Effect of the selective PAF antagonist SM-10661 on an asthmatic model. 1. Effect on passive anaphylactic bronchoconstriction in guinea pigs

The effect of SM-10661, a selective antagonist of platelet-activating factor (PAF), on passive anaphylactic bronchoconstriction was examined in guinea pigs. A challenge of ovalbumin to passively sensitized guinea pigs induced bronchoconstriction, which peaked at 4 min. When SM-10661 was administered intravenously 2 min before ovalbumin challenge, bronchoconstriction was inhibited dose-dependently with an ID₅₀ of 68 mg/kg. In guinea pigs pretreated with 15 μg/kg mepyramine which is a suboptimal dose, antigen-induced bronchoconstriction peaked at 4–6 min, but was inhibited by SM-10661 with an ID₅₀ of 21 mg/kg. When guinea pigs were pretreated intravenously with 2.5 mg/kg mepyramine, 1 mg/kg indomethacin and 0.01 mg/kg propranolol, the antigen-induced bronchoconstriction peaked at 6 min. SM-10661 inhibited the response with an ID₅₀ of 45 mg/kg. Histamine- and leukotriene D₄-induced bronchoconstrictions were unaffected by up to 100 mg/kg SM-10661. Ovalbumin challenge of minced lungs from passively sensitized guinea pigs triggered the release of leukotrienes and histamine. SM-10661 had no effect on the antigen-induced release of peptide leukotrienes or histamine up to 10⁻⁴ M. These results indicate that SM-10661 may be a useful tool to investigate the role of PAF in antigen-induced anaphylactic bronchoconstriction. Based on a paper presented at the Third International Conference on Platelet-Activating Factor and Structurally Related Alkyl Ether Lipids, Tokyo, Japan, May 1989.