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 leukotrie ne C-4 were significantly potentiated by the cyclooxygenase inhibitor indom ethacin (1.7 mu M) and after endothelial denudation. Measurements of 6-keto prostaglandin F-1 alpha showed that cysteinyl-leukotrienes stimulated the release of prostacyclin. A single concentration (1 mu M) of either leukotri ene C-4 or leukotriene D-4 resulted in both contraction and relaxation. Ind omethacin abolished the relaxant phase and enhanced the amplitude of the co ntraction, supporting that cysteinyl-leukotriene-induced contractions of th e 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-(dimethyl-amino-3-oxopropyl)thio)methyl)th io propanoic acid, 1 mu M) and BAY u9773 (6(R)-(4'-carboxyphenylthio)-5(S)- hydroxy-7(E), 11(Z)14(Z)-eicosatetrenoic acid, 3 mu M), both in the absence and presence of indomethacin. These findings suggest a functional cysteiny l-leukotriene receptor in the human pulmonary artery with antagonist proper ties not previously described in human tissue. (C) 2000 Elsevier science B. V. All rights reserved.