Mechanisms of impaired β-adrenoceptor-induced airway relaxation by interleukin-1β in vivo in the rat

Abstract

We studied the in vivo mechanism of β-adrenergic receptor (β-AR) hyporesponsiveness induced by intratracheal instillation of interleukin-1β (IL-1β, 500 U) in Brown-Norway rats. Tracheal and bronchial smooth muscle responses were measured under isometric conditions ex vivo. Contractile responses to electrical field stimulation and to carbachol were not altered, but maximal relaxation induced by isoproterenol (10-6-10-5 M) was significantly reduced 24 h after IL-1β treatment in tracheal tissues and to a lesser extent, in the main bronchi. Radioligand binding using [125I]iodocyanopindolol revealed a 32±7% reduction in β-ARs in lung tissues from IL-1β-treated rats, without any significant changes in β2-AR mRNA level measured by Northern blot analysis. Autoradiographic studies also showed significant reduction in β2-AR in the airways. Isoproterenol- stimulated cyclic AMP accumulation was reduced by IL-1β at 24 h in trachea and lung tissues. Pertussis toxin reversed this hyporesponsiveness to isoproterenol but not to forskolin in lung tissues. Western blot analysis revealed an IL-1β-induced increase in G(i)α protein expression. Thus, IL- 1β induces an attenuation of β-AR-induced airway relaxation through mechanisms involving a reduction in β-ARs, an increase in G(i)α subunit, and a defect in adenylyl cyclase activity.