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1. Histamine (0.004-2 microm) induced a concentration-dependent shape change of human eosinophils, but not of neutrophils or basophils, detected as an increase in forward scatter (FSC) in the gated autofluorescence/forward scatter (GAFS) assay. 2. The histamine-induced eosinophil shape change was completely abolished by thioperamide (10 microm), an H3/H4 receptor antagonist, but was not inhibited by pyrilamine or cimetidine (10 microm), H1 and H2 receptor antagonists, respectively. The H4 receptor agonists, clobenpropit and clozapine (0.004-2 microm), which are also H3 receptor antagonists, both induced eosinophil shape change, which was inhibited by thioperamide (10 microm). The H3/H4 receptor agonists, imetit, R-alpha-methyl histamine and N-alpha-methyl histamine (0.004-2 microm) also induced eosinophil shape change. 3. Histamine induced actin polymerisation (0.015-10 microm), intracellular calcium mobilisation (10-100 microm) and a significant upregulation of expression of the cell adhesion molecule CD11b (0.004-10 microm) in eosinophils, all of which were inhibited by thioperamide (10-100 microm). In addition, the H4 receptor agonist/H3 receptor antagonist clozapine (20 microm) stimulated a rise in intracellular calcium in eosinophils. 4. Activation of H4 receptors by histamine (1 microm) primed eosinophils for increased chemotactic responses to eotaxin, but histamine (0.1-10 microm) did not directly induce chemotaxis of eosinophils. 5. Pertussis toxin (1 microg ml-1) inhibited shape change and actin polymerisation responses induced by histamine showing that these effects are mediated by coupling to a Galphai/o G-protein. 6. This study demonstrates that human eosinophils express functional H4 receptors and may provide a novel target for allergic disease therapy.

Na/H exchanger-1 (NHE-1) isoform regulates intracellular pH and protects the esophageal mucosa. These functions are compromised in gastroesophageal reflux disease (GERD); however, the role and the underlying mechanism of NHE-1 regulation are obscure. To address this issue, NHE-1 protein and mRNA levels were measured by ECL western blot analysis and a semiquantitative RT-PCR using alpha-actin as an internal control. Ouabain-sensitive and K-stimulated p-nitrophenylphosphatase activity was measured as a marker of the sodium pump. The level of NHE-1 protein and mRNA and sodium pump activity was increased in GERD patients with or without esophagitis. Interestingly, myeloperoxidase (MPO) activity and infiltration of inflammatory cells were significantly increased in the GERD patients with esophagitis as compared to the GERD without esophagitis and the normal controls. This induction of NHE-1 and sodium pump was reversed in the GERD patients taking an H2 blocker, but not in those taking antacids. The internal control alpha-actin did not change under these conditions. Yield of total RNA and crude microsomal proteins was also statistically similar in all the test groups. These findings demonstrate that induction of NHE-1 is regulated posttranscriptionally through a possible interaction of histamine receptor. Induction of NHE-1 and sodium pump activity together might be a mechanism underlying the GERD pathogenesis and suggests a significance of NHE-1 inhibition in the treatment of GERD.

Histamine was the first mediator implicated in mechanisms of allergy, asthma, and anaphylactic shock because it has been discovered to mimic several features of these diseases. In addition to its well-characterized effects in the acute inflammatory and allergic responses, it was recently demonstrated that histamine regulates several essential events in the immune response. Histamine affects the maturation of immune system cells and alters their activation, polarization, chemotaxis, and effector functions. Histamine also regulates antigen-specific T(H)1 and T(H)2 cells, as well as related antibody isotype responses. Histamine binds to 4 different G protein-coupled receptors that transduce signals to cells through distinct pathways. The expression of these receptors on different cells and cell subsets is regulated, and apparently, the diverse effects of histamine on immune regulation are due to differential expression of 4 histamine receptors and their distinct intracellular signals. This article highlights novel discoveries in histamine immunobiology and discusses clinical findings or disease models that indicate immune regulation by histamine.

Improgan, a chemical congener of the H(2) antagonist cimetidine, induces antinociception following intracerebroventricular (i.c.v.) administration in rodents, but the mechanism of action of this compound remains unknown. Because the chemical structure of improgan closely resembles those of histamine and certain histamine blockers, and because neuronal histamine is known to participate in pain-relieving responses, the antinociceptive actions of improgan were evaluated in mice containing null mutations in the genes for three histamine receptors (H(1), H(2), and H(3)) and also in the gene for histidine decarboxylase (the histamine biosynthetic enzyme). Similar to earlier findings in Swiss-Webster mice, improgan induced maximal, reversible, dose-related reductions in thermal nociceptive responses in ICR mice, but neither pre-improgan (baseline) nor post-improgan nociceptive latencies were changed in any of the mutant mice as compared with wild-type controls. Improgan also had weak inhibitory activity in vitro (pK(i)=4.7-4.9) on specific binding to three recently-discovered, recombinant isoforms of the rat H(3) receptor (H(3A), H(3B), and H(3C)). The present findings strongly support the hypothesis that neuronal histamine and its receptors fail to play a role in improgan-induced antinociception.

RNA interference (RNAi), a gene silencing process, has been recently exploited to determine gene function by degrading specific mRNAs in several eukaryotic organisms. We constructed a double stranded RNA (dsRNA) from a previously cloned putative Amblyomma americanum histamine binding protein (HBP) to test the significance of using this methodology in the assessment of the function and importance of gene products in ectoparasitic ticks. The female salivary glands incubated in vitro with HBP dsRNA had a significantly lower histamine binding ability. In addition, the injection of HBP dsRNA into the unfed females led both to a reduced histamine binding ability in the isolated salivary glands and to an aberrant tick feeding pattern or host response. Molecular data demonstrated less expression of the HBP mRNA in the RNAi group. Taken together, these results suggest that RNAi might be an important tool for assessing the significance of tick salivary gland secreted proteins modulating responses at the tick-host interface.

Histamine and antihistamines are so deeply woven into the fabric of allergic diseases that it is sometimes difficult to see how this field could advance beyond our current, potent histamine H1-receptor drugs. Investigations of other actions of histamine and the identification of H2, H3, and now H4 receptors have suddenly reignited the search for new mono- and multi-receptor-specific agonists and antagonists. There is great excitement due to preliminary findings that H3 receptors act as neural inhibitory autoreceptors, and H4 receptors might modulate immune cell functions.

The great majority of the sustained secretory response of adrenal chromaffin cells to histamine is due to extracellular Ca(2+) influx through voltage-operated Ca(2+) channels (VOCCs). This is likely to be true also for other G protein-coupled receptor (GPCR) agonists that evoke catecholamine secretion from these cells. However, the mechanism by which these GPCRs activate VOCCs is not yet clear. A substantial amount of data have established that histamine acts on H(1) receptors to activate phospholipase C via a Pertussis toxin-resistant G protein, causing the production of inositol 1,4,5-trisphosphate and the mobilisation of store Ca(2+); however, the molecular events that lead to the activation of the VOCCs remain undefined. This review will summarise the known actions of histamine on cellular signalling pathways in adrenal chromaffin cells and relate them to the activation of extracellular Ca(2+) influx through voltage-operated channels, which evokes catecholamine secretion. These actions provide insight into how other GPCRs might activate Ca(2+) influx in many excitable and non-excitable cells.

In the present study, the effects of the histamine and cholinergic systems on memory retention in adult male rats were investigated. Post-training intracerebroventricular injections were carried out in all the experiments. Cholinoceptor agonist, acetylcholine (1-10 microg/rat) or nicotine (1-10 microg/rat), increased, while a cholinoceptor antagonist, scopolamine (5-20 microg/rat), decreased memory retention. The response to acetylcholine was attenuated by scopolamine. Administration of histamine (5-20 microg/rat) reduced, but the histamine H(1) receptor antagonist, pyrilamine (10-50 microg/rat), and the histamine H(2) receptor antagonist, cimetidine (1-50 microg/rat), increased memory retention in rats. The histamine receptor antagonists attenuated the response to histamine. Histamine reduced the acetylcholine- or nicotine-induced enhancement. The histamine receptor antagonists enhanced the nicotine- or acetylcholine-induced response. Histamine potentiated the inhibitory effect induced by scopolamine. It is concluded that histaminergic and cholinergic systems have opposing effects on memory retention. Also, the histaminergic system elicits an interaction with the cholinergic system in memory retention.

To determine the effect of stress on carotid sinus baroreceptor reflex (CSR) and whether or not central histaminergic receptors modulate the CSR under stress, the characteristics of CSR were analyzed by using an isolated carotid sinus preparation in Wistar rats. Animals were divided into two groups at random: unstressed group (n=42) and stressed group (n=41). According to the site of microinjection of histaminergic receptor antagonists, each group was subdivided into a group of intracerebroventricular injection (i.c.v.) and a group of microinjection into the nucleus of the solitary tract (NTS). The volume of injection into the lateral cerebroventricle and NTS was 5 microl and 1 micro1, respectively. Stressed groups were subjected to unavoidable electric foot-shock twice daily for a week, each session of foot-shock lasted 2 hours. The left and right carotid sinus regions were isolated from the systemic circulation under anesthesia with pentobarbital sodium in all rats. The intracarotid sinus pressure (ISP) was altered in a stepwise manner to trigger CSR from 0 to 280 mmHg at every step of 40 mmHg and 4 s, and then returned to 0 mmHg in similar steps. ISP and mean arterial pressure (MAP) were recorded simultaneously. ISP-MAP relationship curve was constructed by fitting to the logistic function with five parameters. The CSR parameters and the ISP-MAP relationship curve were separately compared statistically. The main results obtained are as follows. (1) Stress significantly shifted the ISP-MAP relationship curve upwards and obviously moved the middle part of ISP-Gain relationship curve downwards, and decreased the value of the MAP range and maximum gain (G(max)), but increased the threshold pressure (TP), saturation pressure (SP), set point and ISP at G(max) (ISP(Gmax)). (2) I.c.v. of H1 receptor antagonist chlorpheniramine (CHL, 5 microg) or H2 receptor antagonist cimetidine (CIM, 15 g) significantly diminished the above-mentioned changes in CSR performance induced by stress; the alleviative effect of CIM was less remarkable than that of CHL. The responses of CSR in stressed rats to H(1) or H(2) receptor antagonists generally occurred 20 min after the administration and lasted approximately for 15 min. (3) After microinjection of CHL (0.5 microg) or CIM (1.5 microg) into the NTS, the responses of CSR in stressed groups were similar to those after i.c.v. injection of CHL or CIM. (4) However, microinjection of CHL or CIM into the lateral cerebroventricle or the NTS could not completely abolish the stress-induced changes in CSR. These findings suggest that stress results in a resetting of CSR, a decrease in reflex sensitivity. The stress-induced changes in CSR may be mediated, at least in part, by activating the brain histaminergic system. The central histaminergic receptors (H(1) and H(2) receptors) may play an important role in the resetting of CSR under stress. The descending histaminergic pathway from the hypothalamus to NTS may be involved in these effects.

Histamine has been suggested to have roles as a neurotransmitter or a neuromodulator. Direct fiber connections between the hypothalamus and the cerebellum have recently been demonstrated and it is suggested that the cerebellum is involved in the control of autonomic and emotional functions. These fibers include histaminergic fibers. The components of histaminergic signal transmission are demonstrated in the cerebellum as follows: (1) the histaminergic fibers are visualized immunohistochemically in the cerebellar cortex of rat, guinea pig and human; (2) histamine H1 receptors are visualized by autoradiographic studies in the molecular layer of mouse and guinea pig. In situ hybridization study also detects the expression of H1 receptors in the Purkinje cells. H2 receptors are expressed in the Purkinje cells and granule cells of guinea pig; and (3) the application of histamine to the slices of guinea pig or rat cerebellar cortex elicits an increase in the turnover of phosphoinositides, so H1 receptors in the cerebellum are functional. Additionally, we have recently shown in the guinea pig that Purkinje cells express one of the histamine inactivating enzymes, and that inhibition of this enzyme enhances phosphoinositide turnover by histamine. Therefore, all the components of histaminergic neurotransmission are demonstrated in the cerebellum. These data suggest that histamine is involved in the signal transmission from the hypothalamus to the cerebellum. Here we review each component of histaminergic neurotransmission in the cerebellum.

Histamine is a potent bioamine with multiple activities in various pathological and physiological conditions. In addition to its well-characterised effects in the acute inflammatory and allergic responses, histamine regulates several aspects of antigen-specific immune response development. Histamine affects the maturation of dendritic cells and alters their T cell-polarising capacity. Histamine also regulates antigen-specific T helper 1 and T helper 2 cells, as well as related antibody isotype responses. Apparently, diverse effects of histamine on immune regulation are because of differential expression of four types of histamine receptors and their distinct intracellular signals.

By screening Drosophila mutants that are potentially defective in synaptic transmission between photoreceptors and their target laminar neurons, L1/L2, (lack of electroretinogram on/off transients), we identified ort as a candidate gene encoding a histamine receptor subunit on L1/L2. We provide evidence that the ort gene corresponds to CG7411 (referred to as hclA), identified in the Drosophila genome data base, by P-element-mediated germ line rescue of the ort phenotype using cloned hclA cDNA and by showing that several ort mutants exhibit alterations in hclA regulatory or coding sequences and/or allele-dependent reductions in hclA transcript levels. Other workers have shown that hclA, when expressed in Xenopus oocytes, forms histamine-sensitive chloride channels. However, the connection between these chloride channels and photoreceptor synaptic transmission was not established. We show unequivocally that hclA-encoded channels are the channels required in photoreceptor synaptic transmission by 1) establishing the identity between hclA and ort and 2) showing that ort mutants are defective in photoreceptor synaptic transmission. Moreover, the present work shows that this function of the HCLA (ORT) protein is its native function in vivo.

The present study investigated the effect of interactions between histamine receptor agents and the opioid peptidergic system on memory retention of passive avoidance learning in rats. Post-training intracerebroventricular (i.c.v.) injections were carried out in all the experiments. Administration of histamine (20 micro g/rat) reduced, but the histamine H(1) receptor antagonist, pyrilamine (20 and 50 micro g/rat), and the histamine H(2) receptor antagonist, cimetidine (10 and 50 micro g/rat), increased memory retention in rats. The histamine receptor antagonists decreased the response induced by histamine. Morphine (1-10 micro g/rat) reduced, while pentazocine (5 and 10 micro g/rat) or the opioid receptor antagonist, naloxone (5 and 15 micro g/rat), increased memory retention. The combination of histamine with morphine showed potentiation. Effects of pyrilamine and cimetidine were attenuated by morphine. The responses to pentazocine and naloxone also were decreased by histamine. It is concluded that the histaminergic system has an interaction with opioidergic system that is involved in the memory retention process.

Histamine is known to trigger the release of interleukin (IL)-16 from human CD8(+) cells. However, the individual roles of the presently known histamine receptor subtypes (H(1)-H(4)) in this inflammatory response have not been fully characterized. Histamine stimulation of human CD8(+) T lymphocytes purified from peripheral blood led to a 5- to 8-fold increase in the basal release of IL-16 within 24 h, and this increase was significantly blocked by the H(2)-selective antagonist, cimetidine, or by thioperamide, an antagonist of H(3) and H(4) receptors, respectively. The H(1) antagonist pyrilamine showed limited effects. Agonists selective for H(2) (dimaprit), H(3/4) (R-(-)-alpha-methylhistamine), and H(4) (clobenpropit) were capable of inducing the release of bioactive IL-16 because CD8(+) cell supernatants induced CD4(+) cell migration, which was abrogated by an anti-IL-16 antibody. Furthermore, preincubation of lymphocytes with pertussis toxin abolished IL-16 release triggered by activation of the G(i/o)-coupled H(4) receptor but not by the H(2) receptor. Messenger RNA expression studies confirmed H(4), H(2), and H(1) expression in human CD8(+) lymphocytes, whereas H(3) mRNA was completely absent. All leukocyte populations investigated expressed mRNA for H(4), with highest levels found in eosinophils, dendritic cells, and tonsil B cells. H(4) expression was also detected in human lung, trachea, and various cells of human lung origin, such as fibroblasts, bronchial smooth muscle cells, epithelial, and endothelial cells. Since many of those are known sources of IL-16, immune cell- and lung cell-expressed H(4) receptors may have a general role in the control of this mediator of inflammatory disorders such as asthma.

Murine tumor necrosis factor-alpha (mTNF-alpha) results in the sensitization of mechanisms underlying plasma corticosterone activity and sickness behavior, the latter being reminiscent of septic or anaphylactic shock. The mTNF-alpha induced a sensitization of sickness and corticosterone in mice that was attenuated by pretreatment with the combinations of histamine H(1) (diphenhydramine, mepyramine) and H(2) (cimetidine) antagonists. Likewise, coadministration of diphenhydramine and cimetidine prevented the mTNF-alpha-provoked rise of monoamine activity within the posterior hypothalamus. Although dexamethasone ameliorated the mTNF-alpha-induced sensitization of corticosterone, illness behavior was unaffected. It is suggested that mTNF-alpha-induced illness and the neuroendocrine sensitization are mediated by endogenous histamine.

Background: Interleukin (IL)-18 was identified as an interferon (IFN)-gamma-inducing factor and was demonstrated to up-regulate the expression of intercellular adhesion molecule (ICAM)-1 on human monocytes. In organ transplantation, elevation of plasma IL-18 levels has been reported during acute rejection. In the present study, we examined the effect of IL-18 on human mixed lymphocyte reaction (MLR), an in vitro model of acute rejection after organ transplantation. We also investigated the modulatory effects of histamine on IL-18 action because histamine has been demonstrated to be a modulator of IL-18 effect and a mediator of inflammation., Methods: We measured the expression of ICAM-1 on human monocytes in MLR in the presence or absence of IL-18 by flow cytometer and determined the associated production of IFN-gamma and IL-12 by ELISA. The modulatory effects of histamine and the relevant histamine receptor subtypes were characterized pharmacologically., Results: The expression of ICAM-1 on monocytes in MLR was markedly enhanced by the addition of IL-18 in a concentration- and time-dependent manner. In parallel to ICAM-1 up-regulation, IL-18 significantly enhanced the production of IFN-gamma and IL-12 in MLR. Histamine concentration-dependently inhibited ICAM-1 expression and cytokine production in MLR stimulated with IL-18, whereas histamine alone did not show any effects on these responses in the absence of IL-18. The effects of histamine on both ICAM-1 expression and cytokine production were mimicked by the selective H2-receptor agonists 4-methylhistamine and dimaprit and were antagonized by the H2-receptor antagonist famotidine but not by H1- and H3-receptor antagonists., Conclusion: IL-18 strongly enhanced human MLR with respect to ICAM-1 expression and cytokine production. The fact that histamine could inhibit the IL-18-stimulated MLR implies that immunomodulation by histamine and selective H2-receptor agonists may have an important role in future immunosuppressive strategies.

1. This work was designed to introduce human uterine arteries as a new model for cardiovascular research. Advantages of this model include considerable availability of tissue because of the appearance of uterus myomatosus in post-menopausal women who undergo surgery and the chance to work on dysfunctional and healthy vessels. 2. Histamine evoked relaxation of the uterine artery that was prevented by removal of the endothelium or by the presence of N(G)-nitro-L-arginine. 3. Receptor antagonists for histamine H(1) (mepyramine) and H(2) (ranitidine) receptors increased the EC(50) of histamine by 112- and 67-fold, respectively. 4. Remarkably, isolated uterine arteries could be stored in incubators for 5 days without any change in contractility to phenylephrine and endothelium-dependent relaxation to acetylcholine and histamine. 5. Endothelial cells could be isolated and cultured in high purity, as demonstrated by histochemical staining of factor VIII, low CD45-RO for macrophages and no smooth muscle alpha-actin. In addition, cultured human uterine artery endothelial cells could be used for single cell Ca(2+) measurements. 6. In agreement with our findings in the intact vessel, histamine-initiated elevation of the intracellular free Ca(2+) concentration was reduced in the presence of mepyramine and ranitidine by 59 and 55%, respectively. 7. These data indicate that, in the human uterine artery, H(1) and H(2) receptors are involved in histamine-induced endothelium-dependent relaxation that is mediated by nitric oxide. 8. In addition, this vessel can be stored for possible virus-mediated gene expression for 5 days without any loss of reagibility. 9. Finally, endothelial cells can be isolated and cultured from the human uterine artery and maintain their reactivity to histamine in culture.

The effects of different histamine receptor agonists and antagonists on the nociceptive threshold were investigated in mice by two different kinds of noxious stimuli: thermal (hot plate) and chemical (acetic acid-induced abdominal writhing). Intracerebroventricular (icv) injection of the histamine H(1) receptor agonist, HTMT (6-[2-(4-imidazolyl)ethylamino]-N-(4-trifluoromethylphenyl) heptanecarboxamide) (50 microg/mouse), produced a hypernociception in the hot plate and writhing tests. Conversely, intraperitoneal (ip) injection of dexchlorpheniramine (30 and 40 mg/kg) and diphenhydramine (20 and 40 mg/kg) increased the pain threshold in both tests. The histamine H(2) receptor agonist, dimaprit (50 and 100 microg/mouse icv), or antagonist, ranitidine (50 and 100 microg/mouse icv), raised the pain threshold in both hot plate and writhing tests. In the mouse hot plate test, the histamine H(3) receptor agonist, imetit (50 mg/kg ip), reduced the pain threshold, while the histamine H(3) receptor antagonist, thioperamide (10 and 20 mg/kg ip), produced an antinociception. The hypernociceptive effects of HTMT and imetit were antagonized by dexchlorpheniramine (20 mg/kg ip) and thioperamide (5 mg/kg ip), respectively. The results suggest that histaminergic mechanisms may be involved in the modulation of nociceptive stimuli.

Background: Histamine is a well-known mediator eliciting different responses in immune and nonimmune cells, but its role in modulating dendritic cell (DC) functions has been marginally investigated., Objective: The purpose of this investigation was to analyze whether human monocyte-derived DCs express functional histamine receptors according to their maturation stage., Methods: DCs were derived from monocytes and used as immature or LPS-differentiated cells. DCs were tested for histamine receptor expression, chemotaxis, cytokine release, and the capacity to induce T-cell differentiation in response to specific histamine receptor agonists., Results: Immature and mature DCs expressed the mRNA for H1, H2, and H3 histamine receptors. Histamine induced intracellular Ca2+ transients, actin polymerization, and chemotaxis in immature DCs. Maturation of DCs resulted in the loss of these responses. In maturing DCs, however, histamine dose-dependently enhanced intracellular cAMP levels and stimulated IL-10 secretion while inhibiting production of IL-12. As a consequence, histamine might contribute to the impairment of generation of allogeneic type 1 responses via maturing DCs. Specific histamine receptor agonists or antagonists revealed that Ca2+ transients, actin polymerization, and chemotaxis of immature DCs were due to stimulation of H1 and H3 subtypes. Modulation of IL-12 and IL-10 secretion by histamine involved the H2 and H3 receptors exclusively., Conclusions: Our study suggests that histamine has important biological effects on DC activities, opening the possibility that histamine released during inflammatory or immune responses could regulate DC functions and ultimately favor type 2 lymphocyte-dominated immunity.

1. Although monumental efforts have been made to define the action sites of cough, the importance of neurotransmitter systems in the cough reflex has received limited attention. We studied the roles for four major neurotransmitters [acetylcholine, histamine, serotonin (5-hydroxytryptamine, 5-HT) and dopamine] in the modulation of the cough reflex. 2. Atropine (muscarinic cholinergic blocking agent), pyrilamine maleate (PM, histamine H1 blocker), cimetidine (histamine H2 blocker), 8-hydroxy-2-(di-n-propylamino)-tetralin (8-OH-DPAT, specific 5-HT1A receptor agonist) and SCH-23390 (selective dopamine D1 receptor antagonist) were examined on the cough response to inhaled capsaicin in conscious guinea-pigs. 3. All the drugs significantly decreased the number of capsaicin-induced coughs in a dose-dependent manner. To compare the sensitivity of these drugs on cough response, we calculated the effective doses for 50% inhibition of cough (ED50) when the animals were exposed to 3 x 10-4 m capsaicin. The ED50 values were 0.03 microm kg-1 for atropine, 0.2 microm kg-1 for 8-OH-DPAT, 6.2 microm kg-1 for SCH-23390, 8.5 microm kg-1 for PM and 13.9 microm kg-1 for cimetidine. 4. These findings indicated that all these four neurotransmitters may be involved in the regulation of the cough reflex. Multiple changes of these neurotransmitters in disorders of the central nervous system might synergically affect the cough reflex.

During the past few years, there has been a tremendous increase in our understanding of the histamine receptors. Important progress has been made in the development of H1-receptor agonists and the rationalization of H1-receptor-ligand interaction. The recent observation of constitutive H1- and H2-receptor activity has led to a reclassification of H1- and H2-antagonists. For the H3-receptor, a wide variety of selective and potent ligands are currently available and await clinical application. The recent cloning of the H3-receptor gene and the anticipated generation of transgenic mice will facilitate this development. Within the field of signal transduction, a previously unanticipated complexity has been unravelled. With the cloning of the H3-receptor gene, a similar complexity is to be expected.

In allergic rhinoconjunctivitis, histamine is known to contribute predominantly to nasal itch, sneeze, rhinorrhea, conjunctival itch, and lacrimation and these symptoms benefit most from H1-antihistamine therapy. The discovery in the early 1980s of nonsedating H1-receptor antagonists contributed dramatically to the more widespread acceptance of this mode of therapy. This also led to the undertaking of well-designed clinical trials that have added significantly to our understanding of allergic rhinitis. Oral treatment modifies both nasal and ocular symptoms and provides effective control throughout a 24-h period with once- or twice-daily medication. The advent of topical H1-receptor antagonists offers a wider choice of treatments and provides equal or greater efficacy with lower systemic bioavailability. While having a major impact on rhinoconjunctivitis symptoms, H1-antihistamines do not fully modify disease since histamine is not the only contributor to symptom generation in allergic rhinoconjunctivitis. While the search for oral H1-antihistamines with more widespread "antiallergic" activity continues, the currently available medications modify predominantly histamine-regulated events despite in vitro evidence of greater potential. The development of these new medications may be the next significant advance in this mode of treatment.

In the elderly, H1-antihistamine therapy is commonly prescribed for treatment of rhinitis, conjunctivitis, pruritus, eczema, urticaria, and for prophylaxis of anaphylactoid reactions. Second-generation H1-receptor antagonists provide excellent, safe, and effective alternatives to first-generation antihistamines in this population, as in younger patients. As with all medications, the choice of which agent to use must be tailored to the needs of the individual. Treatment should be planned with consideration of concomitant medications and potential drug-drug interactions and drug-disease interactions. First-generation antihistamines should not be used for treatment of allergic rhinitis or urticaria in the elderly. Age-related physiological changes can enhance or complicate the actions of H1-receptor antagonists, especially when these drugs are taken concurrently with other medications and/or in the presence of comorbid disease. Adjustments in dosages are necessary when some agents are used in patients with renal and/or hepatic disease; however, overall, the use of the newer nonsedating antihistamines is safe, effective, and gratifying in the elderly.

Anaphylaxis and anaphylactoid reactions are potentially fatal. These disorders are sometimes iatrogenic, and increase with increased exposure to drugs, synthetic substances, and medical procedures. Non-IgE-mediated anaphylactoid reactions are common in medical settings and are clinically indistinguishable from anaphylaxis. These reactions may be unrecognized if a rigid classic definition of anaphylaxis is used. Histamine is a primary mediator of anaphylaxis and signs and symptoms of anaphylaxis can be reproduced by histamine infusion. Histamine triggers a cascade of inflammatory mediators and modulates its own release. H1-antihistamines are adjunctive treatment therapy for acute anaphylaxis and anaphylactoid reactions, in which many mediators of inflammation are involved. Compared with epinephrine, the first-response medication of choice, antihistamines have a slow onset of action, and they cannot block events that occur subsequent to histamine binding to its receptors. Antihistamines are an important component of regimens for the prevention of anaphylaxis and anaphylactoid reactions in patients at risk, and may eventually have more widespread application in the perioperative setting. In some instances, such as with exercise-induced anaphylaxis and reactions to latex in sensitized individuals, prophylaxis regimens are not always effective. H2-antagonists are not detrimental in the therapy of anaphylaxis and many studies show a favorable outcome when combining H1- and H2-antagonist therapy for prophylaxis. They should be added to therapy at the discretion of the treating physician. Because of decreased antimuscarinic and central nervous system side effects, the newer antihistamines can be given in high doses, allowing more complete blockade of histamine receptors. These agents should lead to a reevaluation of the usefulness of antihistamines in both the treatment of acute anaphylaxis and in prophylactic regimens. The unavailability of parenterally administered second-generation H1-antagonists limits their usefulness in acute anaphylaxis and perioperative prophylaxis.

Atopic diseases such as allergy and asthma are characterized by increases in Th2 cells and serum IgE antibodies. The binding of allergens to IgE on mast cells triggers the release of several mediators, of which histamine is the most prevalent. Here we show that histamine, together with a maturation signal, acts directly upon immature dendritic cells (iDCs), profoundly altering their T cell polarizing capacity. We demonstrate that iDCs express two active histamine receptors, H1 and H2. Histamine did not significantly affect the LPS-driven maturation of iDCs with regard to phenotypic changes or capacity to prime naive T cells, but it dramatically altered the repertoire of cytokines and chemokines secreted by mature DCs. In particular, histamine, acting upon the H2 receptor for a short period of time, increased IL-10 production and reduced IL-12 secretion. As a result, histamine-matured DCs polarized naive CD4(+) T cells toward a Th2 phenotype, as compared with DCs that had matured in the absence of histamine. We propose that the Th2 cells favor IgE production, leading to increased histamine secretion by mast cells, thus creating a positive feedback loop that could contribute to the severity of atopic diseases.

Repetitive induction of audiogenic seizures (AGSs) ("AGS kindling") results in expansion of the AGS neuronal network from the brainstem to forebrain structures. AGSs in kindled genetically epilepsy-prone rats (GEPR-9s) exhibit a significant increase in the duration of posttonic clonus (PTC). The amygdala (AMG) does not appear to be a required network component before AGS kindling, but this structure is implicated in the seizure network after AGS kindling. gamma-Aminobutyric acid (GABA) is a major neurotransmitter in AMG, and histamine receptor activation is also reported to stimulate GABA release. The present study examined the effect on audiogenically kindled seizures of focal microinjections into the AMG of GEPR-9s. AGS kindling involved induction of 14 AGSs in GEPR-9s. Bilateral microinjection of a GABA(A) agonist, muscimol (0.3 nmol/side), into the AMG significantly reduced the duration of PTC, starting 0.5 h after drug infusion, with recovery by 24 h. Microinjection of histamine (60 nmol/side) suppressed PTC at 0.5 h, with total blockade at 24 h, but the seizure pattern did not revert to that observed before kindling until 120 h. This long duration suggests that mechanisms in addition to modulation of GABA function may be involved in the effect of histamine. The wild running and tonic components of AGS were never affected by microinjection of these agents into the AMG. These findings confirm previous work suggesting that the AMG is not a required nucleus in the AGS neuronal network before kindling. However, the AMG becomes critical in expansion of the seizure network during AGS kindling, and audiogenically kindled seizures are negatively modulated by increased GABA function., ((c)2001 Elsevier Science.)

Acetylcholine modulates histaminergic transmission via M(1) receptors. On the other hand, cholinergic transmission is modulated by neighbouring histaminergic neurons via H(1), H(2) and H(3) receptors. Dopaminergic and GABAergic neurons are also involved in these modulatory mechanisms. Furthermore, the release of histamine is modulated by glutamatergic neurons and nitric oxide of neuronal origin. The release of histamine in the brain oscillates according to circadian, slow ultradian and fast ultradian rhythms. Ultradian fluctuations have also been observed in the theta- and delta-frequency bands of the EEG spectral power. Simultaneous recordings of histamine outflow and EEG in the hypothalamus revealed that the ultradian histamine release rhythm coincides temporally with ultradian fluctuations in the EEG spectral power. Histamine receptor ligands used in pharmacotherapy, like H(1) and H(2) antagonists, modify the frequency of the EEG fluctuations. Brain histamine seems to be involved in memory processes, since inhibition of histamine synthesis deteriorates, while H(3) antagonists, histamine and histidine improve short-term memory. The latter finding may open new horizons in pharmacological treatment of memory disorders.

Histamine is known to play a role in the regulation of waking behavior as well as in processes of memory and reinforcement. The striatum and thalamic nuclei as the intralaminar complex and the anterior group can be involved in these functions. Little is known about the action of histamine on neurons of these brain structures. Single unit activity was extracellularly recorded in rats anesthetized with urethane. Firing of anterior and intralaminar thalamic neurons that responded to iontophoretically administered histamine was predominantly reduced (Wilcoxon test (Wt), P<0.05, n=49 and 63, respectively), whereas striatal neurons were mainly activated by the drug (Wt, P<0.05, n=29). Thalamic neurons also significantly reduced the number of burst discharges and the proportion of spikes involved in bursts. The histaminergic effects could be blocked by H1 or H2 receptor antagonists. In conclusion, histamine may control waking behavior also via nonspecific thalamic nuclei and basal ganglia circuits. Through modulation of the transmission in the anterior thalamus it may exert an influence on learning and emotional processes.

The aim of this review is to survey biochemical, electrophysiological and behavioral evidence of the interactions between the cholinergic and histaminergic systems and evaluate their possible involvement in cognitive processes. The cholinergic system has long been implicated in cognition, and there is a plethora of data showing that cholinergic deficits parallel cognitive impairments in animal models and those accompanying neurodegenerative diseases or normal aging in humans. Several other neurotransmitters, though, are clearly implicated in cognitive processes and interact with the cholinergic system. The neuromodulatory effect that histamine exerts on acetylcholine release is complex and multifarious. There is clear evidence indicating that histamine controls the release of central acetylcholine (ACh) locally in the cortex and amygdala, and activating cholinergic neurones in the nucleus basalis magnocellularis (NBM) and the medial septal area-diagonal band that project to the cortex and to the hippocampus, respectively. Extensive experimental evidence supports the involvement of histamine in learning and memory and the procognitive effects of H(3) receptor antagonists. However, any attempt to strictly correlate cholinergic/histaminergic interactions with behavioral outcomes without taking into account the contribution of other neurotransmitter systems is illegitimate. Our understanding of the role of histamine in learning and memory is still at its dawn, but progresses are being made to the point of suggesting potential treatment strategies that may produce beneficial effects on neurodegenerative disorders associated with impaired cholinergic function.

I have been studying the functions of the histaminergic neuron system in the brain, the location and distribution of which we elucidated with antibody raised against L-histidine decarboxylase (a histamine-forming enzyme) as a marker in 1984. For this purpose, we used two methods employing (1) pharmacological agents like alpha-fluoromethylhistidine, an HDC inhibitor, and agonists and antagonists of H1, H2 and H3 receptors and (2) knockout mice of the HDC- and H1- and H2-receptor genes. In some cases, we used positron emission tomography (PET) of H1 receptors in living human brains. It turned out that histamine neurons are involved in many brain functions, and particularly, histamine is one of the neuron systems to keep awakefulness. Histamine also plays important roles in bioprotection against various noxious or unfavorable stimuli (convulsion, nociception, drug sensitization, ischemic lesions, stress and so on). Finally, I briefly described interesting phenotypes found in peripheral tissues of HDC-KO mice; the most striking finding is that mast cells in HDC-KO mice are fewer in number, smaller in size and less dense in granule density than those of wild type mice, indicating that histamine is related to the proliferation and differentiation of mast cells. In conclusion, histamine is important not only in the central and peripheral systems as studied so far but also may be related to some new functions that are now under investigation in our laboratories.

Recently, we and other groups have identified cDNA encoding the novel histamine H4 receptor. All of the groups have initially found a clue for the H4 receptor-nucleotides sequence in the human draft genomic DNA database. The primary structure of H4 receptor reveals the highest homology with H3 receptor among known G-protein coupled receptors (37.4%). H4 receptor binds to histamine with high affinity, which results in the down-regulation of intracellular cAMP level. H4 receptor is activated not only by histamine, but also R-(alpha)-methylhistamine (H3 receptor agonist), clobenpropit (H3 receptor antagonist), clozapine (neuroleptic) and other histaminergic compounds, while it is antagonized by thioperamide (H3 receptor antagonist). The H4 receptor is localized in the peripheral blood leukocytes, spleen, thymus, small intestine, colon, bone marrow and so on. The tissue distribution of the H4 receptor and known physiological function of histamine tempts us to speculate about its function as an immune modulator. Although there needs much additional work on characterization of the H4 receptor, the discovery of this receptor subtype will unveil a new phase for determining the physiological role of histamine.

Histamine activates pain-transmitting nerve fibres, releases pain-related neuropeptides, and is painful when injected into the skin. Histamine agonists mimic these effects, suggesting that histamine plays a role in mediating the signal transduction of tissue damage or other painful stimulus. Certain 'antihistamines' (histamine H1 receptor antagonists) and other antihistaminics are 'analgesic' in preclinical or clinical models. Potential sites of action of these agents include the brain and spinal cord and a specific histamine receptor subtype might be involved (three subtypes have been identified). However, it is possible that other mechanisms account for the analgesic effect.

The possible functional regional distribution of the histamine sensitive sites controlling the behavioral performance of learning of an active avoidance response in the hippocampal structure was studied. Adult male rats were stereotaxically implanted with microinjection cannula into three different regions of the hippocampus: the ventral, the dorsal posterior and the dorsal anterior hippocampus. Different groups of rats were microinjected into these subregions with either saline, 9, 45 or 90 nmol of histamine. Five min later all groups were subjected to learning of a conditioned response to an ultrasonic tone warning an electric shock to the feet of the animals. Three sessions of 8 trials were necessary in order to control animals learn the task. Results show that histamine microinjections into the ventral hippocampus were able to significantly inhibit the natural decrease of the latency to escape during trials, impairing the efficiency of learning. Histamine administration into the dorsal posterior hippocampus was slightly effective in prolonging latency and impairing learning, while injections into the dorsal anterior region of the hippocampus had no effect. Results give a further support to the idea that histamine sensitive neurons in the ventral hippocampus are modulating the memory and learning mechanisms in the rat. In addition, evidence has been found suggesting a regional distribution of histamine sensitive neurons controlling learning of avoidance responses along the septo-temporal axis of the rat hippocampus.

Zymosan-induced peritonitis was investigated in mast cell-deficient WBB6F1 mice and in Balb/c mice pretreated with mast cell stabilizer (cromolyn) or antagonists of histamine receptors (mepyramine, triprolidine, cimetidine, or ranitidine). The inherited mast cell deficiency in W/Wv knockouts of WBB6F1 mice impaired significantly the level of histamine and plasma exudation (measured 30 min after stimulation) as well as the influx of exudatory leukocytes, accumulation of plasma and exudate chemoattractants, and the release of proinflammatory cytokines (TNF-alpha, IL-1beta, and IL-6) measured at 6 h of inflammation. All of those factors were fully restored after selective intraperitoneal reconstitution of W/Wv mice with bone marrow-derived mast cells from their control +/+ counterparts. Cromolyn pretreatment of Balb/c mice reduced exclusively the early plasma exudation and histamine influx. Blocking of histamine receptors inhibited not only the early plasma exudation but also temporarily diminished primary leukocyte influx and levels of MCP-1 and IL-1beta. In conclusion, mast cells play an important role in the initiation of zymosan-induced peritonitis and modulate its further course.

Atypical antipsychotics such as clozapine represent a significant improvement over typical antipsychotics in the treatment of schizophrenia, particularly regarding extrapyramidal symptoms. Despite their benefits, use is limited by the occurrence of adverse reactions such as sedation and weight gain. This article provides a comprehensive review and discussion of obesity-related pathways and integrates these with the known mechanisms of atypical antipsychotic action to identify candidate molecules that may be disrupted during antipsychotic treatment. Novel preliminary data are presented to genetically dissect these obesity pathways and elucidate the genetic contribution of these candidate molecules to clozapine-induced weight gain. There is considerable variability among individuals with respect to the ability of clozapine to induce weight gain. Genetic predisposition to clozapine-induced weight gain has been suggested. Therefore, genetic variation in these candidate molecules may predict patient susceptibility to clozapine-induced weight gain. This hypothesis was tested for 10 genetic polymorphisms across 9 candidate genes, including the serotonin 2C, 2A, and 1A receptor genes (HTR2C/2A/1A); the histamine H1 and H2 receptor genes (H1R/H2R); the cytochrome P450 1A2 gene (CYPIA2); the beta3 and alpha,alpha-adrenergic receptor genes (ADRB3/ADRAIA); and tumor necrosis factor alpha (TNF-alpha). Prospective weight gain data were obtained for 80 patients with schizophrenia who completed a structured clozapine trial. Trends were observed for ADRB3, ADRA1A, TNF-alpha, and HTR2C; however, replication in larger, independent samples is required. Although in its infancy, psychiatric pharmacogenetics will in the future aid clinical practice in the prediction of response and side effects, such as antipsychotic-induced weight gain, and minimize the current "trial and error" approach to prescribing.

A new histamine receptor, HH4R, was cloned from human leukocyte cDNA. The deduced amino acid sequence showed about 40% identity to that of the human histamine H3 receptor, HH3R. HH4R-expressing cells responded to histamine, inhibiting forskolin-induced cAMP accumulation. An H3 agonist, N-alpha-methylhistamine (NAMHA), bound specifically to HH4R, while another H3 agonist, R(-)-alpha-methylhistamine (RAMHA), and the H3 antagonist, thioperamide, competed with this binding. RAMHA, NAMHA, and imetit inhibited forskolin-induced cAMP accumulation in HH4R-expressing cells. However, the binding affinities and agonistic activities of H3 agonists to HH4R were weaker than those to HH3R. Low expression of HH4R was detected in a wide variety of peripheral tissues by RT-PCR; however, in contrast with HH3R, expression was not detected in the brain. These observations indicate that the clone is a distinct histamine receptor from HH3R, and thus is named HH4R., (Copyright 2000 Academic Press.)

Several investigations reported modulation of lymphocyte functions following activation of the histamine H2 receptor. However, few data have accumulated with regard to the distribution of histamine H2 receptors on different lymphocyte subsets. Conversely, the distribution of histamine H1 receptors on different lymphocyte subsets has been thoroughly analyzed using specific radioligands, whereas the functional significance of histamine H1 receptor ligation on lymphocytes has not been fully elucidated yet. Recent investigations suggest that H1R signaling on lymphocytes may enhance whereas activation of the H2R may inhibit lymphocyte responses. In this review, the authors discuss the current knowledge on distribution and functional significance of histamine H1 and histamine H2 receptors on human lymphocytes.

The non-receptor tyrosine kinase PYK2 appears to function at a point of convergence of integrins and certain G protein-coupled receptor (GPCR) signaling cascades. In this study, we provide evidence that translocation of PYK2 to focal adhesions is triggered both by cell adhesion to extracellular matrix proteins and by activation of the histamine GPCR. By using different mutants of PYK2 as green fluorescent fusion proteins, we show that the translocation of PYK2 to focal adhesions is not dependent on its catalytic activity but rather is mediated by its carboxyl-terminal domain. Translocation of PYK2 to focal adhesions was attributed to enhanced tyrosine phosphorylation of PYK2 and its association with the focal adhesion proteins paxillin and p130(Cas). Translocation of PYK2 to focal adhesions, as well as its tyrosine phosphorylation in response to histamine treatment, was abolished in the presence of protein kinase C inhibitors or cytochalasin D treatment, whereas activation of protein kinase C by phorbol ester resulted in focal adhesion targeting of PYK2 and its tyrosine phosphorylation in an integrin-clustering dependent manner. Overexpression of a wild-type PYK2 enhanced ERK activation in response to histamine, whereas a kinase-deficient mutant substantially inhibited this response. Furthermore, inhibition of PYK2 translocation to focal adhesions abolished ERK activation in response to histamine treatment. These results suggest that PYK2 apparently links between GPCRs and focal adhesion-dependent ERK activation and can provide the molecular basis underlying PYK2 function at a point of convergence between signaling pathways triggered by extracellular matrix proteins and certain GPCR agonists.

1. The modifications of hippocampal release of norepinephrine following the administration of R-(-)-alpha-methylhistamine and thioperamide, respectively agonist and antagonist of histamine H3 receptors, were assessed in freely moving rats by microdialysis. 2. Both the systemic (2 mg/kg i.p.) and local (100 microM via the probe) administration of thioperamide caused no modifications of basal release, indicating that the histaminergic system is not tonically involved in regulating the hippocampal noradrenergic activity. 3. R-(-)-alpha-methylhistamine (1 and 100 microM) produced a slight, short-lasting and dose-dependent reduction of norepinephrine release antagonized by local perfusion (100 microM) and prevented by systemic administration of thioperamide 2 mg/kg. 4. The results seem to indicate that the modulation of norepinephrine release through presynaptic H3-receptors in the rat hippocampus plays a minor role in the memory-enhancing effects of thioperamide.

Recent findings suggest that astrocytes respond to neuronally released neurotransmitters with Ca2+ elevations. These Ca2+ elevations may trigger astrocytes to release glutamate, affecting neuronal activity. Neuronal activity is also affected by modulatory neurotransmitters that stimulate G protein-coupled receptors. These neurotransmitters, including acetylcholine and histamine, might affect neuronal activity by triggering Ca2+-dependent release of neurotransmitters from astrocytes. However, there is no physiological evidence for histaminergic or cholinergic receptors on astrocytes in situ. We asked whether astrocytes have these receptors by imaging Ca2+-sensitive dyes sequestered by astrocytes in hippocampal slices. Our results show that immunocytochemically identified astrocytes respond to carbachol and histamine with increases in intracellular free Ca2+ concentration. The H1 histamine receptor antagonist chlorpheniramine inhibited responses to histamine. Similarly, atropine and the M1-selective muscarinic receptor antagonist pirenzepine inhibited carbachol-elicited responses. Astrocyte responses to histamine and carbachol were compared with responses elicited by alpha1-adrenergic and metabotropic glutamate receptor agonists. Individual astrocytes responded to different subsets of receptor agonists. Ca2+ oscillations were the prevalent response pattern only with metabotropic glutamate receptor stimulation. Finally, functional alpha1-adrenergic receptors and muscarinic receptors were not detected before postnatal day 8. Our data show that astrocytes have acetylcholine and histamine receptors coupled to Ca2+. Given that Ca2+ elevations in astrocytes trigger neurotransmitter release, it is possible that these astrocyte receptors modulate neuronal activity.

The functions of intratumoral lymphocytes in many human malignant tumors are inhibited by reactive oxygen species (ROS), generated by adjacent monocytes/macrophages (MO). In vitro data suggest that immunotherapeutic cytokines such as interleukin-2 (IL-2) or interferon-alpha (IFN-alpha) only weakly activate T cells or natural killer (NK) cells in a reconstituted environment of oxidative stress and that inhibitors of the formation of ROS or scavengers of ROS synergize with IL-2 and IFN-alpha to activate T cells and NK cells. In this review, we focus on the immunoenhancing properties of histamine, a biogenic amine. Histamine inhibits ROS formation in MO via H2-receptors; thereby, histamine protects NK cells from MO-mediated inhibition and synergizes with IL-2 and IFN-alpha to induce killing of NK cell-sensitive human tumor cells in vitro. Histamine also optimizes cytokine-induced activation of several subsets of T cells by affording protection against MO-inflicted oxidative inhibition. The putative clinical benefit of histamine as an adjunct to immunotherapy with IL-2 and/or IFN-alpha is currently evaluated in clinical trials in metastatic malignant melanoma and acute myelogenous leukemia.

The aim of this study was to investigate whether the inhibition of one of the endothelial receptor sites in the rat pulmonary artery (muscarinic, histaminergic, purinergic, alpha2-adrenergic) affects the NO-mediated relaxation induced by the activation of the other type of receptors. Acetylcholine (ACh)-, histamine (Hist)-, adenosine (Ade)-, and clonidine (Clon)-induced endothelium-dependent relaxations were reduced by the administration of specific antagonists of muscarinic, H1-histaminergic, purinergic or alpha2-adrenergic receptors, respectively. The inhibition of H1-histaminergic receptors by chlorphenyramine did not prevent ACh-induced relaxation. Similarly, the inhibition of muscarinic receptors by atropine did not prevent the relaxations to histamine, adenosine and clonidine. On the other hand, the relaxations induced by acetylcholine, histamine, adenosine or clonidine were regularly reduced by NO-synthase inhibitor N(G)-nitro-L-arginine methyl ester (10(-4) mol/l). These results suggest that the inhibition of NO-synthase abolished arterial relaxations induced by all agonists. After inhibition of one type of the endothelial receptors, the NO-dependent relaxation could still be evoked by activation of one of the others.

Aim: To investigate characteristics of the cell receptor systems in bronchial asthma (BA) patients with bronchial hyperreactivity (BHR) induced by hyperosmolar provocation., Materials and Methods: 15 patients with BA, in most cases atopic, in remission were studied. The bronchoprovocative test (BPT) with ultrasonically nebulized 3.6% hypertonic NaCl solution (UNHS) FEV1-control was performed. Cell receptors reactivity was analysed on the model of erythrocyte resistance (ER) to hyperosmolar provocation (HP) under the modulation by adrenergic and histaminergic agents., Results: It was revealed that ER was significantly higher (p < 0.05) in BA patients with BHR to UNHS under histaminergic modulation, but ER did not differ in BA patients with or without BHR to UNHS under the adrenergic modulation. The correlation was found between DFEV1 on BPT and magnitude of ER to HP under the blockade of H1-histaminergic receptors (r = 0.72; p < 0.02)., Conclusion: The development of BHR to hyperosmolar stimulus may be due primarily to disturbance of histaminergic receptor system.

Background: Gastrin release by Helicobacter pylori may be an important step in the pathway leading to duodenal ulceration. A histamine H3-receptor agonist was found to release gastrin from antral mucosal fragments; this was interpreted as being due to suppression of somatostatin release. H. pylori is reported to produce Nalpha-methyl histamine (NalphaMH), which is an agonist of H3 as well as other histamine receptors. H. pylori infection also recruits mast cells, which release histamine., Aim: To determine the direct effects of histamine receptor agonists on isolated gastrin cells., Methods: Rabbit G-cells were prepared by countercurrent elutriation and cultured on 24-well plates., Results: NalphaMH (10-6-10-4 M) caused a dose-dependent increase in gastrin release from a basal level of 2.3 +/- 0.2% total cell content (TCC; mean +/- S.E.M.) to a maximum of 5.1 +/- 0.7%, an increase of 117% (P < 0. 005) above basal. This was abolished by the H2-antagonist ranitidine (10-5 M), but not by immunoblockade with anti-somatostatin antibody, the H1-antagonist chlorpheniramine (10-5 M) or the H3-antagonist thioperamide (10-4 M). The histamine H2-receptor agonist dimaprit (10-6-10-4 M) increased gastrin release from 2.4 +/- 0.2% to 3.6 +/- 0.2% TCC (P < 0.001). Gastrin release was also stimulated by histamine (10-7-10-4 M) from a basal value of 3.0 +/- 0.3% to 5.4 +/- 0.5% TCC (P < 0.001). This also was inhibited by ranitidine (10-5 M) (P < 0.01)., Conclusion: NalphaMH and histamine release gastrin from G-cells via H2-receptors; this might contribute to H. pylori-associated hypergastrinaemia.

Hemodynamic responses to histamine were investigated in the anesthetized rabbit. Intravenous injections of histamine induced dose-dependent decreases in systemic arterial pressure that were blocked by the H(1)-receptor antagonist pyrilamine but not the H(2) antagonist cimetidine. Injections of histamine and the H(1) agonist 6-[2-(4-imidazolyl)ethylamine]-N-(4-trifuormethylphenyl)-heptan ecardo xamide dimaleate (HTMT) into the hindlimb perfusion circuit increased hindlimb perfusion pressure, whereas the H(2) agonist dimaprit decreased perfusion pressure and the H(3)-receptor agonist R-(-)-alpha-methylhistamine did not alter perfusion pressure. Pyrilamine reduced hindlimb vasoconstrictor responses to histamine and HTMT but did not alter vasodilator responses to dimaprit. Cimetidine reduced the response to dimaprit but did not alter vasoconstrictor responses to histamine or HTMT. The H(3)-receptor antagonist thioperamide was without effect on responses to the histamine agonists. These data suggest the presence of H(1) and H(2) receptors and that histamine for the most part acts by stimulating H(1) receptors to produce vasoconstriction in the hindlimb vascular bed of the rabbit. Responses to histamine, HTMT, and norepinephrine were significantly enhanced by a nitric oxide synthase inhibitor at a time when vasodilator responses to dimaprit were unaltered and responses to acetylcholine were significantly reduced. Responses to histamine and the H(1) and H(2) agonists were not affected by the cyclooxygenase inhibitor meclofenamate or by ATP-sensitive K(+) channel, alpha-adrenergic, or angiotensin AT(1) receptor antagonists. The present data suggest that H(1) receptors mediate both systemic vasodepressor and hindlimb vasoconstrictor responses to histamine.