权益分类	功能权益	普通用户	{{item.name}}会员
{{category.name}}	{{benefitItem.name}}

NEUROHORMONAL MECHANISMS IN HYPERTENSION

高血压的神经激素机制

基本信息

批准号：
3097410
负责人：
Karen Barnes
金额：
$ 115.51万
依托单位：
CLEVELAND CLINIC FOUNDATION
依托单位国家：
美国
项目类别：
财政年份：
1988
资助国家：
美国
起止时间：
1988-12-01 至 1993-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/3097410
关键词：
angiotensin /renin /aldosterone hypertension neuroendocrine system neuropharmacology

项目摘要

The multidisciplinary research efforts of this Program Project continue to focus on the elucidation of the cellular, biochemical, and functional mechanisms by which the renin-angiotensin- aldosterone system participates in the control of cardiovascular function and the pathogenesis of arterial hypertension. The broad objective of the proposed studies is to explore the biochemical, neuroanatomical, and physiological substrate for the central actions of angiotensin II (Ang II), its congener peptides, and aldosterone on the neuronal circuits of the medulla oblongata and hypothalamus involved in tonic and reflex regulation of cardiovascular function, and integration of neural and humoral factors that maintain extracellular fluid volume and composition. Specifically, we seek to determine the mechanism(s) by which angiotensin peptides (Angs) influence neuronal pathways in the medulla involved in cardiovascular regulation by establishing: 1) the capacity of Angs to alter the electrophysiological characteristics of neurons in an in vitro slice of the dorsomedial medulla (DMM); 2) the ability of Angs to alter the release of substance P, norepinephrine, and serotonin from DMM slices and nodose ganglion explants; 3) the transport mechanisms and functional significance of Ang binding sites in the DMM and cervical vagus; and 4) the anatomical, electrophysiological, and neurohormonal mechanisms involved in the pressor actions of Ang II in the ventrolateral medulla. In addition, we will investigate whether the differing central actions of Ang II are explained by: 1) the location of Ang receptors within vs. outside the blood-brain or cerebrospinal fluid (CSF)-brain barriers, 2) the presence of molecular variants of Angs that act on a common receptor or subpopulations, or 3) a combination of both possibilities. These alternatives will be investigated by determining: 1) the expression and regulation of Ang II and its fragments, and those processing enzymes that may contribute to the generation of multiple biologically active Angs; 2) structure-activity relationships between Ang II and its heptapeptide fragments (Ang- (1-7), Ang-(2-8) that determine receptor binding and impart different roles in neuronal or neurosecretory events: and 3) the physiological mechanisms by which Ang II, Ang-(1-7), and Ang-(2-8) participate in the relate of vasopressin from the neurohypophysis and modulation of the reflex control of arterial pressure by the DMM. Finally, we will examine the hemodynamic and neurohumoral effects of aldosterone given into the CSF in sub-pressor amounts to establish the role of this steroid in central cardiovascular regulation. The proposed studies will take advantage of the multidisciplinary expertise of our group to uncover new information about the neurohormonal mechanisms that regulate homeostasis and can produce hypertension.

本计划项目的多学科研究工作继续专注于细胞、生化、以及肾素-血管紧张素-的功能机制醛固酮系统参与心血管的控制动脉高血压的功能和发病机制。广义的拟议研究的目的是探索生化、中枢的神经解剖学和生理学基础血管紧张素 II (Ang II) 及其同源肽的作用，以及醛固酮对延髓神经元回路的影响下丘脑参与强直和反射调节心血管功能以及神经和体液的整合维持细胞外液体积和成分的因素。具体来说，我们寻求确定机制血管紧张素肽（Angs）影响神经元通路髓质通过以下方式参与心血管调节：1) Angs改变电生理的能力背内侧体外切片神经元的特征髓质（DMM）； 2）Angs改变释放的能力 DMM 切片中的 P 物质、去甲肾上腺素和血清素结状神经节外植体； 3）运输机制和 DMM 中 Ang 结合位点的功能意义和颈迷走神经； 4) 解剖学、电生理学和 Ang II 升压作用涉及的神经激素机制在延髓腹外侧。此外，我们还将调查 Ang II 的不同中心作用是否可以通过以下方式解释： 1) 血管紧张素受体在血脑内和血脑外的位置或脑脊液（CSF）脑屏障，2）存在作用于共同受体的Angs分子变体或亚群体，或 3) 两种可能性的组合。这些将通过确定以下内容来研究替代方案： 1) Ang II及其片段的表达和调节，以及那些加工酶可能有助于产生多种生物活性Angs； 2）结构-活性 Ang II 与其七肽片段之间的关系（Ang- (1-7)、Ang-(2-8) 决定受体结合并赋予在神经元或神经分泌事件中的不同作用：3） Ang II、Ang-(1-7) 和 Ang-(2-8) 的生理机制参与神经垂体加压素的关系和调节动脉压的反射控制数字万用表。最后，我们将检查血流动力学和神经体液以次加压量给予脑脊液的醛固酮的影响确定这种类固醇在中枢心血管中的作用规定。拟议的研究将利用我们团队的多学科专业知识发现新信息关于调节体内平衡的神经激素机制和可产生高血压。