NOVEL ENDOGENOUS CARDIOVASCULAR REGULATORS

新型内源性心血管调节剂

• 批准号: 6044008
• 负责人: GEORGE KUNOS
• 金额: $ 19.62万
• 依托单位: VIRGINIA COMMONWEALTH UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 1998
• 资助国家: 美国
• 起止时间: 1998-08-14 至 2002-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6044008
• 关键词: anandamide; cannabinoid receptor; endotoxins; gene targeting; genetically modified animals; hemorrhagic shock; hypotension; laboratory mouse; ligands; lipopolysaccharides; paracrine; platelets; receptor expression; septic shock; tachycardia; vascular endothelium; vascular smooth muscle; vasodilation

DESCRIPTION: (Adapted from the application) Cannabinoids affect not only neurobehavioral but also cardiovascular functions. The neurobehavioral effects are mediated by the CB1 receptor, which is localized primarily in the brain and recognizes not only plant-derived but also endogenous cannabinoids, such as anandamide, or the selective CB1 antagonist, SR141716A. The PI has recently published observations demonstrating that anandamide elicits prolonged hypotension in anesthetized rats, which is mediated by peripherally located CB1 receptors and that activation of peripheral CB1 receptors, likely by anandamide derived from macrophages, contributes to hemorrhagic hypotension via a NO-independent mechanism. The general aim of the present proposal is to test the hypothesis that activation of peripheral CB1 cannabinoid receptors by endogenous ligands represents a novel vasodilator mechanism involved in regulating vascular tone in certain forms of shock. First, the investigators will extend findings that implicate vascular CB1 receptors in the hypotension elicited by bacterial endotoxin (LPS), by a mechanism similar to that in hemorrhagic shock. The role of CB1 receptors in LPS-induced hypotension will be further tested by the use of CB1 "knockout" mice, and the potential role of CB2 receptors in LPS-induced tachycardia will also be explored. Since both macrophages and platelets activated in vivo by hemorrhage or in vitro by LPS can elicit CB1 receptor-mediated hypotension in normal rats, but only macrophages produce detectable levels of anandamide, a second aim will be to identify the substance(s) generated by platelets that is responsible for this effect. Third, they will attempt to identify the upstream mechanism responsible for activating the endogenous cannabinoid system in hemorrhagic and endotoxic shock, with special emphasis on platelet-activating factor (PAF) and the CD14 pathway. Fourth, they will determine the relative importance of vascular vs presynaptic sympathoinhibitory CB1 receptors in shock-related hypotension. They will also use an isolated perfused mesenteric arterial bed preparation to determine the relative importance of endothelium vs smooth muscle as a target of the direct vasodilator action of anandamide. The findings of the proposed research will significantly expand our understanding of paracrine mechanisms involved in the control of vascular tone.

描述：（从应用程序改编）大麻素不仅影响 神经行为和心血管功能。 神经行为 效果是由CB1受体介导的，该受体主要定位于 大脑，不仅识别植物来源，而且识别内源性 大麻素，例如anandamide或选择性CB1拮抗剂， SR141716A。 PI最近发表了观察结果，表明 阿甘酰胺引起麻醉大鼠的长度低血压，这是 由外围位置的CB1受体介导，并激活 外围CB1受体，可能由源自巨噬细胞的anandamide， 通过无独立的机制导致出血性低血压。 这 本提案的一般目的是检验以下假设。 内源配体激活周围CB1大麻素受体 代表一种与调节血管的新型血管扩张机制 以某些形式的冲击形式。 首先，调查人员将扩展 引起的低血压中暗示血管CB1受体的发现 通过细菌内毒素（LPS），通过类似于出血的机制 震惊。 CB1受体在LPS诱导的低血压中的作用将进一步 通过使用CB1“敲除”小鼠测试，CB2的潜在作用 还将探索LPS诱导的心动过速的受体。 两者既是 巨噬细胞和血小板通过出血在体内激活或在体外通过LPS激活 可以引起正常大鼠的CB1受体介导的低血压，但仅 巨噬细胞产生可检测水平的仙人掌水平，第二个目标是 识别血小板产生的物质 这个效果。 第三，他们将尝试识别上游机制 负责在出血中激活内源性大麻素系统 和内毒性休克，特别强调血小板激活因子 （PAF）和CD14途径。 第四，他们将确定亲戚 血管与突触前抑制性CB1受体的重要性 与冲击相关的低血压。 他们还将使用孤立的灌注 肠系膜动脉床的准备，以确定 内皮与平滑肌作为直接血管扩张剂作用的目标 anandamide。 拟议研究的发现将大大扩展 我们对控制的旁分泌机制的理解 血管音。