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，现在广泛认为交感神经活动在许多形式的人类高血压（HTN）中起关键作用。我们将使用我们的血管紧张素II依赖性盐敏感的HTN模型（AngII盐HTN）来探索该项目中的一些创新，其中第一个是概念性的。我们假设，血管紧张素II-盐HTN的神经原性阶段的支持夸张的放电血管神经元在延髓头端腹外侧（RVLM）在响应兴奋性输入从中央呼吸网络。 因此，假设夸大的血管紧张素-血管紧张素神经元偶联支持AngII盐HTN中SNA和ABP升高。 具体来说，我们建议，吸气后爆发振幅内脏SNA（SSNA）是特别重要的。 这一概念与SSNA是强烈呼吸调节的事实一致，并且与已发表的数据一致，这些数据表明通过腹腔神经节切除术中断SSNA可预防AngII盐HTN的神经源性阶段。 第二个主要创新是这样一个概念，即夸大的抑制性-SSNA偶联是由RVLM中的[1] AngII AT 1受体和[2]前列腺素E2（PGE 2）EP 3受体的激活介导的。我们建议，AT 1受体激活的结果从输入RVLM从下丘脑PVN。 应用程序中的初步数据支持这一观点。 我们进一步提出，EP 3受体激活与血管紧张素II盐HTN的大鼠可能是由于在RVLM的局部生产的PGE 2。支持PGE 2在RVLM发挥功能性作用的AngII盐HTN来自我们的显微注射研究，其中PGE 2在RVLM增加SSNA和ABP在高血压大鼠，但不是在血压正常的控制。总的来说，这些数据使我们制定了以下具体目标：（1）为了验证PVN输入和RVLM中的AT 1 R激活在AngII盐HTN的发展和维持中很重要的假设。(2)为了验证RVLM中PGE 2和EP 3R激活也显著促进HTN的假设。(3)为了验证这一假设，即局部AT 1 R和EP 3R的激活各自有助于RVLM血管神经元的夸张的间歇性节律性爆发放电。在目标3研究中，我们还将采用最先进的基因分析方法来鉴定RVLM中的参与基因网络，并鉴定这些神经元的表型标志物，以便将来可以进行详细的细胞电生理学和成像研究，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.