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，也是美国主要的死亡原因。血压(BP)对食盐操作的反应程度在不同人类之间差别很大。许多成年人的血压变化很小，尽管饮食中的盐发生了很大的变化，这被称为耐盐血压。然而，除了盐对血压的影响外，人类高盐饮食可能还有病理生理后果。动物模型支持这一结论，即过量的饮食盐会导致内皮细胞异常，而不是BP。食盐诱导的氧化应激增加可能是影响一氧化氮(NO)释放的因素之一。基于前述，我们的全球假设是，饮食盐摄入量将对血管内皮功能产生不利影响，而不是独立于人类的平均动脉血压。我们建议研究饮食盐对导管动脉(即臂动脉)内皮依赖性扩张和一氧化氮介导的皮肤微血管扩张的影响。我们特别假设高盐饮食会导致内皮依赖的扩张和一氧化氮介导的皮肤血管扩张的下降。我们还假设，在高盐饮食条件下，氧化应激会增加，饮食盐引起的皮肤血管扩张的下降将通过局部抗坏血酸输注来缓解，这为氧化应激的作用提供了功能证据。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的含量。这些假说将在患有耐盐性BP的成年人身上进行测试。年轻人和中年人将接受为期21天的受控喂养研究，他们将摄入1.3克盐饮食7天，6克盐饮食7天，20克盐饮食7天(交叉设计，饮食顺序随机；固定的钾摄入量)。在每种饮食条件下，24小时动态血压和尿液采集将允许对BP的盐敏感性进行个人评估。血管内皮依赖性扩张和局部加热引起的皮肤血管扩张将使用激光多普勒血流测定仪进行评估，前臂皮内微透析将用于评估微血管系统。对局部加热反应的皮肤血管扩张将在Ringers(对照)站点、L命名的站点(以评估NO的贡献)和抗坏血酸站点(以评估氧化应激的作用)进行评估。这些措施将在1.3g、6g和20g食盐条件的最后一天进行。饮食盐摄入量的范围特意广泛，以便评估内皮细胞反应中的剂量-反应关系。这项在受控喂养研究中对人类进行的全面的内皮细胞评估将使我们能够确定过量的饮食盐是否在大血管和微血管水平上损害内皮依赖的血管扩张。

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.