Hypertension and alpha 2 adrenergic receptors

高血压和 α2 肾上腺素能受体

• 批准号: 6643295
• 负责人: HARALAMBOS GAVRAS GAVRAS
• 金额: $ 4.2万
• 依托单位: BOSTON UNIVERSITY MEDICAL CAMPUS
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-04-01 至 2005-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6643295
• 关键词: alpha adrenergic receptor; angiotensin /renin /aldosterone hypertension; antisense nucleic acid; cardiovascular pharmacology; genetic susceptibility; hemodynamics; laboratory mouse; laboratory rat; neuroregulation; protein isoforms; protein structure function; receptor expression; transfection

DESCRIPTION (provided by applicant): Alteration in the expression or function of one or more a2-adrenergic receptor (a2-AR) subtypes may be involved in the development and/or maintenance of salt-induced hypertension. This proposal seeks to dissect the roles of the a2A-AR and a2B-AR subtypes in blood pressure (BP) regulation. Our working hypothesis is that the a2A-AR and a2B-AR subtypes located in the centers of cardiovascular control of the brain have opposing effects on BP: The predominant presynaptic a2A-AR's exert a tonic sympathoinhibitory by potensive action and their pharmacologic stimulation further attenuates sympathetic activity, On the contrary, the a2B-ARs exert a hypertensive effect and their activation (e.g., by sodium overload) leads to an accentuated hyperadrenergic hypertensive response. We propose the following Specific Aims:1. To further clarify in mice the role of the a2A-AR and a2B-AR, each acting unopposed, in shaping the cardiovascular phenotype, by assessing the hemodynamic and hormonal profile as well as BP responses to salt loading, selective pharmacologic agents and renal artery clipping. 2. To dissect in rats the central and peripheral effects of the two a2-AR subtypes after temporarily inhibiting the generation of each subtype by targeting selected gene sequences with antisense oligonucleotides injected either stereotaxically in the lateral cerebral ventriclear or the brainstem, or systemically, while monitoring BP, catecholamines and pharmacologic responses. Genetic engineering and gene treatment will be used along with pharmacologic probes in order to differentiate responses to activation or inhibition of each a2-AR subtype. The ultimate goal of this research is to develop the means to prevent or treat certain types of hypertension by selectively altering the central a2B AR subtype without affecting other a2-AR-mediated functions, such as mental alertness, as occurs with current nonselective central sympatholytic agents.

描述（申请人提供）：表达式或功能的更改 一个或多个A2-肾上腺素能受体（A2-AR）亚型可能参与 盐引起的高血压的开发和/或维持。这个建议 试图剖析A2A-AR和A2B-AR亚型在血压中的作用 （BP）调节。我们的工作假设是A2A-AR和A2B-AR子类型 位于大脑心血管控制的中心有相对 对BP的影响：主要突触前A2A-AR发挥滋补作用 通过强化作用及其药理刺激的交感神经抑制 相反，进一步削弱了同情活动，A2B-ARS发挥了A 高血压作用及其激活（例如，通过钠超负荷）导致 强调高肾上腺素能高血压反应。我们提出以下内容 具体目的：1。为了进一步阐明小鼠A2A-AR和A2B-AR的作用， 每种行动无反对，在塑造心血管表型时，通过评估 血液动力学和激素谱以及BP对盐负荷的反应， 选择性药理学剂和肾动脉剪切。 2。在大鼠中剖析 两个A2-AR亚型的中心和外围效应暂时 通过靶向选定的基因序列来抑制每种亚型的产生 用反义寡核苷酸立体定位在侧面注入的寡核苷酸 监测BP时脑室或脑干或系统的脑干， 儿茶酚胺和药理反应。基因和基因 治疗将与药理学探针一起使用 区分对每个A2-AR亚型的激活或抑制的反应。这 这项研究的最终目标是开发预防或治疗的手段 通过选择性更改中央A2B AR，某些类型的高血压 亚型不影响其他A2-AR介导的功能，例如心理 当前非选择性的中央交感剂时，警觉性。