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)

The intravenous injection of the mast cell degranulator C 48/80 (1 mg/kg) in rats did not produce thrombocytopenia nor circulating platelet aggregates but sensitized the platelets to aggregate upon turbulence challenge. Such turbulence-induced platelet aggregation was not accompanied by formation of thromboxane B2. Electron microscopy revealed absence of platelet degranulation. Turbulence-induced platelet aggregation was completely prevented by pre-treatment of the rats with cyproheptadine, dipyridamole and VK 774, partially with ketanserin (5HT2-receptor antagonist), but not with methysergide (antiserotonergic drug), pyrilamine (antihistaminic drug), suprofen, aspirin (cyclo-oxygenase inhibitors), phentolamine, propranolol, flunarizine, lidoflazine, oxycoumarin or Trasylol. Combined treatment with the anti-histaminic drug pyrilamine and the 5HT2-receptor antagonist ketanserin resulted in a dose-related inhibition for ketanserin of the turbulence-induced platelet aggregation. These experiments point to an interaction between histamine and 5-hydroxytryptamine in the platelet activation by mast cell released mediators.
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PMID:Platelet activation by endogenous 5-hydroxytryptamine and histamine released by mast cell degranulation with compound 48/80 in the rat. 685 90

We have previously shown that mast cell stabilization attenuates peritoneal adhesion formation in the rat. The present study investigated the mechanism of this protection. Adhesions were created in weanling rats using cecal scraping and application of 95% ethanol. Rats received specific blockers for the mast cell products histamine, serotonin (5HT), leukotriene D4, and platelet activating factor intraperitoneally 30 min before laparotomy and at the time of abdominal closure. Control animals received saline. Adhesions were assessed blindly 1 week later using a standardized scale. Adhesion formation was not affected by histamine blockade using combined mepyramine and ranitidine, 5-HT1 blockade using methysergide, 5-HT3 blockade using ondansetron, leukotriene D4 blockade using MK-571, or platelet activating factor blockade using WEB-2086. However, blockade of the 5-HT2 receptor using ketanserin resulted in significant dose-dependent attenuation of adhesions compared to saline. These data suggest that mast cells mediate peritoneal adhesion formation in the rat through release of serotonin acting on 5HT2 receptors. Further understanding of this process may lead to new strategies for the prevention of postoperative adhesions.
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PMID:Mast cell mediators and peritoneal adhesion formation in the rat. 764 92

Mechanisms underlying the hyperalgesia induced by a single systemic injection of nerve growth factor (NGF) in adult rats were studied in vivo. A single dose of NGF initiated a prolonged thermal hyperalgesia to a radiant heat source within minutes that lasted for days. Animals which had been pretreated with the mast cell degranulating compound 48/80 or either one of two specific 5-hydroxytryptamine receptor antagonists (ICS 205-930 and methiothepin) also developed an NGF-induced thermal hyperalgesia, but onset was delayed by more than 3 h. In the presence of ICS 205-930 or methiothepin the early component NGF-induced hyperalgesia was reversed and the animals responded with an initial hypoalgesia to the thermal stimuli. Whereas these results indicate a peripheral mechanism for the initial thermal hyperalgesia, the later phase (7 h-4 days after NGF) appeared to be centrally maintained, since it could be selectively blocked by the non-competitive NMDA receptor antagonist MK-801. In contrast to the almost immediate thermal hyperalgesia following a single injection of NGF, a significant mechanical hyperalgesia began only after a 7 h latency. This NGF-induced mechanical hyperalgesia was not blocked by any of the treatments that attenuated the thermal hyperalgesia, indicating that a separate mechanism may be involved. Additional electrophysiological experiments showed that NGF-induced hyperalgesia was not maintained by an increased amount of spontaneous activity in C-fibres. A final result showed that endogenous release of NGF in a model of acute inflammation (complete Freund's adjuvant-induced inflammation) may be involved in the development of thermal hyperalgesia, since it could be blocked by concomitant treatment with anti-NGF antisera. These data indicate that NGF-induced thermal and mechanical hyperalgesia are mediated by different mechanisms. The rapid onset component of thermal hyperalgesia is due to a peripheral mechanism involving the degranulation of mast cells, whereas the late component involves central NMDA receptors. In contrast, the NGF-induced mechanical hyperalgesia seems to be independent of mast cell degranulation or central NMDA receptor sites.
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PMID:Peripheral and central mechanisms of NGF-induced hyperalgesia. 770

Mast cells are tissue-resident immune cells that are capable of signaling many different cell types in vascularized tissue including epithelia and smooth muscle. We have developed an in vitro coculture system in which secretion of serotonin by a mucosal mast cell line (RBL-2H3) can be studied at a single cell level by measuring Ca2+ transients in fura-2 loaded mast cells and serotonin-sensitive A7r5 smooth muscle cells using fluorescence video microscopy and digital image processing. A7r5 cells elevate intracellular Ca2+ via 5HT2 receptors in response to bath-applied serotonin with an ED50 for serotonin of 550nM. Crosslinking IgE receptors with antigen caused Ca2+ transients in the mucosal mast cells. Ca2+ responses in the smooth muscle were detected approximately 30-240 sec after the initiation of the mast cell Ca2+ responses. Smooth muscle Ca2+ responses were dependent on preloading mast cells with serotonin and were blocked by the 5HT2 antagonist ketanserin. The timing and magnitude of the smooth muscle responses indicated that secretion from mast cells can lead to local concentrations of serotonin in the range of 300 nM within 1 min of antigen stimulation. This coculture technique has allowed the first direct demonstration of serotonin-mediated signaling between immune cells and vascular elements.
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PMID:Paracrine Ca2+ signaling in vitro: serotonin-mediated cell-cell communication in mast cell/smooth muscle cocultures. 804 Jan 94

Altered intestinal motility and diarrhea are features of food protein-induced intestinal anaphylaxis in the conscious rat. These experiments were performed to determine the mediator(s) responsible for jejunal circular smooth muscle contraction during this response. Hooded-Lister rats were sensitized by intraperitoneal injection of 10-micrograms egg albumin, and controls were sham-sensitized with saline. Fourteen days later the contractility of the circular muscle in jejunal segments (mucosa intact) was examined in standard tissue baths in response to antigen (Ag) or other agents. While control and sensitized tissues contracted in similar fashion in response to stretch, bethanechol, histamine, or 5-hydroxytryptamine (5HT), Ag contracted only the segments of sensitized animals. The contractile response was: (1) specific to the sensitizing Ag, as bovine serum albumin did not induce contraction and (2) could be passively transferred with serum containing specific immunoglobulin E antibody (IgE-Ab). Concanavalin A, which degranulates both mucosal and connective tissue-type mast cells, and compound 48/80, which degranulates only connective tissue-type mast cells produced contractile responses. Ag-induced contraction was significantly inhibited by the mucosal and connective tissue-type mast cell stabilizer doxantrazole, but not the connective tissue mast cell stabilizer disodium cromoglycate. Diphenhydramine and cimetidine together significantly inhibited histamine-induced contraction, but failed to effect the Ag-induced contraction in sensitized tissues. While the contractile response to 5HT was reduced in the presence of methysergide (5HT1-receptor antagonist), cinanserin (5HT2-receptor antagonist), and ICS 205-930 (5HT3-receptor antagonist), only cinanserin significantly inhibited the contractile response to Ag. Indomethacin significantly inhibited Ag-induced contraction. Ag-induced contraction was resistant to atropine and tetrodotoxin.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Mediation of anaphylaxis-induced jejunal circular smooth muscle contraction in rats. 844 68

After challenge of sensitized individuals, food protein-induced colonic anaphylaxis may contribute to the symptom of diarrhoea. The aim of this study was to characterize the effect of food protein-induced anaphylaxis on colonic circular muscle in vitro, identify the mediators involved, and then evaluate the effect of antigen challenge on colonic transit in vivo. Hooded-Lister rats were sensitized by intraperitoneal injection of egg albumin and controls were sham-sensitized with saline. Rings of distal colonic tissue were suspended in standard tissue baths (mucosa intact) and circular muscle contractility was measured in response to antigen or other agents on day 14. In conscious animals, Na2(51)CrO4 was instilled alone, or with antigen, via proximal colostomy and the geometric centre of distribution of51Cr calculated. Following antigen challenge, a contractile response occurred only in animals that were sensitized (specific IgE antibody levels > or = 1:64), and was specific for the sensitizing antigen. Mast cell involvement was suggested when (1) concanavalin A (a degranulator of both mucosal and connective tissue mast cells) mimicked the antigen-induced response, and (2) Ag-induced contraction was significantly inhibited by mast cell stabilizers. The Ag-induced response was significantly and independently inhibited by a lipo-oxygenase enzyme inhibitor and by LTD4 and platelet activating factor receptor antagonists. The antigen-induced response was resistant to histamine and 5-hydroxytryptamine receptor antagonists, indomethacin, atropine and tetrodotoxin. The geometric centre of distribution of 51Cr was significantly more distal in sensitized animals challenged with antigen rather than placebo, and only sensitized animals challenged with antigen developed diarrhoea. These results suggest that colonic antigen challenge of sensitized rats is associated with IgE-mediated mast cell activation, the release of membrane derived mediators which, in vitro, act directly on smooth muscle to induce contraction, and in vivo result in an increased rate of aboral transit and diarrhoea.
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PMID:Colonic motor response to IgE-mediated mast cell degranulation in the Hooded-Lister rat. 878 96

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

We investigated the effect of sodium nitroprusside (SNP), a donor of nitric oxide, on the formation of platelet-activating factor (PAF) and uterine contractility in mouse uterine horns from mice treated with estrogen. Because the major pathway of PAF synthesis is the remodeling pathway in uterine tissue, we evaluated the incorporation of 14C-acetate into PAF-like molecules. Our results showed that SNP (100-300 mumol/L) caused a transient increase in the synthesis of PAF, which remained cell-associated. The addition of SNP (100-300 mumol/L) to a mouse uterine horn in an isolated organ bath preparation evoked a transient increase in contractility, which was inhibited by hemoglobin (2 micrograms/mL), a nitric oxide scavenger, but not by methylene blue (10 mumol/L), a guanylate cyclase inhibitor. The pharmacological characteristics of the contractions evoked by SNP resembled those evoked after mast cell activation, in that they were blocked by ritodrine (a beta 2 adrenergic agonist, 0.1 mumol/L); indomethacin (a cyclooxygenase inhibitor, 10 mumol/L); ketotifen (a mast cell stabilizer, 1.0 mumol/L); cromolyn sodium (a mast cell stabilizer, 100 mumol/L); pyrilamine (an H1 antagonist, 10 mumol/L); and ketanserine (5HT2 antagonist, 0.1 mumol/L). These data demonstrate that nitric oxide generated from SNP stimulated the synthesis of PAF and evoked contractility in uterine horns from mice treated with estrogen. This result suggests the possibility that these tissue conditions might be favorable for the generation of peroxynitrites, possible mediators of both effects. It is also shown that the contractility evoked by the addition of SNP was not due to production of PAF, because its antagonist, WEB 2086 (10-30 mumol/L, a concentration that blocked contractions evoked by PAF 1 nmol/L), had no effect on the SNP-evoked contractions.
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PMID:Nitroprusside stimulates contractility and the synthesis of 14C-acetylated PAF-like substances in estrogen primed-mouse uterine horns. 1036 96

Bacillus anthracis lethal toxin (LT) is a bipartite toxin composed of protective antigen (PA) and lethal factor (LF). Injection of LT produces clinical signs characteristic of anthrax infection, including pleural edema and vascular collapse in various animal models. We utilized the classic Miles leakage assay to quantify vascular leakage in mice. LT injected intradermally induced leakage as early as 15 to 25 min in some inbred mouse strains, but not in others, whereas PA or LF individually did not induce leakage. A third component of anthrax toxin, edema factor, did not induce leakage alone or with PA. Leakage was quantified in eight mouse strains, and no correlation was found between sensitivity to intradermal leakage and sensitivity to the lethality of systemically administered LT. The leakage could be inhibited by ketotifen, an inhibitor of mast cell degranulation, but not by azelastine, a histamine receptor 1 antagonist, or by ketanserin, a serotonin 5-HT2A receptor antagonist. LT was cytotoxic to MC/9 mast cells (in vitro) by 7 h after toxin treatment but did not induce histamine release from these cells. Mast cell-deficient mice exhibited the leakage event and had no increased resistance to systemic LT. Human umbilical vein endothelial cells were resistant to LT over 12 h, with only 20% of cells succumbing by 24 h, suggesting that endothelial cell killing is not the cause of the rapid LT-mediated leakage event. We describe here a ketotifen-sensitive vascular leakage event induced by LT which is the most rapid in vivo or in vitro LT-mediated effect reported to date.
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PMID:Anthrax lethal toxin induces ketotifen-sensitive intradermal vascular leakage in certain inbred mice. 1642 76

The present study examined the contribution of 5-hydroxytryptamine (5-HT) to acute peripheral inflammatory pain in rats. We used formalin test in this study. After formalin injection into the rat hind paw, biphasic pain-related behavior (phases 1 and 2) was observed. A microdialysis study revealed that 5-HT was released into the formalin injection site in a formalin concentration-dependent manner (1.25-5%), and its peak time was 18min after the injection. Previous studies suggest that peripheral 5-HT2 receptors are involved in inflammatory pain. Therefore, we next examined whether 5-HT2A and 5-HT2C receptors are involved, and from where 5-HT is released in the formalin test. Local pretreatment with a selective 5-HT2A receptor antagonist, ketanserin, and selective 5-HT2C receptor antagonists, RS102221 and SB242084, inhibited the number of flinches in early part of phase 2 (phase 2A) of the formalin test in a dose-dependent manner. Peripheral pretreatment with sodium cromoglycate (cromolyn), a mast cell membrane stabilizer, completely suppressed 5-HT release and inhibited phase 2 responses of the formalin test. These drugs inhibited c-fos expression in the superficial layer of the spinal dorsal horn of segments L4-5 at 2h after formalin injection. These results indicate that 5-HT released into peripheral tissue and its receptors, 5-HT2A as well as 5-HT2C, at the periphery have an important role in pain-related behaviors during acute peripheral inflammation.
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PMID:The nociceptive mechanism of 5-hydroxytryptamine released into the peripheral tissue in acute inflammatory pain in rats. 1865


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