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We studied changes in airway responsiveness to acetylcholine (ACh) after antigen inhalation in Ascaris suum (A. suum)-allergic dogs. Airway responsiveness was determined by obtaining a dose-response curve of lung resistance plotted against increasing concentrations of ACh aerosol before and after inhalation of A. suum antigen. To determine the role of thromboxane A2 (TXA2) in the airway response, we tested the effect of a TXA2 receptor antagonist, AA-2414, in A. suum-allergic dogs. The procedure was repeated in each dog at an interval of 2 weeks to evaluate the effect of AA-2414 in a crossover manner. The dogs showing an airway response to antigen showed an increase in airway responsiveness to ACh 2, 4 and 6 h after antigen inhalation. The increase in airway responsiveness was significantly inhibited by administration of AA-2414 (5 mg/kg, i.v.) before antigen inhalation. These results suggest that TXA2 may be involved in antigen-induced airway hyperresponsiveness (AHR) in dogs.

The anti-asthmatic activity of AA-2414 [(±)-7-(3,5,6-trimethyl-1,4-benzoquinon-2-yl-7-phenylheptanoic acid)] has been studied in vivo and in vitro . Experimental allergic asthma was inhibited by orally administered AA-2414 in a dose-dependent manner. AA-2414, 0.08∼1.25 mg/kg (p.o.), inhibited the bronchoconstriction in guinea pigs induced by a prostaglandin endoperoxide analogue (U-46619), leukotriene D 4 (LTD 4 ), and platelet activitating factor (PAF) with a long duration of action. The compound did not inhibit histamine-induced bronchoconstriction. AA-2414 reduced the induction of pulmonary inflation caused by LTD 4 aerosol inhalation. AA-2414 competitively inhibited the contractile response to U-46619 in guinea pig tracheal and parenchymal strips and dog saphenous vein strips with pA2 values of 7.69, 8.29 and 6.79, respectively. Furthermore, the contractile responses of guinea pig tracheal strip to PGD 2 , 9 a , 11s-PGF 2 and PGF 2 a were inhibited with pA2 values of 7.20, 7.79 and 5.71, respectively. These results suggest that AA-2414, a quinone derivative, is a novel, potent and orally active antagonist of a variety of spasmogenic prostanoids.