leukotriene-b4 and 2-methyl-3-(4-(3-pyridinylmethyl)phenyl)-2-propenoic-acid

In vitro pharmacological profiles of E3040, 6-hydroxy-5, 7-dimethyl-2-(methylamino)-4-(3-pyridylmethyl) benzothiazole were investigated. Against the 5-lipoxygenase activity of rat basophilic leukemia cells, E3040 and zileuton (a 5-lipoxygenase inhibitor) had an IC(50) of 0.23 and 0.93 microM, respectively. Against the thromboxane A(2) synthetase activity of human platelets, E3040 had an IC(50) of 0.01 microM, which was comparable to that of OKY-1581 (sodium (E)-3-[4-(3-pyridylmethyl) phenyl]-2-methylacrylate, a thromboxane A(2) synthetase inhibitor). Against cyclooxygenase activity of sheep seminal vesicles, E3040 showed no inhibition (IC(50), >300 microM). Sulfasalazine and 5-aminosalicylic acid, therapeutic drugs for inflammatory bowel disease, inhibited 5-lipoxygenase activity with an IC(50) of 293 and 970 microM, respectively. Sulfasalazine inhibited thromboxane A(2) synthetase activity with an IC(50) of 20 microM. In rat peritoneal leukocytes, E3040 inhibited leukotriene B(4) and thromboxane B(2) production with an IC(50) of 0.17 and 0.24 microM, respectively. E3040 inhibited leukotriene B(4) production in human neutrophils and thromboxane B(2) production in human platelets (IC(50) of 0.21 and 0.09 microM, respectively). These results indicated that E3040 potently inhibited 5-lipoxygenase and thromboxane A(2) synthetase and blocked leukotriene B(4) and thromboxane B(2) production in rat peritoneal and human blood cells.

Topics: Animals; Arachidonate 5-Lipoxygenase; Benzothiazoles; Dinoprostone; Dose-Response Relationship, Drug; Eicosanoids; Humans; Hydroxyurea; Indomethacin; Leukocytes; Leukotriene B4; Lipoxygenase Inhibitors; Male; Mesalamine; Methacrylates; Neutrophils; Peritoneal Cavity; Prostaglandin-Endoperoxide Synthases; Pyridines; Rats; Rats, Inbred F344; Sheep; Sulfasalazine; Thiazoles; Thromboxane B2; Thromboxane-A Synthase

Eicosanoids, as modulators of inflammation, may be involved in the pathogenesis of inflammatory bowel disease. We investigated their potential role in a rat model of chronic granulomatous colonic inflammation induced by trinitrobenzene sulphonic acid. Luminal eicosanoid release was quantified in vivo using a dialysis bag placed into the distal colon. We tested the effect of drugs known to modify inflammatory activity or arachidonic acid metabolism. Three days after intracolonic injection of trinitrobenzene sulphonic acid at different dose levels, the dialysates showed a highly significant increase of prostaglandin E2, 6-keto-prostaglandin F1 alpha, thromboxane B2 (TXB2), and leukotriene B4, compared with levels in controls not subjected to the toxic agent. Remarkably, the release of TXB2 continued to increase during the stage of chronic inflammation (up to day 21), whereas the levels of the remainder eicosanoids declined. Treatment with prednisone or 5-aminosalicylic acid reduced TXB2 levels in the chronic stage of the inflammatory disease and improved the morphological damage as assessed macroscopically and histologically. Moreover, two selective thromboxane synthetase inhibitors, OKY 1581 and R70416, significantly reduced the development of chronic inflammatory lesions in the colon while inhibiting the release of TXB2. Our results indicate that (1) luminal release of thromboxane increases in the chronic stage of colonic inflammation, (2) anti-inflammatory treatment reduces tissue damage and thromboxane release, and (3) selective thromboxane synthetase inhibition improves the course of the disease in our experimental model.

Topics: 6-Ketoprostaglandin F1 alpha; Aminosalicylic Acids; Animals; Colitis; Dinoprostone; Indomethacin; Leukotriene B4; Male; Mesalamine; Methacrylates; Pentanoic Acids; Prednisone; Pyridines; Rats; Rats, Inbred Strains; Thromboxane B2; Thromboxane-A Synthase; Trinitrobenzenesulfonic Acid

Leukotriene B4 contracts guinea pig lung parenchymal strips by an indirect mechanism dependent upon formation of myotropic cyclooxygenase metabolites. In contrast to the prevailing notion, our data indicate that thromboxane A2 is not necessarily the sole or essential mediator involved. Several points support this conclusion. First, the quantitative and temporal aspects of thromboxane B2 release and the myotropic response to leukotriene B4 were weakly correlated (r = 0.73). Second, the dose-response curve for thromboxane A2, based on the amount of thromboxane B2 generated by lung strips contracted with leukotriene B4, was inconsistent with dose-response curves for lung strips contracted with a stable thromboxane A2 mimetic, U-46619 or with synthetic thromboxane A2 itself. Third, thromboxane synthetase inhibitors, typified by OKY-1581 and UK-37248, did not inhibit the myotropic activity of leukotriene B4 under conditions in which thromboxane B2 formation was reduced by 80 to 90%. A thromboxane A2 receptor antagonist, BM 13.177, did not inhibit the myotropic activity of leukotriene B4 under conditions in which it antagonized the effects of U-46619. Cyclooxygenase metabolites other than thromboxane A2 must contribute to the mechanism of action of leukotriene B4 or leukotriene B4 effects may be mediated directly on certain cells or receptors.

Topics: Animals; Dose-Response Relationship, Drug; Guinea Pigs; In Vitro Techniques; Leukotriene B4; Lung; Male; Methacrylates; Muscle Contraction; Thromboxane A2; Thromboxane B2; 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

Topics: Animals; Arachidonic Acid; Arachidonic Acids; Blood Pressure; Humans; Leukotriene B4; Lung; Methacrylates; Muscle Contraction; Natriuresis; Prostaglandins; SRS-A; T-Lymphocytes, Regulatory; Thromboxanes