NOVEL ENDOGENOUS CARDIOVASCULAR REGULATORS

新型内源性心血管调节剂

• 批准号: 2702586
• 负责人: GEORGE KUNOS
• 金额: $ 20.63万
• 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 2001-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2702586
• 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：(改编自应用程序)大麻不仅影响 神经行为和心血管功能。神经行为 作用是由CB1受体介导的，它主要定位于 大脑，不仅识别植物来源的，还识别内源的 大麻素，如阿南达胺，或选择性的CB1拮抗剂， SR141716A。PI最近发表的观察结果表明， 阿南达胺引起麻醉大鼠长时间低血压，这是 由外周定位的CB1受体和激活 外周CB1受体，可能是由来自巨噬细胞的脱氢表雄胺， 通过非独立的机制导致出血性低血压。这个 本提案的总体目标是检验以下假设 内源性配体对外周CB1受体的激活作用 代表了一种新的血管扩张剂机制，参与调节血管 以某种形式的震惊的语气。首先，调查人员将延长 发现血管CB1受体与低血压有关 通过细菌内毒素(LPS)，通过与出血性疾病相似的机制 令人震惊。CB1受体在脂多糖诱导的低血压中的作用有待进一步研究 通过使用CB1“基因敲除”小鼠进行测试，以及CB2的潜在作用 此外，还将探讨脂多糖诱导的心动过速中的受体。因为这两个 巨噬细胞和血小板在体内失血激活或在体外被内毒素激活 可引起正常大鼠CB1受体介导的低血压，但仅 巨噬细胞产生可检测到的anandamide水平，第二个目标将是 确定血小板产生的负责物质(S) 这种效果。第三，他们将试图确定上游机制 在出血性疾病中负责激活内源性大麻素系统 和内毒素休克，特别强调血小板激活因子 (PAF)和CD14途径。第四，他们将确定相对的 血管与突触前交感神经抑制CB1受体在中枢神经系统中的作用 休克相关性低血压。他们还将使用隔离灌流 确定肠系膜动脉床准备的相对重要性 血管内皮细胞与平滑肌作为血管直接扩张剂作用的靶点 阿南达胺。拟议中的研究结果将显著扩大 我们对旁分泌机制参与控制的理解 血管张力。