6-ketoprostaglandin-f1-alpha and verlukast

The contractile response to cysteinyl-leukotrienes was studied in isolated human pulmonary arterial rings. Concentration-response curves for leukotriene C(4) were significantly potentiated by the cyclooxygenase inhibitor indomethacin (1.7 microM) and after endothelial denudation. Measurements of 6-keto prostaglandin F(1alpha) showed that cysteinyl-leukotrienes stimulated the release of prostacyclin. A single concentration (1 microM) of either leukotriene C(4) or leukotriene D(4) resulted in both contraction and relaxation. Indomethacin abolished the relaxant phase and enhanced the amplitude of the contraction, supporting that cysteinyl-leukotriene-induced contractions of the human pulmonary artery may be functionally antagonised by the release of prostacyclin. The contractions induced by leukotriene C(4) were resistant to the two cysteinyl-leukotriene receptor antagonists MK 571 ((3-(-2(7-chloro-2-quinolinyl)ethenyl)phenyl)((3-(dimethylamino-3-oxo propyl)thio)methyl)thio propanoic acid, 1 microM) and BAY u9773 (6(R)-(4'-carboxyphenylthio)-5(S)-hydroxy-7(E),9(E), 11(Z)14(Z)-eicosatetrenoic acid, 3 microM), both in the absence and presence of indomethacin. These findings suggest a functional cysteinyl-leukotriene receptor in the human pulmonary artery with antagonist properties not previously described in human tissue.

Topics: 6-Ketoprostaglandin F1 alpha; Cysteine; Dose-Response Relationship, Drug; Endothelium, Vascular; Epoprostenol; Female; Humans; In Vitro Techniques; Indomethacin; Leukotriene Antagonists; Leukotriene C4; Leukotriene D4; Leukotrienes; Male; Membrane Proteins; Middle Aged; Propionates; Pulmonary Artery; Quinolines; Receptors, Leukotriene; SRS-A; Vasoconstriction

This study investigated, in isolated human internal mammary artery, the involvement of the cyclooxygenase and the lipoxygenase pathways of arachidonic acid metabolism in the contraction induced by angiotensin II.. Rings of human internal mammary arteries were suspended in organ baths for recording of isometric tension. In addition, the release of eicosanoids in response to angiotensin II (0.3 microM) was measured by enzyme immunoassay.. In human arterial rings without endothelial dependent relaxation in response to substance P or acetylcholine, the angiotensin II-induced contractions were significantly (P<0.05) reduced by 27% in the presence of GR32191 0.3 microM (thromboxane A(2) (TXA(2)) receptor antagonist) but remained unchanged in the presence of dazoxiben 100 microM (thromboxane synthase inhibitor). In addition, angiotensin II failed to modify TXB(2) and 6-keto-PGF(1alpha) production. These results suggest the contribution of a TXA(2)/PGH(2) agonist other than TXA(2) in angiotensin II-induced contractions. However, indomethacin increased (P<0.05) angiotensin II-mediated contractile response and cysteinyl leukotriene production, suggesting a redirection of arachidonic acid metabolism from the cyclooxygenase pathway to the lipoxygenase pathway. Indeed, the contractions induced by angiotensin II were inhibited (P<0.05) by phenidone 100 microM (cyclooxygenase and lipoxygenase inhibitor), baicalein 100 microM (5-, 12- and 15-lipoxygenases inhibitor), AA861 10 microM (5-lipoxygenase inhibitor) and MK571 1 microM (CysLT(1) receptor antagonist). Cysteinyl leukotrienes were released in response to angiotensin II (pg/mg dry weight tissue: 32+/-9 (basal, n=6) vs. 49+/-9 (angiotensin II 0.3 microM, n=6), P<0.05). LTD(4), and at a lesser degree LTC(4), induced contractions of internal mammary artery and MK571 1 microM abolished the contraction to LTD(4).. This study suggests that the in vitro vasoconstrictor effects of angiotensin II in human internal mammary artery are enhanced at least in part by eicosanoids produced by the cyclooxygenase pathway, probably PGH(2), acting on TXA(2)/PGH(2) receptors, and by lipoxygenase-derived products, particularly cysteinyl leukotrienes acting on CysLT(1) receptors.

Topics: 6-Ketoprostaglandin F1 alpha; Acetylcholine; Angiotensin II; Benzoquinones; Biphenyl Compounds; Cyclooxygenase Inhibitors; Depression, Chemical; Dose-Response Relationship, Drug; Enzyme Inhibitors; Flavanones; Flavonoids; Heptanoic Acids; Humans; Imidazoles; In Vitro Techniques; Indomethacin; Leukotrienes; Lipoxygenase Inhibitors; Mammary Arteries; Propionates; Pyrazoles; Quinolines; Receptors, Thromboxane; Substance P; Thromboxane B2; Thromboxane-A Synthase; Vasoconstriction

To determine the role of inflammatory products of phospholipid metabolism in acute otitis media (AOM), we infected 128 chinchillas with Streptococcus pneumoniae and randomly assigned them to one of four equal-sized treatment groups receiving intramuscular ampicillin sodium (control) or intramuscular ampicillin plus receptor blockers of platelet activating factor (WEB 2086, 5 mg/d orally), of leukotriene (MK 571, 0.5 mg/d orally), or of thromboxaneA2 (GR 32191B, 5 mg/d orally). All treatments were begun on day 2 postinoculation and continued for 10 days. On days 3, 6, 9, and 12, 8 animals from each group were sacrificed. Effusions were recovered for biochemical assay, and the right middle ears were prepared for histologic study. Differences among groups in the number of ears with effusion or in effusion volume were not statistically significant. In comparison to the control group, mucosal thickness and the number of ears with histopathologic signs of inflammation were significantly less in the GR and WEB treatment groups, but not the MK group. Also, effusion concentrations of free fatty acids, protease, and hydrolytic enzymes were significantly less in those groups. These results show that the addition of a receptor blocker for either platelet activating factor and/or thromboxane to ampicillin in the treatment of AOM reduces mucosal inflammation and decreases the production of other inflammatory chemicals. The failure of a receptor blocker of leukotrienes to moderate disease expression suggests either a less important role for these chemicals in AOM or an insufficient bioavailability of the specific MK 571 inhibitor. These results confirm that platelet activating factor and thromboxane are active mediators of inflammation in AOM.

Topics: 6-Ketoprostaglandin F1 alpha; Acute Disease; Animals; Azepines; Biphenyl Compounds; Chinchilla; Dinoprostone; Ear, Middle; Fatty Acids, Nonesterified; Heptanoic Acids; Hydrolases; Leukotriene Antagonists; Leukotriene C4; Mucous Membrane; Otitis Media; Phospholipids; Platelet Activating Factor; Platelet Membrane Glycoproteins; Pneumococcal Infections; Propionates; Quinolines; Receptors, Cell Surface; Receptors, G-Protein-Coupled; Receptors, Thromboxane; Thromboxane B2; Triazoles