SUBSTANCE P-MEDIATED CARDIOVASCULAR INFLAMMATION

P 物质介导的心血管炎症

• 批准号: 6351555
• 负责人: William Bernard Weglicki
• 金额: $ 36.66万
• 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/6351555
• 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乏镁的动物的心血管病变有显著的保护作用(镁缺乏9%或RDA的9%)，这意味着神经源性过度激活是与这种病理相关的关键事件。我们的数据表明，P物质升高可诱导一氧化氮(NO)的产生。和其他可能增加镁D9动物对缺血/再灌流(I/R应激)敏感性的活性氧物种。这项建议将确定镁的最低饮食阈值水平，这将继续引起与镁D9饮食观察到的类似神经源性过度活动。具体地说，采用中度(40%RDA)和边际(60-85%)膳食MGD大鼠模型来检测5个特定目标：1)建立长期镁缺乏时循环和组织神经源性事件的检测时程，以及饮食镁限制水平的最低阈值，该水平仍然导致严重镁缺乏时观察到的心血管病理生物学；2)确定中度和边缘镁限制饮食是否增加对I/R应激的敏感性，以及神经肽和N0升高的贡献。研究MGD的神经源性反应：3)研究内源性NMDA受体激活是否在中度和边缘MGD中介导神经肽的释放，以及这是否为钙触发机制；4)确定镁限制是否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源性和非神经源性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，从而促进细胞产生超氧化物和NO。降低动物组织对外加I/R应激的耐受性。这些研究将提供有关神经源性炎症在临床可达的镁缺乏症的心血管病理后果中的作用的见解。