First discovered as a potent vasodilator released from vascular endothelium, EDRF/nitric oxide is now recognized as an important signal transduction system for the activation of guanylyl cyclase and cyclic GMP production in a wide variety of cell types including brain. Understanding of the synthesis and regulation of EDRF/NO and its modulation by disease and by clinical pharmacotherapy has broad implications in terms of our understanding of the physiology and pathophysiology of the cardiovascular system, the central nervous system and host defense mechanisms. Our long-term research goals are to understand the regulation of the EDRF/NO-cyclic GMP pathway. Inhalational anesthetics are potent inhibitors of EDRF/NO dependent vasodilation, although the specific sites and mechanisms of this action remain unknown. The intravenous infusion of specific inhibitors of NO synthase dose-dependently and reversibly decrease the anesthetic requirement for halothane anesthesia suggesting a novel function of the NO pathway in modulating consciousness and a role in the central nervous system actions of anesthetics. This proposal will aim to (1) determine the site(s) and mechanism(s) by which anesthetics inhibit the NO signalling pathway at the cell and subcellular level and (2) will further investigate the inhalational anesthetic inhibition of the NO pathway in the central nervous system. Column bioassay and guanylate cyclase preparations will be used to definitively determine the relative effect of anesthetics on NO production versus an inactivation of NO once produced versus an inhibition of NO action at its effector site (guanylyl cyclase). The effect of anesthetics on calcium availability for NO synthase activation as well as the direct actions of anesthetics on NO synthase activity and on its essential cofactors will be determined. Additional studies will confirm the role of NO synthase inhibition in decreasing the minimum alveolar concentration (potency) of anesthesia using other anesthetics and other NO synthase inhibitors, will determine if stimulation of the NO signalling pathway in the CNS enhances awareness or results in increased anesthetic requirement, and will determine the effect of inhalational anesthetics on NO signalling in specific brain regions and neural pathways related to anesthesia, consciousness and analgesia at the cell and subcellular levels. These studies will provide insight into the potent cardiovascular side effects of anesthetics, the mechanisms of anesthesia, and may lead to an entirely new class of anesthetic agents. This is the first investigation of a novel central nervous system function of nitric oxide signalling in mediating consciousness, anesthesia or sedation.
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