Vascular effects of dietary salt in humans with salt-resistant BP

描述（由申请人提供）： 心血管疾病仍然是一个主要的公共卫生问题，是美国的主要死亡原因。血压（BP）对饮食盐操纵的反应变化程度在人类中差异很大。许多成年人的血压变化很小，尽管饮食中的盐变化很大，这被称为耐盐BP。然而，除了盐对血压的影响外，人类高盐饮食可能会产生病理生理学后果。动物模型支持这一结论，即过量的饮食盐有助于独立于BP的内皮异常。饮食中盐诱导的氧化应激的增加可能是一氧化氮（NO）释放受损的因素之一。基于上述，我们的总体假设是，饮食中的盐摄入量会对人体血管内皮功能产生不利影响，而与平均动脉血压无关。我们建议研究膳食盐对导管动脉内皮依赖性扩张的影响（即，肱动脉）和NO介导的皮肤微血管舒张。我们特别假设高盐饮食会导致内皮依赖性舒张功能和NO介导的皮肤血管舒张功能下降。我们还假设，在高饮食盐条件下，氧化应激将增加，和饮食盐引起的皮肤血管舒张功能下降将被削弱的局部抗坏血酸输液提供功能证据的氧化应激的作用。将获得内皮细胞以评估氧化剂损伤以及氧化剂和抗氧化酶含量。这些假设将在患有耐盐BP的成人中进行测试。青年和中年成年人将接受为期21天的对照喂养研究，其中他们将摄入1.3 g盐饮食7天，6 g盐饮食7天，20 g盐饮食7天（交叉设计，饮食顺序随机化;固定钾摄入量）。在每种饮食条件下24小时动态血压和尿液收集将允许对血压的盐敏感性进行个体评估。肱动脉的血流介导扩张将用于评估导管内皮依赖性扩张和皮肤血管舒张对局部加热的反应，使用激光多普勒血流仪，并将在前臂中评估皮内微透析以评价微血管系统。将在林格氏（对照）部位、L-NAME部位（评估NO贡献）和抗坏血酸部位（评估氧化应激的作用）评估局部加热引起的皮肤血管舒张。这些措施将在1.3g、6 g和20 g膳食盐条件的最后一天进行。膳食盐摄入量的范围故意较宽，以评估内皮反应的剂量-反应关系。在控制喂养研究期间对人类进行的这种全面的内皮评估将使我们能够确定过量的膳食盐是否在大血管和微血管水平上损害内皮依赖性血管舒张。

DESCRIPTION (provided by applicant): Cardiovascular disease remains a major Public Health problem and is the leading cause of death in the US. The degree to which blood pressure (BP) changes in response to a dietary salt manipulation varies widely among humans. Many adults have a minimal change in BP despite large changes in dietary salt, which is termed salt-resistant BP. However, there may be pathophysiological consequences to a high salt diet in humans apart from the effect of salt on BP. Animal models support the conclusion that excess dietary salt contributes to endothelial abnormalities independent of BP. Dietary salt-induced increases in oxidative stress may be one of the factors impairing nitric oxide (NO) release. Based on the foregoing, our global hypothesis is that dietary salt intake will adversely affect vascular endothelial function independently of mean arterial BP in humans. We propose to investigate the effects of dietary salt on endothelial-dependent dilation of a conduit artery (i.e., brachial) and NO-mediated vasodilation of the cutaneous microvessels. We specifically hypothesize that high dietary salt will cause a decline in endothelial-dependent dilation and NO-mediated cutaneous vasodilation. We also hypothesize that oxidative stress will increase during the high dietary salt condition, and that the dietary salt-induced decline in cutaneous vasodilation will be attenuated by local ascorbic acid infusion providing functional evidence for a role of oxidative stress. Endothelial cells will be obtained to assess oxidant damage as well as oxidant and antioxidant enzyme content. These hypotheses will be tested in adults with salt-resistant BP. Young and middle-aged adults will undergo a 21-day controlled feeding study where they will consume a 1.3 g salt diet for 7 days, a 6 g salt diet for 7 days, and a 20 g salt diet for 7 days (crossover design, diet order sequence randomized; fixed potassium intake). Twenty-four hour ambulatory BP and urine collections during each diet condition will permit the individual assessment of salt sensitivity of BP. Flow mediated dilation of the brachial artery will be used to assess conduit endothelial- dependent dilation and cutaneous vasodilation in response to local heating using laser Doppler flowmetry and intradermal microdialysis will be assessed in the forearm to evaluate the microvasculature. Cutaneous vasodilation in response to local heating will be assessed at a Ringers (control) site, L-NAME site (to assess the NO contribution), and an ascorbic acid site (to assess the role of oxidative stress). These measures will be made during the last day of the 1.3g, 6 g, and 20g dietary salt conditions. The range of dietary salt intakes is purposely wide to allow the assessment of dose-response relationships in endothelial responses. This comprehensive endothelial assessment in humans during a controlled feeding study will allow us to determine if excess dietary salt is impairing endothelial-dependent vasodilation at both macro- and microvascular levels.