EFFECTS OF MKS-492 ON ANTIGEN-INDUCED BRONCHOCONSTRICTION AND ALLERGIC REACTION IN GUINEA-PIGS AND RATS

Effects of -[2-methoxyethyl]-1,3-dimethyl-1H-purine-2,6-dione (MKS-492 ), a reported type III isozyme inhibitor of cyclic nucleotide phosphod iesterase, on antigen- or platelet activating factor (PAF)-induced bro nchoconstriction and allergic reactions in guinea pigs and rats were i nvestigated. 1) MKS-492 inhibited antigen-induced bronchoconstriction in guinea pigs. Aminophylline also inhibited the reaction. 2) MKS-492 inhibited PAF-induced bronchoconstriction and inhibited the increase i n airway responsiveness to histamine in guinea pigs, although aminophy lline failed to affect these reactions. 3) MKS-492 relaxed guinea pig tracheal muscle in vitro more potently than aminophylline. 4) MKS-492 inhibited leukotriene B-4 (LTB(4))-induced airway eosinophilia in guin ea pigs. 5) MKS-492 inhibited passive cutaneous anaphylaxis and mediat or-induced skin reactions in rats more potently than aminophylline. Bo th drugs inhibited antigen- and phospholipase A(2)-induced histamine r elease from guinea pig lung tissue. 6) MKS-492 inhibited PAF-induced O -2(-) generation from guinea pig alveolar macrophages. These results i ndicate that MKS-492 is a more potent inhibitor of allergic bronchocon striction and PAF- or LTB(4)-induced inflammatory reactions in guinea pigs and the allergic cutaneous reactions in rats when compared to ami nophylline.