Pharmacological evidence for a novel cysteinyl-leukotriene receptor subtype in human pulmonary artery smooth muscle

1 To characterize the cysteinyl-leukotriene receptors (CysLT receptors) in isolated human pulmonary arteries, ring preparations were contracted with leukotriene C-4 (LTC4) and leukotriene D-4 (LTD4) in either the absence or presence of the selective CysLT(1) receptor antagonists, ICI 198615, MK 571 or the dual CysLT(1)/CysLT(2) receptor antagonist, BAY u9773. 2 Since the contractions induced by the cysteinyl-leukotrienes (cysLTs) in intact preparations failed to attain a plateau response over the concentration range studied, the endothelium was removed and the tissue treated continuously with indomethacin (Rubbed+ INDO). In these latter preparations, the pEC(50) for LTC4 and LTD4 were not significantly different (7.61 +/- 0.07, n = 20 and 7.96 +/- 0.09, n = 22, respectively). However, the LTC4 and LTD4 contractions were markedly potentiated when compared with data from intact tissues. 3 Leukotriene E-4 (LTE4) did not contract human isolated pulmonary arterial preparations. In addition, treatment of preparations with LTE4 (1 mum; 30 min) did not modify either the LTC4 or LTD4 contractions. 4 Treatment of preparations with the S-conjugated glutathione (S-hexyl-GSH; 100 pm, 30 min), an inhibitor of the metabolism of LTC4 to LTD4, did not modify LTC4 contractions. 5 The pEC(50) values for LTC4 were significantly reduced by treatment of the preparations with either ICI 198615, MK 571 or BAY u9773 and the pK(B) values were: 7.20, 7.02 and 6.26, respectively. In contrast, these antagonists did not modify the LTD4 pEC(50) values. 6 These findings suggest the presence of two CysLT receptors on human pulmonary arterial vascular smooth muscle. A CysLT(1) receptor with a low affinity for CysLT(1) antagonists and a novel CysLT receptor subtype, both responsible for vasoconstriction. Activation of this latter receptor by LTC4 and LTD4 induced a contractile response which was resistant to the selective CysLT(1) antagonists (ICI 198615 and MK 571) as well as the non-selective (CysLT(1)/CysLT(2)) antagonist, BAY u9773.