SUBSTANCE P-MEDIATED CARDIOVASCULAR INFLAMMATION

P 物质介导的心血管炎症

• 批准号: 6345816
• 负责人: William Bernard Weglicki
• 金额: $ 3.85万
• 依托单位: GEORGE WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2000
• 资助国家: 美国
• 起止时间: 2000-08-01 至 2002-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6345816
• 关键词: NMDA receptors; antiinflammatory agents; calcium channel; calcium channel blockers; dietary mineral; inflammation; laboratory rat; magnesium deficiency; myocardial ischemia /hypoxia; neuroimmunomodulation; neuropeptide receptor; neurotoxicology; neurotransmitter biosynthesis; neurotransmitter transport; nitric oxide; nutrient requirement; nutrition related tag; oxidative stress; receptor expression; reperfusion; substance P

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.

物质P受体阻断对在置于严重Mg缺乏饮食（MgD 9或Mg的RDA的9%）的动物中观察到的心血管病理具有显著的保护作用，暗示神经原性超活化是与该病理相关的关键事件。我们的数据表明，升高的P物质诱导一氧化氮（NO）的产生。和其它活性氧物质，其可提高MgD 9动物对缺血/再灌注（I/R应激）的敏感性。该提案将确定镁的最低饮食阈值水平，其继续引起用MgD 9饮食观察到的类似的神经源性活动过度。具体地，将使用中等（40%RDA）和边缘（60-85%）饮食MgD大鼠模型来检查五个特定目标：1）建立在长期Mg缺乏期间循环和组织神经原性事件的检测时程，以及在严重Mg缺乏中观察到的仍然引起心血管病理学的饮食Mg限制水平的最小阈值; 2）确定对I/R应激的敏感性是否通过中等和边缘Mg限制饮食增强，以及升高的神经肽和NO的贡献。3）研究内源性NMDA受体激活是否介导中度和边缘MgD期间神经肽的释放，以及这是否是钙触发的机制; 4）确定Mg限制是否诱导神经肽受体的细胞上调;和5）确定与MgD相关的神经原性反应是否是来自神经元和非神经元来源的P物质新合成的结果。我们推测，不太严重的镁饮食可以诱导超激活的NMDA受体引起过度释放的神经元介质，提高细胞生产的超氧化物和NO。在体内，并降低动物组织的耐受性施加I/R应力。这些研究将提供关于神经源性炎症在临床上可实现的镁缺乏的心血管病理后果中的作用的见解。