thromboxane-b2 and 15-hydroperoxy-5-8-11-13-eicosatetraenoic-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 mechanism of action of LTB4 has been investigated on the guinea-pig lung parenchymal strip. Mepacrine (20 microgram/ml), an inhibitor of phospholipase A2, abolished the action of LTB4 on parenchymal strips. Eicosatetraynoic acid (10 microgram/ml) and BW755C (40 microgram/ml) which are inhibitors of cyclooxygenase and lipoxygenase pathways, produced a marked inhibition of the lung strip contraction to LTB4. Similarly, aspirin (30 micrograms/ml) and flufenamate (1 microgram/ml) showed a strong inhibition of the contraction of parenchymal strips to LTB4; these results suggested that cyclooxygenase products mediate the action of LTB4. The response to LTB4 was unaffected by 15-hydroperoxyeicosatatraenoic acid (15-HPETE; 1 microgram/ml) while L8027 (25 ng/ml) reduced the contraction by 50%, suggesting that thromboxane A2 rather than prostacyclin was involved. Since parenchymal strips do not appear to be very sensitive to PGF2 alpha, PGE2 and the endoperoxides, and since effluents from LTB4-treated lungs produced contractions of lung strip and rabbit aorta which were reduced after 5 min. at 25 degrees, thromboxane A2 was postulated to mediate the lung effect of LTB4. The release of thromboxane B2 (TxB2) from lungs stimulated with LTB4 was confirmed by gas-chromatography-mass spectrometric (GC-MS) analyses.

Topics: Animals; Arachidonic Acids; Aspirin; Female; Flufenamic Acid; Guinea Pigs; Imidazoles; Indoles; Leukotriene B4; Leukotrienes; Lipid Peroxides; Lung; Male; Muscle Contraction; Peroxides; Prostaglandins; Pyridines; Quinacrine; Thromboxane A2; Thromboxane B2; Thromboxanes

Topics: Arachidonic Acids; Blood Platelets; Humans; In Vitro Techniques; Leukotrienes; Lipid Peroxides; Peroxides; Thrombin; Thromboxane B2