prostaglandin-h2 and 2-methyl-3-(4-(3-pyridinylmethyl)phenyl)-2-propenoic-acid

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

The appearance of the arachidonic acid metabolic pathway in human promyelocytic leukemia (HL-60) cells was investigated during 1 alpha,25-dihydroxyvitamin D-3-induced monocytic differentiation. 1 alpha,25-Dihydroxyvitamin D-3-treated HL-60 cells acquired the ability to convert [1-14C]arachidonic acid to thromboxane B2 and prostaglandin E2 during monocytic differentiation. The major cyclooxygenase product synthesized by the HL-60 cells after 3-4 days exposure to 1 alpha,25- dihydroxyvitamin D-3 (48 nM) was thromboxane B2 and its production was about 19-25-times higher than that of untreated HL-60 cells. The percent conversion of thromboxane B2 from [1-14C]arachidonic acid in the 1 alpha,25-dihydroxyvitamin D-3 (48 nM, 3 day exposure)-treated HL-60 cells was about 4.4% as compared to that (about 0.3%) of the untreated cells, whereas the percent conversion of thromboxane B2 from [1-14C]prostaglandin H2 in the 1 alpha,25-dihydroxyvitamin D-3-treated cell homogenate was about 22.4% as compared to that (about 13.6%) of the untreated cell homogenate. The stimulatory effect of 1 alpha,25-dihydroxyvitamin D-3 on thromboxane B2 production from [1-14C]arachidonic acid and from [1-14C]prostaglandin H2 in HL-60 cells was inhibited by the addition of cycloheximide (1 microgram/ml). However, 1 alpha,25-dihydroxyvitamin D-3 (48 nM) did not significantly stimulate the arachidonic acid release either in HL-60 cells or in 1 alpha,25-dihydroxyvitamin D-3-induced cells. These results suggest that the stimulatory effect of 1 alpha,25-dihydroxyvitamin D-3 on the thromboxane production in HL-60 cells was not due to the activation of phospholipase A2 but due to the induction of fatty acid cyclooxygenase and thromboxane synthetase activities. Thromboxane A2 actively produced during the monocytic differentiation of HL-60 cells could influence the cell adhesiveness of the monocyte-macrophage-differentiated cells.

Topics: Arachidonic Acid; Arachidonic Acids; Calcitriol; Carbon Radioisotopes; Cell Differentiation; Cell Line; Cycloheximide; Dimethyl Sulfoxide; Dose-Response Relationship, Drug; Humans; Leukemia, Myeloid, Acute; Methacrylates; Monocytes; Prostaglandin Endoperoxides, Synthetic; Prostaglandin H2; Prostaglandins H; Thromboxane B2; Time Factors; Tretinoin

Arachidonic acid causes dose-dependent increases in pulmonary vascular resistance in perinatal lambs. The specific metabolites that produce this effect are not known; however, a role for thromboxanes (TX's), potent constrictors of vascular smooth muscle, has been proposed. The effects of a specific inhibitor of TX synthase, OKY-1581, were tested in newborn and ventilated fetal lambs using an in situ pump-perfused lower left lobe preparation. Pulmonary and systemic responses of newborns and ventilated fetuses to infusions of arachidonic acid were evaluated in the presence and absence of OKY-1581. Increases in pulmonary vascular resistance caused by arachidonic acid were diminished by TX synthase inhibition. The degree of systemic hypotension observed with arachidonic acid infusions was significantly greater in animals receiving OKY-1581 than in animals without the inhibitor. The effect of OKY-1581 on periods of hypoxia was also evaluated in newborn lambs. There were no significant differences in the hypoxic pressor response in lambs with and without TX synthase inhibition. These results suggest that OKY-1581 can reduce most of the pulmonary vasoconstriction produced by arachidonic acid in perinatal lambs.

Topics: Acrylates; Animals; Animals, Newborn; Arachidonic Acid; Arachidonic Acids; Fetus; Hypoxia; Lung; Methacrylates; Oxidoreductases; Prostaglandin Endoperoxides, Synthetic; Prostaglandin H2; Prostaglandins H; Pulmonary Circulation; Respiration, Artificial; Sheep; Thromboxane A2; Thromboxane-A Synthase; Time Factors; Vascular Resistance; Vasoconstriction

The effects of 1-iodo-3-aminomethyl-5,6,7,8-tetrahydro-2-naphthol (ONO-3122) which increases endogenous PGH2, and sodium (E)-2-methyl-3-[4-3-pyridylmethyl)phenyl]-2-methylpropenoate (OKY-1581) which inhibits thromboxane A2 synthesis, on vasopressin-induced osmotic water flow in the bladder of the toad, Bufo bufo japonicus, were examined. ONO-3122 significantly inhibited the vasopressin-induced water flow at a concentration of 1 X 10(-4) M. OKY-1581 inhibited the vasopressin-induced water flow at 1 X 10(-6) M, but enhanced it at 1 X 10(-4) M. These results suggest that ONO-3122 indirectly inhibits the vasopressin-induced osmotic water flow in the toad bladder; that is, ONO-3122 causes an increase in the conversion of arachidonic acid into PGH2. These results also suggest that OKY-1581 at a low concentration suppresses the vasopressin-induced water flow due to inhibition of cyclooxygenase activity. Both ONO-3122 and OKY-1581 provide a useful means for studying the action of prostaglandins.

Topics: Acrylates; Animals; Body Water; Bufo bufo; In Vitro Techniques; Methacrylates; Naphthols; Osmolar Concentration; Oxidoreductases; Prostaglandin Endoperoxides, Synthetic; Prostaglandin H2; Prostaglandins H; Thromboxane A2; Thromboxane-A Synthase; Urinary Bladder; Vasopressins

We and other investigators have recently shown that inhibitors of lipoxygenase reversibly inhibit natural cytotoxic (NC) or natural killer (NK) cell activity, whereas some inhibitors of cyclooxygenase enhance these functions. In addition, exogenous LTB4 augments NC and NK activity, whereas PGE2 depresses it. In the present studies, we sought to investigate the possible role of the TxA2 synthase pathway in NC function. Inhibition of this pathway by OKY-1581 or dazoxiben significantly inhibited NC activity against HSV-infected cells as well as NK function against K562 target cells. The inhibition was dose dependent, reversible, and not due to direct toxicity. NC activity was also significantly inhibited by the addition of PGE2 or PGI2 to the 4-hr assay, whereas addition of 6-keto-PGF1 alpha had no effect. Addition of PGH2, which could be converted to TxA2 or other PG, had no significant effect, but concomitant use of OKY-1581 produced a greater inhibition of NC function than by using OKY-1581 alone. U44069, a TxA2 analog, was inhibitory by itself and could not alter the inhibition caused by OKY-1581 or dazoxiben. In contrast, the TxA2 receptor blocker 13-APA significantly enhanced NC activity and even reversed the inhibitory effect of U44069 at equimolar (10(-7)M) concentrations. Taken together, these data suggest that most of the inhibitory effect of the TxA2 synthase inhibitors on NC and NK cell function derives from their ability to reorient cyclic endoperoxide metabolism toward more inhibitory compounds. In addition, TxA2 itself could exert a negative feedback on NC function through its receptor, as evidenced by the use of a TxA2 analog and a TxA2 blocker.

Topics: Cytotoxicity Tests, Immunologic; Cytotoxicity, Immunologic; Dose-Response Relationship, Immunologic; Humans; Imidazoles; Immunosuppressive Agents; Killer Cells, Natural; Methacrylates; Prostaglandin Endoperoxides, Synthetic; Prostaglandin H2; Prostaglandins H; Thromboxane-A Synthase

Pulmonary vascular responses to leukotriene D4 were investigated in the intact-chest animal under conditions of controlled pulmonary blood flow. Intralobar injections of leukotriene D4 in the sheep caused dose-dependent increases in lobar arterial and small vein pressures without influencing left atrial or systemic arterial pressure. Leukotriene D4 was very potent in increasing pulmonary vascular resistance in the sheep, with activity similar to that of U-46619, a thromboxane A2 mimic. Pulmonary vascular responses to leukotriene D4 in the sheep were similar when the lung was ventilated and when lobar ventilation was arrested. Responses to leukotriene D4 were similar when the lung was perfused with blood or with dextran. Pulmonary vascular responses to leukotriene D4 but not U-46619 in the sheep were reduced by inhibitors of cyclooxygenase and thromboxane synthesis. In contrast, leukotriene D4 had modest pressor activity in the pulmonary vascular bed of the cat whereas U-46619 had marked activity in this species. Responses to leukotriene D4 in the cat were not altered by cyclooxygenase inhibitors. It is concluded that leukotriene D4 has marked pulmonary vasoconstrictor activity in the sheep, increasing pulmonary vascular resistance by constricting intrapulmonary veins and upstream segments. In this species, responses to leukotriene D4 were independent of changes in ventilation or interaction with formed elements but were dependent on the formation of cyclooxygenase products including thromboxane A2. However, in the cat, leukotriene D4 had very modest pressor activity, and this activity was not dependent on the integrity of the cyclooxygenase pathway. These data suggest considerable species difference in responses to leukotriene D4, a major component of the slow-reacting substance of anaphylaxis, in the pulmonary vascular bed.

Topics: Animals; Arachidonic Acid; Arachidonic Acids; Blood Pressure; Cats; Dose-Response Relationship, Drug; Female; Lung; Male; Meclofenamic Acid; Methacrylates; Microsomes; Prostaglandin Endoperoxides, Synthetic; Prostaglandin H2; Prostaglandins H; Pulmonary Circulation; Regression Analysis; Sheep; Species Specificity; SRS-A; Vascular Resistance; Vasoconstriction

Topics: 15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; Acrylates; Animals; Arachidonic Acid; Arachidonic Acids; Cats; Chromatography, Thin Layer; Female; Indomethacin; Male; Methacrylates; Oxidoreductases; Prostaglandin Endoperoxides, Synthetic; Prostaglandin H2; Prostaglandins H; Pulmonary Artery; Thromboxane A2; Thromboxane-A Synthase; Thromboxanes; Vasoconstriction; Vasodilation