Inhibitory Effect of a Novel Phosphodiesterase IV Inhibitor, T-440, on Antigen- and Chemical Mediator-Induced Bronchoconstrictions in Guinea Pigs In Vivo

Abstract

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 rig/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.