ANGIOTENSIN, SODIUM AND GENES IN PRIMATE HYPERTENSION

灵长类高血压的血管紧张素、钠和基因

• 批准号: 7957889
• 负责人: ROBERT E SHADE
• 金额: $ 15.69万
• 依托单位: TEXAS BIOMEDICAL RESEARCH INSTITUTE
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-06-06 至 2010-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7957889
• 关键词: Aldosterone; Angiotensins; Animals; Automobile Driving; Blood Pressure; Computer Retrieval of Information on Scientific Projects Database; Data; Defect; Dietary Sodium; Experimental Models; Family; Funding; Genes; Genetic; Goals; Grant; Human; Hypertension; Individual; Institution; Intake; Lithium; Modeling; Neuraxis; Papio; Patients; Peripheral; Phenotype; Plasma; Primates; Process; Regulation; Renal function; Renin-Angiotensin-Aldosterone System; Research; Research Personnel; Resources; Role; Sodium; Source; Sympathetic Nervous System; System; Testing; United States National Institutes of Health; Work; experience; nonhuman primate; pressure; research study; response; salt sensitive

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. 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.

该子项目是利用该技术的众多研究子项目之一 资源由 NIH/NCRR 资助的中心拨款提供。子项目和 研究者 (PI) 可能已从 NIH 的另一个来源获得主要资金， 因此可以在其他 CRISP 条目中表示。列出的机构是 对于中心来说，它不一定是研究者的机构。 钠依赖性高血压长期以来一直与肾功能缺陷有关。实验模型和人体研究也表明，基因表达的改变可能会导致高血压过程。钠锂逆向转运 (SLC) 活性是帮助维持细胞内钠浓度的一种机制，在一些高血压患者中，SLC 活性增加。这些人还会对钠挑战产生不适当的反应，这似乎是由于肾素-血管紧张素-醛固酮系统 (RAAS) 缺乏抑制所致。 SLC 活动与高血压之间的关联是由基因决定的，因为它发生在家庭中。目前还不确定这是否反映了 SLC 基因的改变（可能增加 RAAS 功能的基因之一），或者两个系统基因之间的相互作用。拟议研究的目的是在 SLC 表型高或低的非人类灵长类动物模型中检查 SLC 活性与 RAAS 之间的关系。待检验的假设是，高 SLC 活性与不适当的高 RAAS 功能以及动脉压对膳食钠的敏感性较高有关。在三个目标中，将在具有高和低 SLC 表型的狒狒中研究外周和中枢 RAAS 成分对钠依赖性高血压的贡献。第一个目标是在逐步增加钠摄入量的过程中，对高和低 SLC 动物的 RAAS 调节进行检查。这些实验将确定具有高 SLC 活性的动物抑制 RAAS 的能力是否降低并发展为盐敏感性高血压。第二个目标是研究血管紧张素和醛固酮在钠刺激高血压中的作用，以及它们导致高和低 SLC 动物血压升高的能力。这一目标将确定是否通过提高血浆血管紧张素或醛固酮，高 SLC 动物更有可能患高血压。第三个目标将重点关注高和低 SLC 动物中与不适当高 RAAS 相关的中枢神经系统机制。这些研究将确定高 SLC 活性是否会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来确定不适当的高 RAAS 活动是否会导致高血压。重要的是，这项工作还将揭示高 SLC 的遗传决定表型对于动物易患钠依赖性高血压是否很重要。