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-ylmethyl)-3-methoxy-N-o-tolylsulfonylbenzamide, 1 mu M) or BAY u9773 (6(R)-(4'-carboxyphenylthio)-5(S)-hydroxy-7( E),9(E), 11(Z)14(Z)-eicosatetrenoic acid, 3 mu M). Indomethacin (1.7 mu M) 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. (C) 2000 Elsevier Science B.V. All rights reserved.