VOLATILE ANESTHETICS AND CARDIAC MUSCARINIC SYSTEMS

拟议研究的目的是了解波动性有多大。 麻醉药对大鼠脑内M胆碱受体功能的影响 心脏。所有的挥发性麻醉剂都会对 心血管系统，其中一些可能通过 胆碱能效应器机制。我们已经展示了几个 麻醉剂，包括氟烷和异氟烷，改变配体 与心脏和中枢神经的M受体结合 神经系统。另外，我们最近发现了一部小说 M受体介导的血管内皮细胞损伤的机制 大脑受到挥发性麻醉剂的抑制，即通过干扰 鸟嘌呤核苷酸依赖转导的受体偶联 蛋白质。 要检验的假设是：挥发性全麻药Alter 乙酰胆碱受体与效应器的偶联 心肌膜的作用机制，从而影响配基 与受体结合和心功能的调节 毒鼠强的激动剂。相应地，四种挥发性物质的影响 麻醉药物(氟烷、异氟烷、安氟醚、环丙烷) 大鼠心脏的几种M受体功能将是 确定，包括1)拮抗剂结合(受体密度， 亲和力和热力学)使用(~3H)甲基东莨菪胺作为 探针，2)激动剂结合(亲和力和亚群分布) 以氨基甲酰胆碱和(~3H)氧-三乙醇胺为探针，3) 鸟嘌呤核苷酸对激动剂结合的调节，作为一种指标 受体-G蛋白偶联，4)M受体介导 腺苷环化酶活性抑制，以及5)阴性 M受体激动剂的变时性和变力性作用 孤立的心房。麻醉作用的可逆性将是 在去除每种麻醉剂后测定。 这项研究将增加我们对毒鼠强的了解 在心房中的受体组织和功能，并提供 对麻醉作用的分子基础的洞察 心脏中的毒鼠碱过程。

The aim of the proposed research is to understand how volatile anesthetics affect muscarinic acetylcholine receptor function in the heart. All volatile anesthetics have undesirable effects on the cardiovascular system, some of which may be mediated through cholinergic effector mechanisms. We have shown that several anesthetics, including halothane and isoflurane, alter ligand binding to the muscarinic receptor in the heart and central nervous system. In addition, we have recently discovered a novel mechanism by which muscarinic receptor-mediated processes in the brain are inhibited by volatile anesthetics, i.e. by disruption of receptor coupling to guanine nucleotide dependent-transducer proteins. The hypothesis to be tested is: Volatile general anesthetics alter the coupling of muscarinic acetylcholine receptors to effector mechanisms in cardiac membranes, thereby affecting ligand binding to the receptor and regulation of cardiac function by muscarinic agonists. Accordingly, the effects of four volatile anesthetics (halothane, isoflurane, enflurane, cyclopropane) on several muscarinic receptor functions in rat hearts will be determined, including 1) antagonist binding (receptor density, affinity, and thermodynamics) using (3H)methylscopolamine as the probe, 2) agonist binding (affinities and subpopulation distribution) using carbamylcholine and (3H)oxotremorine-M as probes, 3) guanine nucleotide regulation of agonist binding, as an index of receptor-G protein coupling, 4) muscarinic receptor-mediated inhibition of adenylate cyclase activity, and 5) negative chronotropic and inotropic influences of muscarinic agonists on isolated atria. The reversibility of anesthetic actions will be determined after removal of each anesthetic. This research will increase our understanding of muscarinic receptor organization and function in the atrium and provide insight into the molecular bases for anesthetic action on muscarinic processes in the heart.