Angiotensin, Sodium and Genes in Primate Hypertension

灵长类高血压中的血管紧张素、钠和基因

• 批准号: 6625835
• 负责人: ROBERT E SHADE
• 金额: $ 48.34万
• 依托单位: TEXAS BIOMEDICAL RESEARCH INSTITUTE
• 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 2006-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6625835
• 关键词: angiotensin /renin /aldosterone hypertension; baboons; dietary sodium; genetic susceptibility; hypertension; ion transport; lithium; nutrition related tag; renin angiotensin system; sodium ion

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）：依赖钠的高血压长期很长 与肾功能缺陷有关。实验模型以及 人类研究还表明，遗传表达的改变可能 有助于高血压过程。硫钠反射钠（SLC） 活动是一种有助于维持细胞内钠的机制 浓度以及一些高血压患者，SLC活性增加。 这些人也对钠的反应不当 由于缺乏压制而造成的挑战 肾素 - 血管紧张素 - 醛固酮系统（RAAS）。 SLC之间的关联 活性和高血压是遗传确定的，因为它发生在 家庭。不确定这是否反映了基因的改变 SLC，可能增加RAAS功能或相互作用的基因之一 在两个系统的基因之间。拟议研究的目的是 检查非人类中SLC活动与RAA之间的关系 SLC表型高或低的灵长类动物模型。假设是 测试的是，高SLC活性与不恰当的高raas有关 功能和对饮食钠的动脉压敏感。在 三个目的，外围和中央RAAS组件的贡献 将在高和低的狒狒中研究依赖钠的高血压 SLC表型。在第一个目标中，将在 在钠摄入量的逐步增加期间，高和低的SLC动物。这些 实验将确定SLC活性高的动物是否具有 降低抑制RAA并产生盐敏感性高血压的能力。 第二个目标将研究血管紧张素和醛固酮在 通过钠刺激高血压及其引起血压的能力 在高和低SLC动物中崛起。这个目标将决定是否通过 血浆血管紧张素或醛固酮高SLC动物更有可能 变得高血压。第三个目标将重点放在中枢神经系统上 与高和低SLC中不恰当高的RAA相关的机制 动物。这些研究将确定高SLC活性是否导致 更敏感的中心机制推动了交感神经系统 增加动脉压。这些研究将有助于提供数据以确定 不适当的RAAS活性是否会导致高血压。 重要的是，这项工作还将揭示遗传确定的 高SLC的表型对于使动物易于 依赖钠的高血压。