Effects of MKS-492 on Antigen-Induced Bronchoconstriction and Allergic Reaction in Guinea Pigs and Rats

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Abstract
Effects of R[+]-8-{[1-[3, 4-dimethoxyphenyl]-2-hydroxyethyl]amino}-3, 7-dihydro-7-[2-methoxyethyl]-1, 3-dimethyl-1H-purine-2, 6-dione (MKS-492), a reported type III isozyme inhibitor of cyclic nucleotide phosphodiesterase, on antigen or platelet activating factor (PAF)-induced bronchoconstriction and allergic reactions in guinea pigs and rats were investigated. 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 in airway responsiveness to histamine in guinea pigs, although aminophylline failed to affect these reactions. 3) MKS-492 relaxed guinea pig tracheal muscle invitro more potently than aminophylline. 4) MKS-492 inhibited leukotriene B4 (LTB4)-induced airway eosinophilia in guinea pigs. 5) MKS-492 inhibited passive cutaneous anaphylaxis and mediator-induced skin reactions in rats more potently than aminophylline. Both drugs inhibited antigen and phospholipase A2-induced histamine release from guinea pig lung tissue. 6) MKS-492 inhibited PAF-induced O21 generation from guinea pig alveolar macrophages. These results indicate that MKS-492 is a more potent inhibitor of allergic bronchoconstriction and PAF- or LTB4-induced inflammatory reactions in guinea pigs and the allergic cutaneous reactions in rats when compared to aminophylline.

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