Anesthetics' Effects on Physiological Responses Modulated by Peripheral GABAA Receptors

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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.