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

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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.