dinoprost and 2-methyl-3-(4-(3-pyridinylmethyl)phenyl)-2-propenoic-acid

Radiotracer studies and radioimmunoassay measurements demonstrate that minced tissues of human decidua produce chiefly thromboxane B2 (TxB2) (70% of total eicosanoids) and small amounts of prostaglandin F2 alpha (PGF2 alpha) (13%) PGD2 (8%), 6-keto-PGF1 alpha (5%) and PGE2 (4%). Inhibition of thromboxane synthesis with a specific inhibitor (OKY-1581: sodium (E)-3-[4(-3-pyridylmethyl)-phenyl]-2-methyl propenoate) increased prostaglandin formation in general, with the main product being PGF2 alpha (38%), a nonenzymic derivative of PGH2. Crude particulate fractions prepared from the same tissue synthesized two major products from [3H]arachidonate, TxB2 and 6-keto-PGF1 alpha (54 and 30%, respectively) and some PGF2 alpha and PGE2 (8-8%). However, in the presence of reduced glutathione (GSH), PGE2 became the main product (81%) (TxB2, 15%; PGF2 alpha, 2%; and 6-keto-PGF1 alpha, 2%). Half-maximal stimulation of PGE2 synthesis occurred at 46 microM GSH. The GSH concentration of tissue samples was found to be 110 +/- 30 microM. We conclude that human first trimester decidua cells possess the key enzymes of prostaglandin and thromboxane synthesis. Apparently, the production of these compounds is controlled by a specific mechanism in the tissue, which keeps PGE and prostacyclin synthesis in a reversibly suppressed state, whereas the formation of thromboxane is relatively stimulated.

Topics: 6-Ketoprostaglandin F1 alpha; Arachidonic Acid; Arachidonic Acids; Cell-Free System; Decidua; Dinoprost; Dinoprostone; Female; Glutathione; Humans; Methacrylates; Pregnancy; Prostaglandin D2; Prostaglandins; Thromboxane B2; Thromboxane-A Synthase

Topics: 15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; Acrylates; Animals; Arachidonic Acid; Arachidonic Acids; Bridged Bicyclo Compounds, Heterocyclic; Cats; Dinoprost; Fatty Acids, Unsaturated; Hydrazines; Lung; Methacrylates; Prostaglandin Endoperoxides, Synthetic; Respiratory Function Tests; Thromboxane A2; Thromboxane-A Synthase

The influence of OKY 1581, a thromboxane synthase inhibitor, on airway responses to arachidonic acid and endoperoxide, [prostaglandin (PG) H2], were investigated in anesthetized, paralyzed, mechanically ventilated cats. Intravenous injections of arachidonic acid and PGH2 caused dose-related increases in transpulmonary pressure and lung resistance and decreases in dynamic and static compliance. OKY 1581 significantly decreased airway responses to arachidonic acid but not to PGH2. Sodium meclofenamate, a cyclooxygenase inhibitor, abolished airway responses to arachidonic acid but had no effect on airway responses to PGH2. OKY 1581 or meclofenamate has no effect on airway responses to PGF2 alpha, PGD2, or U 46619, a thromboxane mimic. In microsomal fractions from the lung, OKY 1581 inhibited thromboxane formation without decreasing prostacyclin synthesis or cyclooxygenase activity. These studies show that OKY 1581 is a selective thromboxane synthesis inhibitor in the cat lung and suggest that a substantial part of the bronchoconstrictor response to arachidonic acid is due to thromboxane A2 formation. Moreover, the present data suggest that airway responses to endogenously released and exogenous PGH2 are mediated differently and that a significant part of the response to exogenous PGH2 may be due to activation of an endoperoxide/thromboxane receptor, since responses to PGH2 are blocked by the thromboxane receptor antagonist SQ 29548.

Topics: Acrylates; Airway Resistance; Animals; Arachidonic Acid; Arachidonic Acids; Bronchi; Cats; Dinoprost; Methacrylates; Prostaglandin D2; Prostaglandin Endoperoxides; Prostaglandin Endoperoxides, Synthetic; Prostaglandin H2; Prostaglandins D; Prostaglandins F; Prostaglandins H; Receptors, Prostaglandin; Receptors, Thromboxane; Thromboxane-A Synthase

Leukotrienes (LT) LTA4, LTB4, LTC4, LTD4 and LTE4 induced marked contractions of guinea pig lung parenchymal strips mounted in organ baths. These contractions were inhibited differentially (40-50% for LTA4, LTC4, LTD4 and LTE4, and 90% for LTB4) by indomethacin (20 micrograms.ml-1; 55.9 microM). Two novel inhibitors of thromboxane synthetase (OKY-1581 and OKY-046) reduced the myotropic activity of the lung strips and the release of prostaglandins and thromboxanes from the perfused guinea pig lungs stimulated by LTB4 and LTD4. The release of cyclooxygenase products prostaglandin F2 alpha, thromboxane B2 and 12-hydroxyheptadecatrienoic acid by guinea pig lungs following stimulation with LTB4 and LTD4 was also measured by gas chromatography-mass spectrometry. The role of prostaglandins and thromboxanes in the lung actions of leukotrienes was confirmed using a cascade superfusion system and classical organ baths. Although prostaglandins and thromboxanes contribute to the contractile effect of LTB4 on the guinea pig lung whereas they may play a lesser role in the action of the peptidoleukotrienes (approx. 40-50%), stimulation of their release by the peptidoleukotrienes is many times more effective than by LTB4.

Topics: Animals; Arachidonic Acids; Dinoprost; Female; Gas Chromatography-Mass Spectrometry; Guinea Pigs; Indomethacin; Leukotriene A4; Leukotriene B4; Leukotriene E4; Lung; Male; Methacrylates; Prostaglandin-Endoperoxide Synthases; Prostaglandins F; SRS-A; Thromboxane B2

When non-stimulated rat alveolar macrophages were incubated with exogenous 14C-arachidonic acid (7 microM) both cyclo-oxygenase and lipoxygenase metabolites were formed. The major cyclo-oxygenase metabolites were PGE2, PGF2 alpha and TXB2. The detected amounts of 5-lipoxygenase metabolites were small. Aspirin inhibited the formation of all cyclo-oxygenase metabolites, but had no effect on the formation of the lipoxygenase metabolites. In the presence of OKY-1581, an inhibitor of thromboxane synthetase, the formation of thromboxane B2 was decreased and that of the other cyclo-oxygenase metabolites was correspondingly increased. The present study indicates that OKY-1581 is a specific inhibitor of thromboxane synthetase also in rat alveolar macrophages and that the rate of formation of leukotrienes via the 5-lipoxygenase pathway is rather small in non-stimulated rat alveolar macrophages.

Topics: Acrylates; Animals; Arachidonic Acid; Arachidonic Acids; Aspirin; Dinoprost; Dinoprostone; Macrophages; Methacrylates; Oxidoreductases; Prostaglandins E; Prostaglandins F; Pulmonary Alveoli; Rats; Thromboxane B2; Thromboxane-A Synthase

Addition of arachidonic acid (AA) to human platelet rich plasma caused a reversible platelet aggregation and a concomitant formation of thromboxane B2 (TXB2). Both AA-induced platelet aggregation and TXB2 formation were inhibited by OKY-1581 and the amounts of PGE2 and PGF2 alpha formed were correspondingly increased. The formation of 6-keto-PGF1 alpha was smaller and was increased only slightly by OKY-1581. ADP-induced platelet aggregation did not result in the formation of TXB2 and it was inhibited only slightly by OKY-1581. When ADP was added to platelet rich plasma six minutes after the addition of AA, the ADP-induced aggregation was greatly decreased in the presence and absence of OKY-1581. The present study indicates that the AA-induced platelet aggregation is inhibited by OKY-1581 and that OKY-1581 is a specific inhibitor of thromboxane synthesis in platelet rich human plasma.

Topics: 6-Ketoprostaglandin F1 alpha; Acrylates; Adenosine Diphosphate; Adult; Arachidonic Acid; Arachidonic Acids; Dinoprost; Dinoprostone; Humans; In Vitro Techniques; Male; Methacrylates; Platelet Aggregation; Prostaglandins E; Prostaglandins F; Thromboxane B2; Thromboxanes