Enhancement by Reproterol of the Ability of Disodium Cromoglycate to Stabilize Rat Mastocytes (original) (raw)
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Effects ofβ 2-adrenergic agonists on isolated guinea pig lung mast cells
Agents and Actions, 1994
The mast cell protective effects of the newly developed long-acting fiz-agonists salmeterol and formoterol were compared with those of conventionally used fiz-agonists, non-specific fl-agonists, disodium cromoglycate (DSCG) and theophylline. With the exception of DSCG, all the test agents inhibited ovalbumin-induced histamine release from enzymically dispersed guinea pig lung mast cells in a dose-dependent fashion. At the maximum concentration tested, theophylline produced the highest level of protection, inhibiting up to 90% of ovalbumin-induced histamine release whereas DSCG produced only 10% inhibition. The maximum inhibition produced by all the fiz-agonists tested was around 45%. While salmeterol was equipotent with salbutamol, formoterol was at least a 100-fold more potent. Hence the present study confirmed the previously reported mast cell stabilizing actions of conventional fi2-agonists and extended the observation to the newly developed long-acting analogues.
Desensitisation of mast cell β 2 -adrenoceptor-mediated responses by salmeterol and formoterol
British Journal of Pharmacology, 2004
1 The long-acting b 2 -adrenoceptor agonist formoterol (10 À10 -10 À6 M) inhibited the IgE-dependent release of histamine from human lung mast cells in a concentration-dependent manner. Formoterol was more potent and a full agonist relative to the nonselective b-adrenoceptor agonist isoprenaline. By contrast, the long-acting b 2 -adrenoceptor agonist salmeterol (10 À10 -10 À6 M) was about two-thirds less efficacious than either formoterol or isoprenaline as an inhibitor of histamine release. 2 Isoprenaline, formoterol and salmeterol (all at 10 À5 M) increased total cell cAMP levels in mast cells over basal by 361790 (Po0.05), 321789 (Po0.05) and 64724% (P40.05), respectively. 3 Long-term (24 h) incubation of mast cells with formoterol (10 À6 M) or salmeterol (10 À6 M) essentially abolished the subsequent ability of isoprenaline to inhibit histamine release. Both formoterol and salmeterol were more effective at inducing the functional desensitisation than isoprenaline (10 À6 M) or the short-acting b 2 -adrenoceptor agonist salbutamol (10 À6 M). 4 The desensitisation induced by long-term treatments with salmeterol and formoterol was specific for b 2 -adrenoceptor-mediated inhibition of histamine release as the inhibitory effects of alternative cAMP-elevating compounds, prostaglandin E 2 , a receptor-mediated activator of adenylate cyclase, and forskolin, a direct activator of adenylate cyclase, were unaffected by desensitising treatments. 5 Radioligand binding studies were performed to determine b 2 -adrenoceptor density in cell membranes after pretreatment (24 h) of cells with agonists. Isoprenaline, formoterol and salmeterol (all at 10 À6 M) reduced b 2 -adrenoceptor density by 1375 (P40.05), 49713 (Po0.05) and 35717% (P40.05), respectively. 6 These data indicate that long-term exposure of mast cells to both salmeterol and formoterol can cause substantial levels of desensitisation to b 2 -adrenoceptor-mediated responses in mast cells.
PLoS ONE, 2013
Background and Purpose: Although the 'cromones' (di-sodium cromoglycate and sodium nedocromil) are used to treat allergy and asthma, their 'mast cell stabilising' mechanism of pharmacological action has never been convincingly explained. Here, we investigate the hypothesis that these drugs act by stimulating the release of the anti-inflammatory protein Annexin-A1 (Anx-A1) from mast cells. Experimental approach: We used biochemical and immuno-neutralisation techniques to investigate the mechanism by which cromones suppress histamine and eicosanoid release from cord-derived human mast cells (CDMCs) or murine bone marrow-derived mast cells (BMDMCs) from wild type and Anx-A1 null mice. Key results: CDMCs activated by IgE-FcRe1 crosslinking, released histamine and prostaglandin (PG) D 2 , which were inhibited (30-65%) by 5 min pre-treatment with cromoglycate (10 nM) or nedocromil (10 nM), as well as dexamethasone (2 nM) and human recombinant Anx-A1 (1-10 nM). In CDMCs cromones potentiated (2-5 fold) protein kinase C (PKC) phosphorylation and Anx-A1 phosphorylation and secretion (3-5 fold). Incubation of CDMCs with a neutralising anti-Anx-A1 monoclonal antibody reversed the cromone inhibitory effect. Nedocromil (10 nM) also inhibited (40-60%) the release of mediators from murine bone marrow derived-mast cells from wild type mice activated by compound 48/80 and IgE-FcRe1 crosslinking, but were inactive in such cells when these were prepared from Anx-A1 null mice or when the neutralising anti-Anx-A1 antibody was present. Conclusions and Implications: We conclude that stimulation of phosphorylation and secretion of Anx-A1 is an important component of inhibitory cromone actions on mast cells, which could explain their acute pharmacological actions in allergy. These findings also highlight a new pathway for reducing mediator release from these cells.
British Journal of Pharmacology, 1987
The ability of the anti-allergic drugs, sodium cromoglycate (SCG), lodoxamide, traxanox, RU31156 and the P-adrenoceptor agonist sulbutamol to inhibit IgE-dependent histamine and prostaglandin D2 (PGD2) release was assessed using human dispersed lung mast cells. 2 The anti-allergic drugs were weak inhibitors of histamine release, high concentrations (1I00O-I000 M) producing <35% inhibition. Salbutamol produced 39% inhibition at 10 M. 3 The efficacy of both SCG and salbutamol was inversely related to the concentration of anti-IgE used for challenge and to the degree of histamine release. 4 Rapid tachyphylaxis was observed with all anti-allergic drugs but not with salbutamol. 5 Cross-tachyphylaxis was observed between SCG and the other anti-allergic drugs, suggesting a common mechanism of action. No cross-tachyphylaxis was observed between SCG and salbutamol. 6 SCG was significantly (P <0.001) more effective in inhibiting PGD2 than it was histamine release. Preferential inhibition of PGD2 compared with histamine release was less marked (P <0.05) with salbutamol and not significant with the other anti-allergic drugs. 7 Mast cells dispersed by enzymatic digestion of human lung released more histamine on immunological challenge than mechanically dispersed cells obtained by fine chopping of tissue. Enzyme treatment of mechanically dispersed cells removed this difference. Enzymatically and mechanically dispersed cells responded similarly to the inhibitory effects of SCG and salbutamol. 8 Our results suggest that salbutamol is a more effective inhibitor of mediator release from human lung mast cells than anti-allergic drugs. However, with the low levels of mediator release achieved during an allergic reaction in man in vivo, both salbutamol and SCG are likely to be effective inhibitors of both preformed and newly generated mediators.
Apomorphine-induced inhibition of histamine release in rat peritoneal mast cells
British Journal of Pharmacology, 1986
1 The apomorphine-induced inhibition of histamine release in rat peritoneal mast cells was studied by means of secretagogues stimulating different pathways of mast cell activation. 2 Apomorphine inhibited the mast cell response to all releasing agents (lysophosphatidylserine plus nerve growth factor, compound 48/80, substance P. ATP, tetradecanoylphorbolacetate, melittin). The IC50 ranged from 4 pM to 24 gM at concentrations of secretagogues releasing 30-50% of mast cell histamine. However, the potency of the drug decreased at higher segretagogue concentrations. 3 Mast cells, pretreated with apomorphine and washed, released little histamine upon stimulation. The secretory response could be partially restored on increasing the concentration of secretagogues. 4 The results suggest that apomorphine affects a regulatory step controlling the terminal sequence of mast cell secretory activity. As indicated by the reduced potency of the drug, the control by the apomorphine-sensitive reaction loses efficiency under conditions of massive histamine release.
Effect of disodium cromoglycate on mast cell-mediated immediate-type allergic reactions
Life Sciences, 2004
We investigated the effect of disodium cromoglycate (DSCG) on mast cell-mediated immediate-type hypersensitivity. DSCG inhibited systemic allergic reaction induced by compound 48/80 dose-dependently. Passive cutaneous anaphylaxis was inhibited by 71.6% by oral administration of DSCG (1 g/kg). When DSCG was pretreated at concentration rang from 0.01-1000 g/kg, the serum histamine levels were reduced in a dose dependent manner. DSCG also significantly inhibited histamine release from rat peritoneal mast cell (RPMC) by compound 48/80. We confirmed that DSCG inhibited compound 48/80-induced degranulation of RPMC by alcian blue/nuclear fast red staining. In addition, DSCG showed a significant inhibitory effect on anti-dinitrophenyl IgE-mediated tumor necrosis factor-a production. These results indicate that DSCG inhibits mast cell-mediated immediate-type allergic reaction.
European Journal of Pharmacology, 2016
Mast cells play a critical role in type 1 hypersensitivity reactions. Indeed mast cell mediators are implicated in many different conditions including allergic rhinitis, conjunctivitis, asthma, psoriasis, mastocytosis and the progression of many different cancers. Thus, there is intense interest in the development of agents which prevent mast cell mediator release or which inhibit the actions of such mediators once released into the environment of the cell. Much progress, into the design of new agents, has been made since the initial discovery of the mast cell stabilising properties of khellin from Amni visnaga and the clinical approval of disodium cromoglycate. This review critically examines the progress that has been made in the intervening years from the design of new agents that target a specific signalling event in the mast cell degranulation pathway to those agents which have been developed where the precise mechanism of action remains elusive. Particular emphasis is also placed on clinically used drugs for other indications that stabilise mast cells and how this additional action may be harnessed for their clinical use in disease processes where mast cells are implicated.
Journal of immunology, 1982
Functional mast cells have been isolated from the lamina propria of the small intestine of rats infected with the nematode Nippostrongylus brasiliensis. The cells released histamine on challenge with specific antigen, anti-rat IgE, concanavalin A, and calcium ionophores but were less responsive than peritoneal mast cells (MMC) from the same animals. Intestinal mucosa mast cells (PMC) were refractory to the action of the basic secretagogues peptide 401 from bee venom and compound 48/80. The anti-allergic compounds disodium cromoglycate (less than or equal to 10(-3) M), AH 9679 (less than or equal to 10(-4) M), and theophylline (less than or equal to 10(-2)) did not inhibit antigen-induced histamine secretion by MMC, although these compounds were effective against PMC. In contrast, doxantrazole (10(-5) to 10(-3) M) inhibited the secretion of histamine from both MMC and PMC in a comparable dose-dependent fashion. Thus, we have established that mast cells from different sites are functi...