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

Abstract

1. To characterize the cysteinyl-leukotriene receptors (CysLT receptors) in isolated human pulmonary arteries, ring preparations were contracted with leukotriene C(4) (LTC(4)) and leukotriene D(4) (LTD(4)) 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 LTC(4) and LTD(4) were not significantly different (7.61+/-0.07, n=20 and 7.96+/-0.09, n=22, respectively). However, the LTC(4) and LTD(4) contractions were markedly potentiated when compared with data from intact tissues. 3. Leukotriene E(4) (LTE(4)) did not contract human isolated pulmonary arterial preparations. In addition, treatment of preparations with LTE(4) (1 microM; 30 min) did not modify either the LTC(4) or LTD(4) contractions. 4. Treatment of preparations with the S-conjugated glutathione (S-hexyl-GSH; 100 microM, 30 min), an inhibitor of the metabolism of LTC(4) to LTD(4), did not modify LTC(4) contractions. 5. The pEC(50) values for LTC(4) 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 LTD(4) 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 LTC(4) and LTD(4) 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.