ANGIOTENSIN, SODIUM AND GENES IN PRIMATE HYPERTENSION

本子项目是利用由NIH/NCRR资助的中心赠款提供的资源的众多研究子项目之一。子项目和研究者（PI）可能已经从另一个NIH来源获得了主要资金，因此可以在其他CRISP条目中表示。列出的机构是中心的，不一定是研究者的机构。钠依赖性高血压一直被认为与肾功能缺陷有关。实验模型和人体研究也表明，基因表达的改变可能有助于高血压的过程。钠锂反转运（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活性升高。这些人也会经历对钠挑战的不适当反应，这似乎是由于缺乏对肾素-血管紧张素-醛固酮系统（RAAS）的抑制。SLC活性与高血压之间的关系是遗传决定的，因为它发生在家族中。目前尚不确定这是否反映了SLC基因的改变，SLC基因是可能增加RAAS功能的基因之一，还是两个系统基因之间的相互作用。本研究的目的是在SLC表型高或低的非人灵长类动物模型中研究SLC活性与RAAS之间的关系。待验证的假设是，高SLC活性与不适当的高RAAS功能和更高的动脉压对膳食钠的敏感性有关。在三个目的中，外周和中枢RAAS成分对钠依赖性高血压的贡献将在高和低SLC表型的狒狒中进行研究。在第一个目标中，将在钠摄入量逐步增加的高和低SLC动物中检查RAAS的调节。这些实验将确定具有高SLC活性的动物是否抑制RAAS的能力降低并发生盐敏感性高血压。第二个目的是研究血管紧张素和醛固酮在钠刺激高血压中的作用，以及它们在高和低SLC动物中引起血压升高的能力。这个目的将决定是否通过提高血浆血管紧张素或醛固酮，高SLC动物更有可能成为高血压。第三个目标将集中在与高和低SLC动物中不适当的高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，以确定不适当的高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决定的高SLC表型是否在使动物易患钠依赖性高血压中起重要作用。

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.