Angiotensin, Sodium and Genes in Primate Hypertension

说明(申请人提供)：钠依赖型高血压长期存在 与肾功能缺陷有关。实验模型以及 人类研究也表明，基因表达的变化可能会 在高血压过程中起重要作用。钠锂逆向转运(SLC) 活性是帮助维持细胞内钠离子的一种机制 在一些高血压患者中，SLC活性增加。 这些人也会经历对钠的不适当反应。 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 活动和高血压是由基因决定的，因为它发生在 家人。目前还不确定这是否反映了基因的变化 SLC，可能增加RAAS功能的基因之一，或者是一种相互作用 两个系统的基因之间的关系。拟议研究的目标是 研究非人类SLC活性与RAAS的关系 SLC表型为高或低的灵长类动物模型。假设是 测试表明，高SLC活性与不适当的高RAA相关 功能和对饮食钠的更大的动脉压敏感性。在……里面 三个目标，外围和中央RAAS组件对 钠依赖型高血压的研究将分高、低两种情况进行 SLC表型。在第一个目标中，将研究对RAAS的监管 高SLC动物和低SLC动物期间钠摄入量逐步增加。这些 实验将确定具有高SLC活性的动物是否有 抑制RAAS和发展成盐敏感型高血压的能力降低。 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酶中的作用。 钠对高血压的刺激作用及其引起血压的能力 在高、低SLC动物中升高。这一目标将决定是否通过提高 高SLC动物更有可能血浆血管紧张素或醛固酮 变得高血压。第三个目标将集中在中枢神经系统上 高、低SLC患者RAAS过高的相关机制 动物。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 提高动脉压。这些研究将有助于提供数据来确定 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决定的 高SLC的表型在动物易患高血压中起重要作用 钠依赖型高血压。

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.