sq-29548 and 12-hydroxy-5-8-10-heptadecatrienoic-acid

There is mounting evidence that lipid peroxides contribute to pathophysiological processes and can modulate cellular functions. The aim of the present study was to investigate the effects of lipid hydroperoxides on platelet aggregation and arachidonic acid (AA) metabolism. Human platelets, isolated from plasma, were incubated with subthreshold (i.e. non-aggregating) concentrations of AA in the absence or presence of hydroperoxyeicosatetraenoic acids (HPETEs). Although HPETEs alone had no effect on platelet function, HPETEs induced the aggregation of platelets co-incubated with non-aggregating concentrations of AA, HPETEs being more potent than non-eicosanoid peroxides. The priming effect of HPETEs on platelet aggregation was associated with an increased formation of cyclo-oxygenase metabolites, in particular thromboxane A2, and was abolished by aspirin, suggesting an activation of cyclo-oxygenase by HPETEs. It was not receptor-mediated because the 12-HPETE-induced enhancement of AA metabolism was sustained in the presence of SQ29, 548 or RGDS, which blocked the aggregation. These results indicate that physiologically relevant concentrations of HPETEs potentiate platelet aggregation, which appears to be mediated via a stimulation of cyclo-oxygenase activity.

Topics: 12-Hydroxy-5,8,10,14-eicosatetraenoic Acid; Arachidonic Acid; Aspirin; Blood Platelets; Bridged Bicyclo Compounds, Heterocyclic; Deferoxamine; Enzyme Activation; Fatty Acids, Unsaturated; Humans; Hydrazines; Hydrogen Peroxide; Leukotrienes; Lipid Peroxides; Oligopeptides; Peroxides; Platelet Aggregation; Prostaglandin-Endoperoxide Synthases; tert-Butylhydroperoxide; Thromboxane B2; Vitamin E

The leukotactic responsiveness of human peripheral blood monocytes is regulated by the cell-directed inhibitor of monocyte leukotaxis, CDI-MLx. The actions of CDI-MLx on normal monocytes in vitro were abrogated by co-incubation with inhibitors of cyclooxygenase and thromboxane synthetase with indomethacin and dazmegrel (UK-38,485) being most active. The actions of CDI-MLx were mimicked by the thromboxane A2 analogue, U-46619, and by 12-HHT with half-maximal inhibition observed at 10(-10) M; PGE2 was 1000-fold less active. SQ 29,548, a thromboxane A2 receptor antagonist, blocked the effects of CDI-MLx, U-46619, and 12-HHT. Production of PGE2 and thromboxane B2 by purified monocytes was stimulated by CDI-MLx and this effect was also blocked by indomethacin, dazmegrel, and dazoxiben. These data suggest a major regulatory role for thromboxane synthetase products in human monocyte leukotaxis.

Topics: Bridged Bicyclo Compounds, Heterocyclic; Chemotactic Factors; Chemotaxis, Leukocyte; Dinoprostone; Fatty Acids, Unsaturated; Humans; Hydrazines; In Vitro Techniques; Lymphokines; Monocytes; Prostaglandin Endoperoxides, Synthetic; Prostaglandins E; Radioimmunoassay; Thromboxane A2