Rosiglitazone reverses salbutamol-induced β ₂-adrenoceptor tolerance in airway smooth muscle

BACKGROUND AND PURPOSE β 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)IΥ agonist rosiglitazone modulated salbutamol-induced β ₂-adrenoceptor desensitization in vivo and in vitro. EXPERIMENTAL APPROACH An in vivo model of homologous β ₂-adrenoceptor desensitization, established in guinea-pigs by administering salbutamol continuously, was used to study the ability of rosiglitazone to prevent β 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 β ₂-adrenoceptor gene and a marked decrease in β-adrenoceptor number, relative to control values. Treatment with rosiglitazone preserved salbutamol relaxant activity, mitigated carbachol hyperresponsiveness and partially restored β ₂-adrenoceptor binding sites in tracheal tissues from homologously desensitized animals. The highly selective PPARIΥ agonist, GW1929, reproduced the effect of rosiglitazone, in vivo. In vitroβ ₂-adrenoceptor desensitization decreased salbutamol-mediated cAMP production, without affecting forskolin responses and β ₂- adrenoceptor expression. Rosiglitazone and 15-deoxy-Δ ^12,14- prostaglandin J ₂ restored salbutamol sensitivity in homologously desensitized cells. CONCLUSIONS AND IMPLICATIONS These data suggest a potential pharmacodynamic interaction between PPARIΥ agonists and salbutamol on airway smooth muscle responsiveness, supporting the therapeutic potential of this combination in chronic airway disease.