Vol. 280, Issue 2, 959-965, 1997

Nonpeptide Endothelin Receptor Antagonists. IX. Characterization of Endothelin Receptors in Guinea Pig Bronchus With SB 209670 and Other Endothelin Receptor Antagonists

Douglas W. P. Hay and Mark A. Luttmann

Department of Pulmonary Pharmacology, SmithKline Beecham Pharmaceuticals, 709 Swedeland Road, King of Prussia, Pennsylvania

In this study the endothelin (ET) receptors mediating contractions produced by ET-1, ET-3 and the selective ET_B ligands sarafotoxin 6c (S6c) and BQ-3020 in guinea pig bronchus were investigated using SB 209670, a nonpeptide, mixed ET_A/ET_B receptor antagonist, and the peptide ET receptor antagonists BQ-123 (ET_A receptor-selective), BQ-788 (ET_B receptor-selective) and RES-701 (ET_B receptor-selective). SB 209670 (10 µM) antagonized concentrations induced by ET-1 (pK_B = 6.1). In contrast, BQ-788 (10 µM) and BQ-123 (10 µM), either alone or in combination, were without significant effect on ET-1 concentration-response curves. SB 209670 (10 µM) and BQ-788 (10 µM) antagonized S6c concentration-response curves with pK_B values of 6.6 and 5.5, respectively, whereas RES-701 (10 µM) and BQ-123 (10 µM) were without effect. SB 209670 (10 µM) was about a 10-fold less potent antagonist of contractions produced by ET-3 (pK_B = 5.4) than of those elicited by S6c. BQ-788 (10 µM), RES-701 (10 µM) and BQ-123 (10 µM) were without effect on ET-3 concentration-response curves. BQ-788 (10 µM) had similar potencies for inhibition of contractions induced by S6c (pK_B = 5.8) and BQ-3020 (pK_B = 6.25). These data indicate that contractions induced by ET-1, ET-3, S6c and BQ-3020 in guinea pig bronchus appear to be mediated predominantly via stimulation of ET_B receptors. However, these receptors are not very sensitive to the standard ET_B receptor antagonists BQ-788 and RES-701, which suggests that responses produced by these ligands in this tissue involve activation not of the classical ET_B receptor, but rather of an atypical ET receptor population. The results also provide additional evidence that the potencies of ET receptor antagonists depend upon the specific ET agonist.