Antagonist resistant contractions of the porcine pulmonary artery by cysteinyl-leukotrienes

Abstract

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.