SUBSTANCE P-MEDIATED CARDIOVASCULAR INFLAMMATION

P物质受体阻断对严重缺镁饮食（MgD9或每日镁摄入量的9%）的动物的心血管病理有显著的保护作用，暗示神经源性过度激活是与该病理相关的关键事件。我们的数据表明，P物质的升高诱导一氧化氮（NO.）和其他活性氧的产生，这可能会增加mg9动物对缺血/再灌注（I/R）应激的敏感性。该建议将确定Mg的最低膳食阈值水平，这将继续引起与mg9饮食中观察到的类似的神经源性多动。具体而言，将使用中等（40% RDA）和边际（60-85%）膳食镁摄入量的大鼠模型来检验5个特定目标：1)建立长期缺镁时循环和组织神经源性事件的检测时间过程，以及在重度缺镁时仍然引起心血管病理生物学的最低膳食镁限制水平阈值；2)确定中等和边际限镁饲粮是否会增强对I/R应激的敏感性，以及神经肽和N0的升高对I/R应激的贡献。损伤过程中的合成；3)研究内源性NMDA受体激活是否介导中度和边缘性MgD中神经肽的释放，以及这是否是钙触发的机制；4)确定Mg限制是否诱导细胞内神经肽受体的上调；5)确定与MgD相关的神经源性反应是否是神经元和非神经元来源P物质新合成的结果。我们假设不太严重的MgD饮食可以诱导NMDA受体的过度激活，导致神经介质的过度释放，从而增强细胞超氧化物和NO的产生。并降低动物组织对施加I/R应激的耐受性。这些研究将提供关于神经源性炎症在临床可实现的镁缺乏的心血管病理后果中的作用的见解。

Substance P receptor blockage has dramatic protective effects against the cardiovascular pathology observed in animals placed on a severe Mg- deficient diet (MgD9 or 9% of RDA for Mg), implicating neurogenic hyper activation as a key event associated with this pathology. Our data suggest that elevated substance P induces production of nitric oxide (NO.) and other active oxygen species which may heighten the sensitivity of MgD9 animals to ischemia/reperfusion (I/R stress. This proposal will determine the minimal dietary threshold level of Mg which continues to elicit similar neurogenic hyperactivity observed with MgD9 diet. Specifically, moderate (40% RDA) and marginal (60-85%) dietary MgD rat models will be used to examine five specific aims: 1) Establish the detection time-courses of circulating and tissue neurogenic events during prolonged Mg deficiency, and the minimal threshold of level of dietary Mg restriction which still causes the cardiovascular pathobiology observed in severe Mg-deficiency; 2) Determine if susceptibility to I/R stress is enhanced by moderate and marginal Mg restricted diets, and the contribution of elevated neuropeptides and N0. synthesis in the injury process; 3) Investigate whether endogenous NMDA receptor activation mediates release of neuropeptides during moderate and marginal MgD, and if this is a calcium-triggered mechanism; 4) Determine if Mg- restriction induces cellular up-regulation of neuropeptide receptors; and 5) Determine if the neurogenic response associated with MgD is a consequence of new synthesis of substance P from neuronal and non- neuronal sources. We hypothesize that less severe MgD diets can induce hyper activation of NMDA receptors causing excessive release of neuronal mediators which enhance cell production of superoxide and NO. in vivo, and reduce the tolerance of animal tissues to applied I/R stress. These studies will provide insight concerning the role of neurogenic inflammation in the cardiovascular pathologic consequences of clinically- achievable Mg-deficiency.