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Molecular Mechanisms for Modulation of Gene Expression by Anesthetics

麻醉剂调节基因表达的分子机制

基本信息

批准号：
13307046
负责人：
FUKUDA Kazuhiko
金额：
$ 34.61万
依托单位：
Kyoto University
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (A)
财政年份：
2001
资助国家：
日本
起止时间：
2001 至 2003
项目状态：
已结题

来源：
https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-13307046/
关键词：
opioid intravenous anesthetic volatile anesthetic stress response hypoxia ion channel serotonin gene expression 吸入麻酔薬局所麻酔薬 p38 MARK 下垂体ベンゾジアゼピン

项目摘要

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.

在这项调查中，我们分析了围手术期常用药物引起的基因表达变化。得到的结果如下：l.当表达克隆阿片受体的培养细胞被激动剂刺激时，通过丝裂原活化蛋白激酶（MAPK）诱导转录因子c-fos和junB的表达.咪达唑仑是一种苯二氮卓类镇静剂，它通过激活MAPK而增加PC 12大鼠嗜铬细胞瘤细胞中cfos和cfos-1的基因表达.我们分析了药物对垂体前叶细胞中促肾上腺皮质激素（ACTH）前体阿黑皮素原基因表达的影响，该细胞在应激反应中起着重要作用。研究表明，苯二氮卓类镇静药咪达唑仑和地西泮通过增加cAMP的产生，增强CRH诱导的阿黑皮素原基因转录.我们分析了各种药物对缺氧介导的基因表达变化的影响，这些变化由缺氧诱导因子1（HIF-1）介导。研究表明，挥发性麻醉剂氟烷和静脉麻醉剂丙泊酚通过不同的机制抑制缺氧诱导的HIF-1激活.电生理分析了吸入麻醉药对离子通道功能的影响。我们发现，挥发性麻醉剂氟烷抑制IK亚型的Ca 2+激活的K+通道的功能，通过与IK的离子孔的细胞外部分相互作用。挥发性麻醉剂异氟烷对大鼠大脑皮质5-羟色胺释放的抑制程度与慢波睡眠相似。这种现象可能与异氟醚的催眠作用有关。