Desensitisation of mast cell beta2-adrenoceptor-mediated responses by salmeterol and formoterol.
1. The long-acting beta(2)-adrenoceptor agonist formoterol (10(-10)-10(-6) 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 beta-adrenoceptor agonist isoprenaline. By contrast, the long-acting beta(2)-adrenoceptor agonist salmeterol (10(-10)-10(-6) 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(-5) m) increased total cell cAMP levels in mast cells over basal by 361+/-90 (P<0.05), 321+/-89 (P<0.05) and 64+/-24% (P>0.05), respectively. 3. Long-term (24 h) incubation of mast cells with formoterol (10(-6) m) or salmeterol (10(-6) 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(-6) m) or the short-acting beta(2)-adrenoceptor agonist salbutamol (10(-6) m). 4. The desensitisation induced by long-term treatments with salmeterol and formoterol was specific for beta(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 beta(2)-adrenoceptor density in cell membranes after pretreatment (24 h) of cells with agonists. Isoprenaline, formoterol and salmeterol (all at 10(-6) m) reduced beta(2)-adrenoceptor density by 13+/-5 (P>0.05), 49+/-13 (P<0.05) and 35+/-17% (P>0.05), respectively. 6. These data indicate that long-term exposure of mast cells to both salmeterol and formoterol can cause substantial levels of desensitisation to beta(2)-adrenoceptor-mediated responses in mast cells.
Scola
Anne-Marie
AM
Unit of Molecular Pharmacology & Pharmacogenetics, University of Sheffield, The Royal Hallamshire Hospital (Floor L), Glossop Road, Sheffield S10 2JF.
Chong
Lee K
LK
Suvarna
S Kim
SK
Chess-Williams
Russell
R
Peachell
Peter T
PT
D000420:Albuterol / Q000031:analogs & derivatives* / Q000494:pharmacology*; D002462:Cell Membrane / Q000187:drug effects / Q000276:immunology; D005576:Colforsin / Q000494:pharmacology; D000242:Cyclic AMP / Q000378:metabolism; D003888:Desensitization, Immunologic / Q000379:methods*; D004305:Dose-Response Relationship, Drug; D004983:Ethanolamines / Q000494:pharmacology*; D005260:Female; D000068759:Formoterol Fumarate; D006636:Histamine Release / Q000187:drug effects / Q000276:immunology; D006801:Humans; D007073:Immunoglobulin E / Q000276:immunology / Q000378:metabolism; D007545:Isoproterenol / Q000037:antagonists & inhibitors / Q000494:pharmacology; D008168:Lung / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D008297:Male; D008407:Mast Cells / Q000187:drug effects / Q000276:immunology* / Q000378:metabolism; D011869:Radioligand Assay; D018343:Receptors, Adrenergic, beta-2 / Q000187:drug effects* / Q000276:immunology / Q000378:metabolism; D000068299:Salmeterol Xinafoate; D013997:Time Factors
D004983:Ethanolamines; D018343:Receptors, Adrenergic, beta-2; D005576:Colforsin; D007073:Immunoglobulin E; D000068299:Salmeterol Xinafoate; D000242:Cyclic AMP; D007545:Isoproterenol; D000420:Albuterol; D000068759:Formoterol Fumarate