Parathyroid Hormone & Vitamin D Effects on Salt Sensitivity and Vascular Function

描述(申请人提供)：维生素D缺乏症在非裔美国人中比白人更常见。甲状旁腺激素(PTH)升高的患病率在非裔美国人中也很高，这通常是维生素D水平下降和/或钙摄入量不足的结果。肥胖对非裔美国人(特别是女性)的影响不成比例，也与维生素D缺乏和甲状旁腺激素升高的过度流行有关。然而，通过慢性甲状旁腺素升高来维持血钙浓度，已知血管和心肌内的有害生理效应，如血管收缩、成纤维细胞激活、胰岛素抵抗、血脂异常、脂肪沉积和内皮一氧化氮下调--所有这些都可能导致血压升高、血管和压力敏感靶器官损伤、体重增加、血脂异常和糖耐量异常。我们建议对参加NIH资助的ONOSS研究的65名健康、血压正常的非裔美国人进行一项研究，以检查饮食补钠6周前后的下列情况：目的1：测定血压(BP)(袖带和24小时动态血压)、动脉僵硬(AS)、外周血管阻力(PVR)和一氧化氮(NO)的产生及其与25-OH维生素D(25-OH D)和甲状旁腺素(PTH)循环水平的关系；目的2：确定基线25-OH D和PTH水平与饮食盐负荷后BP、AS和PVR的后续变化的关系；目的#3：确定饮食盐负荷后血小板NO代谢产物和刺激NO产生的变化与BP、AS和PVR变化的关系；目的#4：确定基线25-OHD和PTH水平与氧化应激循环标志物(总异前列腺素、核因子kappaβ)和自由基(硝基酪氨酸、二羟酪氨酸、氯酪氨酸)基线水平的关系，进而将氧化应激循环标志物与饮食盐负荷后BP、AS、PVR、尿NO代谢产物和血小板NO产生的变化联系起来。相关性：维生素D缺乏和PTH继发性增加是常见的，尤其是在肥胖者和非洲裔美国人中。它们都有血管和生理效应，导致非裔美国人血压升高、血管和压力相关的靶器官损伤、内皮功能障碍和盐敏感性的过度流行。重要的是要了解维生素D缺乏和甲状旁腺素长期升高对可能导致常见心血管并发症的异常生理的作用，因为补充维生素D是负担得起的，相对无毒，并且可以在口服配方中获得。

DESCRIPTION (provided by applicant): Vitamin D deficiency is much more common in African Americans than whites. The prevalence of elevated parathyroid hormone (PTH), typically a consequence of depressed vitamin D levels and/or low calcium intake, is also high in African Americans. Obesity, which disproportionately affects African Americans (especially women), has also been linked to an excessive prevalence of vitamin D deficiency and elevated PTH. However, maintenance of serum calcium concentrations by chronic PTH elevations has known deleterious physiological effects within the vasculature and myocardium such as vasoconstriction, activation of fibroblasts, insulin resistance, dyslipidemia, fat deposition and down regulation of endothelial nitric oxide - all of which plausibly contribute to elevated blood pressure (BP)and vascular and pressure- sensitive target organ injury, weight gain, dyslipidemia, and glucose intolerance. We propose a study in ~ 65 healthy, normotensive African Americans enrolled in the NIH-funded ONOSS study to examine the following before and after a 6 week period of dietary sodium supplementation: Aim #1: determine blood pressure (BP)(cuff and ambulatory 24 hour), arterial stiffness (AS), peripheral vascular resistance(PVR) and nitric oxide (NO)production and their relation to circulating levels of 25-OH vitamin D (25-OH D) and PTH at baseline; Aim #2: determine the relationship of baseline 25-OH D and PTH levels with subsequent changes in BP, AS, and PVR after dietary salt loading; Aim #3:Determine the relationship of the change in NO metabolites and stimulated NO production in platelets to changes in BP, AS and PVR after dietary salt loading; Aim #4: Determine the association of baseline 25-OH D and PTH levels with baseline levels of circulating markers of oxidative stress (total isoprostanes, nuclear factor kappa beta) and free radicals (nitrotyrosine, dityrosine, chlorotyrosine), and in turn, link circulating markers of oxidative stress to changes in BP, AS, PVR, urinary NO metabolites, and platelet production of NO after dietary salt loading Relevance: Vitamin D deficiency and secondary increase in PTH are common, particularly amongst obese persons and African Americans. They both have vascular and physiological effects that lead to the excessive prevalence of elevated BP, vascular and pressure-related target-organ injury, endothelial dysfunction, and salt sensitivity in African Americans. It is important to understand the role of vitamin D deficiency and prolonged elevation of PTH to the abnormal physiology that likely contributes to common cardiovascular complication since vitamin D supplementation is affordable, relatively non-toxic, and is available in oral formulations.