The effect of perioperatively used drugs on the HIF-1 activation and its downstream gene expressions.

低氧(氧可获得性降低)诱导一系列适应性生理反应。在细胞水平上，这种适应包括能量代谢从氧化磷酸化向无氧糖酵解的转变，葡萄糖摄取的增加，以及与细胞生存相关的应激蛋白的表达，激活氧调节基因表达的最重要的转录因子之一是缺氧诱导因子1(HIF-1)。本研究探讨了围手术期应用麻醉药、血管扩张剂和镇痛剂对缺氧诱导因子-1活性及其下游基因表达的影响，结果如下：1.静脉麻醉剂异丙酚通过阻断缺氧诱导因子-1α亚单位的合成，可逆性地抑制缺氧诱导因子-1活性及其基因表达，但在1%氧气条件下不能。2.局麻药利多卡因或布比卡因不影响依赖缺氧诱导的细胞缺氧诱导的基因反应。3.μ-，κ-和δ-阿片受体的选择性激动剂DAGO、DPDPE和U-50488均不影响缺氧诱导的HIF-1的激活。阿片受体的选择性激动剂不影响依赖HIF-1的细胞缺氧诱导的基因反应。4.我们证明在三种硝酸盐中，只有SNP抑制HIF-1在缺氧时的激活。相反，NTG或ISDN不影响HIF-1的活性。硝普钠抑制缺氧诱导因子-1的调节亚基α的积聚，抑制缺氧诱导因子-1α的转录激活，其机制不依赖于NO或可溶性鸟氨酸环化酶。

Hypoxia (reduced oxygen availability) induces a series of adaptive physiological responses. At the cellular level, the adaptation includes a switch of energy metabolism from oxidative phosphorylation to anaerobic glycolysis, increased glucose uptake, and the expression of stress proteins related to cell survival One of the most important transcription factors that activate the expression of oxygen-regulated genes is hypoxia-inducible factor 1 (HIF-1). In this study, we investigated the effect of perioperatively used drugs including anesthetics, vasodilators, and analgesics on the HIF-1 activation and its downstream gene expressions.Results are as followings.1.The intravenous anesthetic propofol reversibly inhibits HIF-1 activity and the gene expression mediated by HIF-1 by blocking the synthesis of the HIF-1α subunit under 20 or 5% O_2 conditions, but not under 1% O_2 conditions. In contrast, thyamylal and thiopental blocks HIF-1 activation under 1% O_2 conditions.2.The local anesthetics lidocaine or bupivacaine does not affect the HIF-1-dependent cellular hypoxia-induced gene responses.3.Either of DAGO, DPDPE, and U-50488, which are the selective agonists of μ-, κ-, and δ-opioid receptors, respectively did not affect the HIF-1 activation by hypoxia. The selective agonists of opioid receptors do not affect the HIF-1-dependent cellular hypoxia-induced gene responses.4.We demonstrate that among the three nitrates, only SNP inhibits HIF-1 activation in response to hypoxia. In contrast, NTG or ISDN does not affect HIF-1 activity. SNP inhibits the accumulation of HIF-1α, the regulatory subunit of HIF-1, and the transcriptional activation of HIF-1α via a mechanism that is not dependent on either NO or soluble guanylate cyclase.