Using the article, can someone help answer these pharmacology questions? What ha

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Using the article, can someone help answer these pharmacology questions?

What happens when mast cells are exposed to isoprenaline, salbutamol, or terbutaline for a longer period of time (1)?  

Pharmacology in Action l Desensitization of B2-adrenoceptor-mediated responses in human lung mast cells Lee K. Chong, Kim Suvarna, Russell Chess-Williams& Peter T. Peachell. British Journal of Pharmacology, Adapted by JA Cole Introduction Bronchodilator p2-adrenoceptor agonists continue to be critically important in the management of asthma. The principal action of these drugs is to relax airway smooth muscle although additional effects may include the stabilization of inflammatory cell activity (Barnes, 1999). In this regard, pulmonary mast cells may serve as an important target for the actions of bronchodilators because p2 adrenoceptor agonists have been shown to inhibit mast cell responses both in vivo and in vitro (Assem & Schild, 1969, Orange et al, 1971; Butchers et al., 1980, Church & Hiroi. 1987, Beachell et a 1988 Chong et al., 1998). One potential problem that may disadvantage the continued use of bronchodilators is the development of tolerance. Several clinical studies have shown that tolerance to the mast cell- stabilizing effects of 2-adrenoceptor agonists occurs more readily than tolerance to bronchodilation (O'Connor et al., 1992; Cockcroft et al., 1993). These studies are supported by in vitro comparative studies in guinea-pig (Van der Heijden et al., 1984) and man (Chong & Reacbell 1999) showing that airway smooth muscle is relatively resistant to the development of tolerance when compared to mast cells. In the clinical context, selective tolerance to mast cell stabilization could promote a potentially undesirable situation in which the release of spasmogenic and proinflammatory mediators from mast cells could occur unchecked and masked by the continued symptomatic relief that p2- adrenoceptor agonists would continue to provide by bronchodilation. At the molecular level, tolerance to 2-adrenoceptor agonists may reflect ß2-adrenoceptor desensitization Ferguson, 2001, Lefkowitz, 1998). A large number of in vitro studies in tissue and cell systems has shown that exposure to 2-adrenoceptor agonists leads to receptor desensitization. Desensitization is an agonist-induced and time-dependent process that may involve, the rapid (within seconds) uncoupling of receptors, followed by squestration of receptors into intracellular vesicles with longer exposures (hours) leading to receptor degradation (Ferguson, 2001). Phosphorylation of B2 adrenoceptors by cyclic AMP-dependent protein kinase (PKA) and p2-adrenoceptor kinase may contribute to these processes (Benovic et al., 1988; January et al., 1997). Other non-receptor related mechanisms that have been invoked to explain tolerance include the induction of (PDE), enzymes that could be involved in the catabolism of cAMP generated by the p2-adrenoceptor and downregulation of the G protein coupling the p2- adrenoceptor with adenylate cyclase (GiembySz 1996, Finney et al., 2000, 2001) The authors have previously reported that tolerance to ß-adrenoceptor agonists may be readily induced in human lung mast cells (HLMC). Long-term incubation of HLMC with the non-selective p- adrenoceptor agonist, isoprenaline, leads to a situation in which isoprenaline is, consequently, less effective as an inhibitor of mediator release from these cells (Chong et al., 1997, Drury et al., 1998; Chong & Reachell. 1999). The aim of the present study was to extend these observations and to determine whether long-term treatment of HLMC with alternative, clinically-relevant, p2-adrenoceptor agonists would also induce tolerance in HLMC. In this study, the effects of salbutamol and terbutaline, the two most commonly-prescribed short-acting bronchodilators, have been compared. Effects of ß-adrenoceptor agonists on mast cell histamine release Histamine is an inflammatory mediator that contributes to the signs and symptoms of an allergic response to a to a drug. Histamine is stored in mast cells and its release can be caused by

Explanation / Answer

Ans= Isoprenaline is non-selective -adrenoceptor agonist, while salbutamol or terbutaline is selective 2-adrenoceptor agonists, they inhibited the IgE-mediated release of histamine from mast cell.

The principal action of these drugs is to relax airway smooth muscle with stabilization of inflammatory cell activity . In this regard, pulmonary mast cells may serve as an important target for the actions of bronchodilators because 2-adrenoceptor agonists have been shown to inhibit mast cell responses.

Long-term exposure of Mast cell to either salbutamol or terbutaline led to a subsequent reduction in the effectiveness of salbutamol and terbutaline to inhibit histamine release. However, salbutamol was significantly more effective than terbutaline at promoting the functional desensitization.

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