Desensitisation of mast cell β₂‐adrenoceptor‐mediated responses by salmeterol and formoterol

Abstract

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.

Effects of formoterol and salmeterol on cytokine release from monocyte-derived macrophages

“…This concurs with studies examining the effects of these b 2 -agonists on histamine release from mast cells and mediator release from eosinophils [33] where salmeterol is less efficacious than formoterol [34]. The data presented in this study differ from that observed in THP-1 cells that were differentiated towards a macrophage phenotype with phorbol myristate acetate, where neither formoterol nor salmeterol inhibit LPS-stimulated TNF-a release [14].…”

Stereoselective activity of 2-(4-amino-3-chloro-5- trifluomethyl-phenyl)-2-tert-butylamino-ethanol hydrochloride to improve the pulmonary function in asthma

“…Previously, it was shown that the inhibitory effects were associated with the affinity to the β 2 -receptor (15). Formoterol was demonstrated to have a more efficient effect on stabilizing the mast cell membranes than salmeterol as it had a higher affinity to the receptor (15). In the present study, the role of SPFF and its enantiomers in stabilizing mast cells was investigated by determination of the release of inflammatory mediators from the lungs of allergic rats.…”

“…In the fast phase, β 2 agonists exerted inhibitory effects on the mediators released from mast cells and the degranulation of the cells (14). Previously, it was shown that the inhibitory effects were associated with the affinity to the β 2 -receptor (15). Formoterol was demonstrated to have a more efficient effect on stabilizing the mast cell membranes than salmeterol as it had a higher affinity to the receptor (15).…”

Pilot study: The effect of reducing treatment on exercise induced bronchoconstriction

“…11,13,[31][32][33] The increase in sputum inflammatory cells 31,34 after regular use of beta2-agonists suggests they could paradoxically have a proinflammatory effect. Regular exposure to LABAs can cause functional desensitization of the 35 and airway smooth muscle. 36 The complex signaling pathway underlying the relationship between AHR and the β2AR is still being explored.…”

“…11,13,[31][32][33] The increase in sputum inflammatory cells 31,34 after regular use of beta2-agonists suggests they could paradoxically have a proinflammatory effect. Regular exposure to LABAs can cause functional desensitization of the 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 35 and airway smooth muscle.…”