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Nitroxyl (HNO) as novel player in the regulation of gastrointestinal motility

硝酰 (ENT) 作为胃肠道运动调节的新参与者

基本信息

批准号：
334444269
负责人：
Privatdozent Dr. Ervice Vidal Pouokam Kamgne, Ph.D.
金额：
--
依托单位：
Institut für Veterinär-Physiologie und -Biochemie
依托单位国家：
德国
项目类别：
Research Grants
财政年份：
2017
资助国家：
德国
起止时间：
2016-12-31 至 2020-12-31
项目状态：
已结题

来源：
https://gepris.dfg.de/gepris/projekt/334444269?language=en
关键词：
Nitroxyl HNO novel player regulation

项目摘要

An emerging class of regulators of gastrointestinal functions are gaseous molecules, the so-called gasotransmitters. There are two well-established gases with transmitter function in the gut: nitric oxide (NO) and hydrogen sulphide (H2S). Both induce gastrointestinal smooth muscle relaxation via different mechanisms. While NO activates soluble guanylate cyclase, the production of cGMP and consequently activates protein kinase G (or potentially directly activates K+ channels), H2S activates e.g. ATP-sensitive and small conductance Ca2+-dependent K+ channels.A third gasotransmitter, nitroxyl (HNO), whose actions on gastrointestinal motility shall be investigated in the present study, is getting more attention recently. All what is known about HNO regarding the gastrointestinal tract is that it exerts a prosecretory action, which is strongly dependent on Ca2+ and involves Ca2+-dependent and ATP-sensitive K+ channels and is in part mediated by cyclooxygenase metabolites (Pouokam et al. 2013). Preliminary experiments revealed that an HNO donor, Angelis salt, evokes intestinal relaxation measured at longitudinal strips from rat ileum and colon. The mechanisms underlying this relaxation shall be investigated in the present study by patch-clamp experiments at isolated myocytes, imaging experiments at spontaneously contracting smooth muscle cell reaggregates and isometric muscle contraction measurements. Special focus will be placed on the characterization of the involved ion conductances, the possible mediation by thiol group modification (due to the high thiophylic character of HNO) and the involvement of typical components of the cGMP signalling pathway. In parallel, preliminary experiments revealed a hyperpolarization of myenteric neurons concomitant with an inhibition of inward-currents carried by voltage-dependent Na+ channels. The ionic mechanisms underlying the change in membrane potential induced by HNO of myenteric neurons, i.e. the part of the enteric nervous system responsible for autonomous control of gut motility, are unknown and shall be identified in the present study.Recent studies in the literature showed a cross-talk between NO, H2S and HNO signalling pathways; for example exogenous H2S may interact with endogenous NO to form HNO, which rises the possibility that some actions of H2S may indeed be mediated by HNO. This hypothesis shall be investigated by testing the sensitivity of the relaxant response to H2S against identified inhibitors of the HNO-stimulated pathway. With these experiments it is hoped to get a better insight into the regulation of gastrointestinal motility by a new member of the emerging class of gasotransmitters.

一类新兴的胃肠功能调节器是气体分子，即所谓的气体传递器。肠道中有两种公认的具有递质功能的气体：一氧化氮(NO)和硫化氢(H2S)。两者通过不同的机制诱导胃肠平滑肌松弛。NO激活可溶性鸟苷环化酶，cGMP的产生进而激活蛋白激酶G(或潜在地直接激活K+通道)，而H_2S激活ATP敏感和小电导依赖的K~+通道。第三种气体递质氮氧自由基(HNO)对胃肠动力的作用最近受到越来越多的关注。关于胃肠道，HNO所知的是，它发挥着强烈依赖于钙离子的前分泌作用，涉及钙依赖和ATP敏感的K+通道，部分是由环氧合酶代谢产物介导的(Pouokam等人)。2013年)。初步实验表明，HNO供体Angelis盐在大鼠回肠和结肠的纵向条带上引起肠道松弛。本研究将通过分离心肌细胞的膜片钳实验、自发收缩的平滑肌细胞聚集体的成像实验和等长肌肉收缩测量来研究这种松弛的机制。将特别关注所涉及的离子电导的特征，硫醇基团修饰(由于HNO的高硫基性质)可能的调节作用，以及cGMP信号通路的典型成分的参与。同时，初步实验显示，肌间神经元的超极化伴随着电压依赖性钠离子通道携带的内向电流的抑制。HNO引起肌间神经元膜电位变化的离子机制，即肠神经系统负责自主控制肠道运动的部分，目前尚不清楚，将在本研究中确定。最近的研究表明，NO、H2S和HNO信号通路之间存在串扰；例如，外源H2S可能与内源NO相互作用形成HNO，这增加了H2S的某些行为确实可能是由HNO介导的可能性。这一假说应通过测试对H_2S的松弛反应对HNO刺激途径的已识别抑制剂的敏感性来进行研究。通过这些实验，人们希望能更好地了解一种新兴的气体传递器对胃肠运动的调节。