MOREHOUSE CCRE DP3- SALT AND VASCULAR FUNC IN NON-HYPERTENSIVE AFRICAN AMERICANS

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。 早期识别非洲裔美国人(AA)有高血压(HTN)的风险可能为预防疾病的进展提供机会。一种与HTN相关的中间表型是可变血压(BP)对盐和水的动态平衡变化的反应。这种对BP的盐敏感性(SS)可能是遗传决定的，因为超过50%的高血压AA对NaCI敏感，并有更大的倾向发生高血压靶器官损害。本项目的主要目的是研究遗传性非高血压AA患者在盐摄入后血管和心肾功能的生理变化，并评估介导这些终末器官对盐反应的潜在病理生物学途径。我们的假设是，高盐/低钾饮食，典型的AA，抑制经典的循环肾素血管紧张素-醛固酮系统(RAAS)，但激活组织血管紧张素-醛固酮系统。当地人 血管紧张素和醛固酮在组织内的产生促进了活性氧的产生，从而损害了一氧化氮(NO)介导的血管扩张功能。据推测，这种内皮功能的损害通过盐诱导的血压升高之外的机制，导致血管功能障碍和增加亚临床终末器官功能障碍的早期发展的易感性；然而，在非高血压AA的实质性样本中，仔细描述盐对血压和RAAS下游靶点的影响的尝试有限，循环中的氧化应激标志物是内皮功能受损的潜在决定因素。我们建议进行仔细的生理学实验，将血管紧张素水平的调节与氧化应激和血管功能的新标记物结合起来，以评估有终末器官功能障碍风险的非HTN AA患者。拟议的项目将是第一个系统地确定盐摄入量的变化对这些特定的 以血管和心脏/肾功能的标记物，并在这一独特的以人群为基础的样本中表征这种反应的效果。

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. Early identification of African Americans (AA) at risk for hypertension (HTN) may provide an opportunity to prevent progression of the disease. One HTN-related intermediate phenotype of interest is the variable blood pressure (BP) response to changes in salt and'water homeostasis. This salt-sensitivity (SS) to BP may be genetically determined as over 50% of hypertensive AA are NaCI-sensitive and have a greater propensity to develop hypertensive target-organ damage. The -main objective of this project is to characterize physiologic alterations in vascular and cardio-renal function in response to salt intake in genetically susceptible non-hypertensive AA and to assess the potential pathobiological pathways mediating these end-organ responses to salt. Our hypothesis is that a high salt/low potassium diet, typical of AA, inhibits the classic circulating reninangiotensin- aldosterone system (RAAS) but activates the tissue angiotensin-aldosterone system. The local generation of angiotensin and aldosterone within tissue compartments promotes the generation of reactive oxygen species that impairs nitric oxide (NO)-mediated vasodilatory function. It is postulated that this impairment in endothelial function contributes to vascular dysfunction and increased susceptibility to the early development of sub-clinical end-organ dysfunction, by mechanisms additional to the salt-induced rise in BP; However, there have been limited attempts to carefully characterize the effects of salt on BP and downstream targets of the RAAS, circulating markers of oxidative stress as potential determinants of impaired endothelial function in a substantive sample of non-hypertensive AA. We propose careful physiologic experiments that will combine manipulations of angiotensin levels and novel marker of oxidative stress and vascular function in non-HTN AA at risk for end-organ dysfunction. The proposed project will be among the first to systematically define the early influence of variations in salt intake on these specific markers of vascular and cardiac/renal function and to characterize the effect of this response in this unique population-based sample of otherwise healthy subjects.