Effect of fenoterol-induced constitutive β 2-adrenoceptor activity on contractile receptor function in airway smooth muscle

Abstract

In the present study, we investigated the effect of fenoterol-induced constitutive β 2-adrenoceptor activity on muscarinic receptor agonist- and histamine-induced bovine tracheal smooth muscle contractions. Bovine tracheal smooth muscle strips were incubated with 10 μM fenoterol or vehicle for various periods of time (5, 30 min, 18 h) at 37 °C. After extensive washout (3 h, 37 °C), isometric contractions were measured to the full muscarinic receptor agonist methacholine, the partial muscarinic receptor agonist 4-( m-chlorophenyl-carbamoyloxy)-2-butynyltrimethylammonium (McN-A-343) and histamine. Fenoterol treatment significantly reduced the sensitivity (pEC 50) to methacholine in a time-dependent manner, without affecting maximal contraction ( E max). Fenoterol treatment similarly reduced the pEC 50 of McN-A-343 and histamine; however, E max values were also reduced, to approximately 70% of control after 18-h treatment. The inverse agonist timolol, having no effect on control preparations, consistently restored the reduced pEC 50 and E max values of the contractile agonists. Remarkably, in the presence of timolol the pEC 50 values of McN-A-343 and histamine in fenoterol-treated airways were significantly enhanced compared to controls. In conclusion, fenoterol-induced constitutive β 2-adrenoceptor activity reduces muscarinic receptor agonist- and histamine-induced contractions of bovine tracheal smooth muscle, which can be reversed by the inverse agonist timolol. Moreover, after β 2-adrenoceptor agonist treatment, inverse agonism by β-adrenoceptor antagonists may cause enhanced airway reactivity to contractile mediators.