VOLATILE ANESTHETICS AND CARDIAC MUSCARINIC SYSTEMS

挥发性麻醉剂和心脏毒蕈碱系统

• 批准号: 3293829
• 负责人: Robert S. Aronstam
• 金额: $ 10.37万
• 依托单位: AUGUSTA UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 1987
• 资助国家: 美国
• 起止时间: 1987-07-01 至 1990-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/3293829
• 关键词: acetylcholine; anesthetics; carbachol; cyclic compound; cyclopropanes; enflurane; guanine nucleotides; halothane; ligands; scopolamine; thermodynamics; tritium

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.

这项研究的目的是了解 麻醉剂影响毒蕈碱型乙酰胆碱受体功能 心脏 所有的挥发性麻醉剂都有不良影响， 心血管系统，其中一些可以通过介导 胆碱能效应机制。 我们已经证明， 麻醉剂，包括氟烷和异氟烷，改变配体 与心脏和中枢神经系统中的毒蕈碱受体结合 神经系统 另外，我们最近发现了一本小说 毒蕈碱受体介导的过程的机制 大脑被挥发性麻醉剂抑制，即通过破坏 受体偶联鸟嘌呤核苷酸依赖性转导物 proteins. 待检验的假设是：挥发性全身麻醉药改变 毒蕈碱型乙酰胆碱受体与效应子的偶联 心脏膜中的机制，从而影响配体 与受体结合并通过 毒蕈碱激动剂。 因此，四个挥发性的影响 麻醉剂（氟烷、异氟烷、恩氟烷、环丙烷） 大鼠心脏中的几种毒蕈碱受体功能将被 测定包括1）拮抗剂结合（受体密度， 亲和性和热力学），使用（3 H）甲基东莨菪碱作为 探针，2）激动剂结合（亲和力和亚群分布） 使用氨甲酰胆碱和（3 H）氧震颤素-M作为探针，3） 激动剂结合的鸟嘌呤核苷酸调节，作为 受体-G蛋白偶联，4）毒蕈碱受体介导 腺苷酸环化酶活性抑制，和5）阴性 毒蕈碱受体激动剂的变时性和变力性影响 孤立心房 麻醉作用的可逆性 在去除每种麻醉剂后测定。 这项研究将增加我们对毒蕈碱的了解 受体组织和功能在心房，并提供 深入了解麻醉作用的分子基础， 心脏中的毒蕈碱过程