Desensitisation of mast cell β 2 ‐adrenoceptor‐mediated responses by salmeterol and formoterol

The long‐acting β 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 β ‐adrenoceptor agonist isoprenaline. By contrast, the long‐acting β 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. 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. 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 β 2 ‐adrenoceptor agonist salbutamol (10 −6 M ). The desensitisation induced by long‐term treatments with salmeterol and formoterol was specific for β 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. Radioligand binding studies were performed to determine β 2 ‐adrenoceptor density in cell membranes after pretreatment (24 h) of cells with agonists. Isoprenaline, formoterol and salmeterol (all at 10 −6 M ) reduced β 2 ‐adrenoceptor density by 13±5 ( P >0.05), 49±13 ( P <0.05) and 35±17% ( P >0.05), respectively. These data indicate that long‐term exposure of mast cells to both salmeterol and formoterol can cause substantial levels of desensitisation to β 2 ‐adrenoceptor‐mediated responses in mast cells.British Journal of Pharmacology (2004) 141 , 163–171. doi: 10.1038/sj.bjp.0705599