ANGIOTENSIN, SODIUM AND GENES IN PRIMATE HYPERTENSION

这个子项目是许多研究子项目中利用 资源由NIH/NCRR资助的中心拨款提供。子项目和 调查员(PI)可能从NIH的另一个来源获得了主要资金， 并因此可以在其他清晰的条目中表示。列出的机构是 该中心不一定是调查人员的机构。 长期以来，钠依赖型高血压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的发生。钠锂逆向转运(SLC)活性是帮助维持细胞内钠浓度的机制之一，在一些高血压患者中，SLC活性增加。这些人还经历了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活动和高血压之间的关联是由遗传决定的，因为它发生在家庭中。目前尚不确定这是否反映了SLC基因的变化，SLC是可能增加RAAS功能的基因之一，还是两个系统的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检测SLC活性和RAAS之间的关系。需要检验的假设是，SLC活性高与RAAS功能异常高和动脉压对饮食钠的敏感性更高有关。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央RAAS成分在钠依赖型高血压中的作用。在第一个目标中，将在高和低SLC动物中检测在逐步增加钠摄入量的过程中RAAS的调节。这些实验将确定具有高SLC活性的动物是否具有抑制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。这一目标将决定是否通过升高血浆血管紧张素或醛固酮，高SLC动物更有可能患高血压。第三个目标将集中在与高和低SLC动物不适当的高RAAS相关的中枢神经系统机制上。这些研究将确定SLC的高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，以确定不适当的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表型是否在使动物易患钠依赖型高血压方面起重要作用。

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.