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 resp onse to leukotriene C-4 was not blocked by either CysLT(1)/CysLT(2) recepto r antagonism or by pre-treatment with leukotriene E-4. In preparations with an intact endothelium, leukotriene C-4 was somewhat more potent than leuko triene D-4 and the concentration-response curves were only slightly depress ed 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 reduce d the response to leukotriene C-4 whereas the response to leukotriene D-4 w as unchanged. These findings suggest that a CysLT receptor subtype resistan t to current antagonists mediated the major part of the contractions to leu kotriene C-4 and leukotriene D-4 in intact preparations, and was the sole r eceptor associated with contractions of endothelium-denuded preparations. ( C) 2000 Elsevier Science B.V. All rights reserved.