NOVEL ENDOGENOUS CARDIOVASCULAR REGULATORS

新型内源性心血管调节剂

基本信息

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
项目类别：
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

项目摘要

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）大麻素不仅影响神经行为以及心血管功能。神经行为学作用由 CB1 受体介导，该受体主要位于大脑不仅识别植物来源的，还识别内源性的大麻素，例如 anandamide，或选择性 CB1 拮抗剂， SR141716A。 PI 最近发表的观察结果表明 anandamide 会在麻醉大鼠中引起长时间的低血压，这是由位于外周的 CB1 受体介导，并且激活外周CB1受体，可能是来自巨噬细胞的anandamide，通过不依赖于 NO 的机制导致出血性低血压。这本提案的总体目标是检验以下假设：内源性配体激活外周 CB1 大麻素受体代表了一种参与调节血管的新型血管舒张机制语气中带有某种形式的震惊。首先，调查人员将延长研究结果表明血管 CB1 受体与低血压有关由细菌内毒素 (LPS) 引起，其机制与出血性疾病相似震惊。 CB1受体在LPS引起的低血压中的作用将进一步得到证实通过使用 CB1“敲除”小鼠进行测试，以及 CB2 的潜在作用还将探索 LPS 诱导的心动过速中的受体。既然两者巨噬细胞和血小板在体内通过出血激活或在体外通过LPS激活可以在正常大鼠中引起 CB1 受体介导的低血压，但仅巨噬细胞产生可检测水平的 anandamide，第二个目标是确定血小板产生的物质负责这个效果。第三，他们将尝试找出上游机制负责激活出血性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，他们将确定亲属关系血管与突触前交感神经抑制 CB1 受体的重要性休克相关的低血压。他们还将使用隔离灌注肠系膜动脉床准备以确定其相对重要性内皮与平滑肌作为直接血管舒张作用的目标阿那达酰胺。拟议研究的结果将显着扩展我们对参与控制的旁分泌机制的理解血管张力。