An estimation of β 2-adrenoceptor reserve on human bronchial smooth muscle for some sympathomimetic bronchodilators

Abstract

Background and purpose: The β 2-Adrenoceptor on human pro-inflammatory cells is exquisitely sensitive to desensitization, whereas β 2-adrenoceptor-mediated relaxation of human airways smooth muscle (HASM) is relatively resistant to this phenomenon. An explanation for this discrepancy is that a large β 2-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 β 2-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, β 2-adrenoceptor inactivation and, for salbutamol and terbutaline only, by the comparative method of Barlow et al. The affinity of salbutamol for the β 2- 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 log 10 unit). However, affinity values more closely agreed (difference <0.47 log 10 unit), when operational analysis was performed on data corrected for 'fade' of the MCh-induced contraction. Plots of fractional β 2-adrenoceptor occupancy versus relaxation indicated a receptor 'reserve' for all agonists tested at all levels of response. In contrast, minimal receptor reserve was detected for the ability of salbutamol to suppress respiratory burst activity in eosinophils. Conclusions and implications: These data may help explain the relative inability of sympathomimetic bronchodilators to render HASM tolerant to β 2-adrenoceptor-mediated relaxation. © 2009 The British Pharmacological Society.