文章基本信息

标题：Bronchial Anti-spasmogenic Effects and Selectivity of T-440, Phosphodiesterase Type 4 Inhibitor, in the Dog
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作者：Shinsuke YAMAGATA ; Kazuteru WADA ; Takeshi SUGAYA 等
期刊名称：Biological and Pharmaceutical Bulletin
印刷版ISSN：0918-6158
电子版ISSN：1347-5215
出版年度：1997
卷号：20
期号：12
页码：1261-1265
DOI：10.1248/bpb.20.1261
出版社：The Pharmaceutical Society of Japan
摘要：We investigated the selectivity of T-440 for the inhibition of phosphodiesterases (PDEs) in vitro and for bronchial anti-spasmogenic effects in vivo. Using a fast protein liquid chromatography system, five PDE isozymes, PDE 1, PDE 2, PDE 3, PDE 4 and PDE 5 were prepared from guinea pig and dog tissues. T-440 selectively inhibited PDE 4 with an IC₅₀ of 0.071 μM and 0.13 μM for guinea pig lung and dog trachea, respectively. The IC₅₀ values for all other PDE isozymes were over 20 μM. In contrast, theophylline nonselectively inhibited all the tested PDE isozymes, and the inhibition did not exceed 50%, even at 100 μM. T-440 inhibited the histamine-induced bronchoconstriction of anesthetized dogs in a dose-dependent manner with an ED₅₀ of 0.029 mg/kg, indicating that T-440 is 600 times more potent than theophylline. Both T-440 and theophylline increased LV dp/dt/P (LVP; left ventricular pressure) in anesthetized dogs with ED₅₀ values of 3.6 mg/kg and 4.4 mg/kg, respectively. This potency was 1/125 times the bronchial anti-spasmogenic effects for T-440 and 4.2 times that of theophylline. Rolipram, a PDE 4 inhibitor, also showed selective bronchial anti-spasmogenic effects in anesthetized dogs. These results suggest that T-440, which specifically inhibits PDE 4 activity, has potent and selective bronchial anti-spasmogenic effects.
关键词：phosphodiesterase inhibitor;bronchoconstriction;cardiotonic effect;theophylline