Desensitization of β 2 ‐adrenoceptor‐mediated responses by short‐acting β 2 ‐adrenoceptor agonists in human lung mast cells

The principal aim of the present study was to determine whether long‐term treatment of human lung mast cells (HLMC) with the clinically‐relevant β 2 ‐adrenoceptor agonists, salbutamol and terbutaline, leads to desensitization of β 2 ‐adrenoceptor‐mediated responses in these cells. The non‐selective β‐adrenoceptor agonist, isoprenaline, and the selective β 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). 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. 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. Radioligand binding studies, using iodinated cyanopindolol, were performed to determine β 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 β 2 ‐adrenoceptor density in membranes to about the same extent (∼25% reduction) but these changes in receptor density were not statistically significant ( P >0.05). These data indicate that long‐term exposure of mast cells to salbutamol causes greater levels of desensitization to β 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.British Journal of Pharmacology (2003) 138 , 512–520. doi: 10.1038/sj.bjp.0705050