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Circumventricular Organs and Cardiovascular Regulation

室周器官和心血管调节

基本信息

批准号：
7227882
负责人：
JOHN P COLLISTER
金额：
$ 27.47万
依托单位：
UNIVERSITY OF MINNESOTA
依托单位国家：
美国
项目类别：
财政年份：
2004
资助国家：
美国
起止时间：
2004-05-01 至 2009-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7227882
关键词：
Acute Address Angiotensin II Animals Antihypertensive Agents Area Arts Attention Attenuated Blood Pressure Brain Brain region Cardiac Output Cardiovascular system Catheters Cell Nucleus Chronic Conscious Daily Data Diet Dose Drops Ganglionic Blockers Heart Rate Hexamethonium Hormones Hour Hypertension Individual Infusion procedures Intravenous Knowledge Lateral Lead Lesion Link Long-Term Effects Losartan Maintenance Measurement Measures Mediating Methods Modeling Neuraxis Neurons Norepinephrine Nucleus solitarius Numbers Organ Output Pathway interactions Peripheral Peripheral Resistance Phase Plasma Play Pressoreceptors Prevention Principal Investigator Radio Rattus Regulation Regulatory Pathway Reporting Research Personnel Resistance Role Series Signal Transduction Sodium Sodium Chloride Sodium-Restricted Diet Structure of area postrema Subfornical Organ Sympathetic Nervous System System Techniques Technology Testing Thinking Time Transducers Urine Vasomotor Venous Water consumption Week Work attenuation base blood pressure regulation concept day extracellular falls hemodynamics instrument normotensive novel paraventricular nucleus pressure programs receptor research study response salt intake treatment duration urinary

项目摘要

DESCRIPTION (provided by applicant): Central nervous system control over long-term blood pressure (BP) regulation is not completely understood. Many investigators have studied the individual roles of the subfornical organ (SFO) and area postrema (AP) in the central effects of Angiotensin II (Angll). Angll is thought to modulate sympathetic nervous system (SNS) activityat these circumventricular organs (CVOs) and regulate blood pressure (BP). This proposal suggests there is redundancy in the actions of Angll via these CVOs. This is the first study to simultaneously examine effects of both endogenous and exogenous Angll at these 2 CVOs. First, we propose endogenous Angll acts via these CVOs. AIM 1: What are the combined roles of the SFO and AP in the long-term effects of endogenous Angll? BP and cardiac output (CO) will be measured in SFOx, APx and XX rats treated with the AT1 antagonist, Iosartan, for 10 days. Furthermore, we propose changing levels of endogenous Angll act via these CVOs to regulate BP. AIM 2: What are the combined roles of the SFO and AP in the maintenance of BP during changes in dietary salt intake? BP and CO will be measured in SFOx, APx and XX rats subjected to 2 week periods of increased and decreased dietary salt. Lastly, we propose chronic Angll hypertension is mediated through effectsat these CVOs. AIM 3: What are the combined roles of the SFO and AP in the prevention of Angll induced hypertension? BP and CO measurements will be made in APx, SFOx, and XX rats during a 10 day infusionof Angll. We predict that XX rats will have an attenuated hypotensive response to Iosartan, dysregulation of BP during changes in dietary salt, and an attenuated Angll mediated hypertension. Furthermore, AIM3a: What are the combined roles of the SFO and AP in Angll induced Fos expression in the RVLM? Fos expression will be measured in the RVLM in APx, SFOx and XX rats subjected to Angll infusion. We predicteither or both the SFO and AP are necessary for Angll induced Fos expression in the RVLM. Our hypothesis is based on the idea that lesioned animals will not be able to alter SNS activity appropriatelyin the same manner as sham rats during the above manipulations, and this will lead to the altered blood pressure responses. In order to address this underlying hypothesis, and link the SNS to the observed changes in blood pressure, we will measure acute depressor responses to the ganglionic blockingagent, hexamethonium, as well as plasma norepinephrine levels in all rats during control and treatment periods. These multiple methods will allow us to determine the sympathetic contribution to vasomotor tone during the observed changes in blood pressure. The results of these studies will greatly enhance our understanding of the central effects of Angll at two specific brain regions, and how these interactions play a role in the long-term control of arterial pressure.

描述（由申请人提供）：中枢神经系统对长期血压（BP）调节的控制尚不完全清楚。许多研究者研究了穹窿下器官 (SFO) 和后区 (AP) 在血管紧张素 II (Angll) 中枢作用中的个体作用。 Angll 被认为可以调节这些室周器官 (CVO) 的交感神经系统 (SNS) 活动并调节血压 (BP)。该提案表明 Angll 通过这些 CVO 采取的行动存在冗余。这是第一项同时检查内源性和外源性 AngII 对这 2 个 CVO 的影响的研究。首先，我们提出内源性 Angll 通过这些 CVO 发挥作用。目标 1：SFO 和 AP 在内源性 AngII 的长期影响中的综合作用是什么？将测量用 AT1 拮抗剂艾奥沙坦治疗 10 天的 SFOx、APx 和 XX 大鼠的血压和心输出量 (CO)。此外，我们建议通过这些 CVO 改变内源性 Angll 的水平来调节血压。目标 2：膳食盐摄入量变化期间，SFO 和 AP 在维持血压方面的综合作用是什么？将在 2 周期间增加和减少饮食盐的 SFOx、APx 和 XX 大鼠中测量 BP 和 CO。最后，我们提出慢性 Angll 高血压是通过这些 CVO 的作用介导的。目标 3：SFO 和 AP 在预防 AngII 诱导的高血压中的联合作用是什么？将在 AngII 输注 10 天期间对 APx、SFOx 和 XX 大鼠进行血压和 CO 测量。我们预测 XX 大鼠对艾奥沙坦的低血压反应减弱，饮食盐变化期间血压失调，以及 AngII 介导的高血压减弱。此外，AIM3a：SFO 和 AP 在 Angll 诱导 RVLM 中 Fos 表达中的联合作用是什么？将在接受AngII输注的APx、SFOx和XX大鼠的RVLM中测量Fos表达。我们预测 SFO 和 AP 之一或两者对于 RVLM 中 Angll 诱导的 Fos 表达是必需的。我们的假设基于这样的想法：在上述操作过程中，受损动物将无法以与假大鼠相同的方式适当改变 SNS 活动，这将导致血压反应改变。为了解决这一基本假设，并将 SNS 与观察到的血压变化联系起来，我们将测量所有大鼠在对照和治疗期间对神经节阻滞剂六甲铵的急性降压反应，以及血浆去甲肾上腺素水平。这些多种方法将使我们能够确定在观察到的血压变化期间交感神经对血管舒缩张力的贡献。这些研究的结果将极大地增强我们对 Angll 在两个特定大脑区域的中枢作用以及这些相互作用如何在动脉压的长期控制中发挥作用的理解。