Antagonist resistant contractions of the porcine pulmonary artery by cysteinyl-leukotrienes.
The contractile response to cysteinyl-leukotrienes was studied in isolated porcine pulmonary arterial rings. In endothelium-denuded preparations, the concentration-response curves for leukotriene C(4) and leukotriene D(4) were identical, whereas leukotriene E(4) did not contract these tissues. The response to leukotriene C(4) was not blocked by either CysLT(1)/CysLT(2) receptor antagonism or by pre-treatment with leukotriene E(4). In preparations with an intact endothelium, leukotriene C(4) was somewhat more potent than leukotriene D(4) and the concentration-response curves were only slightly depressed in the presence of either ICI 204,219 (4-(5-cyclopentyloxycarbonylamino-1-methylindol-3-ylmethy l)-3-methoxy -N-o-tolylsulfonylbenzamide, 1 microM) or BAY u9773 (6(R)-(4'-carboxyphenylthio)-5(S)-hydroxy-7(E),9(E), 11(Z)14(Z)-eicosatetrenoic acid, 3 microM). Indomethacin (1.7 microM) significantly reduced the response to leukotriene C(4) whereas the response to leukotriene D(4) was unchanged. These findings suggest that a CysLT receptor subtype resistant to current antagonists mediated the major part of the contractions to leukotriene C(4) and leukotriene D(4) in intact preparations, and was the sole receptor associated with contractions of endothelium-denuded preparations.
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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Mazmanian
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Dahlén
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Brink
D015121:6-Ketoprostaglandin F1 alpha / Q000378:metabolism; D000818:Animals; D003545:Cysteine / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D004730:Endothelium, Vascular / Q000502:physiology; D066298:In Vitro Techniques; D007211:Indoles; D007213:Indomethacin / Q000494:pharmacology; D020024:Leukotriene Antagonists / Q000494:pharmacology; D017997:Leukotriene C4 / Q000494:pharmacology; D017998:Leukotriene D4 / Q000494:pharmacology; D017999:Leukotriene E4 / Q000494:pharmacology; D015289:Leukotrienes / Q000494:pharmacology*; D008297:Male; D008565:Membrane Proteins; D048448:Phenylcarbamates; D011651:Pulmonary Artery / Q000187:drug effects* / Q000378:metabolism / Q000502:physiology; D018077:Receptors, Leukotriene / Q000502:physiology; D013189:SRS-A / Q000031:analogs & derivatives / Q000494:pharmacology; D013449:Sulfonamides; D013552:Swine; D013928:Thromboxane A2 / Q000378:metabolism; D014105:Tosyl Compounds / Q000494:pharmacology; D014661:Vasoconstriction / Q000187:drug effects*
C071435:BAY u9773; D007211:Indoles; D020024:Leukotriene Antagonists; D015289:Leukotrienes; D008565:Membrane Proteins; D048448:Phenylcarbamates; D018077:Receptors, Leukotriene; D013189:SRS-A; D013449:Sulfonamides; D014105:Tosyl Compounds; C112381:cysteinyl-leukotriene; D017997:Leukotriene C4; D013928:Thromboxane A2; D015121:6-Ketoprostaglandin F1 alpha; D017998:Leukotriene D4; D017999:Leukotriene E4; C412375:cysteinyl leukotriene receptor 2; D003545:Cysteine; C083169:leukotriene D4 receptor; D007213:Indomethacin; C062735:zafirlukast