Role of Ca(2+) mobilization in desensitization of beta-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 beta-adrenergic desensitization, the present study was designed to determine whether pre-exposure to PDGF deteriorates beta-adrenoceptor function in airway smooth muscle. We focused on Ca(2+) signaling as an intracellular mechanism involved in this phenomenon. Isometric tension and F(340)/F(380) (an indicator of intracellular Ca(2+) 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 beta-adrenoceptor agonist, and forskolin, a direct inhibitor of adenylyl cyclase, against methacholine-induced contraction were markedly reduced with increasing F(340)/F(380). However, in the presence of verapamil, an inhibitor of voltage-dependent Ca(2+) channels, the reduced responsiveness to isoprenaline and forskolin induced by pre-exposure to PDGF was reversed with reducing F(340)/F(380). Reduced responsiveness to isoprenaline by PDGF was also not observed in the presence of Ca(2+)-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 beta-adrenoceptors/adenylyl cyclase processes in airway smooth muscle that is independent of cyclooxygenase synthesis by PDGF. Ca(2+) mobilization by Ca(2+) influx through voltage-dependent Ca(2+) channels is involved in this heterologous desensitization of beta-adrenoceptors.
Ikenouchi
Tadasuke
T
Department of Respiratory Medicine, Nagoya University Graduate School of Medicine, Showa-ku, Nagoya 466-8550, Japan.
Kume
Hiroaki
H
Oguma
Tetsuya
T
Makino
Yasushi
Y
Shiraki
Akira
A
Ito
Yasushi
Y
Shimokata
Kaoru
K
D000262:Adenylyl Cyclases / Q000378:metabolism; D000818:Animals; D001249:Asthma / Q000503:physiopathology*; D002118:Calcium / Q000378:metabolism*; D015220:Calcium Channels / Q000378:metabolism; D020013:Calcium Signaling; D006168:Guinea Pigs; D007537:Isometric Contraction; D008297:Male; D009130:Muscle, Smooth / Q000378:metabolism; D010982:Platelet-Derived Growth Factor / Q000378:metabolism* / Q000494:pharmacology; D011451:Prostaglandin-Endoperoxide Synthases / Q000378:metabolism; D011943:Receptors, Adrenergic, beta / Q000378:metabolism*; D014132:Trachea / Q000378:metabolism
D015220:Calcium Channels; D010982:Platelet-Derived Growth Factor; D011943:Receptors, Adrenergic, beta; D011451:Prostaglandin-Endoperoxide Synthases; D000262:Adenylyl Cyclases; D002118:Calcium