NOVEL ENDOGENOUS CARDIOVASCULAR REGULATORS

描述：（改编自应用程序）大麻素不仅影响 神经行为和心血管功能。 神经行为 作用是由CB1受体介导的，CB1受体主要位于 大脑不仅能识别植物来源的， 大麻素，如大麻素，或选择性CB 1拮抗剂， SR141716A。 PI最近发表的观察结果表明， 花生四烯酸酰胺能延长麻醉大鼠的低血压， 介导的外周定位CB1受体和激活 外周CB1受体，可能是来自巨噬细胞的花生四烯酸， 通过NO非依赖性机制导致出血性低血压。 的 本提案的总体目的是检验以下假设： 内源性配体对外周CB 1大麻素受体的激活作用 代表了一种新的血管扩张机制，涉及调节血管 以某种形式的冲击。 首先，调查人员将 结果表明，血管CB1受体在低血压引起的 通过细菌内毒素（LPS），通过与出血性 冲击. CB1受体在LPS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 受体在LPS诱导的心动过速也将探讨。 由于两 体内出血或体外LPS激活的巨噬细胞和血小板 能引起正常大鼠CB1受体介导的低血压，但仅 巨噬细胞产生可检测水平的大麻素，第二个目标将是 确定血小板产生的物质， 这种效果。 第三，他们将试图确定上游机制 负责激活内源性大麻素系统， 和内毒素休克，特别强调血小板活化因子 (PAF)和CD14通路。 第四，确定相对 血管与突触前交感神经抑制性CB1受体在 休克相关性低血压 他们还将使用一个隔离的灌注 肠系膜动脉床准备，以确定 内皮与平滑肌作为直接血管舒张作用的靶点 花生四烯酸 拟议研究的结果将大大扩大 我们对旁分泌机制的理解， 血管张力

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.