ozagrel and kadsurenone

Platelet-activating factor (PAF) has recently been described as a mediator of inflammatory processes. In this study, we quantitated the dose-response effects of topically applied PAF on microvascular permselectivity and investigated the biochemical pathways of this compound. Permselectivity alterations were assessed by measuring the clearance of macromolecules with fluorescein isothiocyanate dextran 150 (FITC-dx 150) as a tracer. The microvascular bed of the hamster cheek pouch served as a model. PAF was found to induce leakage of macromolecules from postcapillary venules. Control FITC-dx 150 plasma clearance (+/- SEM) was 72 +/- 10 nl/90 min. Clearances of 61 +/- 10 474 +/- 145, 622 +/- 57, 301 +/- 86, and 142 +/- 3 nl/90 min were obtained at PAF concentrations of 10(-9), 10(-8), 10(-7), 10(-6), and 10(-5) M, respectively. A one-way analysis of variance showed that the population means were not equal. Multiple comparison by the Student-Newman-Keuls test demonstrated that the clearances obtained with 10(-8), 10(-7), and 10(-6) M were significantly greater than controls. Significant differences existed between 10(-7) M PAF and 10(-9), 10(-6), and 10(-5) M PAF. In an effort to elucidate the biochemical pathways of PAF activity, several inhibitors of the arachidonic acid cascade and receptor blockers were used. Dexamethasone and kadsurenone attenuated the clearance response to PAF in a statistically significant manner, while indomethacin, OKY-046, and chlorpheniramine were without effect.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Animals; Benzofurans; Blood Pressure; Capillary Permeability; Cheek; Cricetinae; Dexamethasone; Dextrans; Dose-Response Relationship, Drug; Fluorescein-5-isothiocyanate; Fluoresceins; Hematocrit; Indomethacin; Lignans; Macromolecular Substances; Male; Mesocricetus; Methacrylates; Microcirculation; Platelet Activating Factor

The myotropic activities of PAF-acether, leukotriene B4, leukotriene D4 and histamine were compared on superfused guinea-pig lung parenchymal strip and were shown to have the following order of potency: PAF-acether greater than LTD4 greater than LTB4 greater than histamine. The contractile response of the lung parenchyma to PAF-acether was inhibited by aspirin, imidazole and OKY-046, which suggested that thromboxane A2 might play a mediator role in PAF-induced contractions. Neither an antagonist of leukotriene D4, FPL-55712, nor an antihistamine, mepyramine, had any effect on PAF contractions. The activity of a novel antagonist of PAF-acether, BN 52021, was also studied on superfused lung parenchyma contracted by histamine, leukotriene B4, leukotriene D4 and PAF-acether. This compound was without effect on the histamine response but it slightly reduced the contractions elicited by leukotriene D4 and potentiated those by leukotriene B4. BN 52021 (7.1 X 10(-6) M) inhibited by 63% the contraction induced by 5.7 X 10(-13) M PAF-acether and by 52% that induced by 5.7 X 10(-10) M PAF-acether and kadsurenone (8.4 X 10(-6) M), another PAF-acether antagonist, inhibited the same PAF-induced contractions by 75% and 20% respectively.

Topics: Animals; Aspirin; Benzofurans; Chromones; Diterpenes; Ginkgolides; Guinea Pigs; Histamine; Imidazoles; Lactones; Leukotriene B4; Lignans; Lung; Male; Methacrylates; Muscle Contraction; Muscle, Smooth; Plant Extracts; Platelet Activating Factor; Prostaglandin Antagonists; Pyrilamine; SRS-A