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

AngII-盐高血压增加 RVLM 中的呼吸-血管运动神经元耦合

• 批准号: 7985963
• 负责人: GLENN M TONEY
• 金额: $ 48.36万
• 依托单位: UNIVERSITY OF TEXAS HLTH SCIENCE CENTER
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-07-01 至 2014-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7985963
• 关键词: Accounting; Acute; Angiotensin II; Antihypertensive Agents; Arts; Biological; Brain; Cardiac; Cardiovascular Diseases; Cause of Death; Cessation of life; Chemicals; Chronic; Coupling; Data; Development; Diet; Dinoprostone; Disease; Disinhibition; Electrophysiology (science); Enzymes; Functional disorder; Future; Ganglionectomy; Gene Expression; Genes; Human; Hypertension; Hypothalamic structure; Image; Injection of therapeutic agent; Interruption; Ketoprofen; Lesion; Literature; Maintenance; Mediating; Methods; Microinjections; Modeling; National Heart, Lung, and Blood Institute; Nerve; Neural Pathways; Neurons; Norepinephrine; Osmolalities; PTGS1 gene; PTGS2 gene; Pathway interactions; Phase; Play; Production; Prosencephalon; Prostaglandin-Endoperoxide Synthase; Publishing; Rattus; Receptor Activation; Renin-Angiotensin System; Risk Factors; Role; Sodium Chloride; Testing; United States National Institutes of Health; Vasomotor; Work; World Health Organization; disability; effective therapy; gamma-Aminobutyric Acid; in vivo; inhibitor/antagonist; innovation; insight; neurogenic hypertension; neuromechanism; normotensive; novel; preoptic nucleus; prevent; progesterone 11-hemisuccinate-(2-iodohistamine); prostaglandin EP3 receptor; prostanoid receptor EP1; public health relevance; receptor; receptor function; respiratory; response; restraint; salt sensitive; statistics; treatment duration

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.

描述（由申请人提供）：该项目将研究交感神经活动升高（SNA）的神经机制，目前人们普遍认为交感神经活动在多种形式的人类高血压（HTN）中发挥着关键作用。我们将利用我们的血管紧张素II依赖性盐敏感HTN模型（AngII-salt HTN）来探索该项目中的多项创新，其中第一个是概念性的。我们假设 AngII-盐 HTN 的神经源性阶段受到延髓头端腹外侧 (RVLM) 血管运动神经元响应中枢呼吸网络兴奋性输入的过度放电的支持。 因此，假设夸大的呼吸-血管运动神经元耦合支持 AngII-盐 HTN 中 SNA 和 ABP 的升高。 具体来说，我们认为内脏 SNA (SSNA) 中的吸气后爆发幅度尤其重要。 这一概念与 SSNA 受到强烈呼吸调节这一事实一致，并且已发表的数据表明，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。 第二个重大创新是这样的概念：过度的呼吸-SSNA 耦合是由 RVLM 中 [1] AngII AT1 受体和 [2] 前列腺素 E2 (PGE2) EP3 受体的激活介导的。我们认为 AT1 受体激活是由下丘脑 PVN 对 RVLM 的输入引起的。 申请中的初步数据支持这一观点。 我们进一步提出，AngII-盐 HTN 大鼠中 EP3 受体的激活可能是由于 RVLM 中 PGE2 的局部产生所致。我们的显微注射研究支持 RVLM 中的 PGE2 在 AngII-盐 HTN 中发挥功能作用，其中 RVLM 中的 PGE2 增加了高血压大鼠的 SSNA 和 ABP，但在正常血压对照组中则没有增加。总的来说，这些数据使我们制定了以下具体目标：（1）检验 RVLM 中 PVN 输入和 AT1R 激活对于 AngII-salt HTN 的发育和维持很重要的假设。 (2) 检验 RVLM 中 PGE2 和 EP3R 激活对 HTN 也有显着贡献的假设。 (3) 检验以下假设：局部 AT1R 和 EP3R 的激活均会导致 RVLM 血管运动神经元过度呼吸节律爆发放电。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 中的参与基因网络，并识别这些神经元的表型标记，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标。 公共健康相关性：高血压 (HTN) 是心血管疾病死亡的主要危险因素，根据 NIH NHLBI 统计，2004 年，高血压 (HTN) 占美国死亡人数的 36%。 世界卫生组织预测，到 2020 年，高血压将成为全球死亡和残疾的最大单一原因。 由于大多数（65-70%）高血压未得到有效治疗，因此迫切需要了解该疾病的生物学机制，以便开发更有效的治疗方法。