SUBSTANCE P-MEDIATED CARDIOVASCULAR INFLAMMATION

P 物质介导的心血管炎症

• 批准号: 6629015
• 负责人: William Bernard Weglicki
• 金额: $ 31.99万
• 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: 2000-02-01 至 2004-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6629015
• 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.

P 物质受体阻断对严重缺镁饮食（MgD9 或镁 RDA 的 9%）的动物中观察到的心血管病理具有显着的保护作用，这表明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，升高的 P 物质会诱导一氧化氮 (NO.) 和其他活性氧的产生，这可能会提高 MgD9 动物对缺血/再灌注（I/R 应激）的敏感性。该提案将确定 Mg 的最低膳食阈值水平，该水平继续引起与 MgD9 饮食观察到的类似的神经源性过度活跃。具体来说，中度（40% RDA）和边缘 (60-85%)饮食镁缺乏大鼠模型将用于检查五个具体目标：1)建立长期镁缺乏期间循环和组织神经源性事件的检测时间过程，以及饮食镁限制水平的最小阈值，该水平仍然导致在严重镁缺乏时观察到的心血管病理学； 2) 确定适度和边缘镁限制饮食是否会增强对 I/R 应激的易感性，以及神经肽和 N0 升高的贡献。损伤过程中的合成； 3) 研究中度和边缘 MgD 期间内源性 NMDA 受体激活是否介导神经肽的释放，以及这是否是钙触发机制； 4) 确定镁限制是否会诱导细胞神经肽受体上调； 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的 P 物质新合成的结果。我们假设不太严格的 MgD 饮食可以诱导 NMDA 受体过度激活，导致神经元介质过度释放，从而增强细胞超氧化物和 NO 的产生。体内，并降低动物组织对 I/R 应激的耐受性。这些研究将深入了解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。