Osamu Kaminuma, Hideo Kikkawa, Shigeki Matsubara and Katsuo Ikezawa
Lead Optimization Research Laboratory, Tanabe Seiyaku Co., Ltd., 2-2-50 Kawagishi, Toda, Saitama 335, Japan
Abstract: We demonstrated the effect of a novel selective type IV phosphodiesterase (PDE) IV inhibitor, T-440 (1-[1-(2-methoxyethyl)pyrid-2-one-4-yl]-2,3-bis(hydroxymethyl)-6,7- diethoxynaphthalene), on antigen- and chemical mediator-induced bronchoconstrictions in anesthetized guinea pigs in vivo. Intravenously (i.v.) administered T-440 inhibited antigen-induced bronchoconstriction dose-dependently in passively sensitized guinea pigs (ED50 = 2.3 mg/kg). Histamine-, leukotriene (LT) D4-, U-46619-, acetylcholine (ACh)-, neurokinin A- and endothelin-1-induced bronchoconstrictions were also inhibited by i.v. injected T-440. Most potent suppression was produced against the bronchoconstriction induced by LTD4 (ED50 = 0.89 microg/kg), whereas the effect against ACh was very weak (ED50 = 1.8 mg/kg). Additionally, T-440 inhibited histamine-induced bronchoconstriction by intraduodenal and intratracheal administration (ED50 and EC50 = 1.6 mg/kg and 0.50 mg/ml, respectively). Bronchoconstrictions induced by antigen and chemical mediators were also suppressed by theophylline. However, all of these anti-spasmolytic effects of theophylline were less potent than those of T-440 (1.8 - 110 times). Our results indicate the importance of PDE IV in bronchodilation, and PDE IV inhibitors may have potential as anti-asthma drugs.
Phosphodiesterase, Airway, Asthma, Bronchoconstriction
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