Molecular Mechanisms for Modulation of Gene Expression by Anesthetics

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In this investigation, we analyzed gene expression changes induced by drugs frequently used during perioperative period. The results obtained are as follows.l. When cultured cells expressing cloned opioid receptors are stimulated with agonists, expression of transcription factors c-fos and junB was induced via mitogen-activated protein kinase (MAPK).2. It was demonstrated that midazolam, a benzodiazepine-type sedative drug, increases the gene expression of cfos and egr-1 through the activation of MAPK in PC12 rat pheochromocytoma cells.3. We analyzed drug effects on gene expression of proopiomelanocortin, the precursor of ACTH, in anterior pituitary cells, which play a central role in the stress response. It was demonstrated that benzodiazepine-type sedative drugs, midazolam and diazepam, potentiate the CRH-induced proopiomelanocortin gene transcription by increasing cyclic AMP prodiction.4. We analyzed effects of a variety of drugs on hypoxia-mediated gene expression changes, that are mediated by hypoxia-inducible factor 1 (HIF-1). It was demonstrated that a volatile anesthetic halothane and a intravenous anesthetic propofol inhibit hypoxia-induced HIF-1 activation by differential mechanisms.5. Effects of volatile anesthetics on ion channel functions were electrophysiologically analyzed. We showed that a volatile anesthetic halothane inhibits the function of IK subtype of Ca2+-activated K+ channel by interacting with the extracellular part of the ionic pore of IK.6. A volatile anesthetic isoflurane was shown to inhibit serotonin release in the rat cerebral cotex to a similar extent as the case of slow-wave sleep. This phenomenon was suggested to be involved in hypnotic action of isoflurane.