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

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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 (ED<SUB>50</SUB>= 2.3 mg/kg). Histamine-, leukotriene (LT) D<SUB>4</SUB>-, 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 LTD<SUB>4</SUB>(ED<SUB>50</SUB>= 0.89 μg/kg), whereas the effect against ACh was very weak (ED<SUB>50</SUB>= 1.8 mg/kg). Additionally, T-440 inhibited histamine-induced bronchoconstriction by intraduodenal and intratracheal administration (ED<SUB>50</SUB>and EC<SUB>50</SUB>= 1.6mg/kg and 0.50mg/ml, respectively). Bronchoconstrictions induced by antigen and chemical mediators were also suppressed by theophylline. However, all of these anti-spasmolyiic effects of theophylline were less potent than those of T-440 (1.8-110times). Our results indicate the importance of PDE IV in bronchodilation, and PDE IV inhibitors may have potential as anti-asthma drugs.


  • The Japanese Journal of Pharmacology

    The Japanese Journal of Pharmacology 72(1), 1-8, 1996-09-01

    The Japanese Pharmacological Society

References:  26

Cited by:  2


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