title: Desensitization of beta2-adrenoceptor-mediated responses by short-acting beta2-adrenoceptor agonists in human lung mast cells.
abstract: 1 The principal aim of the present study was to determine whether long-term treatment of human lung mast cells (HLMC) with the clinically-relevant beta(2)-adrenoceptor agonists, salbutamol and terbutaline, leads to desensitization of beta(2)-adrenoceptor-mediated responses in these cells. 2 The non-selective beta-adrenoceptor agonist, isoprenaline, and the selective beta(2)-adrenoceptor agonists, salbutamol and terbutaline, inhibited the IgE-mediated release of histamine from HLMC. Salbutamol (pD(2); 7.7+/-0.3) and terbutaline (pD(2); 7.3+/-0.2) were roughly equipotent as inhibitors of histamine release although both agonists were less potent than isoprenaline (pD(2); 8.6+/-0.2). 3 Isoprenaline (10(-5) M), salbutamol (10(-5) M) and terbutaline (10(-5) M) enhanced total cell cAMP levels in HLMC over basal by 361+/-90, 150+/-38 and 165+/-35%, respectively. 4 Long-term exposure (24 h) of HLMC to either salbutamol (10(-7) M) or terbutaline (10(-7) M) led to a subsequent reduction in the effectiveness of salbutamol and terbutaline (both 10(-9)-10(-4) M) to inhibit histamine release. However, salbutamol was significantly (P<0.05) more effective than terbutaline at promoting the functional desensitization. 5 Radioligand binding studies, using iodinated cyanopindolol, were performed to determine beta(2)-adrenoceptor density in cell membranes after pretreatment (24 h) of cells with either salbutamol (10(-6) M) or terbutaline (10(-6) M). Both agonists reduced beta(2)-adrenoceptor density in membranes to about the same extent (approximately 25% reduction) but these changes in receptor density were not statistically significant (P>0.05). 6 These data indicate that long-term exposure of mast cells to salbutamol causes greater levels of desensitization to beta(2)-adrenoceptor-mediated responses in HLMC than terbutaline. These findings may have wider clinical significance in the context of asthma treatment as compromised mast cell inhibition could result following long-term exposure of mast cells to short-acting bronchodilators.
authors.affiliation: Unit of Molecular Pharmacology & Pharmacogenetics, University of Sheffield, The Royal Hallamshire Hospital (Floor L), Glossop Road, UK.
authors.forename: Lee K
authors.initials: LK
authors.lastname: Chong
authors.forename: Kim
authors.initials: K
authors.lastname: Suvarna
authors.forename: Russell
authors.initials: R
authors.lastname: Chess-Williams
authors.forename: Peter T
authors.initials: PT
authors.lastname: Peachell
mesh_terms: D000318:Adrenergic beta-Agonists / Q000494:pharmacology*; D000420:Albuterol / Q000494:pharmacology; D002021:Buffers; D000242:Cyclic AMP / Q000378:metabolism; D003888:Desensitization, Immunologic; D004361:Drug Tolerance; D006636:Histamine Release / Q000187:drug effects; D006801:Humans; D066298:In Vitro Techniques; D007545:Isoproterenol / Q000494:pharmacology; D008168:Lung / Q000166:cytology; D008407:Mast Cells / Q000166:cytology / Q000187:drug effects* / Q000502:physiology; D011869:Radioligand Assay; D018343:Receptors, Adrenergic, beta-2 / Q000187:drug effects* / Q000502:physiology; D013726:Terbutaline / Q000494:pharmacology
chemical_list: D000318:Adrenergic beta-Agonists; D002021:Buffers; D018343:Receptors, Adrenergic, beta-2; D000242:Cyclic AMP; D007545:Isoproterenol; D013726:Terbutaline; D000420:Albuterol