Functional characterization of receptors for cysteinyl-leukotrienes in sheep trachealis muscle

Cysteinyl-leukotrienes (CysLTs: LTC4, LTD4 and LTE4) are inflammatory mediators which significantly contribute to the airway obstruction in asthma, At least two distinct receptor subtypes exist for cysteinyl-leukotrienes, the CysLT(1)- and CysLT(2)-receptor. The purpose of this study was to test whether sheep trachealis muscle is a useful preparation for further characterization of CysLT(2)-receptors, previously implicated in contraction of human pulmonary veins, Leukotriene C-4 and leukotriene D-4 evoked contractile responses, leukotriene C-4 being significantly more potent than leukotriene D-4, whereas leukotriene E-4 failed to elicit contractions, The response to leukotriene C-4 exhibited tachyphylaxis upon repeated administration, There were no significant effects of epithelial denudation, NO-synthesis inhibition (L-NAME) or cyclooxygenase inhibition (indomethacin) on the responses to cysteinyl-leukotrienes or cholinergic agonists, Neither was responsiveness to different agonists changed by overnight storage, The responses to leukotriene C-4 and leukotriene D-4 were markedly potentiated when their metabolism was inhibited by S-hexyl glutathione and L-cysteine, The selective CysLT(1)-antagonist PCI 198,615 had no significant effect on these responses, However, the combined CysLT(1)- and CysLT(2)-antagonist BAY u9773 competitively antagonized leukotriene C-4, and leukotriene D-4 (pA(2) values of 7.0 and 6.8 against leukotriene C-4 and leukotriene D-4, respectively), The findings support that leukotriene C-4 and leukotriene D-4 act predominantly on CysLT(2)-receptors in sheep trachea. (C) 1997 Academic Press Limited.