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: 10393015
• 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/10393015
• 关键词: Absence of pain sensation; Amnesia; Anesthesia procedures; Anesthetics; Benzodiazepines; Bronchoconstriction; CD4 Positive T Lymphocytes; Cells; Clinical; Diagnostic Procedure; Disease; Goals; Human; Hypertension; Hypnosis; Hypotension; Immune; Immune System Diseases; Knowledge; Laboratories; Life; Ligands; Mediating; Muscle function; Neuraxis; Neurons; Operative Surgical Procedures; Organ; Patients; Penetration; Peripheral; Peripheral Nervous System; Physiological; Physiology; Propofol; Receptor Cell; Rodent; Sedation procedure; Signal Transduction; Smooth Muscle; Source; Time; Tissues; Unconscious State; Vascular Smooth Muscle; immunoregulation; in vivo Model; neurotransmission; new therapeutic target; novel; programs; receptor; relating to nervous system; 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 数以百万计的患者每年接受麻醉剂，以促进手术和诊断程序。尽管 麻醉剂在实现其预期目标中的中枢神经系统中非常成​​功 无意识，健忘症和镇痛，麻醉伴随着无数的周围生理 有时会威胁生命的变化（例如低血压）。大多数常用麻醉药 如今，中枢神经系统中的GABA能神经传递会导致其预期的作用。 长期以来一直认为，发生的参与周围生理扰动是由 神经元出口的改变从中央到周围神经系统以及末端器官的变化。 但是，现在感谢这些最终器官本身表达功能性GABAA接收器 GABA能麻醉药的许多生理作用实际上可能是由于直接Gabaa接收器引起的 这些外围器官和细胞中的细胞信号传导。知道有关的差距很大 了解GABA能麻醉药如何与末端器官上的外围GABAA受体相互作用（例如 免疫细胞，平滑肌）以改变其功能。对直接的更彻底的机械理解 GABA能麻醉药对外围GABAA受体的生理影响不仅会减轻 麻醉药对周围生理学的潜在威胁生命的影响（例如低血压），但会允许 外周GABAA受体是高血压，支气管收缩和 免疫功能障碍。但是，外周GABAA受体的治疗靶向将不得不避免 中央GABAA接收器调节中央镇静效果。我们的实验室是第一个发现加巴的人 受体在气道平滑肌上表达 经过修改以选择性地靶向包含4或5亚基的GABAA接收器的衍生物 渗透到中枢神经系统。这些是重要的发现，因为大多数外围Gabaa 受体包含4或5亚基，而中央GABAA受体调节镇静剂 包含1和2亚基。随后，我们显示了GABAA的表达和功能效应 免疫细胞和血管平滑肌上的受体。我们将在当前利用这些发现 可以更好地了解经典GABA能麻醉（即建议）的生理影响的程序和这些 新颖的4和5亚基选择性苯二氮卓类配体在CD4+淋巴细胞上，血管平滑肌和 气道平滑肌功能使用细胞，体内组织以及来自人类和啮齿动物来源的体内模型。 我们的发现将改变对麻醉剂生理影响的机械理解，但更多 重要的是，确定高血压，支气管收缩和免疫的潜在新型热目标 调制。