MECHANISM OF CEREBRAL VASODILATION DUE TO ISOFLURANE

本提案的目的是通过以下方式确定机制： 哪些挥发性麻醉剂影响脑血管控制。 我们将测试 挥发性麻醉剂通过以下方式引起脑血管舒张的假设 干扰脑血管收缩， α 2-肾上腺素受体通过G蛋白与环腺苷酸连接。 在项目1中，我们将检验α 2受体 位于或邻近脑脊液间隙影响全局 挥发性麻醉期间的脑血流。 我们将比较注射 在不同的鞘内位置静脉注射α 2 激动剂，比较放射性标记的α 2激动剂与 局部脑血管变化，并评估a 在挥发性麻醉期间特异性α 2拮抗剂。 在项目2中，我们 将检验α 2受体作用需要G蛋白的假设 用于转导至cAMP效应物。 我们将评估G蛋白的阻断 功能（百日咳毒素预处理）和cAMP的直接操作 水平（毛喉素）对挥发性麻醉期间脑血流的影响， 在挥发性麻醉期间施用的α 2激动剂的效果。 在项目3中，我们将检验α 2受体刺激 影响脑血管反应性。 我们将 评估脑血管对灌注压和血气的反应性 高度特异性α 2激动剂给药前后的变化 在挥发性麻醉期间。 在项目4中，我们将测试以下假设： 软膜小动脉直接对α 2激动剂，α 2拮抗剂， 毛喉素和百日咳毒素，从而区分中枢神经源性 α 2机制与直接血管α 2肾上腺素能机制。 这一建议将有助于了解 挥发性麻醉期间的脑血管控制， 预测与改变α 2的药物和疾病的相互作用-- 肾上腺素受体或G蛋白功能。

The purpose of this proposal is to determine the mechanism by which volatile anesthetics affect cerebrovascular control. We will test the hypothesis that volatile anesthetics causes cerebral vasodilation by interfering with cerebral vasoconstriction mediated by an alpha2-adrenoreceptor linked by G protein to cyclic AMP. In project 1, we will test the hypothesis that alpha2 receptors located in or adjacent to the cerebrospinal fluid space affect global cerebral blood flow during volatile anesthesia. We will compare injection at different intrathecal locations with intravenous injection of an alpha2 agonist, compare distribution of a radiolabelled alpha2 agonist with regional cerebrovascular changes, and assess cerebrovascular effects of a specific alpha2 antagonist during volatile anesthesia. In project 2, we will test the hypothesis that alpha2 receptor action requires a G protein for transduction to a cAMP effector. We will assess blockade of G protein function (pertussis toxin pretreatment) and direct manipulation of cAMP levels (forskolin ) on cerebral blood flow during volatile anesthesia and on the effect of an alpha2 agonist administered during volatile anesthesia. In project 3, we will test the hypothesis that alpha2 receptor stimulation during volatile anesthesia affects cerebrovascular responsivity. We will assess cerebrovascular responsivity to perfusion pressure and blood gas changes before and after administration of a highly specific alpha2 agonist during volatile anesthesia. In project 4, we will test the hypothesis that pial arterioles respond directly to an alpha2 agonist, alpha2 antagonist, forskolin and pertussis toxin, and thereby differentiate central neurogenic alpha2 mechanisms versus direct vascular alpha2 adrenergic mechanisms. This proposal will improve understanding of the mechanism of cerebrovascular control during volatile anesthesia and will allow prediction of interactions with drugs and diseases which alter alpha2-- adrenoreceptor or G protein function.