BLOOD PRESSURE CONTROL IN JUVENILES--LONGITUDINAL STUDY

描述：(改编自《调查者摘要》)拟议的研究 是纵向研究的延伸，其机制是 原发性高血压的发展。他们是在混音乐曲上表演的 一群儿童、青少年和年轻人，他们大多是 血压正常。这些研究是基于这样一个前提： 高血压的病理生理学在生命早期就开始了，而且血液 在这个年龄段进行的压力(BP)研究避免了混淆 心血管和肾脏的变化通常发生在受试者 高血压。在上一期的资助中，明显的种族 观察到与血压调节相关的差异：第一，纵向血压 随着时间的推移，黑人的增长速度比白人快；第二，醛固酮 黑人的排泄量低于白人，部分原因是抑制了 肾素-血管紧张素系统(RAS)；第三，血清水平 血管紧张素原含量较高，是血管紧张素原基因(AGT)的变种， 与高血压有关的T235是主要的 黑人的等位基因。在拟议的研究中，重点将是 主要是关于钠滞留的作用以及如何通过 血管紧张素II(AII)，一种源自血管紧张素原的产物，以及 阿米洛利敏感钠通道(ENaC)，一个重要的部位 钠在远端肾单位的重吸收。这些研究利用了 队列的纵向BP-多个值的平均值以及 随着时间的推移，BP的变化。该队列将通过招聘补充 增加成员和增加家长的参与。具体而言 目标1将进行三个子研究：(1)由于T235等位基因可能 与增加血管紧张素原的基因座连锁不平衡 申请者现在将用T235构建单倍型，以识别 与较高血管紧张素原相关的T235等位基因亚集(S) 水平，并且可能是AGT上的一个高血压基因座。(2)审查 黑人儿童血管紧张素原水平升高是否与种族有关 单独或与较高的高血压患病率有关 他们的父母。(3)最后，新鉴定的变种之间的关系 ENaC基因对纵向BP、RAS和尿液排泄的影响 用来寻找这种离子的分子变异 我们将考察作为更高BP贡献者的渠道。具体目标2 将在综合临床研究中心进行，在那里 可检测AII对肾脏血流动力学和钠吸收的影响。自.以来 肾脏血管阻力增加可能由AII介导 可能会增加钠的吸收，申请者将测量肾脏血液 Flow(RBF)，以检验黑人的RBF低于 白蛋白，并与血管紧张素原和 纵向BP。作为对输液施加的钠挑战的回应 生理盐水，内源性锂的清除，一种衡量 近端肾小管上皮细胞的部分钠重吸收 钠的排泄量，一个衡量整体排钠能力的指标，将是 检查与种族、血管紧张素原水平和纵向血压的关系。 一项正在进行的BP纵向研究扩展了横断面 分析潜在的遗传和肾脏对血压的影响，这些因素可能 与原发性高血压的病因学有关。

DESCRIPTION: (Adapted from Investigator's Abstract) The proposed studies are an extension of longitudinal investigations of mechanisms for the development of primary hypertension. They are performed on a biracial cohort of children, adolescents, and young adults who are mostly normotensive. These studies are based on the premise that the pathophysiology of hypertension begins early in life, and further that blood pressure (BP) studies carried out at this age avoid the confounding cardiovascular and renal changes that typically occur when subjects are hypertensive. In the previous period of funding, distinct racial differences relevant to BP regulation were observed; first, longitudinal BP increased over time faster in blacks than in whites; second, aldosterone excretion was lower in blacks than in whites due in part to suppression of the renin-angiotensin system (RAS); and third, the level of serum angiotensinogen was higher and a variant of the angiotensinogen gene (AGT), T235, which has been associated with hypertension, was the predominant allele in the blacks. In the proposed studies, the focus will be principally on the role of sodium retention and how this is regulated by angiotensin II (AII), a product derived from angiotensinogen, and the amiloride-sensitive sodium channel (ENaC), an important site for reabsorption of sodium in the distal nephron. The studies utilize the longitudinal BPs of the cohort - the mean of multiple values as well as the change in BP over time. The cohort will be supplemented through recruitment of additional members and increased participation by parents. In Specific Aim No. 1 three substudies will be performed: (1) Since the T235 allele may be in linkage disequilibrium with a locus that increases the angiotensinogen level, the applicants will now construct haplotypes with T235 to identify a subset(s) of T235 alleles that associate with a higher angiotensinogen level, and potentially a hypertensinogenic locus on AGT. (2) To examine whether a higher angiotensinogen level in black children is related to race alone or is related specifically to the higher prevalence of hypertension in the parents. (3) Finally, the relation of newly identified variants of genes for ENaC to longitudinal BP, the RAS, and the urinary excretion of aldosterone and potassium to look for molecular variations of this ion channel as contributors to a higher BP will be examined. Specific Aim No. 2 will be performed in the General Clinical Research Center where the effects of AII on renal hemodynamics and sodium resorption can be examined. Since increases in vascular resistance in the kidney that may be mediated by AII may increase resorption of sodium, the applicants will measure renal blood flow (RBF) to test the hypotheses that RBF is lower in blacks than in whites, and is inversely related to level of angiotensinogen and longitudinal BP. In response to a sodium challenge imposed by an infusion of normal saline, the clearance of endogenous lithium, a measure of AII-directed sodium reabsorption in proximal tubule, and the fractional excretion of sodium, a measure of overall natriuretic capacity, will be examined in relation to race, angiotensinogen level, and longitudinal BP. An ongoing longitudinal study of BP is extended with cross-sectional analyses of potential genetic and renal influences on BP, factors that could contribute to the etiology of primary hypertension.