Prostacyclin modulation of contractions of the human pulmonary artery by cysteinyl-leukotrienes.
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.
Experimental Asthma and Allergy Research, Institute of Environmental Medicine, Karolinska Institutet, 171 77, Stockholm, Sweden. magnus.back.imm.ki.se
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Bäck
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Norel
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Walch
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Gascard
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de Montpreville
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Dahlén
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Brink
D015121:6-Ketoprostaglandin F1 alpha / Q000378:metabolism; D003545:Cysteine / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D004730:Endothelium, Vascular / Q000502:physiology; D011464:Epoprostenol / Q000378:metabolism*; D005260:Female; D006801:Humans; D066298:In Vitro Techniques; D007213:Indomethacin / Q000494:pharmacology; D020024:Leukotriene Antagonists / Q000494:pharmacology; D017997:Leukotriene C4 / Q000494:pharmacology; D017998:Leukotriene D4 / Q000494:pharmacology; D015289:Leukotrienes / Q000494:pharmacology*; D008297:Male; D008565:Membrane Proteins; D008875:Middle Aged; D011422:Propionates / Q000494:pharmacology; D011651:Pulmonary Artery / Q000187:drug effects* / Q000378:metabolism / Q000502:physiology; D011804:Quinolines / Q000494:pharmacology; D018077:Receptors, Leukotriene / Q000502:physiology; D013189:SRS-A / Q000031:analogs & derivatives / Q000494:pharmacology; D014661:Vasoconstriction / Q000187:drug effects*
C071435:BAY u9773; D020024:Leukotriene Antagonists; D015289:Leukotrienes; D008565:Membrane Proteins; D011422:Propionates; D011804:Quinolines; D018077:Receptors, Leukotriene; D013189:SRS-A; C112381:cysteinyl-leukotriene; D017997:Leukotriene C4; D015121:6-Ketoprostaglandin F1 alpha; C059141:verlukast; D017998:Leukotriene D4; C412375:cysteinyl leukotriene receptor 2; D011464:Epoprostenol; D003545:Cysteine; C083169:leukotriene D4 receptor; D007213:Indomethacin