Agonist-independent alteration in β-adrenoceptor-G-protein-adenylate cyclase system in an equine model of recurrent airway obstruction

We examined the inhibitory sympathetic β-adrenergic mechanisms in peripheral lung, bronchi and trachea of an equine model of recurrent airway obstruction (RAO), to support the hypothesis that the β-adrenergic receptor dysfunction is not only restricted to cell surface receptor density but rather encompasses a mechanistic defect apart from the receptor, to the intracellular signaling components. The non-asthmatic lung possessed 3.2-fold more β-adrenergic receptors than bronchi (496±19.4 vs. 155.1±19.6 fmol/mg protein; P<0.01) and 6.2-fold higher than in the trachea (79.8±12.6 fmol/mg protein; P<0.001) (assessed by radioligand binding assays using (−)-[125I]-iodocyanopindolol, ICYP) and in all tissues a greater proportion of the β2- than the β1-subtype (75–80%). The receptor density (Bmax) in lung parenchyma and bronchial membranes was 33 and 42%, respectively, lower (P<0.001) in RAO than in control animals, attributable to a decrease in the β2-subtype. This receptor down-regulation was accompanied with an attenuated coupling efficiency of the receptor to the stimulatory GS-protein (P<0.05 vs. control). Concomitantly, activation of adenylate cyclase evoked by isoproterenol was significantly reduced in lung and bronchial membranes of animals with RAO, whereas effects of 10 μM GTP, 10 mM NaF, 10 μM forskolin and 10 mM Mn2+ were not altered. There was no difference in β-adrenergic receptor density, GS-protein or adenylate cyclase coupling in the trachea between asthmatic and control animals. In conclusion, in stable asthma the pulmonary β-adrenergic receptor-GS-protein-adenylate cyclase system is impaired, thus the pathologic process involves all signaling components, and due to its close similarity, this animal model seems to serve as a suitable model, at least partly, of chronic asthmatic patients.