Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P15088 (mast cell)
 14,925 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

We describe 4 children with seronegative inflammatory arthritis who had persistent, severe nausea and abdominal pain over several months, in spite of vigorous medical therapy, including antacids and histamine H2 receptor antagonists. Endoscopy and biopsy of gastric and duodenal mucosa showed antral gastritis and an increased number of mast cells in 3 of the 4 patients. In the fourth patient, urinary histamine levels were elevated. These findings suggest an association between inflammatory arthritis and localized mast cell disease in some individuals. Further studies are needed to determine whether this association represents an independent syndrome or whether mast cell-related disease is secondary to long-term treatment with nonsteroidal antiinflammatory drugs in children with mild arthritis.
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PMID:Seronegative juvenile rheumatoid arthritis and mast cell-associated gastritis. 167 Jun 19

Using specific histamine H1 and H2 receptor antagonists, evidence is presented for the existence of both H1 and H2 receptors on human articular chondrocytes in vitro. Stimulation of the H1 receptor by histamine (range 0.18 to 17.8 mumol/l) significantly increased prostaglandin E (PGE) production, while activation of the histamine H2 receptor increased intracellular cyclic adenosine-5'-monophosphate (AMP). The histamine H1 antagonists mepyramine and tripelennamine blocked the histamine induced increase in PGE production, and the H2 antagonists cimetidine and ranitidine prevented the increase in intracellular cyclic AMP. These observations suggest that mast cell-chondrocyte interactions mediated via histamine may contribute to some of the pathophysiological changes observed in joint disease.
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PMID:Evidence for both histamine H1 and H2 receptors on human articular chondrocytes. 282 Mar 19

We evaluated the inhibitory effect of DS-4574, a peptidoleukotriene antagonist with mast cell stabilizing action, on rat gastric mucosal lesions induced by compound 48/80 (C48/80: a mast cell degranulator), in comparison with those of disodium cromoglycate (DSCG: a mast cell stabilizer), LY171883 (a peptidoleukotriene antagonist) and cimetidine (a histamine H2 receptor antagonist). Subcutaneous administration of C48/80 (1 mg/kg) once daily for four consecutive days produced extensive gastric lesions in the fundic mucosa. DS-4574 (20, 50 and 100 mg/kg/day, oral) and DSCG (200 mg/kg/day, intraperitoneal) treatment markedly inhibited formation of these mucosal lesions, but LY171883 (100 and 200 mg/kg/day, oral) and cimetidine (400 mg/kg/day, oral) treatment did not. Moreover, DS-4574 and DSCG significantly suppressed both hyperhistaminemia and histamine release from rat peritoneal mast cells induced by C48/80. These results indicate that the inhibitory effect of DS-4574 on gastric lesions induced by C48/80 may be related to its mast cell stabilizing action, but to neither its antisecretory nor its peptidoleukotriene antagonistic activity.
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PMID:Inhibitory effect of DS-4574, a peptidoleukotriene antagonist with mast cell stabilizing action, on compound 48/80-induced gastric mucosal lesions in rats. 752 68

The aim of the present study was to investigate whether or not release of endogenous mast cell mediators modulates exocytotic noradrenaline overflow. Therefore, we perfused rat isolated hearts with the right sympathetic innervation intact and investigated the effect of mast cell degranulation on the efflux of noradrenaline. Compound 48/80 (48/80), a mast cell degranulating agent, caused a large release of histamine and serotonin and a facilitation of evoked noradrenaline overflow. When 48/80 was introduced into the perfusion medium 4 min before sympathetic nerve stimulation (SNS), evoked noradrenaline overflow was increased by about 60%. In the presence of the uptake 1-blocker cocaine, facilitation was attenuated (increase by only 30%). This effect was abolished by the histamine H2 receptor antagonist cimetidine or the inhibitor of nitric oxide synthesis NG-nitro-(L)-(-)-arginine. When the preexposure time to 48/80 was reduced to 30 s, the facilitation was less pronounced (15%) and inverted to an inhibition in the presence of cocaine (plus idazoxan) by 17% and/or cimetidine (by about 30%). The resulting inhibition of noradrenaline efflux was attenuated by the serotonin 5-HT1/2 receptor antagonist methiothepin or the 5-HT2 antagonist ketanserin. Infusion of ovalbumin into hearts of not specifically sensitized, but sham treated rats (in vivo injection of a saline-alumina mixture 10-12 days before the in vitro experiment) did not affect histamine, serotonin or (basal and evoked) noradrenaline efflux. In hearts from rats that were previously sensitized by an injection of an ovalbumin-alumina adsorbate, ovalbumin induced a marked increase of histamine and serotonin efflux. When the infusion of the antigen started 30 s before SNS, evoked noradrenaline overflow was inhibited by about 60%. The inhibition was unaffected by histamine receptor antagonists, but attenuated by purinoceptor (suramin plus 1,3-dipropyl-8-cyclopentylxanthine), or serotonin receptor (methiothepin, rauwolscine or ketanserin) antagonists. When the preexposure time to ovalbumin was prolonged to 4 min before SNS, no significant change of stimulation-induced noradrenaline overflow was observed. Basal, immunologically and non-immunologically induced histamine and serotonin efflux were not significantly affected by SNS or any of the drugs tested. The results indicate a complex influence of various mediators released upon mast cell degranulation induced by two different stimuli on exocytotic noradrenaline release from rat heart. Depending on the stimulus and on the time interval between the start of the application of the mast cell degranulating agent and SNS, a histamine- and nitric oxide-mediated facilitation, or a serotonin- and purine-mediated inhibition prevails.
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PMID:Differential effects on sympathetic neurotransmission of mast cell degranulation by compound 48/80 or antigen in the rat isolated perfused heart. 753 Jul 91

A rat model of inflammation was used to investigate the biological effects of thrombin. The thrombin-specific inhibitor Hirulog markedly attentuated the carrageenin-induced edema of the paw of the rat. Injection of thrombin into the paw also produced edema. The effect of thrombin was due to activation of its receptor; a thrombin receptor activating peptide (TRAP) reproduced the effects of thrombin in causing edema. TRAP also increased vascular permeability as demonstrated by extravasation of Evans blue and 125I-labeled serum albumin. The release of bioactive amines played an important role in mediating the TRAP-induced edema; the serotonin/histamine antagonist cryproheptadine and the histamine H2 receptor antagonist cimetidine reduced significantly the edema caused by TRAP. Treatment of rats with the mast cell degranulator 48/80 to deplete these cells of their stores of histamine and serotonin abolished completely the ability of TRAP to produce edema. Histochemical examination confirmed that TRAP treatment led to mast cell degranulation. Thus, it has been possible to demonstrate that thrombin acts as an inflammatory mediator in vivo by activating its receptor, which in turn leads to release of vasoactive amines from mast cells.
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PMID:Thrombin functions as an inflammatory mediator through activation of its receptor. 864 86

We have investigated the potential of tryptase to stimulate an increase in microvascular permeability following injection into the skin of guinea pigs. Tryptase was isolated from high salt extracts of human lung tissue by octyl-agarose and heparin-agarose chromatography. Injection of purified tryptase (2.5 ng-2.5 microg/site) into the skin of guinea pigs which had been injected intravenously with Evans blue dye provoked a dose-dependent increase in microvascular permeability. The skin reactions elicited by tryptase were apparent up to 80 min following injection, while histamine-induced microvascular leakage resolved completely by 40 min. Heat-inactivation of tryptase, or preincubating the proteinase with certain proteinase inhibitors, significantly reduced the extent of microvascular leakage, suggesting dependency on an intact catalytic site. No evidence was found for a synergistic or antagonistic interaction between tryptase (2.5 ng-2.5 microg/site) and histamine (1-10 microg/site) when these mast cell products were injected together. Addition of heparin to tryptase (10:1; w/w) prior to injection was without effect on tryptase-induced microvascular leakage. Pretreatment of guinea pigs with a combination of the histamine H1 receptor antagonist pyrilamine and the histamine H2 receptor antagonist cimetidine (both 10 mg/kg), partially abolished tryptase-induced microvascular leakage as well as attenuating the reaction to histamine. Reasoning that the microvascular leakage induced by tryptase is likely to involve the release of histamine, we investigated the ability of tryptase to stimulate histamine release from dispersed guinea-pig skin and lung cells in vitro. Tryptase was found to induce concentration-dependent histamine release from both sources of tissue. Mast cell activation stimulated by tryptase in vitro was inhibited by heat treating the enzyme or by addition of proteinase inhibitors, suggesting a requirement for an intact catalytic site. Histamine release was inhibited also by preincubating cells with the metabolic inhibitors antimycin A and 2-deoxy-D-glucose indicating that the mechanism was energy-requiring and non-cytotoxic. We conclude that human mast cell tryptase may be a potent stimulus of microvascular leakage. The activation of mast cells by this proteinase may represent an amplification process in allergic inflammation.
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PMID:Human mast cell tryptase: a stimulus of microvascular leakage and mast cell activation. 920 74

Scratching behavior associated with passive cutaneous anaphylaxis was examined and compared to that induced by compound 48/80 or histamine in ICR mice. Elicitation of passive cutaneous anaphylaxis, and intradermal injections of compound 48/80, histamine or serotonin induced both scratching behavior and vascular permeability increase in ICR mice. In mast cell-deficient WBB6F1-W/Wv mice, although histamine induced scratching behavior and vascular permeability increase, passive cutaneous anaphylaxis was not observed. Cetirizine and terfenadine significantly inhibited the scratching behavior and vascular permeability increase caused by passive cutaneous anaphylaxis, compound 48/80 and histamine. The histamine H1 receptor antagonists inhibited the vascular permeability increase almost completely, whereas they failed to abolish the scratching behavior. Famotidine and ranitidine significantly inhibited the scratching behavior caused by histamine. The histamine H2 receptor antagonists did not affect the vascular permeability increase caused by histamine. The combination of cetirizine and ranitidine abolished the histamine-induced scratching behavior. The combination, however, failed to potentiate the inhibition of passive cutaneous anaphylaxis-induced scratching behavior significantly. The results indicated that histamine induces scratching behavior in ICR mice through both histamine H1 and H2 receptors, and that histamine plays a major role in passive cutaneous anaphylaxis-induced scratching behavior. Histamine might also play an important role in compound 48/80-induced scratching behavior.
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PMID:Participation of histamine H1 and H2 receptors in passive cutaneous anaphylaxis-induced scratching behavior in ICR mice. 1007 12

Over 30 million people in the world take non-steroidal anti-inflammatory drugs (NSAID's). A large percentage of these individuals will develop gastric ulcers and related complications, a condition known as "NSAID gastropathy". NSAID gastropathy differs from classic peptic ulcer disease in many ways, and traditional peptic ulcer therapy is largely ineffective in preventing NSAID-induced gastropathy. The prostaglandin misoprostol has been shown to be effective and is approved for the prevention of NSAID gastropathy. However, misoprostol has side effects that limit its general use. For this reason, considerable effort throughout the 1990's has focused on the identification of new gastroprotective molecules. Some synthetic studies have been aimed at the preparation of new prostaglandins, prostacyclin mimetics, and thromboxane antagonists. New histamine H2 receptor antagonists have also been developed which, unlike cimetidine or ranitidine, now appear to couple true gastroprotective activity with antisecretory properties. One new H2 antagonist, ebrotidine, has shown clinical utility in preventing NSAID gastropathy. Many other types of structures (flavonoids, peptides, terpenoids, xanthines, others), as well as compounds displaying certain pharmacological actions (5-hydroxytryptamine receptor binding, adrenergic receptor binding, mast cell stabilization, others) have been linked in some way to gastroprotection. This article reviews many of these recent gastroprotection findings, with emphasis on those of potential use for prevention of NSAID gastropathy.
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PMID:Gastroprotective agents for the prevention of NSAID-induced gastropathy. 1019 31

The pathogenic mechanism of ASA-induced urticaria/angioedema (AIU) is still poorly understood, but it has been known that histamine releasing by cutaneous mast cell activation is considered to be an important role. Considering the importance of histamine in AIU, we speculated that a genetic abnormality of histamine-related genes such as a high-affinity IgE receptor, a metabolic enzyme of histamines and histamine receptors, may be involved in the development of AIU. Enrolled in the study were 110 patients with AIU, 53 patients without ASA hypersensitivity who had various drug allergies presenting as exanthematous skin symptoms, and 99 normal healthy controls (NC). Eleven single nucleotide polymorphisms (SNPs) of the beta chain of the high-affinity IgE receptor (FCER1B) and three histamine-related genes-histamine N-methyltransferase (HNMT), histamine H1 receptor (HRH1), histamine H2 receptor (HRH2)-were screened using the SNP-IT assay based on a single base extension method. No significant differences were observed in allele and genotype frequencies, and haplotype frequencies of all the SNPs of FCER1B, HNMT, HRH1, and HRH2 among the three groups (p>0.05, respectively). These results suggest that the polymorphisms of FCER1B and the three histamine-related genes may not contribute to the development of AIU phenotype in the Korean population.
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PMID:Polymorphisms of high-affinity IgE receptor and histamine-related genes in patients with ASA-induced urticaria/angioedema. 1595 54

We tested the novel hypothesis that endogenous adenosine (eADO) activates low-affinity A3 receptors in a model of neurogenic diarrhea in the guinea pig colon. Dimaprit activation of H2 receptors was used to trigger a cyclic coordinated response of contraction and Cl(-) secretion. Contraction-relaxation was monitored by sonomicrometry (via intracrystal distance) simultaneously with short-circuit current (I(sc), Cl(-) secretion). The short interplexus reflex coordinated response was attenuated or abolished by antagonists at H2 (cimetidine), 5-hydroxytryptamine 4 receptor (RS39604), neurokinin-1 receptor (GR82334), or nicotinic (mecamylamine) receptors. The A1 agonist 2-chloro-N(6)-cyclopentyladenosine (CCPA) abolished coordinated responses, and A1 antagonists could restore normal responses. A1-selective antagonists alone [8-cyclopentyltheophylline (CPT), 1,3-dipropyl-8-(2-amino-4-chlorophenyl)xanthine (PACPX), or 8-cyclopentyl-N(3)-[3-(4-(fluorosulfonyl)benzoyloxy)propyl]-xanthine (FSCPX)] caused a concentration-dependent augmentation of crypt cell secretion or contraction and acted at nanomolar concentrations. The A3 agonist N(6)-(3-iodobenzyl)-adenosine-5'-N-methyluronamide (IB-MECA) abolished coordinated responses and the A3 antagonist 3-ethyl-5-benzyl-2-methyl-4-phenylethynyl-6-phenyl-1,4-(+/-)-dihydropyridine-3,5-dicarboxylate (MRS1191) could restore and further augment responses. The IB-MECA effect was resistant to knockdown of adenosine A1 receptor with the irreversible antagonist FSCPX; the IC(50) for IB-MECA was 0.8 microM. MRS1191 alone could augment or unmask coordinated responses to dimaprit, and IB-MECA suppressed them. MRS1191 augmented distension-evoked reflex I(sc) responses. Adenosine deaminase mimicked actions of adenosine receptor antagonists. A3 receptor immunoreactivity was differentially expressed in enteric neurons of different parts of colon. After tetrodotoxin, IB-MECA caused circular muscle relaxation. The data support the novel concept that eADO acts at low-affinity A3 receptors in addition to high-affinity A1 receptors to suppress coordinated responses triggered by immune-histamine H2 receptor activation. The short interplexus circuit activated by histamine involves adenosine, acetylcholine, substance P, and serotonin. We postulate that A3 receptor modulation may occur in gut inflammatory diseases or allergic responses involving mast cell and histamine release.
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PMID:Activation of adenosine low-affinity A3 receptors inhibits the enteric short interplexus neural circuit triggered by histamine. 1980 60


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