Anesthetics' Effects on Physiological Responses Modulated by Peripheral GABAA Receptors

麻醉药对外周 GABAA 受体调节的生理反应的影响

• 批准号: 10576327
• 负责人: CHARLES W EMALA
• 金额: $ 40.5万
• 依托单位: COLUMBIA UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-05-01 至 2026-02-28
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10576327
• 关键词: Absence of pain sensation; Amnesia; Anesthesia procedures; Anesthetics; Benzodiazepines; Bronchoconstriction; CD4 Positive T Lymphocytes; Cells; Central Nervous System; Clinical; Diagnostic Procedure; Disease; Goals; Human; Hypertension; Hypnosis; Hypotension; Immune; Immune System Diseases; Knowledge; Laboratories; Life; Ligands; Mediating; Muscle function; Neurons; Operative Surgical Procedures; Organ; Patients; Penetration; Peripheral; Peripheral Nervous System; Physiological; Physiology; Propofol; Receptor Cell; Rodent; Sedation procedure; Signal Transduction; Smooth Muscle; Source; Tissues; Unconscious State; Vascular Smooth Muscle; immunoregulation; in vivo Model; neural; neurotransmission; new therapeutic target; novel; programs; receptor; respiratory smooth muscle; response; sedative; therapeutic target

Abstract Millions of patients receive anesthetics every year to facilitate surgical and diagnostic procedures. While anesthetics are remarkably successful in achieving their intended goals in the central nervous system of unconsciousness, amnesia and analgesia, anesthesia is accompanied by a myriad of peripheral physiologic changes (e.g. hypotension) that at times can be life-threatening. The majority of commonly used anesthetics today augment GABAergic neurotransmission in the central nervous system leading to their desired effects. It has long been assumed that the accompanying peripheral physiologic perturbations that occur, result from alterations in neuronal outflow from the central to the peripheral nervous systems and in turn to the end organs. However, it is now appreciated that many of these end organs themselves express functional GABAA receptors and that many of the physiologic effects of GABAergic anesthetics may in fact be due to direct GABAA receptor cell signaling in these peripheral organs and cells. There is a large gap in knowledge regarding the understanding of how GABAergic anesthetics interact with peripheral GABAA receptors on end organs (e.g. immune cells, smooth muscle) to modify their function. A more thorough mechanistic understanding of the direct physiological effects of GABAergic anesthetics on peripheral GABAA receptors will not only mitigate the potentially life-threatening effects of anesthetics on peripheral physiology (e.g. hypotension), but will allow peripheral GABAA receptors to be therapeutic targets in diseases such as hypertension, bronchoconstriction and immune dysfunction. However, therapeutic targeting of peripheral GABAA receptors would have to avoid the central sedative effects modulated by central GABAA receptors. Our laboratory was the first to discover GABAA receptors expressed on airway smooth muscle and we subsequently identified novel imidazobenzodiazepine derivatives that were modified to selectively target GABAA receptors containing 4 or 5 subunits and limit their penetration to the central nervous system. These were important discoveries since most peripheral GABAA receptors contain either 4 or 5 subunits, while central GABAA receptors that modulate sedation primarily contain 1 and 2 subunits. Subsequently, we have shown the expression and functional effects of GABAA receptors on immune cells and vascular smooth muscle. We will leverage these discoveries in the current program to better understand the physiologic effects of a classic GABAergic anesthetic (i.e. propofol) and these novel 4 and 5 subunit-selective benzodiazepine ligands on CD4+ lymphocytes, vascular smooth muscle and airway smooth muscle function using cellular, ex vivo tissue and in vivo models from human and rodent sources. Our findings will transform the mechanistic understanding of the physiologic effects of anesthetics, but more importantly, identify potential novel therapeutic targets in hypertension, bronchoconstriction and immune modulation.

抽象的 每年有数百万患者接受麻醉以促进手术和诊断程序。 麻醉剂在中枢神经系统中非常成​​功地实现了其预期目标 意识不清、失忆和镇痛，麻醉伴随着无数的外周生理反应 有时可能危及生命的变化（例如低血压） 大多数常用麻醉剂。 如今，增强中枢神经系统中的 GABA 能神经传递，从而达到预期的效果。 长期以来，人们一直认为伴随发生的外周生理扰动是由 从中枢到周围神经系统，再到末端器官的神经流出的改变。 然而，现在人们认识到，许多这些终末器官本身表达功能性 GABAA 受体 GABA 能麻醉剂的许多生理效应实际上可能是由于直接的 GABAA 受体 关于这些外周器官和细胞中的细胞信号传导存在很大的知识空白。 了解 GABA 能麻醉剂如何与终末器官（例如，器官）上的外周 GABAA 受体相互作用。 免疫细胞、平滑肌）来修改它们的功能。 GABA 能麻醉剂对外周 GABAA 受体的生理影响不仅会减轻 麻醉药对周围生理机能有潜在的危及生命的影响（例如低血压），但将允许 外周 GABAA 受体成为高血压、支气管收缩等疾病的治疗靶点 然而，针对外周 GABAA 受体的治疗必须避免免疫功能障碍。 由中枢 GABAA 受体调节的中枢镇静作用 我们的实验室是第一个发现 GABAA 的实验室。 受体在气道平滑肌上表达，我们随后鉴定出新型咪唑并苯二氮卓类药物 经过修饰以选择性靶向含有 α4 或 α5 亚基的 GABAA 受体并限制其作用的衍生物 自从大多数外周 GABAA 渗透到中枢神经系统以来，这些都是重要的发现。 受体包含 α4 或 α5 亚基，而中枢​​ GABAA 受体主要调节镇静作用 随后，我们展示了GABAA的表达和功能效应。 我们将在当前利用这些发现。 计划以更好地了解经典 GABA 麻醉剂（即异丙酚）的生理效应以及这些 CD4+ 淋巴细胞、血管平滑肌和 使用来自人类和啮齿动物的细胞、离体组织和体内模型来发挥气道平滑肌功能。 我们的研究结果将改变对麻醉剂生理效应的机械理解，但更多 重要的是，确定高血压、支气管收缩和免疫方面潜在的新治疗靶点 调制。