我们认为AT1受体的激活源于下丘脑PVN对RVLM的输入。应用程序中的初步数据支持此视图。我们进一步提出，血管盐HTN大鼠的EP3受体激活可能是由于RVLM中局部产生PGE2。RVLM中的PGE2在血管盐HTN中发挥功能作用的支持来自我们的显微注射研究，在RVLM中的PGE2增加高血压大鼠的SSNA和ABP，但在正常对照组中没有。总的来说，这些数据使我们制定了以下具体目标：(1)验证RVLM中PVN输入和AT1R激活在AngII-salt HTN的发展和维持中起重要作用的假设。(2)验证RVLM中PGE2和EP3R的激活对HTN也有显著贡献的假设。(3)验证局部AT1R和EP3R的激活分别导致RVLM血管舒缩神经元呼吸节律性爆发性放电的假说。在Aim 3研究中，我们还将采用最先进的基因分析方法来识别RVLM中参与的基因网络，并识别这些神经元的表型标记，以便在未来进行详细的细胞电生理和成像研究，以分离出抗高血压治疗的有利靶点。

DESCRIPTION (provided by applicant): This project will investigate neural mechanisms of elevated sympathetic nerve activity (SNA), which is now widely recognized to play a key role in many forms of human hypertension (HTN). We will use our angiotensin II-dependent salt-sensitive model of HTN (AngII-salt HTN) to explore a number of innovations in this project, the first of which is conceptual. We hypothesize that the neurogenic phase of AngII-salt HTN is supported by exaggerated discharge of vasomotor neurons in the rostral ventrolateral medulla (RVLM) in response to excitatory input from the central respiratory network. Thus exaggerated respiratory-vasomotor neuron coupling is postulated to support elevated SNA and ABP in AngII-salt HTN. Specifically, we propose that post-inspiratory burst amplitude in splanchnic SNA (SSNA) is particularly important. This concept is consistent with the fact that SSNA is strongly respiratory modulated and with published data showing that interruption of SSNA by celiac ganglionectomy prevents the neurogenic phase of AngII-salt HTN. A second major innovation is the concept that exaggerated respiratory-SSNA coupling is mediated by [1] activation of AngII AT1 receptors and [2] prostaglandin E2 (PGE2) EP3 receptors in the RVLM. We propose that AT1 receptor activation results from inputs to RVLM from the hypothalamic PVN. Preliminary data in the application support this view. We further propose that EP3 receptor activation in rats with AngII-salt HTN likely results from local production of PGE2 in the RVLM. Support for PGE2 in the RVLM playing a functional role in AngII-salt HTN comes from our microinjection studies in which PGE2 in the RVLM increases SSNA and ABP in hypertensive rats, but not in normotensive controls. Collectively, these data led us to formulate the following specific aims: (1) To test the hypothesis that PVN inputs and AT1R activation in the RVLM are important in the development and maintenance of AngII-salt HTN. (2) To test the hypothesis that PGE2 and activation of EP3R in the RVLM also contribute significantly to the HTN. (3) To test the hypothesis that activation of local AT1R and EP3R each contribute to exaggerated respiratory-rhythmic burst discharge of RVLM vasomotor neurons. In Aim 3 studies, we will also incorporate state of the art gene profiling methods to identify participating gene networks in the RVLM and to identify phenotypic markers of these neurons so that detailed cellular electrophysiology and imaging studies can be performed in the future to isolate favorable targets for anti-hypertensive treatment. PUBLIC HEALTH RELEVANCE: Hypertension (HTN) is a major risk factor for death due to cardiovascular disease, which accounted for 36% of US deaths in 2004 according to NIH NHLBI statistics. By the year 2020, the World Health Organization predicts that HTN will be the greatest single cause of death and disability worldwide. Because most (65-70%) hypertension is not effectively treated, there is an urgent need to understand the biological mechanisms of this disease so that more effective treatments can be developed.