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Query: UNIPROT:P15088 (mast cell)
 14,925 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Adenosine, a vasodilator metabolite, is often produced in tissues where the demand for oxygen exceeds the supply. We have recently demonstrated in isolated cannulated arterioles that adenosine and its metabolite, inosine, can also cause vasoconstriction by stimulation of mast cells. Secondary release of histamine and thromboxane is responsible for the inosine-induced constriction in vivo. In the present study, we explored the vasomotor effects of adenosine in vivo and investigated the role of the A3 adenosine receptor in mediating vasoconstriction. In vivo, local application of adenosine (10-6 to 10-4 mol/L) to arterioles consistently caused dose-dependent vasodilation. A fraction of arterioles, however, exhibited a biphasic response, with constriction following dilation. This, too, was dose dependent; 37% of arterioles constricted by 12.7 +/- 4.3% of the initial diameter in response to 10-4 mol/L adenosine. In the presence of 8-(p-sulfophenyl)theophylline (8-SPT), an antagonist of A1 and A2 adenosine receptors, dilation in response to the same dose of adenosine was reduced, and constriction was enhanced; 85% of the tested arterioles constricted by -44.3 +/- 6.0% of the initial diameter. The A3 adenosine receptor has been shown to facilitate mediator release from mast cells, and its role was also examined. N6-(3-Iodo-4-aminobenzyl)adenosine (I-ABA), an agonist of A1 and A3 adenosine receptors, produced dose-dependent vasoconstriction. 1,3-Dipropyl-8-(4-acrylate)phenylxanthine (BW-A1433), an antagonist of A1, A2, and A3 receptors, significantly reduced the vasoconstrictor response to adenosine, which was unmasked during treatment with 8-SPT. In addition, both adenosine and I-ABA stimulated mast cell uptake of ruthenium red, indicating degranulation. The I-ABA-induced constriction was abolished by combined histamine and thromboxane receptor antagonists. We conclude that adenosine can cause vasoconstriction in vivo, which is often masked by A2 receptor-mediated vasodilation. Mast cells are stimulated in the course of the response, and the A3 adenosine receptor is involved in mediating constriction.
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PMID:Adenosine-induced vasoconstriction in vivo. Role of the mast cell and A3 adenosine receptor. 863 20

Striated muscle becomes stunned during reperfusion after sublethal ischemia. Resistance vessel tone and reactivity are altered in stunned muscle tissues. The hypothesis that adenosine-regulated mast cell degranulation occurs during reperfusion and leads to constriction of resistance arterioles was tested. The hamster cremaster muscle was subjected to 1 h of ischemia followed by reperfusion. Resistance arterioles constricted during reperfusion (74% of maximal diameter at baseline vs. 42% of maximal diameter after 30 min of reperfusion; P < 0.01). Mast cells degranulated in reperfusion concomitant with arteriolar constriction. Stimulation of mast cell degranulation in control animals with compound 48/80 or cold superfusate (21 degrees C) caused vasoconstriction that mimicked that seen in reperfusion. The mast cell stabilizer cromolyn blocked degranulation and constriction. If mast cell granules were depleted by applying compound 48/80 before inducing ischemia, then arterioles failed to constrict during reperfusion. Adenosine A3-antagonist BW-A1433 abolished constriction. These findings suggest that arterioles constrict in reperfusion due to adenosine-regulated mast cell degranulation. Vasodilation in response to sodium nitroprusside and acetylcholine was normal in stunned, constricted arterioles. However, the dose-response curves to adenosine were shifted to the left in arterioles constricted by either stunning, compound 48/80, exposure to cold superfusate, or cromolyn compared with control vessels. Depletion of granular components via stunning, compound 48/80, cold superfusate, or inhibition of secretion with cromolyn results in unopposed A1- or A2-mediated vasodilation in response to adenosine, whereas the dilatory effects of adenosine are blunted by simultaneous release of vasoconstrictors from mast cells in control animals. In summary, it was found that mast cell degranulation occurs during reperfusion and leads to constriction of resistance arterioles and altered vascular reactivity to adenosine. Adenosine is released in ischemia and stimulates mast cell degranulation via the A3 receptor located on mast cells during reperfusion.
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PMID:Arteriolar constriction in skeletal muscle during vascular stunning: role of mast cells. 917 81

Adenosine is an important mediator of mast cell secretory responses. Adenosine appears to act through one or more adenosine receptor subtypes to activate several signal transduction pathways; however, the specific mechanisms involved are not clearly defined. We studied the pathways involved in adenosine receptor-mediated calcium fluxes in RBL-2H3 cells, a mucosal mast cell-like line. The role of endogenous heterotrimeric G proteins in adenosine mediated calcium mobilization was investigated by microinjection of inhibitory antibodies that block specific G protein subtype function. The calcium transients associated with adenosine and antigen stimulation were compared in noninjected cells and cells that were microinjected with affinity purified neutralizing antibodies to the alpha subunits of Gi3, Gq, or Gs. The percentage of cells responding to adenosine was decreased in the presence of antibodies to Gi3 and Gq, but not Gs. Pertussis toxin decreased the percentage of cells responding to adenosine, but not antigen. These studies demonstrated a functional requirement for the pertussis toxin sensitive Gi3 protein and the pertussis toxin insensitive Gq protein in adenosine mediated calcium mobilization in mast cells.
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PMID:Mast cell adenosine induced calcium mobilization via Gi3 and Gq proteins. 917 22

Adenosine, a naturally occurring purine nucleoside, elicits dose-related bronchoconstriction in asthmatic subjects when administered by inhalation and it is recovered in increased amounts from the bronchial lavage fluid of subjects with active asthma when compared to normal controls. Although the mechanism by which adenosine mediates bronchoconstriction in asthmatic subjects is not clear, recent data indicate an important role for mast cell mediator release. We have recently shown that local airway challenge with adenosine in subjects with asthma and rhinitis provokes an increase in the levels of PGD2, histamine and tryptase. However, airway responsiveness and atopic status are the most important determinants of adenosine-induced responses, regardless of any increases in mast cell mediators in airway fluids. New discoveries suggest that the airway response to adenosine may be an index of mast cell priming and therefore may provide a useful tool to further explore the inflammatory processes in allergic asthma and rhinitis. Therefore adenosine provocation may gain increasing acceptance as an additional measure of disease activity in asthma and rhinitis.
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PMID:Purine derivatives in the study of allergic inflammation in respiratory diseases. 918 54

1. We investigated, by intravital microscopy in rats, the role of the subtypes of adenosine receptors A1 (A1/AR) and A2 (A2AR) in mediating adenosine-induced vasodilatation of second and third order arterioles of the diaphragm. 2. Adenosine, and the A1AR selective agonists R(-)-N6-(2-phenylisopropyl)-adenosine (R-PIA) and N6-cyclo-pentyl-adenosine (CPA) induced a similar concentration-dependent dilatation of diaphragmatic arterioles. The non selective A2AR subtype agonist N6-[2-(3,5-dimethoxyphenyl)-2-(2-methylphenyl) ethyl]adenosine (DPMA) also dilated diaphragmatic arterioles but induced a significantly smaller dilatation than adenosine. By contrast the selective A(2a)AR subtype agonist 2-[p-(2-carboxyethyl)phenyl amino]-5'-N-ethyl carboxamido adenosine (CGS 21680) did not modify diaphragmatic arteriolar diameter. 3. The non selective adenosine receptor antagonist 1,3-dipropyl-8-p-sulphophenylxanthine (SPX, 100 microM) and the selective A1AR antagonist 8-cyclopentyl-1,3-dipropylxanthine (CPX, 50 nM) significantly attenuated adenosine-induced dilatation of diaphragmatic arterioles. By contrast, adenosine significantly dilated diaphragmatic arterioles in the presence of A2AR antagonist 3,7-dimethyl-1-propargylxanthine (DMPX, 10 microM). 4. The dilatation induced by adenosine was unchanged by the mast cell stabilizing agent sodium cromoglycate (cromolyn, 10 microM). 5. The nitric oxide (NO) synthase inhibitor N omega-nitro-L-arginine (L-NOARG, 300 microM) attenuated the dilatation induced by adenosine, and by the A1AR and A2AR agonists. 6. The ATP-dependent K+ channel blocker glibenclamide (3 microM) significantly attenuated diaphragmatic arteriolar dilatation induced by adenosine and by the A1AR agonists R-PIA and CPA. By contrast, glibenclamide did not significantly modify arteriolar dilatation induced by the A2AR agonist DPMA. 7. These findings suggest that adenosine-induced dilatation of diaphragmatic arterioles in the rat is predominantly mediated by the A1AR, via the release of NO and activation of the ATP-dependent K+ channels.
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PMID:Predominant role of A1 adenosine receptors in mediating adenosine induced vasodilatation of rat diaphragmatic arterioles: involvement of nitric oxide and the ATP-dependent K+ channels. 925 14

Adenosine is an endogenous nucleoside that modulates many physiological processes. Its actions are mediated by interaction with specific cell membrane receptors. Four subtypes of adenosine receptor have been cloned: A1, A2A, A2B and A3. Significant advancement has been made in our understanding of the molecular pharmacology and physiological relevance of adenosine receptors but our knowledge of A2B receptors lags behind that of other receptor types. Only recently have potentially important functions been discovered for the A2B receptors, prompting a renewed interest in this receptor type. A2B receptors have been implicated in the regulation of vascular smooth muscle tone, cell growth, intestinal function and neurosecretion. In this review, Igor Feoktistov, Riccardo Polosa, Stephen Holgate and Italo Biaggioni focus on the role of A2B receptors in mast cell activation and the potential relevance of this action on asthma.
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PMID:Adenosine A2B receptors: a novel therapeutic target in asthma? 961 90

Adenosine may play a role in asthma by enhancing inflammatory mediator release from lung mast cells. In this study, we investigated whether adenosine is released from cultured rat basophilic leukaemia (RBL-2H3) cells in response to antigen challenge and whether released adenosine enhances mediator release. RBL-2H3 cells closely resemble mucosal mast cells, the most common type of mast cell in lung tissue, and they express adenosine A3 receptors (which have been associated with asthma). Measurement of adenosine in RBL-2H3 cell incubation medium was possible if adenosine metabolism was inhibited by EHNA (10 microM; an adenosine deaminase inhibitor) and 5-iodotubericidin (5-IT; 10 microM; an adenosine kinase inhibitor). Basal adenosine concentration increased up to 1.0 microM during a 90 min incubation; after antigen challenge, adenosine concentration was increased by 0.3-0.4 microM above basal. Antigen-induced adenosine release ranged from 30-70 nmol/1.25x10(6) cells. Antigen-induced mediator release (beta-hexosaminidase and [3H]5-hydroxytryptamine) was increased by APNEA, an adenosine A3 receptor agonist (EC50 approximately 20 nm) but inhibited by EHNA and 5-IT, despite increased adenosine levels. This inhibition was not blocked by the adenosine A1/A2 receptor antagonist DPSPX (5 microM). Therefore, it is unlikely to be related to adenosine receptor activation. In conclusion, although our data provide no direct support for a positive feedback effect of adenosine on mast cell mediator release, the observation that IgE receptor stimulation increases adenosine production in cells which express stimulatory A3 receptors is consistent with this hypothesis.
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PMID:Evidence that IgE receptor stimulation increases adenosine release from rat basophilic leukaemia (RBL-2H3) cells. 980 62

The aim of this article is to review the interplay between adenosine and mast cells in asthma. Adenosine is an endogenous nucleoside released from metabolically active cells and generated extracellularly via the degradation of released ATP. It is a potent biological mediator that modulates the activity of numerous cell types including platelets, neutrophils and mast cells via action at specific adenosine receptors (A1, A2a, A2b, A3). These receptors are expressed on mast cells but the exact pattern of receptor subtype expression depends on the source of the mast cells. Adenosine is also a potent bronchoconstricting agent and is suggested to contribute to the pathophysiology of asthma. Evidence is provided to suggest that the nucleoside exerts its influence on the asthmatic condition through its ability to modulate the release of mast cell derived mediators. However, the mechanism of adenosine/mast cell interaction which contributes to asthma remains unclear. Progress in the area has been hampered by the heterogeneity of mast cell responses and a lack of highly specific receptor agonists and antagonists. The expression of different adenosine receptor subtypes on mast cells is described. The final section of the review presents data to suggest that BAL mast cells may provide an accurate and relevant model for future investigations and together with the development of superior pharmacological tools, may aid the realisation of the therapeutic potential of adenosine/mast cell interactions in asthma. In conclusion, the role of adenosine in asthma is clearly complex. A better understanding of the contribution of adenosine to the asthmatic condition may lead to novel therapeutic approaches in the treatment of the disease.
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PMID:Adenosine, mast cells and asthma. 1044 81

Adenosine has potent effects on both the cardiovascular and immune systems. Exposure of tissues to adenosine results in increased vascular permeability and extravasation of serum proteins. The mechanism by which adenosine brings about these physiological changes is poorly defined. Using mice deficient in the A(3) adenosine receptor (A(3)AR), we show that increases in cutaneous vascular permeability observed after treatment with adenosine or its principal metabolite inosine are mediated through the A(3)AR. Adenosine fails to increase vascular permeability in mast cell-deficient mice, suggesting that this tissue response to adenosine is mast cell-dependent. Furthermore, this response is independent of activation of the high-affinity IgE receptor (FcepsilonR1) by antigen, as adenosine is equally effective in mediating these changes in FcepsilonR1 beta-chain-deficient mice. Together these results support a model in which adenosine and inosine induce changes in vascular permeability indirectly by activating mast cells, which in turn release vasoactive substances. The demonstration in vivo that adenosine, acting through a specific receptor, can provoke degranulation of this important tissue-based effector cell, independent of antigen activation of the high-affinity IgE receptor, supports an important role for this nucleoside in modifying the inflammatory response.
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PMID:Adenosine and inosine increase cutaneous vasopermeability by activating A(3) receptors on mast cells. 1067 62

Adenosine is a signaling nucleoside that has been suggested to play a role in asthma in part through its ability to influence mediator release from mast cells. Adenosine levels are elevated in the lungs of asthmatics, further implicating this molecule in the regulation of lung inflammation and suggesting that animal models exhibiting endogenous increases in adenosine will be useful for the analysis of adenosine function. Adenosine deaminase (ADA) is a purine catabolic enzyme responsible for regulating the levels of adenosine in tissues and cells. ADA-deficient mice develop lung inflammation and damage reminiscent of that seen in asthma in association with elevated adenosine levels. In the current study, we investigated the status of mast cells in ADA-deficient lungs. ADA-deficient mice exhibited extensive lung mast cell degranulation concurrent with elevated adenosine levels. ADA enzyme therapy prevented the accumulation of lung adenosine as well as mast cell degranulation, suggesting that this process was dependent on elevated lung adenosine levels. Consistent with this, treatment of ADA-deficient mice with broad spectrum adenosine receptor antagonists attenuated degranulation by 30 to 40%, supporting the involvement of adenosine receptor signaling. Moreover, these studies demonstrate the ability of endogenously generated adenosine to influence lung mast cell degranulation in a receptor-mediated manner and establish ADA-deficient mice as a model system to investigate the specific adenosine receptor responses involved in the degranulation of lung mast cells.
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PMID:Adenosine-mediated mast cell degranulation in adenosine deaminase-deficient mice. 1145 3


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