脑内组胺受体的三个亚型

<正> 自Heinz Otto Schild提出组胺受体存在H_1和H_2亚型以来,许多器官,尤其是脑内组胺受体亚型的生理及药理研究取得了重要进展。 一、脑内组胺受体的存在 组胺不能直接通过血脑屏障,因此中枢神经组胺受体的作用是调节脑内胺类递质的效应,这些胺类是局部合成,贮存和释放。十多年前已证明,脑内有神经元和肥大细胞含有组胺,这主要是通过神经化     

常用抗变应性鼻炎药物

变应性鼻炎的治疗药物以抗组胺药物和皮质类激素为主。1　抗组胺类药物引起变态反应的介质很多 ,组胺是其中非常重要之一。所以抗组胺药物是临床上广泛使用的治疗变态反应疾病的药物。变态反应性鼻炎的大多数症状是通过H1 受体来表达的。组胺可通过H1 受体作用于鼻黏膜组织中不同的效应细胞上 ,导致血管渗透性增加、黏液腺分泌亢进、平滑肌收缩和刺激神经末梢等 ,临床上所指的抗组胺药物 ,主要是指组胺受体拮抗药 (或称阻滞药 ) ,作用机制是在靶细胞膜上与组胺H1 受体竞争结合 ,从而达到阻断或减轻由组胺所产生的一系列症状。1.1　第一代抗组胺类药物　这类抗组胺药物都属于脂溶性 ,可以穿过血脑屏障而阻断大脑中的H1 受体功能。所以都具有抑制中枢神经系统作用 ,如嗜睡现象。除副作用外 ,抗组胺药物还可产生其他效应 ,如阻断毒蕈碱胆碱能、α 肾上腺素能和 5 羟色胺受体及局部麻醉等作用。这种抗胆碱能作用可引起心脏兴奋而导致心悸、心动过速、视觉模糊、胃肠道蠕动减慢 (便秘 )和尿潴留 (尤其对患有前列腺肥大的患者 )等。这类抗组胺药物还可和一些药物发生相互作用 ,比如能加强一些药物或物质的作用 ,如单胺氧化酶抑制药、乙醇、抗帕金森...     

组胺对白色脂肪细胞脂肪合成以及调控的机制研究

目的：在体外探索组胺对脂肪合成的影响及其作用机制。方法：培养3T3L1细胞,诱导为白色脂肪细胞,运用RT-PCR技术检测组胺和苯海拉明对白色脂肪细胞中脂肪细胞脂肪酸结合蛋白2（aP2 mRNA）水平的影响。结果：组胺可以增加分化成熟的3T3L1小鼠胚胎成纤维细胞（前脂肪细胞）aP2的表达,剂量效应图显示组胺为20μmol/L时aP2表达量为最高,时间效应图显示在共同孵育6 h后aP2表达量达到最高;苯海拉明与同剂量组胺相比,可以显著降低aP2的表达（P〈0.05）。结论：组胺可以刺激分化成熟的3T3L1细胞的aP2的表达,苯海拉明可以抑制组胺的效应。组胺能增加脂肪细胞的脂肪合成,维持白色脂肪细胞能量代谢的平衡。     

H_3-受体存在部位及药理研究

组胺受体原分为 H_1-受体和 H_2-受体。1983年在脑组胺传出神经元突触前膜发现抑制组胺游离、合成的自身受体,这种受体的药理学特性与H3一和H2一受体不同,被命名为H3一受体     

五步蛇毒对大鼠海马组胺受体H_1 mRNA和蛋白质表达的影响

目的研究五步蛇毒对大鼠海马组胺受体H1mRNA及蛋白质表达的影响。方法用半定量RT-PCR和Western blot方法,检测腹腔注射五步蛇毒后不同时相大鼠海马组胺受体H1mRNA及蛋白质表达的变化。结果五步蛇毒处理后,大鼠海马组胺受体H1mRNA及蛋白质的表达在各时相点均发生变化,且其mRNA和蛋白质表达均为先下调后上调。结论五步蛇毒对大鼠脑区海马组胺H1受体mRNA和蛋白质表达都有影响。H1受体mRNA和蛋白质表达的改变对大脑的生理功能有一定的影响,可能是该蛇毒致脑功能障碍的分子基础之一。     

组胺及组胺受体研究近况

<正> 本文着重介绍近几年来组胺H_3受体的研究情况,概述组胺受体的亚型及各亚型的分布、生理效应,对各受体亚型介导的效应及产生的机制进行初步探讨。组胺是人体分布广泛,作用很强的生物活性物质之一。一般认为,组胺与其它神经递质一样,首先与靶器官的特异性受体结合改变细胞兴奋性而发挥生物效应。组胺的生理作用在20年代已被发现,首先认     

甲氰咪胺

甲氰咪胺为组胺H_2受体拮抗剂,药理研究证明组胺作用于H_1、H_2二种受体。引起气管收缩和毛细血管扩张作用的,是由于兴奋H_1受体,并能被一般习用的抗组胺药物所拮抗,增进胃壁细胞酸分泌的H_2受体,其作用不为一般抗组胺药物所消除。经过化学结构改造与筛选,发现了一类H_2受体拮抗剂,在这类药物中,以氰胍基取代硫脲部分而合成的甲氰咪胺,其毒性较轻。体内作用 1.抑制胃酸分泌:甲氰咪胺能减少胃在静止状态(基础胃酸)及为食物、组胺、五肽胃泌素、胰岛素、咖啡因等刺激后胃酸分泌的容量与浓度,其效能优于抗胆硷能     

抗组胺药与粘附分子

综述了主要粘附分子的种类、性质、功能及抗组胺药在过敏性炎症中对炎症细胞粘附分子表达的直接调控作用和间接调控作用 ,提示抗组胺药具有多方面抗炎作用。     

角质形成细胞模型中白介素8和单核趋化蛋白1的表达及西替利嗪对诱导的干预作用

目的　探讨人角质形成细胞株HaCaT细胞中组胺H1 受体(H1R)表达及西替利嗪(CET)对组胺诱导炎症因子的干预作用。方法　用RT-PCR和免疫组化技术检测HaCaT细胞H1RmRNA和蛋白表达,用组胺处理细胞为模型组,用酶联免疫吸附实验(ELISA)检测组胺诱导白介素8 (IL-8)和单核趋化蛋白1(MCP-1)的蛋白分泌及CET对诱导的干预作用。结果　HaCaT细胞有H1RmRNA和蛋白表达;组胺(1×10-6 ~1×10-4 mol·L-1 )可显著诱导细胞IL-8蛋白分泌(P<0. 05, vs对照组), 组胺(1×10-5 mol·L-1 )可显著诱导MCP-1分泌(P<0. 05, vs对照组),加入(1×10-6, 1×10-5mol·L-1 )CET共同培养24h,可抑制诱导作用(P<0. 05, vs模型组)。结论　西替利嗪可能通过抑制角质形成细胞趋化因子的表达而发挥抗皮肤过敏炎症作用。     

抗溃疡病药物的临床选择

近几年来,世界各国研制出许多具有临床使用价值的抗溃疡病新药。本文拟对其中主要品种在临床防治溃疡病中的选择及使用方法上作一介绍,供大家参考。一、胃壁细胞受体拮抗剂胃壁细胞含有三种受体,即组胺受体、乙酰胆碱受体和促胃泌素受体。阻断这三种受体便可抑制胃液分泌。于是,有关壁细胞受体掊抗剂(H_2—受体拮抗剂、选择洼毒蕈碱受体拮抗剂、促胃泌素受体拮抗剂)药物     

Histamine receptors are hot in immunopharmacology

In addition to its well-characterized effects in the acute allergic inflammatory responses, histamine has been demonstrated to affect chronic inflammation and regulate several essential events in the immune response. Histamine can selectively recruit the major effector cells into tissue sites and affect their maturation, activation, polarization, and other functions leading to chronic inflammation. Histamine also regulates dendritic cells, T cells and B cells, as well as related antibody isotype responses. In addition, acting through its receptor 2, histamine positively interferes with the peripheral antigen tolerance induced by T regulatory cells in several pathways. The diverse effects of histamine on immune regulation appear to be due to differential expression and regulation of 4 types of histamine receptors and their distinct intracellular signals. In addition, differences in affinities of these receptors for histamine is highly decisive for the biological effects of histamine and drugs that target histamine receptors. This article highlights recent discoveries in histamine immunobiology and discusses their relevance in allergic inflammation.     

The role of histamine H4 receptor in immune and inflammatory disorders

Since its discovery at the beginning of the 20th century, histamine has been established to play a pathophysiological regulatory role in cellular events through binding to four types of G-protein-coupled histamine receptors that are differentially expressed in various cell types. The discovery, at the turn of the millennium, that the histamine H₄ receptor is largely expressed in haemopoietic cells as well as its chemotactic properties designate its regulatory role in the immune system. H₄ receptors modulate eosinophil migration and selective recruitment of mast cells leading to amplification of histamine-mediated immune responses and eventually to chronic inflammation. H₄ receptor involvement in dendritic cell activation and T cell differentiation documents its immunomodulatory function. The characterization of the H₄ as the immune system histamine receptor directed growing attention towards its therapeutic exploitation in inflammatory disorders, such as allergy, asthma, chronic pruritus and autoimmune diseases. The efficacy of a number of H₄ receptor ligands has been evaluated in in vivo and in vitro animal models of disease and in human biological samples. However, before reaching decisive conclusions on H₄ receptor pathophysiological functions and therapeutic exploitation, identification of genetic polymorphisms and interspecies differences in its relative actions and pharmacological profile need to be addressed and taken into consideration. Despite certain variations in the reported findings, the available data strongly point to the H₄ receptor as a novel target for the pharmacological modulation of histamine-transferred immune signals and offer an optimistic perspective for the therapeutic exploitation of this promising new drug target in inflammatory disorders.     

A bioinformatics search for selective histamine h4 receptor antagonists through structure-based virtual screening strategies

The prevalence of allergic disease is increasing dramatically in the developed world. Studies of allergic diseases have clearly demonstrated that histamine plays an important role in the pathogenesis of the early-phase allergic response. Histamine effects are mediated by H1, H2, H3, and H4 receptors. The presence of the histamine H4 receptors on leukocytes and mast cells suggests that the new histamine receptor H4 plays an important role in the modulation of the immune system. Thus, histamine H4 receptor is an attractive target for anti-allergic therapy. In our present study, we have generated a histamine H4 receptor model using I-TASSER based on human B2-adrenergic G-protein-coupled receptor. Structurally similar compounds of the three known antagonists JNJ777120, thioperamide, and Vuf6002 were retrieved from PubChem, and database was prepared. Virtual screening of those databases was performed, and six compounds with high docking score were identified. Also the binding mode revealed that all the six compounds had interaction with Asp94 of the receptor. Our results serve as a starting point in the development of novel lead compounds in anti-allergic therapy.     

Cloning and pharmacological characterization of the dog histamine H4 receptor

The histamine H(4) receptor has been shown to have a role in chemotaxis and mediator release in various types of immune cells and has been implicated in mediating inflammation in vivo. Previous work has shown that there were differences in the histamine H(4) receptor sequence of different species and these translated into changes in the pharmacology of the receptors. To help further understand the nature of these differences, we have cloned and expressed the histamine H(4) receptor of dog (Canis familiaris). The dog histamine H(4) receptor has a 61-71% homology with the receptors from other species, with a 71% homology to the human receptor. The affinity for histamine at the dog histamine H(4) receptor is 18 nM and is 3-fold lower than the human ortholog. A number of previously described histamine H(4) receptor ligands were tested for affinity at the dog histamine H(4) receptor and histamine showed the highest affinity of the ligands tested. In addition, the histamine H(4) receptor selective antagonist, JNJ 7777120, had a K(i) value of 50 nM and acts as an antagonist at the dog receptor. In general, agonists of the human histamine H(4) receptor were also agonists of the dog receptor albeit with different efficacy levels. The cloning and in vitro pharmacological characterization of the dog histamine H(4) receptor provide useful information for future studies using dog models as well as in understanding the ligand-receptor interactions of the receptor.     

Histamine induced elevation of cyclic AMP phosphodiesterase activity in human monocytes

We have previously reported histamine desensitization of human blood mononuclear leukocytes resulting in reduced cAMP responses to beta-adrenergic agonists, histamine and prostaglandin E1. This heterologous desensitization occurred at low, micromolar histamine concentrations and was accompanied by elevation of cAMP-phosphodiesterase (PDE) activity in these cells. We have now investigated the activity of PDE in the lymphocyte and monocyte fractions of mononuclear leukocytes to determine the site of histamine effect. PDE activity per cell was higher in monocytes (0.075 +/- 0.070 units) than lymphocytes (0.026 +/- 0.08) units). Monocytes responded to 10(-6) M histamine stimulation with a much greater increase in PDE activity (0.354 +/- 0.1 units) than did lymphocytes (0.047 +/- 0.015 units). Histamine receptor studies, using thiazolylethylamine and chlorpheniramine as H1-agonist and antagonist respectively and dimaprit and cimetidine as H2-agonists and antagonists respectively, indicated that the histamine stimulation of PDE activity is mediated predominantly through H1 histamine receptor in the monocytes and the H1 receptor in the lymphocytes. Previously histamine had been thought to increase cyclic AMP by acting on H2 receptors to activate adenylate cyclase. Our studies show that stimulation of H1 or H2 receptors by low histamine concentration can cause the opposite effect i.e. increased catabolism and a net reduction in cAMP levels. The localization of this effect predominantly to monocytes indicates a potentially important mechanism for histamine action on immune regulation.     

Surface histamine receptors in rat peritoneal mast cells. Separation of receptor-bearing cells via binding to a histamine-protein conjugate, Cell-ect

The Seragen Cell-ect Total Histamine KitTM was used to separate histamine receptor-bearing rat peritoneal mast cells from cells lacking these receptors. It was found that approximately 75% of the peritoneal mast cell population carried cell surface histamine receptors. The results further suggest that the mast cell histamine receptors present are mainly of an H1-type, as judged by the capacity of a specific H1-antagonist to reduce the histamine receptor-dependent cell adhesion. Moreover, an H1-agonist is less efficient in this respect and an H2-antagonist does not affect the cell adhesion at all. A possible functional role for these receptors, however, remains to be clarified.     

Histamine and its lymphocyte-selective derivatives as immune modulators

Histamine has long been known as a neurotransmitter, inflammatory mediator and a factor in anaphylaxis, cardiac and gastrointestinal functions. Theoretically, it should not be surprising to find that a mediator of inflammation may modulate immunity because receptors for histamine are non-randomly distributed on lymphocytes.Kenneth Melmon andManzoor Khan cite recent data primarily developed inin-vitro models of delayed hypersensitivity that demonstrate the immune modulatory role of histamine. New lymphocyte-specific histamine H₁ and/or H₂ agonists make it pharmacologically feasible to assess the potential of histamine as a selectivein-vivo immune modulator.     

Potential role of store-operated Ca2+ entry in Th2 response induced by histamine in human monocyte-derived dendritic cells

Store-operated calcium entry (SOCE) is the main Ca(2+) influx pathway of dendritic cells (DCs). DCs primed with histamine facilitate Th2 immune response via different types of histamine receptors. Histamine induces DCs to release Ca(2+) from internal store. Therefore, we wonder that whether histamine could activate SOCE in DCs through its receptors, and what's the functional relevance of the Ca(2+) influx through SOCE induced by histamine in Th(2) response. We certificate that histamine induced a transient Ca(2+) release followed by pronounced Ca(2+) influx after re-addition of external Ca(2+) which could be inhibited by SOCE blockers SKF-96365 and BTP-2. Moreover, the percentages of DCs that showed an obvious Ca(2+) release response to histamine were decreased in the presence of histamine 1 (H1) receptor antagonist pyridylethylamine (Pyr) or histamine 4 (H4) receptor antagonist JNJ7777120 (JNJ). Histamine up-regulated the mRNA expression of STIM1 in DCs, one of the two major proteins of SOCE channel. SOCE blocker BTP-2 and histamine receptor antagonists JNJ and Pyr inhibited the increase of CD86 induced by histamine on DCs. Histamine increased the level of IL-10 and decreased the level of IL-12p70 secreted by DCs. SOC blockers SKF and BTP-2 inhibited the level of both IL-10 and IL-12p70 secreted by DCs. Pretreatment of SOC blockers and H1, H4 receptor antagonists with DCs inhibited the Th2 polarization of T helper cells induced by histamine in mixed lymphocyte responses (MLR). We demonstrated that SOCE was involved in histamine-induced maturation and Th(2) response of DCs which was through histamine 1 and 4 receptor.     

Histamine and histamine receptors in pathogenesis and treatment of multiple sclerosis

Multiple sclerosis (MS) is an autoimmune disease associated with chronic inflammatory demyelination of the central nervous system (CNS). Due to disease complexity and heterogeneity, its pathogenesis remains unknown and despite extensive studies, specific effective treatments have not yet been developed. The factors behind the initiation of the inflammatory reactions in CNS have not been identified until now. MS is considered as a complex disease depending on genetic as well as environmental factors. Experimental autoimmune encephalomyelitis (EAE) is the preferential experimental rodent model for MS. Histamine [2-(4-imidazole) ethylamine] is a ubiquitous inflammatory mediator of diverse physiological processes including neurotransmission, secretion of pituitary hormones, and regulation of the gastrointestinal and circulatory systems which can modulate immune responses. Histamine functions are mediated through four G-protein coupled receptors that are named H1-H4 receptor. Histamine is implicated as an important factor in pathophysiology of MS and EAE. It has been shown that histamine can change the permeability of blood brain barrier, which leads to elevation of infiltrated cells in CNS and neuroinflammation. In contrast, there are evidence that show the protective role of histamine in MS and its animal model, EAE. In this review, we try to clarify the role of histamine in pathogenesis of MS, as well as we evaluate the efficacy of histamine receptors agonists and antagonists in treatment of this disease.     

Physiological function mediated by histamine synthesis

Histamine is involved in a variety of physiologic responses, such as inflammation, type I allergy, gastric acid secretion, and neurotransmission. Previous studies have focused on specific receptors for histamine and histamine release through degranulation, and the regulation of histamine synthesis and its physiologic roles remain to be clarified. We have studied histidine decarboxylase (HDC), the rate-limiting enzyme for mammalian histamine synthesis. Immunocytochemical approaches with an anti-HDC antibody revealed that histamine synthesis occurs in two distinct compartments of mast cells, cytosol and granules, and is regulated by the posttranslational processing of HDC. We also found that histamine synthesis in mast cells is markedly induced by IgE even in the absence of antigens, which may be relevant to enhanced responses of mast cells under allergic conditions. We then developed HDC-deficient mice by gene targeting to investigate the physiologic roles of histamine. We not only confirmed that histamine is essential for type I allergy and stimulates gastric acid secretion, but also found that histamine may regulate the proliferation and differentiation of mast cells. Furthermore, in HDC-deficient mice histamine produced by infiltrated neutrophils can suppress the production of antitumoral cytokines, such as interferon-gamma and tumor necrosis factor-alpha through H2 receptors in the tumor tissues. In this review, we describe recent topics in histamine research, including our results focusing on histamine synthesis and its physiologic roles.