Analysis and Clinical Application of Gene Expression Changes Induced by Perioperative Stresses

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This research was aimed to clarify cellular stress responses at molecular levels, to analyze modification of stress responses by perioperatively used drugs, and identify gene expression changes induced by perioperatively used drugs. The results obtained are summarized below.1.Increase in plasma norepinephrine concentration induced by laparotomy in rats was suppressed by CRF-1 receptor antagonists. It was suggested that a pathway exists in the central nervous system which inhibits sympathetic nervous responses induced by surgical insults.2.Effects of perioperatively used drugs on the proopiomelanocortin (POMC) gene expression was analyzed by a pituitary tumor cell line (AtT20PL) which was stably transfected with the POMC gene promoter linked with the luciferase gene. It was shown that calcium channel blockers and local anesthetics can potentiate CRH-induced POMC gene expression.3.Isoflurane, a prototype of volatile anesthetics, suppresses serotonin release in the cerebral cortex, which can be related with sedative action of isoflurane. On the other hand, nitrous oxide was shown to increase serotonin release in the spinal cord, which was suggested to be involved in the antinociceptive action of nitrous oxide at the spinal cord level. Furthermore, analysis of nociceptin receptor knockout mice suggested that the nociceptin receptor is not involved in the anesthetic action of volatile anesthetics but contributes to the antinociceptive action of nitrous oxide.4.Effects of various drugs on the hypoxia-induced gene expression changes mediated by hypoxia-inducible factor (HIF- 1). It was shown that a vasodilator sodium nitroprusside and a n intravenous anesthetic agent propofol inhibit hypoxia-induced HIF-1 activation.5.Morphine-induced gene expression changes in T-lymphocytes were identified. It was shown that expression of apoptosis-related genes was increased by morphine.