Anesthetics' Effects on Physiological Responses Modulated by Peripheral GABAA Receptors

摘要 每年有数百万患者接受麻醉剂，以促进手术和诊断程序。而 麻醉剂在实现其在中枢神经系统中的预期目标方面非常成功， 意识丧失、遗忘和镇痛，麻醉伴随着无数的外周生理变化， 有时可能危及生命的变化（例如低血压）。大多数常用的麻醉剂 今天，增强中枢神经系统中的GABA能神经传递，导致其所需的效果。它 长期以来一直认为，伴随的外周生理扰动的发生，是由于 从中枢到外周神经系统并进而到终末器官的神经元流出的改变。 然而，现在认识到，许多这些终末器官本身表达功能性GABAA受体 并且GABA能麻醉剂的许多生理作用实际上可能是由于直接GABAA受体 这些外周器官和细胞中的细胞信号。在知识上有很大的差距， 了解GABA能麻醉剂如何与终末器官上的外周GABAA受体相互作用（例如， 免疫细胞、平滑肌）以改变它们的功能。更彻底的机械理解的直接 GABA能麻醉剂对外周GABAA受体的生理作用不仅会减轻 麻醉剂对外周生理的潜在危及生命的影响（例如低血压），但将允许 外周GABAA受体作为高血压、支气管收缩和呼吸道疾病的治疗靶点， 免疫功能紊乱然而，外周GABAA受体的治疗靶向必须避免 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 受体表达的气道平滑肌，我们随后确定了新的咪唑苯并二氮杂卓 修饰为选择性靶向含有GABA4或GABA5亚基的GABA4受体并限制其活性的衍生物， 渗透到中枢神经系统这些都是重要的发现，因为大多数外围GABAA 受体含有α 4或α 5亚基，而调节镇静作用的中枢GABAA受体主要是 含有β 1和β 2亚基。随后，我们展示了GABAA的表达和功能作用， 免疫细胞和血管平滑肌上的受体。我们将利用这些发现， 更好地了解经典GABA能麻醉剂（即丙泊酚）的生理作用， CD4+淋巴细胞、血管平滑肌和血管平滑肌上的新型β 4和β 5亚基选择性苯并二氮杂配体 使用来自人类和啮齿动物来源的细胞、离体组织和体内模型的气道平滑肌功能。 我们的发现将改变对麻醉剂生理效应的机械理解，但更多的是， 重要是，在高血压、支气管收缩和免疫性疾病中鉴定潜在的新的治疗靶点， 调变

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.