Role of Ca2+ mobilization in desensitization of β-adrenoceptors by platelet-derived growth factor in airway smooth muscle

Platelet-derived growth factor (PDGF), which is released from eosinophils and fibroblasts, may be implicated in the pathophysiology of bronchial asthma. To examine the involvement of airway inflammation in β-adrenergic desensitization, the present study was designed to determine whether pre-exposure to PDGF deteriorates β-adrenoceptor function in airway smooth muscle. We focused on Ca2+ signaling as an intracellular mechanism involved in this phenomenon. Isometric tension and F340/F380 (an indicator of intracellular Ca2+ concentration) induced by isoprenaline and other cAMP-related agents were simultaneously measured before and after exposure to PDGF in fura-2-loaded guinea-pig tracheal smooth muscle. Indomethacin was applied throughout the experiments to abolish prostaglandin synthesis by PDGF. After exposure of the tissues to 10 ng/ml PDGF for 15 min, the effects of isoprenaline, a β-adrenoceptor agonist, and forskolin, a direct inhibitor of adenylyl cyclase, against methacholine-induced contraction were markedly reduced with increasing F340/F380. However, in the presence of verapamil, an inhibitor of voltage-dependent Ca2+ channels, the reduced responsiveness to isoprenaline and forskolin induced by pre-exposure to PDGF was reversed with reducing F340/F380. Reduced responsiveness to isoprenaline by PDGF was also not observed in the presence of Ca2+-free solution. The inhibitory effects of db-cAMP, an analogue of cAMP, and theophylline, a nonselective inhibitor of phosphodiesterase, were not attenuated by PDGF. In conclusion, pre-exposure to PDGF causes impairment of the β-adrenoceptors/adenylyl cyclase processes in airway smooth muscle that is independent of cyclooxygenase synthesis by PDGF. Ca2+ mobilization by Ca2+ influx through voltage-dependent Ca2+ channels is involved in this heterologous desensitization of β-adrenoceptors.