EFFECTS OF GENERAL ANESTHETICS ON NICOTINIC MEMBRANES

全身麻醉药对烟碱膜的影响

• 批准号: 3466009
• 负责人: LEONARD L FIRESTONE
• 金额: $ 0.35万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 财政年份: 1986
• 资助国家: 美国
• 起止时间: 1986-02-01 至 1987-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/3466009
• 关键词: alkanes; anesthetics; argon; chemical binding; dosage; drug metabolism; electron spin resonance spectroscopy; gas chromatography; general anesthesia; halothane; inhalation anesthesia; membrane lipids; neuropharmacology; radiotracer

The potency of most general anesthetics can be predicted by a shared physical feature, lipid solubility. This originally led to the hypothesis that anesthetics worked on the lipid membrane, and more recently has motivated investigations of the effects of anesthetics on the lipids of synthetic and biological membranes. These studies have inspired more detailed theories of general anesthetic action, each of which specifies some essential perturbation of membrane lipid (e.g. disrupting phase separations or lipid disordering). But such theories share some conspicuous weaknesses. First, the mechanism by which each lipid perturbation leads to inexcitability is vague. Second, they are not more successful at predicting potency than is bulk lipid solubility alone. Third, although these lipid-based theories generate testable predictions, very little work has been done in this area. A more mechanistic approach is to observe the effects of general anesthetics on a highly purified target structure, and relate structural changes to function. Nicotinic acetylcholine receptor-rich membranes from the electric organ of the marine ray, Torpedo can be isolated in the abundance and purity appropriate for molecular level studies. The structure of the acetylcholine receptor is known better than that of any other ion channel, and the functional properties are also known in great detail. The acetylcholine receptor has recently been used to elucidate the membrane actions of other drugs essential to modern anesthetic practice, the local anesthetics, barbiturates, and relaxants. The ability of a chemically and physically diverse group of general anesthetics (e.g. volatiles, alcohols, alkanes, inert gases, fluorinated gases, sterols, long chain alcohols and alkanes) to desensitize the receptor will be studied by radioligand (3H-ACh) binding techniques. In parallel, anesthetic effects on the bulk lipid membrane and the lipid-protein interface will be studied by spin-labeling methods. Does the ability of these structurally diverse general anesthetics and pressure to alter 3H-ACh binding parallel their ability to perturb lipid?

大多数全身麻醉药的效力可以通过共享的 物理特性、脂溶性。 这最初导致了一种假设 麻醉剂作用于脂质膜，最近， 麻醉剂对血脂影响的动机性研究 合成和生物膜。 这些研究激发了更多 全身麻醉作用的详细理论，其中每一个都指定 膜脂质的某些基本扰动（例如，破坏相 分离或脂质紊乱）。 但这些理论有一些共同点， 明显的弱点。 首先，每种脂质的作用机制 扰动导致不兴奋是模糊的。 第二，他们没有更多的 在预测效力方面比单独的整体脂溶性更成功。 第三，尽管这些基于脂质的理论产生了可检验的预测， 在这方面所做的工作很少。 一个更机械的方法是观察一般的影响， 麻醉剂对高度纯化的靶结构的作用，以及相关的结构 功能的变化。 富含烟碱乙酰胆碱受体的膜 电鳐的发电器官，鱼雷可以被隔离在 适合分子水平研究的丰度和纯度。 的 乙酰胆碱受体的结构比任何 其他离子通道和功能特性也是众所周知的， 详细 乙酰胆碱受体最近已被用于阐明 现代麻醉实践所必需的其他药物的膜作用， 局部麻醉剂巴比妥类药物和松弛剂 的能力 化学和物理上不同的全身麻醉药组（例如， 挥发物、醇类、烷烃、惰性气体、氟化气体、固醇、长链 链醇和烷烃）使受体脱敏的研究将通过 放射性配体（3 H-ACh）结合技术。 同时，麻醉效果 将研究在体脂质膜和脂质-蛋白质界面上的 通过自旋标记方法。 这些结构多样的生物 全身麻醉剂和压力改变3 H-ACh结合平行于他们的 干扰脂质的能力？