PAF-induced death in NMRI mice--a suitable shock model for testing new PAF receptor antagonists. Correlation with eicosanoid related substances.
The effects of PAF antagonists, of substances which influence the arachidonic acid metabolism, and of dexamethasone and ketotifen were evaluated in an acute PAF-induced mortality model in female NMRI mice. We established a dependence of sensitivity to PAF on strain (AB mice showed no dose dependence) and on sex of the animals as well as on the PAF charges used in our experiments. PAF produced resistance in surviving animals against the PAF-induced death on repeated application. The PAF antagonists, WEB 2170 and WEB 2086, provided the best dose-dependent protection against PAF toxicity, followed by dexamethasone, by the COX/LOX synthetase inhibitor X 86 (a BW 755 C-analogue) and by the PAF receptor antagonist BN 52021. Particularly remarkable was the excellent prevention by aspirin. Aspirin may not only inhibit the cyclooxygenase pathway but also endogenous PAF synthesis. Other drugs, i.e. indomethacin, the thromboxane receptor antagonist, BM 13177, the thromboxane synthetase inhibitor, HOE 944, as well as the lipoxygenase inhibitors (NDGA, esculetin, SHAM and phenidone) exerted a dose-dependent protection only at high doses.
Martin Luther University Halle-Wittenberg, School of Medicine, Department of Pharmacology and Toxicology, Germany.
K
K
Becker
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G
Lueddeckens
R
R
Grupe
W
W
Förster
D015772:4,5-Dihydro-1-(3-(trifluoromethyl)phenyl)-1H-pyrazol-3-amine / Q000494:pharmacology; D000818:Animals; D001381:Azepines / Q000494:pharmacology; D004195:Disease Models, Animal; D004224:Diterpenes; D015777:Eicosanoids / Q000502:physiology*; D005260:Female; D046934:Ginkgolides; D007783:Lactones / Q000494:pharmacology; D009637:Masoprocol / Q000494:pharmacology; D051379:Mice; D010972:Platelet Activating Factor / Q000037:antagonists & inhibitors / Q000494:pharmacology* / Q000502:physiology; D010980:Platelet Membrane Glycoproteins; D011956:Receptors, Cell Surface / Q000037:antagonists & inhibitors*; D043562:Receptors, G-Protein-Coupled; D012769:Shock / Q000209:etiology* / Q000517:prevention & control; D013045:Species Specificity; D014230:Triazoles / Q000494:pharmacology
D001381:Azepines; D004224:Diterpenes; D015777:Eicosanoids; D046934:Ginkgolides; D007783:Lactones; D010972:Platelet Activating Factor; D010980:Platelet Membrane Glycoproteins; D011956:Receptors, Cell Surface; D043562:Receptors, G-Protein-Coupled; D014230:Triazoles; C039351:platelet activating factor receptor; D015772:4,5-Dihydro-1-(3-(trifluoromethyl)phenyl)-1H-pyrazol-3-amine; D009637:Masoprocol; C063964:bepafant; C045856:ginkgolide B