Bronchodilator and anti-inflammatory activities of glaucine:: In vitro studies in human airway smooth muscle and polymorphonuclear leukocytes
Bronchodilator and anti-inflammatory activities of glaucine:: In vitro studies in human airway smooth muscle and polymorphonuclear leukocytes
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DOI：
10.1038/sj.bjp.0702702
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发表时间：
1999-08-01
影响因子：
7.3
通讯作者：
Morcillo, EJ
中科院分区：
文献类型：
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作者：
Cortijo, J;Villagrasa, V;Morcillo, EJ
1 选择性磷酸二酯酶 4 (PDE4) 抑制剂在治疗哮喘方面具有潜在意义。我们检测了生物碱 S-(+)-glaucine（一种 PDE4 抑制剂）对人离体支气管和粒细胞功能的影响。2Glaucine 以非竞争性方式选择性抑制人支气管和多形核白细胞 (PMN) 中的 PDE4 (K-i=3.4 muM)。 Glaucine 将 [H-3]-咯利普兰从大鼠脑皮质膜的高亲和力结合位点上取代（IC(50) 类似于 100 mu M）。3 Glaucine 抑制人离体支气管中自发的和组胺诱导的张力（pD(2) 类似于 4.5）。格劳辛 (10 μM) 不会增强异丙肾上腺素诱导的松弛，但会增强异丙肾上腺素引起的环 AMP 积累。海氨酸诱导的松弛对 H-89（一种蛋白激酶 A 抑制剂）有抵抗力。格劳辛抑制了对 Ca2+ 的收缩反应（pD'(2) 类似于 3.62），并减少了培养的人气道平滑肌细胞中组胺产生的 [Ca2+](i) 的持续升高（-log IC(50) 类似于 4.3）。4 格劳辛增强了用 N-甲酰基-Met-Leu-Phe 攻击的人多形核白细胞中的环 AMP 水平 (FMLP) 或异丙肾上腺素，并抑制 FMLP 诱导的超氧化物生成、弹性蛋白酶释放、白三烯 B-4 生成、[Ca2+](i) 信号和血小板聚集，以及调理的酵母聚糖、醋酸佛波醇肉豆蔻酸酯和 A23187 诱导的超氧化物释放。结论是，H-89.5 降低了海藻氨酸对 FMLP 产生超氧化物的抑制作用。海氨酸对 Ca2+ 通道的拮抗作用似乎主要是海氨酸在人离体支气管中的松弛作用的原因，而 PDE4 抑制则有助于海氨酸在人粒细胞中的抑制作用。海藻氨酸极低的 PDE4/结合位点比率使得该化合物对进一步的结构活性研究具有吸引力。
1 Selective phosphodiesterase 4 (PDE4) inhibitors are of potential interest in the treatment of asthma. We examined the effects of the alkaloid S-(+)-glaucine, a PDE4 inhibitor, on human isolated bronchus and granulocyte function.2 Glaucine selectively inhibited PDE4 from human bronchus and polymorphonuclear leukocytes (PMN) in a non-competitive manner (K-i=3.4 mu M). Glaucine displaced [H-3]-rolipram from its high-affinity binding sites in rat brain cortex membranes (IC(50)similar to 100 mu M).3 Glaucine inhibited the spontaneous and histamine-induced tone in human isolated bronchus (pD(2)similar to 4.5). Glaucine (10 mu M) did not potentiate the isoprenaline-induced relaxation but augmented cyclic AMP accumulation by isoprenaline. The glaucine-induced relaxation was resistant to H-89, a protein kinase A inhibitor. Glaucine depressed the contractile responses to Ca2+ (pD'(2)similar to 3.62) and reduced the sustained rise of [Ca2+](i) produced by histamine in cultured human airway smooth muscle cells (-log IC(50)similar to 4.3).4 Glaucine augmented cyclic AMP levels in human polymorphonuclear leukocytes challenged with N-formyl-Met-Leu-Phe (FMLP) or isoprenaline, and inhibited FMLP-induced superoxide generation, elastase release, leukotriene B-4 production, [Ca2+](i) signal and platelet aggregation as well as opsonized zymosan-, phorbol myristate acetate-, and A23187-induced superoxide release. The inhibitory effect of glaucine on superoxide generation by FMLP was reduced by H-89.5 In conclusion. Ca2+ channel antagonism by glaucine appears mainly responsible for the relaxant effect of glaucine in human isolated bronchus while PDE4 inhibition contributes to the inhibitory effects of glaucine in human granulocytes. The very low PDE4/binding site ratio found for glaucine makes this compound attractive for further structure-activity studies.