Mechanisms Underlying the Protective Vascular Effects of Dietary Potassium in Humans

摘要/项目摘要 公共卫生为减少盐分作出了重大努力，但大多数都以失败告终。膳食 高钠/低钾饮食等促进心血管疾病发展的因素 (心血管疾病)，如动脉粥样硬化和高血压。这一点很重要，因为CVD是第一 尽管这两种营养素对血压的作用被广泛接受，但它们对血管系统的影响 受到的关注较少。内皮功能障碍，以扩张受损为特征，是一种重要的非 动脉粥样硬化的传统危险因素。我们已经证明，高钠饮食会导致内皮功能障碍， 与血压变化无关(通过测试患有耐盐性BP的成年人来完成)。证据支持 钾对血管健康的有益作用尚不清楚，尽管它可能在 高钠饮食的存在。钠致血管功能障碍的一种机制 活性氧(ROS)的过量产生是否会导致一氧化氮(NO)的减少 生产/生物利用度。已经有人提出，钾可以通过减少钠的影响来抵消钠的影响 罗斯。此外，高钠饮食已被证明通过增加丰富的 内皮钠通道(EnNaC)，而钾在EnNaC中的作用尚不清楚。我们的中心假设 就是饮食中的钾可以保护血管系统免受钠的有害影响，因为它可以保持一氧化氮和 减少氧化应激和内皮细胞僵硬。我们将使用三种为期10天的饮食来验证我们的假设 (受控喂养研究，交叉设计，饮食顺序随机，饮食之间的冲刷)。我们 将中钾/高钠饮食(MK/HS；65 mmoL/300 mmol.)与高钾/高钠饮食进行比较 钠(HK/HS；120 mmo1/300 mmo1)评估钾对血管系统的保护作用 钠摄入量。我们还将比较中钾/低钠(MK/LS；65 mmoL/50 mmoL)饮食与 MK/HS饮食以单独确认耐盐BP状态。关注耐盐的成虫可以让我们分离出 血管效应，没有混淆的血压变化(即，独立于血压)。严谨程度将得到加强 通过在每种饮食条件下利用24小时动态血压和尿液收集；男性、女性和 少数族裔将受到考验。肱动脉血流介导的扩张将用于评估管道内皮细胞- 依赖性扩张。耦合激光多普勒血流仪检测局部加热引起的皮肤血管扩张 与真皮内微透析将被用来评估微血管功能。静脉内皮细胞将是 收集用于通过原子力显微镜和氧化应激标志物直接评估细胞硬度。 我们希望证明饮食中的钾可以保护内皮免受高血压病的有害影响。 钠通过减少氧化应激和内皮细胞硬度，并保存一氧化氮。这些研究都是新颖的。 因为他们将是第一个全面评估膳食钾对血管功能的作用的人 独立于英国石油公司。

ABSTRACT/PROJECT SUMMARY Significant Public Health efforts have been made towards salt reduction but most have met with failure. Dietary factors such high sodium/low potassium diets contribute to the development of cardiovascular diseases (CVDs) such as atherosclerosis and high blood pressure (BP). This is important as CVD is the number one killer in the U.S. While the role of these two nutrients on BP is widely accepted, their impact on the vasculature has received less attention. Endothelial dysfunction, characterized by impaired dilation, is an important non- traditional risk factor for atherosclerosis. We have shown that high sodium diets cause endothelial dysfunction, independent of changes in BP (accomplished by testing adults with salt resistant BP). Evidence supporting potassium's beneficial role on vascular health remains unclear although it may be more effective in the presence of a high sodium diet. A purported mechanism responsible for sodium-induced vascular dysfunction is overproduction of reactive oxygen species (ROS) resulting in reduced nitric oxide (NO) production/bioavailability. It has been suggested that potassium can counteract sodium's effects by reducing ROS. Additionally, high sodium diets have been shown to stiffen the endothelium by increasing abundance of the endothelial sodium channel (EnNaC) while potassium's role on EnNaC is unknown. Our central hypothesis is that dietary potassium will protect the vasculature from sodium's harmful effect by preserving NO and reducing oxidative stress and endothelial cell stiffness. We will use three 10-day diets to test our hypothesis (controlled feeding study, crossover design, diet order sequence randomized with washout between diets). We will compare a moderate potassium/high sodium diet (MK/HS; 65 mmol/300 mmol) to a high potassium/high sodium (HK/HS;120 mmol/300 mmol) to assess potassium's protective effect on the vasculature during a fixed sodium intake. We will also compare a moderate potassium/low sodium (MK/LS; 65 mmol/50 mmol) diet to the MK/HS diet to individually confirm salt resistant BP status. Focusing on salt resistant adults allows us to isolate the vascular effects, without the confound of changes in BP (i.e., independent of BP). Rigor will be enhanced by utilizing twenty-four hour ambulatory BP and urine collections during each diet condition; men, women, and minorities will be tested. Brachial artery flow-mediated dilation will be used to assess conduit endothelial- dependent dilation. Cutaneous vasodilation in response to local heating using laser Doppler flowmetry coupled with intradermal microdialysis will be used to assess microvascular function. Venous endothelial cells will be collected for direct assessment of cell stiffness by atomic force microscopy and markers of oxidative stress. We expect to demonstrate that dietary potassium protects the endothelium from the deleterious effects of high sodium by reducing oxidative stress and endothelial cell stiffness and preserving NO. These studies are novel in that they will be the first to comprehensively evaluate the role of dietary potassium on vascular function independent of BP.