Role of Ca2+ mobilization in desensitization of β-adrenoceptors by platelet-derived growth factor in airway smooth muscle
Role of Ca2+ mobilization in desensitization of β-adrenoceptors by platelet-derived growth factor in airway smooth muscle
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DOI：
10.1016/j.ejphar.2008.06.072
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发表时间：
2008-09-04
影响因子：
5
通讯作者：
Shimokata, Kaoru
中科院分区：
文献类型：
--
作者：
Ikenouchi, Tadasuke;Kume, Hiroaki;Shimokata, Kaoru
血小板源性生长因子（PDGF），这是从嗜酸性粒细胞和成纤维细胞释放，可能涉及支气管哮喘的病理生理。为了研究气道炎症在肾上腺素能脱敏中的作用，本研究旨在确定预先暴露于PDGF是否会恶化气道平滑肌中的P-肾上腺素受体功能。我们专注于Ca 2+信号作为参与这种现象的细胞内机制。在暴露于Fura-2负载的豚鼠气管平滑肌中的PDGF之前和之后，同时测量由异丙肾上腺素和其他cAMP相关剂诱导的等距张力和F-340/F-380（细胞内Ca 2+浓度的指示剂）。在整个实验过程中应用消炎痛以消除血小板源生长因子合成前列腺素。暴露的组织10 ng/ml的PDGF 15分钟后，异丙肾上腺素，β-肾上腺素受体激动剂，和毛喉素，腺苷酸环化酶的直接抑制剂，对乙酰甲胆碱诱导的收缩的影响显着减少与增加F340/F380。然而，在维拉帕米，电压依赖性钙通道的抑制剂的存在下，减少F-340/F-380逆转了由预先暴露于PDGF诱导的对异丙肾上腺素和毛喉素的反应性降低。PDGF对异丙肾上腺素的反应性降低，也没有观察到在无钙溶液的存在下。db-cAMP，cAMP的类似物，和茶碱，磷酸二酯酶的非选择性抑制剂的抑制作用，没有衰减的PDGF。总之，预先暴露于PDGF会导致气道平滑肌中β-肾上腺素受体/腺苷酸环化酶过程受损，这与PDGF合成环氧合酶无关。通过电压依赖性Ca 2+通道的Ca 2+内流的Ca 2+动员参与β-肾上腺素受体的这种异源脱敏。(C)2008 Elsevier B. V.保留所有权利。
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 adrenergic desensitization, the present study was designed to determine whether pre-exposure to PDGF deteriorates P-adrenoceptor function in airway smooth muscle. We focused on Ca2+ signaling as an intracellular mechanism involved in this phenomenon. Isometric tension and F-340/F-380 (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 beta-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-de pendent Ca2+ 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 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 beta-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 beta-adrenoceptors. (C) 2008 Elsevier B.V. All rights reserved.