Inhibitory effect of a novel phosphodiesterase IV inhibitor, T-440, on antigen- and chemical mediator-induced bronchoconstrictions in guinea pigs in vivo.
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 microgram/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.
Lead Optimization Research Laboratory, Tanabe Seiyaku Co., Ltd., Saitama, Japan.
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Kaminuma
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Kikkawa
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Matsubra
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Ikezawa
D019796:15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; D000704:Analysis of Variance; D000818:Animals; D001249:Asthma / Q000188:drug therapy; D016084:Bronchoconstriction / Q000187:drug effects*; D004305:Dose-Response Relationship, Drug; D006168:Guinea Pigs; D006633:Histamine Antagonists / Q000494:pharmacology; D007275:Injections, Intravenous; D017998:Leukotriene D4 / Q000037:antagonists & inhibitors; D008297:Male; D009281:Naphthalenes / Q000494:pharmacology*; D010726:Phosphodiesterase Inhibitors / Q000494:pharmacology*; D011450:Prostaglandin Endoperoxides, Synthetic / Q000037:antagonists & inhibitors; D011728:Pyridones / Q000494:pharmacology*; D011817:Rabbits; D013928:Thromboxane A2 / Q000031:analogs & derivatives / Q000037:antagonists & inhibitors; D014662:Vasoconstrictor Agents / Q000037:antagonists & inhibitors
D006633:Histamine Antagonists; D009281:Naphthalenes; D010726:Phosphodiesterase Inhibitors; D011450:Prostaglandin Endoperoxides, Synthetic; D011728:Pyridones; C101791:T 440; D014662:Vasoconstrictor Agents; D013928:Thromboxane A2; D017998:Leukotriene D4; D019796:15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid