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: 8497524
• 负责人: GLENN M TONEY
• 金额: $ 4.23万
• 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/8497524
• 关键词: Accounting; Acute; Angiotensin II; Antihypertensive Agents; 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; Synapses; 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; prostaglandin EP3 receptor; prostanoid receptor EP1; public health relevance; receptor; receptor expression; receptor function; respiratory; response; restraint; salt sensitive; statistics; treatment duration; Accounting; Acute; Angiotensin II; Antihypertensive Agents; 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; Synapses; 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; prostaglandin EP3 receptor; prostanoid receptor EP1; public health relevance; receptor; receptor expression; 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）：该项目将研究升高的交感神经活动（SNA）的神经机制，现在已被广泛认可在许多形式的人类高血压（HTN）中起关键作用。我们将使用HTN（Angii-Salt HTN）的血管紧张素II依赖性盐敏感模型来探索该项目中的许多创新，其中第一个是概念性的。我们假设Angii-salt HTN的神经源相位通过响应中央呼吸网络的兴奋性输入的响应，支持了血管舒缩神经元的夸大排放。 因此，假定夸张的呼吸道流血症神经元偶联是为了支持Angii-Salt HTN中的SNA和ABP升高。 具体而言，我们提出，sna（SSNA）中的启动后爆发幅度尤为重要。 这个概念与SSNA强烈呼吸调节的事实是一致的，并且与已发表的数据表明，腹腔神经节切除术对SSNA的中断阻止了Angii-Salt HTN的神经发生相。 第二个主要创新是一个概念，即夸张的呼吸 - SSNA耦合是由ANGII AT1受体的[1]激活和[2] RVLM中的[2] Prostaglandin E2（PGE2）EP3受体介导的。我们提出，AT1受体激活来自下丘脑PVN的输入到RVLM。 应用程序中的初步数据支持此视图。 我们进一步提出，具有Angii-salt HTN大鼠的EP3受体激活可能是由R​​VLM中PGE2局部产生引起的。 RVLM中对PGE2在Angii-Salt HTN中起功能的作用的支持来自我们的微注射研究，其中RVLM中的PGE2在高血压大鼠中增加了SSNA和ABP，但在正常的控制中不增加。总的来说，这些数据导致我们制定了以下特定目的：（1）测试RVLM中PVN输入和AT1R激活的假设在Angii-Salt HTN的开发和维护中很重要。 （2）测试了RVLM中PGE2和EP3R激活的假设也对HTN产生了显着贡献。 （3）检验以下假设：局部AT1R和EP3R的激活每种都导致RVLM血管舒缩神经元夸大的呼吸道治疗爆发排出。在AIM 3研究中，我们还将结合最先进的基因分析方法，以鉴定RVLM中参与的基因网络并识别这些神经元的表型标记，以便可以在未来进行详细的细胞电生理学和成像研究，以隔离抗抑制性治疗的有利靶标。 公共卫生相关性：高血压（HTN）是由于心血管疾病而导致死亡的主要危险因素，根据NIH NHLBI统计，该疾病占2004年美国死亡的36％。 到2020年，世界卫生组织预测，HTN将成为全球死亡和残疾的最大唯一原因。 由于大多数（65-70％）的高血压没有有效治疗，因此迫切需要了解该疾病的生物学机制，以便可以开发出更有效的治疗方法。