Search Article Keyword  
PubMed Submission Abstarct PDF Cited  Click Count: 2479 DownLoad Count: 1329 

ISSN 1007-9327 CN 14-1219/R  World J Gastroenterol  2005 May 21;11(19):2851-2857

Roles of histamine and its receptors in allergic and inflammatory bowel diseases

Hua Xie, Shao-Heng He

Hua Xie, Shao-Heng He, Allergy and Inflammation Research Institute, Shantou University Medical College, Shantou 515031, Guangdong Province, China
Supported by the Li Ka Shing Foundation, Hong Kong, China, No. C0200001; the Planned Science and Technology Project of Guangdong Province, China, No. 2003B31502
Correspondence to: Professor Shao-Heng He, Allergy and Inflammation Research Institute, Shantou University Medical College, 22 Xin-Ling Road, Shantou 515031, Guangdong Province, China.
Telephone: +86-754-8900405    Fax: +86-754-8900192
Received: 2004-04-30    Accepted: 2004-07-15

Mast cell has a long history of being recognized as an important mediator-secreting cell in allergic diseases, and has been discovered to be involved in IBD in last two decades. Histamine is a major mediator in allergic diseases, and has multiple effects that are mediated by specific surface receptors on target cells. Four types of histamine receptors have now been recognized pharmacologically and the first three are located in the gut. The ability of histamine receptor antagonists to inhibit mast cell degranulation suggests that they might be developed as a group of mast cell stabilizers. Recently, a series of experiments with dispersed colon mast cells suggested that there should be at least two pathways in man for mast cells to amplify their own activation-degranulation signals in an autocrine or paracrine manner. In a word, histamine is an important mediator in allergic diseases and IBD, its antagonists may be developed as a group of mast cell stabilizers to treat these diseases.

© 2005 The WJG Press and Elsevier Inc. All rights reserved.

Key words: Allergic diseases; Immunoglobulin

Xie H, He SH. Roles of histamine and its receptors in allergic and inflammatory bowel diseases. World J Gastroenterol  2005; 11(19): 2851-2857

Allergic diseases including allergic asthma, allergic rhinitis, food allergy, drug allergy, and allergic atopic eczema/dermatitis syndrome, etc. are a group of common disorders which are regarded to be mediated by immunoglobulin (Ig) E. People at all ages in countries throughout the world suffer from these diseases. The prevalence of allergy has shown an increase in the last few years. At present it affects about 30-40% of world population and has become one of the three key diseases in the 21st century.
    Since last two decades, inflammation has been known as the main pathophysiological characteristics of allergy. Mast cells are major participants of allergic reactions, and their activation may be all that is sufficient and necessary for the rapid development of microvascular leakage and tissue edema in sensitized subjects exposed to allergen. Mast cell is a key source of potent mediators of allergic inflammation including histamine, neutral proteinases, proteoglycans, prostaglandin D2, leukotriene C4 and certain cytokines[1]. Among them, histamine is the first mediator implicated in the pathophysiological changes of asthma when it was found to mimic several features of the disease, and James received the Nobel Prize for medicine in 1988 for his outstanding achievements in histamine research. Recently, some novel findings concerning histamine, mast cell and allergy or IBD have been reported and are summarized herein.

Mast cell has a long history of being recognized as an important mediator-secreting cell in allergic diseases. It has a high capacity to release an array of both preformed and newly generated mediators in response to environmental stimuli, especially allergen exposure. Cross linkage of IgE bound to high affinity receptors on mast cells not only results in the rapid release of autacoid mediators, but also the sustained synthesis and release of cytokines, chemokines and growth factors.
Mature mast cells are ubiquitous in human tissues and can thus participate in the processes of inflammation at different sites. Systemic anaphylaxis, a life-threatening disease, involves mast cell activation in multiple organs. In bronchial asthma, a disease characterized by widespread but potentially reversible bronchial obstruction, there are increased numbers of mast cells and a greater degree of continuous mast cell degranulation in bronchoalveolar lavage fluid from asthmatics compared with normal controls. Increased mast cell numbers and evidence for continuous degranulation of mast cells have been observed also in nasal lavage fluid and the nasal epithelium of the patients with allergic rhinitis.
    Recent population surveys have estimated rates of prevalence of perceived food hypersensitivity of 12-20% in adults though this rate varied largely across different countries (e.g. Spain, 4.6%; Australia, 19.1%) despite a common standardized methodology[2]. Intestinal mast cells, as well as eosinophils, have been shown to be involved in the pathogenesis of food-allergy-related enteropathy.
    Adverse drug reactions are common, but only 6-10% are immunologically mediated[3]. Although allergic drug reactions are just one type of adverse reactions to medications, they are clinically very important because of the morbidity and mortality they cause. Allergic drug reactions may result in anaphylaxis, urticaria, bronchospasm and angioedema. During these reactions, allergic drugs cause direct histamine release from mast cells.

Since its discovery in 1911, histamine has been recognized as a major mediator in allergic diseases. Histamine is a primary amine synthesized from histidine in the Golgi apparatus, from where it is transported to the granule for storage in ionic association with the acidic residues of the glycosaminoglycans side chains of heparin and with proteinases. The histamine content of mast cells dispersed from human lung and skin is similar at 2-5 pg/cell, and the histamine stored ranges from 10 to 12 µg/g in both tissues. Following mast cell activation, histamine is rapidly dissociated from the granule matrix by exchange with sodium ions in the extracellular environment. Proteoglycans comprise the major supporting matrix of the mast cell granule with the sulfate groups binding to histamine, proteinases and acid hydrolases. As only mast cells and basophils contain histamine in man (apart from histaminergic nerve), and there are few basophils in human tissues, histamine can be used as a marker of mast cell degranulation.
    The allergic process is believed to consist of two phases: early and late. The early phase reaction is mainly induced by histamine released from mast cells. Histamine is a potent vasoactive agent, bronchial smooth muscle constrictor, and stimulant of nociceptive itch nerves. In addition to its known effects on glands, vessels and sensory nerves, recent data have provided further evidence of histamine’s proinflammatory actions[4]. Histamine binding specific cell receptors produces clinical allergic symptoms. This mediator also activates neutrophils and eosinophils as well as being a chemoattractant for these cells[5]. Histamine increases IL-8 level and evokes leukocyte rolling on endothelial cells. Thus histamine participates in both early and late-phase allergic responses.

Using segmental jejunal perfusion system with a two-balloon, six-channel small tube, Knutson and colleagues found that the histamine secretion rate was increased in patients with Crohn’s disease compared with normal controls, and the secretion of histamine was related to disease activity, indicating strongly that degranulation of mast cells was involved in active Crohn’s disease[6]. The highly elevated mucosal histamine levels were also observed in allergic enteropathy and ulcerative colitis[7]. Moreover, enhanced histamine metabolism was found in collagenous colitis and food allergy[8], and increased level of N-methylhistamine, a stable metabolite of the mast cell mediator histamine, was detected in the urine of patients with active Crohn’s disease or ulcerative colitis[9,10]. Since increased level of N-methylhistamine was significantly correlated to clinical disease activity, the above findings further strongly suggest the active involvement of histamine in the pathogenesis of these diseases.
    Interestingly, mast cells originated from the resected colon of active Crohn’s disease or ulcerative colitis were able to release more histamine than those from normal colon when being stimulated with an antigen, colon-derived murine epithelial cell-associated compounds[11]. Similarly, cultured colorectal endoscopic samples from patients with IBD secreted more histamine towards substance P alone or substance P with anti-IgE than the samples from normal control subjects under the same stimulation[12]. In a guinea pig model of intestinal inflammation induced by cow’s milk proteins and trinitrobenzene sulfonic acid, both IgE titers and histamine levels were higher than normal control animals[13].
    As a proinflammatory mediator, histamine is selectively located in the granules of human mast cells and basophils and released from these cells upon degranulation. To date, a total of three histamine receptors H1, H2 and H3 have been discovered in human gut[14,15]. It proves that there are some specific targets that histamine can work on in intestinal tract. Histamine was found to cause a transient concentration-dependent increase in short-circuit current, a measure of total ion transport across the epithelial tissue in the gut[16]. This could be due to that histamine interacts with H1 receptors to increase the secretion of Na and Cl ions from epithelium[17]. The finding that H1-receptor antagonist pyrilamine was able to inhibit anti-IgE induced histamine release and ion transport[18] suggested further that histamine is a crucial mediator responsible for diarrhea in IBD and food allergy. The ability of SR140333, a potent NK1 antagonist in reducing mucosal ion transport, was most likely due to its inhibitory actions on histamine release from colon mast cells[19].

Histamine has multiple effects that are mediated by specific surface receptors on target cells. Four types of histamine receptors have now been recognized pharmacologically. Histamine receptors were first differentiated into H1 and H2 by Ash and Schild in 1966, when it was found that some responses to histamine were blocked by low doses of mepyramine (pyrilamine), whereas others were insensitive.  A third histamine receptor subtype, termed H3, was cloned in 1999 by Lovenberg and co-workers[20] and the fourth histamine receptor subtype, termed H4, was first reported in 2000 by Oda and co-workers[21].

H1 receptors
H1 receptors have been cloned from cows, rats, guinea pigs and humans. The published sequences suggest that there are surprisingly large differences among species. H1 receptors mediate most of the effects of histamine that are relevant to asthma. The cardinal features of asthma include smooth muscle spasm, mucosal edema, inflammation and mucous secretion. It has been demonstrated that at least two of these features, bronchospasm and mucosal edema, can be caused by H1-receptor stimulation. Northern analysis has demonstrated that there is a high level of expression of H1 receptor messenger ribonucleic acid in lung.
    Ocular allergy presents unsolved mysteries in molecular and cellular mechanisms, the recent understanding of the key role of the T helper type 2 cytokines, adhesion molecules and chemokines may provide future avenues for pharmacological targeting of releasable inflammatory mediators. More potent topical mast cell stabilizers and H1 receptor antagonists have become commercially available for the management of the prevalent and benign forms of allergic conjunctivitis[22]. Immunostimulatory DNA sequences present an innovative and promising route for the treatment of ocular allergy, but clinical studies are needed to demonstrate their efficacy in humans.
    Bphs controls Bordetella pertussis toxin (PTX)-induced vasoactive amine sensitization elicited by histamine (VAASH) and has an established role in autoimmunity. Ma and co-workers[23] reported that congenic mapping links Bphs to the histamine H1 receptor gene (Hrh1/H1R) and that H1R differs at three amino acid residues in VAASH-susceptible and -resistant mice. Hrh1-/- mice are protected from VAASH, which can be restored by genetic complementation with a susceptible Bphs/Hrh1 allele, and experimental allergic encephalomyelitis and autoimmune orchitis due to immune deviation. Thus, natural alleles of Hrh1 control both the autoimmune T cells and vascular responses regulated by histamine after PTX sensitization.

H2 receptors
H2 receptors have been cloned from dogs and humans. Although H2 receptors are present in the airway, their clinical relevance is unclear, because H2 receptor antagonists have few measurable effects on airway function. Histamine stimulates an increase in cyclic AMP levels in lung fragments that is blocked by H2 receptor antagonists, indicating that H2 receptors are positively coupled to adenylyl cyclase in lung.
    Atopic diseases such as allergic rhinitis 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. Mazzoni and co-workers reported that histamine, together with a maturation signal, acts directly upon immature dendritic cells (DCs), which express H1 and H2, two active histamine receptors. 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. 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[24].

H3 receptors
The identification of H3 receptor cDNA allowed several groups to reveal the complexity of the histamine-mediated systems. Comparison of the cDNA with available genome databases revealed that the gene encoding H3 receptor is located on chromosome 20 and contains at least two introns. In rats, H3 receptors consist of at least three functional isoforms, referred to as H3A, H3B and H3C, which vary in the length of their third intracellular loop (I3) (136 104 and 88 amino acids respectively). In humans, H3 receptor isoforms have been cloned, including one with an 80-amino-acid deletion of I3. Moreover, another isoform has been identified, in which the 80-amino-acid deletion is accompanied by an additional 8 amino acids at the C-terminal tail. Using reverse transcription polymerase chain reaction, the human isoforms have been found to be differentially expressed in various brain areas. The 80-amino-acid sequence located at the C-terminal portion of I3 plays an essential role in H3 agonist-mediated signal transduction. The existence of multiple H3 isoforms with different signal transduction capabilities suggests that H3-mediated biological functions might be tightly regulated through alternative splicing mechanisms. Otherwise, histamine H3 receptor activation inhibits neurogenic sympathetic vasoconstriction in porcine nasal mucosa, suggesting that histamine H3 receptors may play a role in the regulation of vascular tone and nasal patency in allergic nasal congestive disease[25].

H4 receptors
The discovery of the histamine H4 receptor adds a new chapter to the histamine story. The H4 receptor is a G protein-coupled receptor and is most closely related to the H3 receptor, sharing 58% identity in the transmembrane regions. The gene encoding the H4 receptor was discovered initially in a search of the GenBank databases as sequence fragments retrieved in a partially sequenced human genomic contig mapped to chromosome 18[26]. About the histamine-binding site of H4 receptor, Shin reported that Asp94 (3.32) in transmembrane region (TM) 3 and Glu182 (5.46) in TM5 are critically involved in histamine binding. Asp94 probably serves as a counter-anion to the cationic amino group of histamine, whereas Glu182 (5.46) interacts with the N(tau) nitrogen atom of the histamine imidazole ring via an ion pair. These results resemble those for the analogous residues in the H1 histamine receptor but contrast with findings regarding the H2 histamine receptor. It indicates that although histamine seems to bind to the H4 receptor in a fashion similar to that predicted for the other histamine receptor subtypes, there are also important differences that can probably be exploited for the discovery of novel H4-selective compounds[27]. H4 receptor exhibits a very restricted localization, expression is primarily found in intestinal tissue, spleen, thymus and immune active cells, such as T cells, mast cells, neutrophils and eosinophils. It suggests an important role for the H4 receptor in the regulation of immune function and offers novel therapeutic potentials for histamine receptor ligands in allergic and inflammatory diseases[28].

Today, according to action on different receptors, the histamine receptor agonists (Table 1) and antagonists (Table 2) are classified into four subtypes, respectively.  Among H1 receptor antagonists, the first generation antihistamines have considerable sedative effects caused by their ability to cross the blood-brain barrier. The second generation of antihistamines to emerge in the market is devoid of these sedative effects. The third generation antihistamines, metabolites of the earlier drugs, have demonstrated no cardiac effects of the parent drugs and are at least potent[29].

Table 1  Agonists of histamine receptors
Receptor subtype Agonists
H1 Dimethylhistaprodifen[30], methylhistaprodifen[30], histaprodifen[30,31], histamine-trifluoromethyl- toluidine[32], 2-thiazolylethylamine[33], 2-(3- trifluoromethylphenyl) histamine[34], 2-phenylhistamines[31], 2-pyridylethylamine[35]
H2   Dimaprit[30,34]  
H3     Imetit[32], alpha-methylhistamine[33,34]  
H4   Clobenpropit[32], imetit[32]

Table 2  Antagonists of histamine receptors
Receptor subtype Antagonists
H1   First-generation   
  Azatadine, clemastine, chlorpheniramine   
  (chlorphenamine maleate), diphenhydramine,
  dexchlorpheniramine, hydroxyzine, mepyramine   (pyrilamine), promethazine, terfenadine (teldane),
  Acrivastine[37,38], astemizole (hismanal)[38],   
  azelastine[38], cetirizine (virilx, zirtek, zyrtec)[39–41],   
  chlorpheniramine[42,43], desloratadine[44,45], ebastine[37,44],
  emedastine[37], epinastine[41,46], homochlorcyclizine[47],   
  ketotifen[41,48] levocabastine[46], loratadine (claritin,
  clarityne)[41,44,49], olopatadine[41,50], mequitazine[47],   
  mizolastine[47], pseudoephedrine[51,52], rupatadine[53,54],
  tripelennamine (pyribenzamin)[55]   
  Fexofenadine[37,44,56], levocetirizine[37,39]
H2   First-generation   
  Cimetidine[57], metiamide[58]   
  Ranitidine (1979)[59], omeprazole (1982)[60]   
  Famotidine[61], ebrotidine[62], lafutidine[63,64],   
  niperotidine[60], nizatidine[60], potentidine[65],
  roxatidine[60], zolantidine[58]
H3   A-304121[66], A-317920[66], 4-(aminoalkoxy)   
  benzylamines[67], ciproxifan[66], clobenpropit[68],
  D-alanine-piperazine-amides[69], imidazopyridine[70],   
  indole[70], indolizine[70], 4’-[(NR1R2-1-yl)]-propoxy-
  biaryl-4-carboxamides[70], pyrazolopyridine[71],   
  1-(4-(phenoxymethyl)benzyl) piperidines[72], SCH
  79687[73], thioperamide[68,74],
H4   JNJ 7777120[75,76], thioperamide[77]

    Among them, H1 receptor antagonists loratadine and terfenadine were able to inhibit IgE-induced histamine release from human mast cells[78], which may at least partially explain their potent antiallergic activity[79]. However, the extent of H1 receptor antagonists binding to mast cells is quite different. Wescott et al., reported tripelennamine > pyrilamine > diphenhydramine in binding H1 receptor[80]. 
    Fexofenadine, an effective H1 antihistamine, is the active metabolite of terfenadine, but they had different effects on histamine and tryptase release from mast cells.  Terfenadine inhibited release of histamine and tryptase from mast cells during the early allergic response, whereas fexofenadine did not[81].
    In combination with H1 antihistamines, H2 antihistamines famotidine, ranitidine or cimetidine suppressed effectively the chronic swelling. It is deduced that simultaneous blockage of both histamine H1 and H2 receptors may be necessary for sufficient inhibition of the microvascular permeability increase in some kinds of anaphylactic reactions, and that histamine, mainly interacting with H2 receptors, may play an important role in activation of a certain phase of chronic inflammation where mast cell degranulation is involved[82]. Metiamide, one H2 receptor antagonist, can reduce the histamine release from secreting mast cells in mast-cell mediated angiogenesis[83]. H3 antagonists, thioperamide and clobenpropit combined with H1 antihistamine loratadine, not the H2 antagonist ranitidine, reduced nasal congestion[84] in mast cell-deficient mice, indicating that its action was not associated with mast cell degranulation[85].

Tryptase has been proved to be a unique marker of mast cell degranulation in vitro as it is more selective than histamine to mast cells. Inhibitors of tryptase[86,87] and chymase[88] have been discovered to possess the ability to inhibit histamine or tryptase release from human skin, tonsil, synovial[89] and colon mast cells[90], suggesting that they are likely to be developed as a novel class of mast cell stabilizers. Recently, a series of experiments with dispersed colon mast cells suggested that there should be at least two pathways in man for mast cells to amplify their own activation-degranulation signals in an autocrine or paracrine manner, which may partially explain the phenomena that when a sensitized individual contacts allergen only once the local allergic response in the involved tissue or organ may last for days or weeks. These findings included that both anti-IgE and calcium ionophore were able to induce significant release of tryptase and histamine from colon mast cells, histamine is a potent activator of human colon mast cells and the agonists of PAR-2 and trypsin are potent secretagogues of human colon mast cells. Since tryptase was reported to be able to activate human mast cells[86] and H1 receptor antagonists terfenadine and cetirizine[78] were capable of inhibiting mast cell activation, the hypothesis of mast cell degranulation self-amplification mechanisms is that mast cell secretagogues induce mast cell degranulation, and release of histamine, which then stimulates the adjacent mast cells or positively feedbacks to further stimulate its host mast cells through H1 receptors, whereas released tryptase acts similarly to histamine, but through its receptor PAR-2 on mast cells.

1    Parikh SA, Cho SH, Oh CK. Preformed enzymes in mast cell granules and their potential role in allergic rhinitis. 
      Curr Allergy Asthma Rep
2003; 3: 266-272
2    Crespo JF, Rodriguez J. Food allergy in adulthood. Allergy 2003; 58: 98-113
3    Gruchalla RS. Drug allergy. J Allergy Clin Immunol 2003; 111(2 Suppl): S548-559
4    Repka-Ramirez MS, Baraniuk JN. Histamine in health and disease. Clin Allergy Immunol 2002; 17: 1-25
5    He S, Peng Q, Walls AF. Potent induction of a neutrophil and eosinophil-rich infiltrate in vivo by human mast cell 
      tryptase: selective enhancement of eosinophil recruitment by histamine. J Immunol 1997; 159: 6216-6225
6    Knutson L, Ahrenstedt O, Odlind B, Hallgren R. The jejunal secretion of histamine is increased in active Crohn’s 
      disease. Gastroenterology 1990; 98: 849-854
7    Raithel M, Matek M, Baenkler HW, Jorde W, Hahn EG. Mucosal histamine content and histamine secretion in 
      Crohn’s disease, ulcerative colitis and allergic enteropathy. Int Arch Allergy Immunol 1995; 108: 127-133
8    Schwab D, Hahn EG, Raithel M. Enhanced histamine metabolism: a comparative analysis of collagenous colitis and 
      food allergy with respect to the role of diet and NSAID use. Inflamm Res 2003; 52: 142-147
9    Winterkamp S, Weidenhiller M, Otte P, Stolper J, Schwab D, Hahn EG, Raithel M. Urinary excretion of 
      N-methylhistamine as a marker of disease activity in inflammatory bowel disease. Am J Gastroenterol 2002; 
      97: 3071-3077
10    Weidenhiller M, Raithel M, Winterkamp S, Otte P, Stolper J, Hahn EG. Methylhistamine in Crohn’s disease 
       (CD): increased production and elevated urine excretion correlates with disease activity. Inflamm Res 2000; 
       49(Suppl 1): S35-36
11    Fox CC, Lichtenstein LM, Roche JK. Intestinal mast cell responses in idiopathic inflammatory bowel disease. 
       Histamine release from human intestinal mast cells in response to gut epithelial proteins. Dig Dis Sci 1993; 
       38: 1105-1112
12    Raithel M, Schneider HT, Hahn EG. Effect of substance P on histamine secretion from gut mucosa in inflammatory 
       bowel disease. Scand J Gastroenterol 1999; 34: 496-503
13    Fargeas MJ, Theodorou V, More J, Wal JM, Fioramonti J, Bueno L. Boosted systemic immune and local 
       responsiveness after intestinal inflammation in orally sensitized guinea pigs. Gastroenterology 1995; 109: 53-62
14    Bertaccini G, Coruzzi G. An update on histamine H3 receptors and gastrointestinal functions. Dig Dis Sci 1995; 
       40: 2052-2063
15    Rangachari PK. Histamine: mercurial messenger in the gut. Am J Physiol 1992; 262(1 Pt 1): G1-13
16    Homaidan FR, Tripodi J, Zhao L, Burakoff R. Regulation of ion transport by histamine in mouse cecum. Eur 
       J Pharmacol 1997; 331: 199-204
17    Traynor TR, Brown DR, O’Grady SM. Effects of inflammatory mediators on electrolyte transport across the porcine 
       distal colon epithelium. J Pharmacol Exp Ther 1993; 264: 61-66
18    Crowe SE, Luthra GK, Perdue MH. Mast cell mediated ion transport in intestine from patients with and 
       without inflammatory bowel disease. Gut 1997; 41: 785-792
19    Moriarty D, Goldhill J, Selve N, O’Donoghue DP, Baird AW. Human colonic anti-secretory activity of the potent 
       NK(1) antagonist, SR140333: assessment of potential anti-diarrhea activity in food allergy and inflammatory 
       bowel disease. Br J Pharmacol 2001; 133: 1346-1354
20    Lovenberg TW, Roland BL, Wilson SJ, Jiang X, Pyati J, Huvar A, Jackson MR, Erlander MG. Cloning and 
       functional expression of the human histamine H3 receptor. Mol Pharmacol 1999; 55: 1101-1107
21    Oda T, Morikawa N, Saito Y, Masuho Y, Matsumoto S. Molecular cloning and characterization of a novel type 
       of histamine receptor preferentially expressed in leukocytes. J Biol Chem 2000; 275: 36781-36786
22    Solomon A, Pe’er J, Levi-Schaffer F. Advances in ocular allergy: basic mechanisms, clinical patterns and new 
       therapies. Curr Opin Allergy Clin Immunol 2001; 1: 477-482
23    Ma RZ, Gao J, Meeker ND, Fillmore PD, Tung KS, Watanabe T, Zachary JF, Offner H, Blankenhorn EP, Teuscher 
       C. Identification of Bphs, an autoimmune disease locus, as histamine receptor H1. Science 2002; 297: 620-623
24    Mazzoni A, Young HA, Spitzer JH, Visintin A, Segal DM. Histamine regulates cytokine production in maturing 
       dendritic cells, resulting in altered T cell polarization. J Clin Invest 2001; 108: 1865-1873
25    Varty LM, Hey JA. Histamine H3 receptor activation inhibits neurogenic sympathetic vasoconstriction in porcine 
       nasal mucosa. Eur J Pharmacol 2002; 452: 339-345
26    Nguyen T, Shapiro DA, George SR, Setola V, Lee DK, Cheng R, Rauser L, Lee SP, Lynch KR, Roth BL, O’Dowd 
       BF. Discovery of a novel member of the histamine receptor family. Mol Pharmacol 2001; 59: 427-433
27    Shin N, Coates E, Murgolo NJ, Morse KL, Bayne M, Strader CD, Monsma FJ Jr. Molecular modeling and 
       site-specific mutagenesis of the histamine-binding site of the histamine H4 receptor. Mol Pharmacol 2002; 62: 38-47
28    Leurs R, Watanabe T, Timmerman H. Histamine receptors are finally ‘coming out’. TRENDS Pharmacol Sci 2001; 
       22: 337-339
29    Oppenheimer JJ, Casale TB. Next generation antihistamines: therapeutic rationale, accomplishments and 
       advances. Expert Opin Investig Drugs 2002; 11: 807-817
30    Schlicker E, Kozlowska H, Kwolek G, Malinowska B, Kramer K, Pertz HH, Elz S, Schunack W. Novel 
       histaprodifen analogues as potent histamine H1-receptor agonists in the pithed and in the anaesthetized rat. 
       Naunyn Schmiedebergs Arch Pharmacol 2001; 364: 14-20
31    Seifert R, Wenzel-Seifert K, Burckstummer T, Pertz HH, Schunack W, Dove S, Buschauer A, Elz S. Multiple 
       differences in agonist and antagonist pharmacology between human and guinea pig histamine H1-receptor.
       Pharmacol Exp Ther 2003; 305: 1104-1115
32    Bell JK, McQueen DS, Rees JL. Involvement of histamine H4 and H1 receptors in scratching induced by 
       histamine receptor agonists in BALBc mice. Br J Pharmacol 2004; 142: 374-380
33    Lamberti C, Ipponi A, Bartolini A, Schunack W, Malmberg-Aiello P. Antidepressant-like effects of endogenous 
       histamine and of two histamine H1 receptor agonists in the mouse forced swim test. Br J Pharmacol 1998; 
       123: 1331-1336
34    Lecklin A, Etu-Seppala P, Stark H, Tuomisto L. Effects of intracerebroventricularly infused histamine and selective 
       H1, H2 and H3 agonists on food and water intake and urine flow in Wistar rats. Brain Res 1998; 793: 279-288
35    Leurs R, Smit MJ, Meeder R, Ter Laak AM, Timmerman H. Lysine200 located in the fifth transmembrane domain 
       of the histamine H1 receptor interacts with histamine but not with all H1 agonists. Biochem Biophys Res Commun 
       1995; 214: 110-117
36    Assanasen P, Naclerio RM. Antiallergic anti-inflammatory effects of H1-antihistamines in humans. Clin Allergy 
       Immunol 2002; 17: 101-139
37    Verster JC, Volkerts ER. Antihistamines and driving ability: evidence from on-the-road driving studies during 
       normal traffic. Ann Allergy Asthma Immunol 2004; 92: 294-303
38    Aaronson DW. Comparative efficacy of H1 antihistamines. Ann Allergy 1991; 67: 541-547
39    Tillement JP, Testa B, Bree F. Compared pharmacological characteristics in humans of racemic cetirizine 
       and levocetirizine, two histamine H1-receptor antagonists. Biochem Pharmacol 2003; 66: 1123-1126
40    Christophe B, Carlier B, Gillard M, Chatelain P, Peck M, Massingham R. Histamine H1 receptor antagonism by 
       cetirizine in isolated guinea pig tissues: influence of receptor reserve and dissociation kinetics. Eur J Pharmacol 
       2003; 470: 87-94
41    Nishiga M, Fujii Y, Konishi M, Hossen MA, Kamei C. Effects of second-generation histamine H1 receptor antagonists 
       on the active avoidance response in rats. Clin Exp Pharmacol Physiol 2003; 30: 60-63
42    Aslanian R, Mutahi M, Shih NY, Piwinski JJ, West R, Williams SM, She S, Wu RL, Hey JA. Identification of a 
       dual histamine H1/H3 receptor ligand based on the H1 antagonist chlorpheniramine. Bioorg Med Chem Lett 2003; 
       13: 1959-1961
43    Sharma A, Hamelin BA. Classic histamine H1 receptor antagonists: a critical review of their metabolic 
       and pharmacokinetic fate from a bird’s eye view. Curr Drug Metab 2003; 4: 105-129
44    Gelfand EW, Appajosyula S, Meeves S. Anti-inflammatory activity of H1-receptor antagonists: review of 
       recent experimental research. Curr Med Res Opin 2004; 20: 73-81
45    Monroe EW. Desloratidine for the treatment of chronic urticaria. Skin Therapy Lett 2002; 7: 1-2
46    Whitcup SM, Bradford R, Lue J, Schiffman RM, Abelson MB. Efficacy and tolerability of ophthalmic epinastine: 
       a randomized, double-masked, parallel-group, active- and vehicle-controlled environmental trial in patients with 
       seasonal allergic conjunctivitis. Clin Ther 2004; 26: 29-34
47    Suzuki A, Yasui-Furukori N, Mihara K, Kondo T, Furukori H, Inoue Y, Kaneko S, Otani K. Histamine 
       H1-receptor antagonists, promethazine and homochlorcyclizine, increase the steady-state plasma concentrations 
       of haloperidol and reduced haloperidol. Ther Drug Monit 2003; 25: 192-196
48    Kidd M, McKenzie SH, Steven I, Cooper C, Lanz R. Australian Ketotifen Study Group. Efficacy and safety of ketotifen 
       eye drops in the treatment of seasonal allergic conjunctivitis. Br J Ophthalmol 2003; 87: 1206-1211
49    Nelson HS. Prospects for antihistamines in the treatment of asthma. J Allergy Clin Immunol 2003; 
       112(4 Suppl):S96-100
50    Brockman HL, Momsen MM, Knudtson JR, Miller ST, Graff G, Yanni JM. Interactions of olopatadine and 
       selected antihistamines with model and natural membranes. Ocul Immunol Inflamm 2003; 11: 247-268
51    Mahgoub H, Gazy AA, El-Yazbi FA, El-Sayed MA, Youssef RM. Spectrophotometric determination of binary mixtures 
       of pseudoephedrine with some histamine H1-receptor antagonists using derivative ratio spectrum method.
       Pharm Biomed Anal 2003; 31: 801-809
52    Meltzer EO, Casale TB, Gold MS, O’Connor R, Reitberg D, del Rio E, Weiler JM, Weiler K. Efficacy and safety 
       of clemastine-pseudoephedrine- acetaminophen versus pseudoephedrine-acetaminophen in the treatment of 
       seasonal allergic rhinitis in a 1-d, placebo-controlled park study. Ann Allergy Asthma Immunol 2003; 90: 79-86
53    Salmun LM. Antihistamines in late-phase clinical development for allergic disease. Expert Opin Investig Drugs 2002; 
       11: 259-273
54    Izquierdo I, Merlos M, Garcia-Rafanell J. Rupatadine: a new selective histamine H1 receptor and 
       platelet-activating factor (PAF) antagonist. A review of pharmacological profile and clinical management of 
       allergic rhinitis. Drugs Today 2003; 39: 451-468
55    Manohar M, Goetz TE, Humphrey S, Depuy T. H1-receptor antagonist, tripelennamine, does not affect 
       arterial hypoxemia in exercising Thoroughbreds. J Appl Physiol 2002; 92: 1515-1523
56    Simpson K, Jarvis B. Fexofenadine: a review of its use in the management of seasonal allergic rhinitis and 
       chronic idiopathic urticaria. Drugs 2000; 59: 301-321
57    Yamaura K, Yonekawa T, Nakamura T, Yano S, Ueno K. The histamine H2-receptor antagonist, cimetidine, inhibits 
       the articular osteopenia in rats with adjuvant-induced arthritis by suppressing the osteoclast differentiation induced 
       by histamine. J Pharmacol Sci 2003; 92: 43-49
58    Scaccianoce S, Lombardo K, Nicolai R, Affricano D, Angelucci L. Studies on the involvement of histamine in 
       the hypothalamic-pituitary-adrenal axis activation induced by nerve growth factor. Life Sci 2000; 67: 3143-3152
59    Vannay A, Fekete A, Muller V, Strehlau J, Viklicky O, Veres T, Reusz G, Tulassay T, Szabo AJ. Effects of histamine 
       and the H2 receptor antagonist ranitidine on ischemia-induced acute renal failure: involvement of IL-6 and 
       vascular endothelial growth factor. Kidney Blood Press Res 2004; 27: 105-113
60    Mannino S, Troncon MG, Wallander MA, Cattaruzzi C, Romano F, Agostinis L, Marighi PE, Walker A. Ocular disorders 
       in users of H2 antagonists and of omeprazole. Pharmacoepidemiol Drug Saf 1998; 7: 233-241
61    Mozdarani H. Radioprotective properties of histamine H2 receptor antagonists: present and future prospects. J
       Radiat Res 2003; 44: 145-149
62    Arroyo MT, Lanas A, Sainz R. Prevention and healing of experimental indomethacin-induced gastric lesions: effects of
        ebrotidine, omeprazole and ranitidine. Eur J Gastroenterol Hepatol 2000; 12: 313-318
63    Isomoto H, Inoue K, Furusu H, Nishiyama H, Shikuwa S, Omagari K, Mizuta Y, Murase K, Murata I, Kohno S. 
       Lafutidine, a novel histamine H2-receptor antagonist, vs lansoprazole in combination with amoxicillin and 
       clarithromycin for eradication of Helicobacter pylori. Helicobacter 2003; 8: 111-119
64    Sato H, Kawashima K, Yuki M, Kazumori H, Rumi MA, Ortega-Cava CF, Ishihara S, Kinoshita Y. Lafutidine, a 
       novel histamine H2-receptor antagonist, increases serum calcitonin gene-related peptide in rats after 
       water immersion-restraint stress. J Lab Clin Med 2003; 141: 102-105
65    Li L, Kracht J, Peng S, Bernhardt G, Elz S, Buschauer A. Synthesis and pharmacological activity of fluorescent 
       histamine H2 receptor antagonists related to potentidine. Bioorg Med Chem Lett 2003; 13: 1717-1720
66    Esbenshade TA, Krueger KM, Miller TR, Kang CH, Denny LI, Witte DG, Yao BB, Fox GB, Faghih R, Bennani YL, 
       Williams M, Hancock AA. Two novel and selective nonimidazole histamine H3 receptor antagonists A-304121 
       and A-317920: I. In vitro pharmacological effects. J Pharmacol Exp Ther 2003; 305: 887-896
67    Apodaca R, Dvorak CA, Xiao W, Barbier AJ, Boggs JD, Wilson SJ, Lovenberg TW, Carruthers NI. A new class 
       of diamine-based human histamine H3 receptor antagonists: 4-(aminoalkoxy)benzylamines. J Med Chem 2003; 
       46: 3938-3944
68    Munzar P, Tanda G, Justinova Z, Goldberg SR. Histamine H3 receptor antagonists potentiate 
       methamphetamine self-administration and methamphetamine-induced accumbal dopamine 
       release. Neuropsychopharmacology 2004; 29: 705-717
69    Faghih R, Phelan K, Esbenshade TA, Miller TR, Kang CH, Krueger KM, Yao BB, Fox GB, Bennani YL, Hancock 
       AA. D-alanine piperazine-amides: novel non-imidazole antagonists of the histamine H3 receptor. Inflamm Res 
       2003; 52(Suppl 1): S47-48
70    Faghih R, Dwight W, Pan JB, Fox GB, Krueger KM, Esbenshade TA, McVey JM, Marsh K, Bennani YL, Hancock 
       AA. Synthesis and SAR of aminoalkoxy-biaryl-4-carboxamides: novel and selective histamine H3 receptor 
       antagonists. Bioorg Med Chem Lett 2003; 13: 1325–1328
71    Chai W, Breitenbucher JG, Kwok A, Li X, Wong V, Carruthers NI, Lovenberg TW, Mazur C, Wilson SJ, Axe FU, Jones 
       TK. Non-imidazole heterocyclic histamine H3 receptor antagonists. Bioorg Med Chem Lett 2003; 13: 1767-1770
72    Miko T, Ligneau X, Pertz HH, Ganellin CR, Arrang JM, Schwartz JC, Schunack W, Stark H. Novel nonimidazole 
       histamine H3 receptor antagonists: 1-(4-(phenoxymethyl)benzyl) piperidines and related compounds. J Med Chem 
       2003; 46: 1523-1530
73    McLeod RL, Rizzo CA, West RE Jr, Aslanian R, McCormick K, Bryant M, Hsieh Y, Korfmacher W, Mingo GG, Varty 
       L, Williams SM, Shih NY, Egan RW, Hey JA. Pharmacological characterization of the novel histamine 
       H3-receptor antagonist N-(3,5-dichlorophenyl)-N’-[[4-(1H-imidazol-4-ylmethyl)phenyl]- methyl]-urea (SCH 79687). 
       J Pharmacol Exp Ther 2003; 305: 1037-1044
74    Liedtke S, Flau K, Kathmann M, Schlicker E, Stark H, Meier G, Schunack W. Replacement of imidazole by a 
       piperidine moiety differentially affects the potency of histamine H3-receptor antagonists. Naunyn Schmiedebergs 
       Arch Pharmacol 2003; 367: 43-50
75    Thurmond RL, Desai PJ, Dunford PJ, Fung-Leung WP, Hofstra CL, Jiang W, Nguyen S, Riley JP, Sun S, Williams 
       KN, Edwards JP, Karlsson L. A potent and selective histamine H4 receptor antagonist with anti-inflammatory properties. 
       J Pharmacol Exp Ther 2004; 309: 404-413
76    Jablonowski JA, Grice CA, Chai W, Dvorak CA, Venable JD, Kwok AK, Ly KS, Wei J, Baker SM, Desai PJ, Jiang W, 
       Wilson SJ, Thurmond RL, Karlsson L, Edwards JP, Lovenberg TW, Carruthers NI. The first potent and 
       selective non-imidazole human histamine H4 receptor antagonists. J Med Chem 2003; 46: 3957-3960
77    Hofstra CL, Desai PJ, Thurmond RL, Fung-Leung WP. Histamine H4 receptor mediates chemotaxis and 
       calcium mobilization of mast cells. J Pharmacol Exp Ther 2003; 305: 1212- 1221
78    Okayama Y, Benyon RC, Lowman MA, Church MK. In vitro effects of H1-antihistamine on PGD2 release from mast 
       cells of human lung, tonsil, and skin. Allergy 1994; 49: 246-253
79    Sugimoto Y, Umakoshi K, Nojiri N, Kamei C. Effects of histamine H1 receptor antagonists on compound 
       48/80-induced scratching behavior in mice. Eur J Pharmacol 1998; 351: 1-5
80    Wescott SL, Hunt WA, Kaliner M. Histamine H-1 receptors on rat peritoneal mast cells. Life Sci 1982; 31: 1911-1919
81    Allocco FT, Votypka V, deTineo M, Naclerio RM, Baroody FM. Effects of fexofenadine on the early response 
       to nasal allergen challenge. Ann Allergy Asthma Immunol 2002; 89: 578-584
82    Kaneta S, Yanaguimoto H, Kagaya J, Ishizuki S, Fujihira E. Effects of H2-antihistamines in murine models 
       of immediate hypersensitivity and chronic inflammation. Res Commun Chem Pathol Pharmacol 1993; 79: 167-184
83    Sorbo J, Jakobsson A, Norrby K. Mast-cell histamine is angiogenic through receptors for histamine1 and histamine2. 
       Int J Exp Pathol 1994; 75: 43-50
84    McLeod RL, Mingo GG, Herczku C, DeGennaro-Culver F, Kreutner W, Egan RW, Hey JA. Combined histamine H1 and 
       H3 receptor blockade produces nasal decongestion in an experimental model of nasal congestion. Am J Rhinol 1999; 
       13: 391-399
85    Hossen MA, Sugimoto Y, Kayasuga R, Kamei C. Involvement of histamine H3 receptors in scratching behaviour in 
       mast cell-deficient mice. Br J Dermatol 2003; 149: 17-22
86    He S, Gaça MD, Walls AF. A role for tryptase in the activation of human mast cells: modulation of histamine release 
       by tryptase and inhibitors of tryptase. J Pharmacol Exp Ther 1998; 286: 289-297
87    He S, McEuen AR, Blewett SA, Li P, Buckley MG, Leufkens P, Walls AF. The inhibition of mast cell activation by 
       neutrophil lactoferrin: uptake by mast cells and interaction with tryptase, chymase and cathepsin G. Biochem 
       Pharmacol 2003; 65: 1007-1015
88    He S, Gaça MD, McEuen AR, Walls AF. Inhibitors of chymase as mast cell-stabilising agents: the contribution of 
       chymase in the activation of human mast cells. J Pharmacol Exp Ther 1999; 291: 517-523
89    He S, Gaca MD, Walls AF. The activation of synovial mast cells: modulation of histamine release by tryptase 
       and chymase and their inhibitors. Eur J Pharmacol 2001; 412: 223-229
90    He S, Xie H. Modulation of histamine release from human colon mast cells by protease inhibitors. World J 
       Gastroenterol 2004; 10: 337-341

Science Editor Zhu LH and Guo SY Language Editor Elsevier HK 

Reviews Add

Related Articles:
Synthesis of an enzyme-dependent prodrug and evaluation of its potential for colon targeting
Non-invasive investigation of inflammatory bowel disease
Fertility and pregnancy in inflammatory bowel disease
Breastfeeding and genetic factors in the etiology of inflammatory bowel disease in children
Mycobacterium avium subspecies paratuberculosis and its relationship with Crohn's disease