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Angiotensin, Sodium and Genes in Primate Hypertension

灵长类高血压中的血管紧张素、钠和基因

基本信息

批准号：
6881153
负责人：
ROBERT E SHADE
金额：
$ 50.83万
依托单位：
TEXAS BIOMEDICAL RESEARCH INSTITUTE
依托单位国家：
美国
项目类别：
财政年份：
2002
资助国家：
美国
起止时间：
2002-04-01 至 2008-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/6881153
关键词：
angiotensin /renin /aldosterone hypertension baboons dietary sodium genetic susceptibility hypertension ion transport lithium nutrition related tag renin angiotensin system sodium ion

项目摘要

DESCRIPTION (provided by applicant): Sodium-dependent hypertension has long been associated with a defect in renal function. Experimental models as well as human studies have also suggested that an alteration in genetic expression may contribute to the hypertensive process. Sodium-lithium countertransport (SLC) activity is one mechanism that helps maintain intracellular sodium concentrations, and in some hypertensive patients, SLC activity is increased. These individuals also experience an inappropriate response to sodium challenges that appears to result from a lack of suppression of the renin-angiotensin-aldosterone system (RAAS). The association between SLC activity and hypertension is genetically determined since it occurs in families. It is uncertain whether this reflects an alteration in the gene for SLC, one of the genes that may increase RAAS function, or an interaction between genes for the two systems. The goal of the proposed studies is to examine the relationship between SLC activity and the RAAS in a non-human primate model in which the SLC phenotype is high or low. The hypothesis to be tested is that a high SLC activity is associated with inappropriately high RAAS function and a greater arterial pressure sensitivity to dietary sodium. In three aims, the contributions of peripheral and central RAAS components to sodium-dependent hypertension will be studied in baboons with the high and low SLC phenotypes. In the first aim, regulation of the RAAS will be examined in high and low SLC animals during a step-wise increase in sodium intake. These experiments will determine whether animals with high SLC activity have a reduced ability to suppress the RAAS and develop salt-sensitive hypertension. The second aim will investigate the role of angiotensin and aldosterone in the stimulation of hypertension by sodium and their ability to cause blood pressure to rise in high and low SLC animals. This aim will determine whether by raising plasma angiotensin or aldosterone the high SLC animals are more likely to become hypertensive. The third aim will focus on central nervous system mechanisms associated with an inappropriately high RAAS in high and low SLC animals. These studies will determine whether the high SLC activity results in more sensitive central mechanisms driving the sympathetic nervous system to raise arterial pressure. These studies will help provide data to determine whether an inappropriately high RAAS activity can cause hypertension. Importantly, this work will also reveal whether the genetically determined phenotype of high SLC is important in predisposing an animal to sodium-dependent hypertension.

描述（由申请人提供）：钠依赖性高血压长期存在与肾功能缺陷有关。实验模型以及人类研究也表明，基因表达的改变可能会导致高血压钠-锂反向转运（SLC）活性是一种有助于维持细胞内钠在一些高血压患者中，SLC活性增加。这些人也会对钠产生不适当的反应这些挑战似乎是由于缺乏对肾素-血管紧张素-醛固酮系统（RAAS）。SLC之间的关联活动和高血压是遗传决定的，因为它发生在家庭目前还不确定这是否反映了基因的改变， SLC，可能增加RAAS功能的基因之一，或相互作用两个系统的基因之间的联系拟议研究的目标是检查SLC活性与非人RAAS之间的关系， SLC表型高或低的灵长类动物模型。假设是高SLC活性与不适当的高RAAS相关功能和更大的动脉压对膳食钠的敏感性。在三个目标，周边和中央RAAS组件的贡献，钠依赖性高血压将在狒狒中进行研究， SLC表型。在第一个目标中，将在高和低SLC动物在逐步增加钠摄入量。这些实验将确定具有高SLC活性的动物是否具有抑制RAAS的能力降低，并发展成盐敏感性高血压。第二个目的是研究血管紧张素和醛固酮在血管紧张素转换中的作用。钠对高血压的刺激及其引起血压的能力在高和低SLC动物中升高。这一目标将决定是否通过提高血浆血管紧张素或醛固酮高SLC动物更有可能变得高血压。第三个目标将集中在中枢神经系统与高和低SLC中不适当的高RAAS相关的机制动物这些研究将确定高SLC活性是否导致更敏感的中枢机制驱动交感神经系统，升高动脉压这些研究将有助于提供数据， RAAS活性过高是否会导致高血压。重要的是，这项工作还将揭示基因是否决定高SLC表型在使动物倾向于钠依赖性高血压