Antagonism of PAF-induced death in mice.
The ability of three platelet activating factor (PAF) antagonists, BN52021, L652,731 and 48740RP, and the leukotriene antagonist FPL55712 to block iv PAF-induced death was tested in mice. PAF-induced sudden death has been previously characterized as a model of systemic anaphylaxis and circulatory shock related its hypotensive actions. Of the drugs, BN5201 and L652,731 provided dose-dependent protection against PAF toxicity, whereas the others had no effect. 48740RP was, however active against PAF-induced rabbit platelet aggregation. BN52021 was inactive in three other mouse sudden death models in which arachidonic acid, U46619 or collagen combined with epinephrine is injected iv to provoke a thrombotic/ischemic sudden death. In contrast, the TXA2 antagonist SQ29548 inhibited the acute toxicity of two of these latter challenges (arachidonic acid and thromboxane agonist U46619), but was inactive against PAF lethality. These results suggest that PAF toxicity in mice is a specific model for PAF agonism, and is not mediated by TXA2 or peptido-leukotrienes. Further, PAF-induced mortality should be a simple and useful technique for testing potential PAF antagonists for in vivo activity by various routes of administration.
D019796:15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; D000818:Animals; D016718:Arachidonic Acid; D001095:Arachidonic Acids / Q000633:toxicity; D019086:Bridged Bicyclo Compounds, Heterocyclic; D003094:Collagen / Q000633:toxicity; D004224:Diterpenes; D004837:Epinephrine / Q000633:toxicity; D005231:Fatty Acids, Unsaturated; D005663:Furans / Q000494:pharmacology; D046934:Ginkgolides; D006834:Hydrazines / Q000494:pharmacology; D007783:Lactones / Q000494:pharmacology; D008297:Male; D051379:Mice; D010972:Platelet Activating Factor / Q000037:antagonists & inhibitors* / Q000502:physiology; D010975:Platelet Aggregation Inhibitors; D011450:Prostaglandin Endoperoxides, Synthetic / Q000633:toxicity; D011725:Pyridines / Q000494:pharmacology; D013844:Thiazoles / Q000494:pharmacology; D013928:Thromboxane A2 / Q000037:antagonists & inhibitors
D001095:Arachidonic Acids; D019086:Bridged Bicyclo Compounds, Heterocyclic; D004224:Diterpenes; D005231:Fatty Acids, Unsaturated; D005663:Furans; D046934:Ginkgolides; D006834:Hydrazines; D007783:Lactones; D010972:Platelet Activating Factor; D010975:Platelet Aggregation Inhibitors; D011450:Prostaglandin Endoperoxides, Synthetic; D011725:Pyridines; D013844:Thiazoles; D016718:Arachidonic Acid; D013928:Thromboxane A2; D019796:15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; C045749:SQ 29548; D003094:Collagen; C052520:3-(3-pyridinyl)-1H,3H-pyrrolo(1,2-c)thiazole-7-carboxamide; C047504:2,5-bis(3,4,5-trimethoxyphenyl)tetrahydrofuran; C045856:ginkgolide B; D004837:Epinephrine