Anesthetics' Effects on Physiological Responses Modulated by Peripheral GABAA Receptors

摘要 每年有数以百万计的患者接受麻醉药，以促进手术和诊断程序。而当 麻醉药在中枢神经系统中非常成功地实现了它们预期的目标 昏迷、健忘和止痛，麻醉伴随着无数的外周生理 有时可能危及生命的变化(如低血压)。大多数常用麻醉药 今天，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。它 长期以来一直认为，伴随而来的外周生理扰动是由 神经元外流的改变，从中央到周围神经系统，再到末端器官。 然而，现在人们认识到，许多这些末端器官本身都表达功能性的GABAA受体 而GABA能麻醉剂的许多生理作用实际上可能是由于GABA受体的直接作用 这些外周器官和细胞中的细胞信号。关于这方面的知识有很大的差距 了解GABA能麻醉药如何与末梢器官上的外周GABA受体相互作用(例如： 免疫细胞、平滑肌)来改变它们的功能。更透彻地机械地理解直接的 GABA能麻醉药对外周GABA受体的生理作用不仅可以缓解 麻醉剂对外周生理的潜在威胁生命的影响(如低血压)，但将允许 外周GABAA受体将成为高血压、支气管收缩和高血压等疾病的治疗靶点 免疫功能障碍。然而，以外周GABAA受体为靶点的治疗必须避免 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的 受体在气道平滑肌上的表达，我们随后发现了新的咪唑苯并二氮类药物 经修饰以选择性靶向含有4或5亚单位的GABA A受体并限制其 穿透到中枢神经系统。这些都是重要的发现，因为大多数外围GABAA 受体包含4或5亚单位，而中枢GABA受体主要调节镇静 含有1和2亚基。随后，我们展示了GABAA的表达和功能效应 免疫细胞和血管平滑肌上的受体。我们将利用这些发现在当前 更好地了解经典GABA能麻醉剂(即异丙酚)的生理效应的计划以及这些 新型4和5亚单位选择性苯二氮卓类配体对CD4+淋巴细胞、血管平滑肌和 使用来自人类和啮齿动物来源的细胞、体外组织和体内模型来研究呼吸道平滑肌的功能。 我们的发现将改变对麻醉剂生理效应的机械理解，但更重要的是 重要的是，确定潜在的治疗高血压、支气管收缩和免疫的新靶点 调制。

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.