BACKGROUND AND PURPOSE beta(2)-Adrenoceptor agonists are important therapeutic agents in the treatment of asthma and chronic obstructive pulmonary disease. The regular use of these drugs has been associated with proasthmatic-like changes that limit their efficacy and increase the risk of severe adverse reactions. We investigated whether the peroxisome-proliferator-activated receptor (PPAR)gamma agonist rosiglitazone modulated salbutamol-induced beta(2)-adrenoceptor desensitization in vivo and in vitro. EXPERIMENTAL APPROACH An in vivo model of homologous beta(2)-adrenoceptor desensitization, established in guinea-pigs by administering salbutamol continuously, was used to study the ability of rosiglitazone to prevent beta(2)-adrenoceptor tolerance. In vitro experiments on human bronchial smooth muscle cells were performed to increase the clinical relevance of the study. KEY RESULTS In tracheal smooth muscle tissues from desensitized animals, we observed a decrease in the protective effect of salbutamol on carbachol-induced contraction, a hyperresponsiveness to cholinergic stimuli, a modest underexpression of beta(2)-adrenoceptor gene and a marked decrease in beta-adrenoceptor number, relative to control values. Treatment with rosiglitazone preserved salbutamol relaxant activity, mitigated carbachol hyperresponsiveness and partially restored beta(2)-adrenoceptor binding sites in tracheal tissues from homologously desensitized animals. The highly selective PPAR gamma agonist, GW1929, reproduced the effect of rosiglitazone, in vivo. In vitro beta(2)-adrenoceptor desensitization decreased salbutamol-mediated cAMP production, without affecting forskolin responses and beta(2)-adrenoceptor expression. Rosiglitazone and 15-deoxy-Delta 12,14-prostaglandin J(2) restored salbutamol sensitivity in homologously desensitized cells. CONCLUSIONS AND IMPLICATIONS These data suggest a potential pharmacodynamic interaction between PPAR gamma agonists and salbutamol on airway smooth muscle responsiveness, supporting the therapeutic potential of this combination in chronic airway disease.
|Autori:||Fogli S; Pellegrini S; Adinolfi B; Mariotti V; Melissari E; Betti L; Fabbrini L; Giannaccini G; Lucacchini A; Bardelli C; Stefanelli F; Brunelleschi S; Breschi MC|
|Titolo:||Rosiglitazone reverses salbutamol-induced ß(2) -adrenoceptor tolerance in airway smooth muscle.|
|Anno del prodotto:||2011|
|Digital Object Identifier (DOI):||10.1111/j.1476-5381.2010.01021.x|
|Appare nelle tipologie:||1.1 Articolo in rivista|