组胺受体家族新成员:组胺H4受体

组胺H4受体是最近在基因库内筛选寻找新的G蛋白偶联受体时发现的,其cDNA序列与组胺H1、H2受体的同源性很低,与组胺H3受体有很高的同源性。很多组胺受体的配体与组胺H4受体有亲和性,但该受体表现出独特的药理学性质。组胺H4受体激动后可影响细胞内Ca^2 浓度和cAMP的生成,推测其与Gi或Go蛋白相偶联。组胺H4受体主要分布于骨髓、肺、脾脏、小肠和中枢,可能与机体的免疫反应和精神活动有关。     

一种新型的组胺受体：H3受体

组胺受体有H_1、H_2两种亚型。最近又发现,组胺还有一种新型的受体,即H_3受体,它主要分布在中枢神经和外周神经末梢,参与组胺的合成和释放的负反馈调节过程。H_3受体的功能、性质类似于H_2受体,但它对组胺的敏感性要比H_1、H_2受体强。H_3受体的发现,为进一步研究组胺的生理、病理生理作用提供了新的基础。     

中枢组织胺H3受体在睡眠-觉醒调节中的功用及作为治疗睡眠障碍药物干预靶点的依据

中枢组织胺(组胺)神经元位于下丘脑后部并广泛投射到全脑各部,在维持上行觉醒方面发挥重要作用。组胺H3受体调节组胺合成、释放及组胺神经元的活动,还参与调节脑内其它神经递质释放。凭借广泛区域表达和对多种神经递质的调节,H3受体近年备受重视并成为睡眠调节和对抗睡眠-觉醒障碍的有力药物干预靶点。随着对H3受体研究的深入及其在临床领域的应用,有必要对H3受体在睡眠觉醒调节中的作用作一综述,这对进一步探索H3受体的生理功能和临床药理学研究具有重要意义。     

组胺H4受体在胃腺癌组织中的表达及临床意义

目的：研究胃癌腺癌（gastric adenocarcinoma,GAC）中组胺H4受体的表达水平及其临床意义。方法：60例GAC组织（病例组）与配对癌旁组织（adjacent normal tissue,ANT）中应用免疫组织化学技术检测组胺H4受体的表达,应用实时荧光定量RT-PCR方法检测组胺H4受体mRNA的表达,统计分析组胺H4受体表达与临床病理特征之间的关系。结果：①胃腺癌组织中组胺H4受体蛋白的阳性表达率（11.7%）显著低于癌旁正常组织（96.7%）。②胃腺癌组织中组胺H4受体mRNA水平较癌旁组织明显降低（p〈0.001）。③组胺H4受体蛋白和mRNA表达异常和肿瘤的病理分级有相关性（p=0.0027和p=0.0011）,也与有无胃周淋巴结转移有关（p〈0.001和p=0.0049）。结论：组胺H4受体在胃腺癌组织有表达异常,表达量与病理分期相关。组胺H4受体表达异常和组胺水平紊乱可能在胃癌发生发展过程中有重要作用。     

组胺H4 受体在胃腺癌组织中的表达及临床意义

目的:研究胃癌腺癌(gastric adenocarcinoma,GAC)中组胺H4受体的表达水平及其临床意义。方法:60例GAC组织(病例组)与配对癌旁组织(adjacent normal tissue,ANT)中应用免疫组织化学技术检测组胺H4受体的表达,应用实时荧光定量RT-PCR方法检测组胺H4受体mRNA的表达,统计分析组胺H4受体表达与临床病理特征之间的关系。结果:①胃腺癌组织中组胺H4受体蛋白的阳性表达率(11.7%)显著低于癌旁正常组织(96.7%)。②胃腺癌组织中组胺H4受体mRNA水平较癌旁组织明显降低(p<0.001)。③组胺H4受体蛋白和mRNA表达异常和肿瘤的病理分级有相关性(p=0.0027和p=0.0011),也与有无胃周淋巴结转移有关(p<0.001和p=0.0049)。结论:组胺H4受体在胃腺癌组织有表达异常,表达量与病理分期相关。组胺H4受体表达异常和组胺水平紊乱可能在胃癌发生发展过程中有重要作用。     

豚鼠心交感神经末梢突触前膜存在组胺H3受体

本文首次报道豚鼠心肌存在一种新型突触前抑制性受体－组胺Ｈ３受体,选择性Ｈ３受体激动剂α－ＭｅＨＡ可抑制电场刺激诱发的离体豚鼠右心房交感性正性变力效应,以及去甲肾上腺素的释放。以上效应可被Ｈ３受体拮剂所拮抗。Ｎ－乙基马来酰亚胺可取消α－ＭｅＨＡ的作用。增加或减少心肌内源性组胺含量,可分别抑制或增强电场刺激诱发的心交感性反应。以上结果表明,组胺Ｈ３受体参与调节心交感神经冲动的传递,Ｈ３受体可能与Ｇ０－     

组胺受体介导的造血和免疫调控

造血干／祖细胞及白细胞,血小板上均存在组胺H1和H2受体,造血细胞既可在造血生长因子刺激下合成组胺,也可从胞外空间摄取组胺,组胺在造血调控中通过其受体发挥第二信使作用,组胺受体对正常造血与异常造血具有不同的调控机制,激动组胺H2受体可支持正常造血并抑制恶性造血,同时单核巨噬细胞膜上H2受体的激动可有效地抑制ROS的产生,从而逆转ROS对NK细胞活性的抑制,组胺协同IL－2或IFN－α可高效激活NK细胞功能。     

中枢组胺H3受体对哮喘豚鼠呼吸运动的影响

目的:探讨中枢组胺H3受体与哮喘发病的关系。方法:动物经侧脑室插管给药后,记录膈肌放电活动(DA)和呼吸频率(RR)。免疫组织化学方法检测下呼吸道内SP样免疫反应物的含量。荧光分光光度法测定脑内组胺含量。结果:①静脉注射卵蛋白(0.1mg/kg)诱发哮喘急性发作后,动物RR加快,DA幅度减小,同时下呼吸道内SP样免疫反应物的数量明显增加(P<0.01),下丘脑和皮质内组胺含量增多(P<0.01)。②哮喘急性发作后,侧脑室注射H3受体激动剂RAMH(5μg)后,与哮喘组相比,RR明显降低,DA幅度明显增加(P<0.01)。下呼吸道内SP样免疫反应物的数量明显减少(P<0.01)。③哮喘缓解期,侧脑室注射组胺H3受体拮抗剂THIO(20μg)后,RR明显加快,DA幅度减小。下丘脑和皮质内组胺含量均高于对照组(P<0.05)。结论:脑内组胺H3受体参与了对哮喘发作的神经性调控过程。     

正确使用抗过敏药物

组胺H1受体阻断药为常用的抗过敏药，其药理作用主要表现三个方面：(1)H1受体阻断作用；(2)中枢作用；(3)抗胆碱作用。虽然，这类药物的抗过敏作用是肯定的，但也存在不同程度的副作用，特别是与其他药物同时使用不当时，有可能使副作用加重。调查显示，约有25％的人在服用第一     

脑室注射组胺抑制大鼠胃酸分泌的外周机制

本文分析了第三脑室注射组胺（HA）抑制胃酸分泌效应的外周过程。雄性SD大鼠,摘除双侧肾上腺,用37℃的生理盐水通过恒流泵进行连续胃灌流。用注射器泵静脉每小时给药,观察其对五肽促胃液素（10μg/kg,iv）诱导的胃酸分泌的影响。结果如下：（1）切除双侧膈下迷走神经可阻断HA（1μg,icv）的中枢抑酸效应;（2）预先静脉注射硫酸阿托品［0.05mg／（kg·100min）］可阻断HA的中枢抑酸效应;（3）预先静脉注射生长抑素拮抗剂[2～4μg/（kg·100min）],可剂量依赖性地拮抗HA的中枢抑酸效应。结果提示：HA的中枢抑酸效应由迷走神经传出,可能通过乙酰胆碱M受体及引起生长抑素释放实现。     

Reduced histamine levels and H3 receptor antagonist-induced histamine release in the amygdala of Apoe-/- mice

The histamine H(3) receptor is a constitutively active G protein-coupled receptor for the neurotransmitter histamine that serves a negative feedback function. A role for the histamine H(3) receptor has been suggested in neurodegenerative diseases, such as Parkinsons disease and Alzheimer's disease. Mice deficient in apolipoprotein E (apoE), a protein involved in development, regeneration, neurite outgrowth, and neuroprotection, show increased measures of anxiety and reduced sensitivity to effects of histamine H(3) receptor antagonists on measures of anxiety. In this study, we tested whether in mice lacking apoE (Apoe-/-) histamine levels and histamine release in brain areas involved in the regulation of anxiety are altered. H(3) receptor antagonist-induced histamine release was lower in the amygdala of Apoe-/- than wild-type mice. In contrast, there were no genotype differences in histamine release in the hypothalamus. Consistent with these data, histamine immunohistochemistry revealed lower total and synaptic histamine levels in the central nucleus of the amygdala of Apoe-/- than wild-type mice. Such changes were not seen in the hypothalamus, hippocampus, or cortex. In Apoe-/- mice, chronically decreased histamine levels and reduced histamine release in the amygdala might contribute to increased measures of anxiety.     

Histamine protects against NMDA-induced necrosis in cultured cortical neurons through H receptor/cyclic AMP/protein kinase A and H receptor/GABA release pathways

Using histamine and the H3 receptor antagonist thioperamide, the roles of histamine receptors in NMDA-induced necrosis were investigated in rat cultured cortical neurons. Within 3 h of intense NMDA insult, most neurons died by necrosis. Histamine reversed the neurotoxicity in a concentration-dependent manner and showed peak protection at a concentration of 10(-7) m. This protection was antagonized by the H2 receptor antagonists cimetidine and zolantidine but not by the H1 receptor antagonists pyrilamine and diphenhydramine. In addition, the selective H2 receptor agonist amthamine mimicked the protection by histamine. This action was prevented by cimetidine but not by pyrilamine. 8-Bromo-cAMP also mimicked the effect of histamine. In contrast, both the adenylyl cyclase inhibitor 9-(tetrahydro-2-furanyl)-9H-purine-6-amine and the cAMP-dependent protein kinase inhibitor N-[2-(p-bromocinnamylamino) ethyl]-5-isoquinolinesulfonamide reversed the protection by histamine. Thioperamide also attenuated NMDA-induced excitotoxicity, which was reversed by the H3 receptor agonist (R)-alpha-methylhistamine but not by pyrilamine and cimetidine. In addition, the protection by thioperamide was inhibited by the GABA(A) receptor antagonists picrotoxin and bicuculline. Further study demonstrated that the protection by thioperamide was due to increased GABA release in NMDA-stimulated samples. These results indicate that not only the H2 receptor/cAMP/cAMP-dependent protein kinase pathway but also the H3 receptor/GABA release pathway can attenuate NMDA-induced neurotoxicity.     

Regulation of Norepinephrine Release from Isolated Bovine Irides by Histamine

In the present study, we investigated the effect of histamine on sympathetic neurotransmission from isolated, superfused bovine irides. We also studied the pharmacology of prejunctional histamine receptors that regulate the release of norepinephrine (NE) from this tissue. The effect of exogenous histamine and various histamine receptor agonists was examined on the release of [³H]-norepinephrine ([³H]NE) triggered by electrical field stimulation using the Superfusion Method. Histamine receptor agonists caused a concentration-dependent inhibition of field-stimulated [³H]NE overflow with the following rank order of potency: imetit > histamine > R-α-methylhistamine. In all cases, the inhibitory action of histamine receptor agonists was attenuated at high concentrations of these compounds. The histamine receptor antagonists, clobenpropit (H₃-antagonist/H₄-agonist) and thioperamide (H₃-antagonist) blocked the inhibitory response elicited by R-α-methylhistamine and imetit, respectively. Inhibitory effects of R-α-methylhistamine and clonidine were not additive suggesting that prejunctional H₃- and α₂-adrenoceptors coexist at neurotransmitter release sites. We conclude that histamine produces an inhibitory action on sympathetic neurotransmission in the bovine iris, an effect mimicked by selective H₃-receptor agonists and blocked by H₃-antagonists.     

Histamine induces intracellular Ca2+ oscillations and nitric oxide release in endothelial cells from brain microvascular circulation

The neuromodulator histamine is able to vasorelax in human cerebral, meningeal and temporal arteries via endothelial histamine 1 receptors (H₁Rs) which result in the downstream production of nitric oxide (NO), the most powerful vasodilator transmitter in the brain. Although endothelial Ca ²⁺ signals drive histamine-induced NO release throughout the peripheral circulation, the mechanism by which histamine evokes NO production in human cerebrovascular endothelial cells is still unknown. Herein, we exploited the human cerebral microvascular endothelial cell line, hCMEC/D3, to assess the role of intracellular Ca ²⁺ signaling in histamine-induced NO release. To achieve this goal, hCMEC/D3 cells were loaded with the Ca ²⁺- and NO-sensitive dyes, Fura-2/AM and DAF-FM/AM, respectively. Histamine elicited repetitive oscillations in intracellular Ca ²⁺ concentration in hCMEC/D3 cells throughout a concentration range spanning from 1 pM up to 300 μM. The oscillatory Ca ²⁺ response was suppressed by the inhibition of H ₁Rs with pyrilamine, whereas H ₁R was abundantly expressed at the protein level. We further found that histamine-induced intracellular Ca ²⁺ oscillations were initiated by endogenous Ca ²⁺ mobilization through inositol-1,4,5-trisphosphate- and nicotinic acid dinucleotide phosphate-sensitive channels and maintained over time by store-operated Ca ²⁺ entry. In addition, histamine evoked robust NO release that was prevented by interfering with the accompanying intracellular Ca ²⁺ oscillations, thereby confirming that the endothelial NO synthase is recruited by Ca ²⁺ spikes also in hCMEC/D3 cells. These data provide the first evidence that histamine evokes NO production from human cerebrovascular endothelial cells through intracellular Ca ²⁺ oscillations, thereby shedding novel light on the mechanisms by which this neuromodulator controls cerebral blood flow.     

Hypothalamic histamine neurons activate lipolysis in rat adipose tissue

The contribution of hypothalamic histamine neurons to the central regulation of peripheral lipid metabolism was investigated in rats using in vivo microdialysis system. A bolus infusion of L-histamine at doses of 10--10(3) nmol/rat into the third cerebral ventricle (i3vt) dose-dependently increased glycerol concentration in the perfusate from the epididymal adipose tissue. I3vt infusion of 10(2) nmol/rat thioperamide, an autoinhibitory H(3) receptor antagonist that activates histamine neurons to increase synthesis and release of neuronal histamine, convincingly mimicked histamine action in the augmented lipolysis. Intraperitoneal pretreatment with propranolol, a beta-adrenoceptor antagonist, abolished the thioperamide-induced lipolytic action. An electrophysiological study demonstrated that efferent sympathetic nerves innervating the epididymal fat were activated after the i3vt infusion of thioperamide. Hypothalamic histamine neurons thus regulate peripheral lipid metabolism through the accelerating lipolytic action by activation of sympathetic beta-adrenoceptor.     

H3-Receptors Control Histamine Release in Human Brain

The regulation of histamine release was studied on slices prepared from pieces of human cerebral cortex removed during neurosurgery and labeled with L-[3H]histidine. Depolarization by increased extracellular K+ concentration induced [3H]histamine release, although to a lesser extent than from rat brain slices. Exogenous histamine reduced by up to 60% the K+-evoked release, with an EC50 of 3.5 +/- 0.5 X 10(-8) M. The H3-receptor antagonists impromidine and thioperamide reversed the histamine effect in an apparently competitive manner and enhanced the K+-evoked release, indicating a participation of endogenous histamine in the release control process. The potencies of histamine and the H3-receptor antagonists were similar to those of these agents at presynaptic H3-autoreceptors controlling [3H]histamine release from rat brain slices. It is concluded that H3-receptors control histamine release in the human brain.     

Histamine-stimulated and GTP-binding proteins-mediated phospholipase A2 activation in rabbit platelets

Histamine is known to be a mediator of inflammation. In order to understand the role of histamine in platelets, we have examined the effects of histamine on arachidonic acid (AA) release, cAMP accumulation, inositol trisphosphate production, and serotonin secretion. Incubation of rabbit (and human) platelets with histamine resulted in rapid increase of [3H]AA release from the platelets prelabeled with [3H]AA. The effect of histamine was blocked by the addition of H1 receptor antagonist mepyramine. Histamine did not substantially affect the cAMP content and inositol trisphosphate production. Histamine-stimulated AA release was not observed in digitonin-permeabilized platelets, whereas histamine acted synergistically with GTP or GTP analog, guanosine 5'-(3-O-thio)triphosphate. Histamine-stimulated, and GTP analog-dependent AA release was inhibited by guanosine 5'-(2-O-thio) diphosphate. The effects of three receptor stimulants, thrombin, norepinephrine, and histamine were both diminished by 1 microgram/ml of pertussis toxin treatment and by the antiserum against GTP-binding proteins (G proteins) treatment. However, the antiserum against beta gamma subunits of G proteins inhibited the histamine effect, not thrombin effect. 4 beta-Phorbol 12-myristate 13-acetate (PMA) treatment enhanced histamine-stimulated AA release and serotonin secretion but inhibited thrombin-stimulated reactions. The effect of PMA was dose dependent and was due to enhance the coupling of histamine receptors and G proteins. The results show the existence of H1 histamine receptors which couple phospholipase A2 activation via pertussis toxin-sensitive G proteins. Histamine actions differ in sensitivities to anti-beta gamma antiserum treatment and PMA treatment from thrombin actions.     

Histamine enhances cytotrophoblast invasion by inducing intracellular calcium transients through the histamine type-1 receptor

Blastocyst implantation and placentation require molecular and cellular interactions between the uterine endometrium and blastocyst trophectoderm. Previous studies showed that histamine produced in the mouse uterine luminal epithelium interacts with trophoblast histamine type-2 receptors (H2) to initiate blastocyst implantation. However, it is unknown whether similar histamine activity is operative in humans. Using a human cell line (HTR-8/SVneo) derived from first-trimester cytotrophoblasts that expresses both histamine type-1 receptor (H1) and H2, we found that histamine promotes cytotrophoblast invasiveness specifically through activation of H1. Stimulation of H1 in human cytotrophoblasts by histamine induced intracellular Ca2+ (Ca(2+)i) transients by activating phospholipase C and the inositol trisphosphate pathway. The enhanced invasion induced by histamine was blocked by pretreatment with H1 antagonist or by chelation of Ca(2+)i. These findings suggest possible differences between rodents and humans in histamine signaling to the trophoblast.     

Different h2 receptor antihistamines dissimilarly retard the growth of xenografted human melanoma cells in immunodeficient mice

Melanoma cells and tissues contain considerable amounts of histamine and express histamine receptors, suggesting the existence of autocrine and paracrine regulation by histamine. Our previous in vitro results suggested that histamine elevates melanoma cell growth through the H2 receptor. In this work we show that in vivo tumour proliferation in immunodeficient mice xenotransplanted with a human melanoma cell line is diminished by cimetidine, an H2 receptor antagonist, if combined with a tamoxifen derivate acting on cytochrome p450 molecules (DPPE). Ranitidine, another H2 receptor antagonist, has a weaker inhibitory effect, the kinetics and mechanism of which is probably dissimilar to that of the cimetidine/DPPE mixture.     

Pharmacological characterization of the histamine uptake system in HL-60 human promyelocytic leukemia cells

Serotonin and histamine H₁, H₂ receptor agonists or antagonists inhibited [³H]histamine uptake by HL-60 cells, according to the following order of potency: impromidine >4-MH>histamine>AET>PEA and: cimetidine, histamine>diphenhydramine, serotonin. It is concluded that histamine uptake by HL-60 cells was specifically controlled by the H₂ type histamine receptor and that this active process might be involved in pathophysiological regulations in leukemic and normal granulocytic precursors and in the control of histamine levels in peripheral blood and tissues in man.