Desensitization of β2-adrenoceptor-mediated responses by short-acting β2-adrenoceptor agonists in human lung mast cells

Abstract

The principal aim of the present study was to determine whether long-term treatment of human lung mast cells (HLMC) with the clinically-relevant β₂-adrenoceptor agonists, salbutamol and terbutaline, leads to desensitization of β₂-adrenoceptor-mediated responses in these cells. The non-selective β-adrenoceptor agonist, isoprenaline, and the selective β₂-adrenoceptor agonists, salbutamol and terbutaline, inhibited the IgE-mediated release of histamine from HLMC. Salbutamol (pD₂; 7.7±0.3) and terbutaline (pD₂; 7.3±0.2) were roughly equipotent as inhibitors of histamine release although both agonists were less potent than isoprenaline (pD₂; 8.6±0.2). Isoprenaline (10⁻⁵M), salbutamol (10⁻⁵M) and terbutaline (10⁻⁵M) 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 (10⁻⁷M) or terbutaline (10⁻⁷M) led to a subsequent reduction in the effectiveness of salbutamol and terbutaline (both 10⁻⁹–10⁻⁴M) to inhibit histamine release. However, salbutamol was significantly (P2-adrenoceptor density in cell membranes after pretreatment (24 h) of cells with either salbutamol (10⁻⁶M) or terbutaline (10⁻⁶M). Both agonists reduced β₂-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 β₂-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