Mark A Giembycz1. 1. Department of Physiology & Pharmacology, Institute of Infection, Immunity and Inflammation, Faculty of Medicine, University of Calgary, Calgary, AB, Canada. giembycz@ucalgary.ca
Abstract
BACKGROUND AND PURPOSE: The beta(2)-adrenoceptor on human pro-inflammatory cells is exquisitely sensitive to desensitization, whereas beta(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 beta(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 beta(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, beta(2)-adrenoceptor inactivation and, for salbutamol and terbutaline only, by the comparative method of Barlow et al. The affinity of salbutamol for the beta(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 beta(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 beta(2)-adrenoceptor-mediated relaxation.
BACKGROUND AND PURPOSE: The beta(2)-adrenoceptor on human pro-inflammatory cells is exquisitely sensitive to desensitization, whereas beta(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 beta(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 beta(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, beta(2)-adrenoceptor inactivation and, for salbutamol and terbutaline only, by the comparative method of Barlow et al. The affinity of salbutamol for the beta(2)-adrenoceptorguinea-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 beta(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 beta(2)-adrenoceptor-mediated relaxation.
Authors: T Ikeda; A S M Anisuzzaman; H Yoshiki; M Sasaki; T Koshiji; J Uwada; A Nishimune; H Itoh; I Muramatsu Journal: Br J Pharmacol Date: 2012-07 Impact factor: 8.739
Authors: Neil S Holden; Matthew J Bell; Christopher F Rider; Elizabeth M King; David D Gaunt; Richard Leigh; Malcolm Johnson; David P Siderovski; Scott P Heximer; Mark A Giembycz; Robert Newton Journal: Proc Natl Acad Sci U S A Date: 2011-11-11 Impact factor: 11.205