Effect of short- and long-acting β2-adrenoceptor agonists on pulmonary β2-adrenoceptor expression in human lung

β-Adrenoceptor agonists induce the down-regulation of β2-adrenoceptors and mRNA expression in animal lung. The down-regulation of β2-adrenoceptors may limit the therapeutic efficacy of β2-adrenoceptor-mediated bronchodilators in obstructive airways disease. We examined the effects of three selective β2-adrenoceptor agonists, salbutamol, salmeterol and formoterol on β2-adrenoceptor binding and mRNA levels in human lung in vitro. Human lung was obtained from cardiac transplantation donors. Peripheral lung was chopped and incubated with three selective β2-adrenoceptor agonist for 3 h or 24 h at three different concentrations (0.1, 1 and 10 μM). The affinity and density of β2-adrenoceptors was determined by [125I]iodocyanopindolol equilibrium binding in a lung membrane preparation in the presence of 0.1 μM CGP 20712 A (1-{2-[(3-carbamoyl-4-hydroxy)phenoxy]ethylamino}-3-[4-(1-methyl-4 -trifluoromethyl-2-imidazolyl)phenoxy]-propan-2-ol), a selective β1-adrenoceptor antagonist. Although treatment with salbutamol for 3 h did not change β2-adrenoceptor density, both salmeterol and formoterol reduced β2-adrenoceptor density, and exposure to each agonist for 24 h reduced β2-adrenoceptor density at all concentrations. Treatment with 10 μM salmeterol increased the equilibrium dissociation constant (K(d)), and also shifted the competition curves of (-)-isoprenaline to the left. β2-Adrenoceptor mRNA, measured by Northern blot analysis using a human β2-adrenoceptor cDNA probe, was reduced after exposure to all β2-adrenoceptor agonists at 3 h. Our data provide evidence for down-regulation of β2-adrenoceptor protein and mRNA after selective β2-adrenoceptor agonist treatment in human lung.link_to_subscribed_fulltex