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 micrograms/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.
Uchida
M
M
Research Laboratories, Sumitomo Pharmaceuticals Co., Ltd., Osaka, Japan.
Imanishi
N
N
Sugasawa
T
T
Morooka
S
S
D000707:Anaphylaxis; D000818:Animals; D001249:Asthma / Q000188:drug therapy / Q000503:physiopathology*; D016084:Bronchoconstriction / Q000187:drug effects*; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D006168:Guinea Pigs; D007213:Indomethacin / Q000494:pharmacology; D008297:Male; D010047:Ovalbumin; D010972:Platelet Activating Factor / Q000037:antagonists & inhibitors*; D011433:Propranolol / Q000494:pharmacology; D011738:Pyrilamine / Q000494:pharmacology; D013189:SRS-A / Q000494:pharmacology; D013844:Thiazoles / Q000494:pharmacology* / Q000627:therapeutic use; D053778:Thiazolidines
D010972:Platelet Activating Factor; D013189:SRS-A; D013844:Thiazoles; D053778:Thiazolidines; C065776:3,5-dimethyl-2-(3-pyridyl)thiazolidin-4-one; D010047:Ovalbumin; D011433:Propranolol; D011738:Pyrilamine; D007213:Indomethacin