Molecular Mechanisms for Modulation of Gene Expression by Anesthetics

在本研究中，我们分析了围手术期常用药物引起的基因表达变化。所得结果如下：1。当表达克隆阿片受体的培养细胞受到激动剂刺激时，可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。结果表明，苯二氮卓类镇静药物咪达唑仑通过激活MAPK，增加PC12大鼠嗜铬细胞瘤细胞中cfos和egr-1基因的表达。我们分析了药物对垂体前叶细胞中促ACTH前体促肾上腺皮质激素（proopiomelanocortin）基因表达的影响，促肾上腺皮质激素在应激反应中起核心作用。结果表明，苯二氮卓类镇静药物咪达唑仑和地西泮通过增加环AMP的产生，增强crh诱导的促黑素皮质素基因转录。我们分析了多种药物对缺氧诱导因子1 （HIF-1）介导的基因表达变化的影响。结果表明，挥发性麻醉剂氟烷和静脉麻醉剂异丙酚通过不同的机制抑制缺氧诱导的HIF-1激活。电生理分析了挥发性麻醉剂对离子通道功能的影响。我们发现挥发性麻醉剂氟烷通过与ik6离子孔的细胞外部分相互作用抑制Ca2+激活的K+通道IK亚型的功能。一种挥发性麻醉剂异氟醚被证明可以抑制大鼠大脑皮层中血清素的释放，其程度与慢波睡眠的情况相似。这一现象可能与异氟醚的催眠作用有关。

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.