An estimation of β2-adrenoceptor reserve on human bronchial smooth muscle for some sympathomimetic bronchodilators

Background and purpose: The β2-Adrenoceptor on human pro-inflammatory cells is exquisitely sensitive to desensitization, whereas β2-adrenoceptor-mediated relaxation of human airways smooth muscle (HASM) is relatively resistant to this phenomenon. An explanation for this discrepancy is that a large β2-adrenoceptor ‘reserve’ exists on HASM cells for sympathomimetic bronchodilators, which protects against desensitization. Experimental approach: The operational model of agonism was used to estimate the affinity of salbutamol, terbutaline, formoterol and procaterol for the β2-adrenoceptors in methacholine (MCh)-contracted HASM from which the relationship between fractional receptor occupancy and relaxation was determined. This analysis was performed under conditions of fractional, irreversible, β2-adrenoceptor inactivation and, for salbutamol and terbutaline only, by the comparative method of Barlow et al. The affinity of salbutamol for the β2-adrenoceptor guinea-pig eosinophils and the receptor/occupancy-response relationship for the suppression of the respiratory burst (an index of pro-inflammatory cell function) was also determined. Key results: For salbutamol and terbutaline, both pharmacological approaches yielded in HASM discrepant affinity estimates (values differed, maximally, by 0.67 log10 unit). However, affinity values more closely agreed (difference