Comparison of endothelin B (ET B ) receptors in rabbit isolated pulmonary artery and bronchus

1 To explore potential differences between endothelin (ET) receptors in airway versus vascular smooth muscle from the same species, the ET B receptors mediating contractions produced by ET‐1, ET‐3 and the selective ET B ligands, sarafotoxin S6c (S6c) and BQ‐3020, in rabbit bronchus and pulmonary artery were investigated by use of peptide and non‐peptide ET receptor antagonists. 2 In rabbit pulmonary artery SB 209670 (10 μ m ), a mixed ET A /ET B receptor antagonist, was a more potent antagonist of contractions produced by S6c (p K B = 7.7; n = 9; P <0.05), than those elicited by ET‐1 (p K B = 6.7; n = 6) or ET‐3 (p K B = 6.7; n = 5). BQ‐788 (10 μ m ), an ET B receptor antagonist, inhibited responses produced by ET‐3 (p K B = 5.1; n = 8), BQ‐3020 (p K B = 5.2; n = 4) or S6c (p K B = 6.2; n = 9; P <0.05 compared to potency versus ET‐3‐ or BQ‐3020‐induced contractions), but was without inhibitory effect on ET‐1‐induced contractions ( n = 5). RES‐701 (10 μ m ), another selective ET B receptor antagonist, was without effect on contractions produced by S6c ( n = 4) or ET‐1 ( n = 4), and potentiated ET‐3‐ ( n = 5) or BQ‐3020‐induced responses ( n = 4). 3 The combination of BQ‐788 (10 μ m ) and BQ‐123 (10 μ m ), an ET A ‐selective receptor antagonist, antagonized contractions produced by lower concentrations of ET‐1 (1 and 3 nM) in rabbit pulmonary artery, but was without effect on responses elicited by higher concentrations of ET‐1 ( n = 5). The combination of RES‐701 (10 μ m ) and BQ‐123 (10 μ m ) potentiated responses elicited by ET‐1, producing a 3.7 fold shift to the left in the agonist concentration‐response curve ( n = 5). 4 In rabbit bronchus SB 209670 (3 μ m ) had similar potency for antagonism of contractions produced by ET‐1 (p K B = 6.3; n = 6), ET‐3 (p K B = 6.5; n = 6) or S6c (p K B = 6.1; n = 8). BQ‐788 (3 μ m ) was without effect on responses elicited by ET‐1, ET‐3 or S6c ( n = 6) but antagonized BQ‐3020‐induced contractions (p K B = 6.4; n = 4). RES‐701 (3 μ m ) was without effect on contractions produced by S6c ( n = 6) or BQ‐3020 ( n = 4), and potentiated rather than antagonized ET‐1‐ or ET‐3‐induced responses ( n = 6), reflected by a significant (about 6 fold) shift to the left in ET‐1 or ET‐3 concentration‐response curves. The combination of BQ‐788 (3 μ m ) and BQ‐123 (3 μ m ) was without effect on contractions produced by ET‐1 in rabbit bronchus ( n = 6). The combination of RES‐701 (3 μ m ) and BQ‐123 (3 μ m ) potentiated responses elicited by ET‐1, producing a 5.2 fold shift to the left in the agonist concentration‐response curve ( n = 5). 5 BQ‐123 (3 or 10 μ m ), an ET A ‐selective receptor antagonist, was without effect on ET‐1, ET‐3 or S6c concentration‐response curves ( n = 3–6) in rabbit pulmonary artery or rabbit bronchus. 6 These data indicate that contractions induced by ET‐1, ET‐3, S6c and BQ‐3020 in rabbit pulmonary artery or rabbit bronchus appear to be mediated predominantly via stimulation of ET B receptors. However, the qualitative and quantitative differences in the relative profiles of the various structurally diverse peptide and non‐peptide antagonists examined suggests that responses produced by the ET ligands may not be mediated by a homogeneous ET B receptor population. In addition, the results suggest that differences exist in the ET B receptors mediating contraction in pulmonary vascular versus airway tissues in the same species. These receptors are not very sensitive to the standard ET B receptor antagonists, BQ‐788 and RES‐701. Furthermore, the results also provide further evidence that the potencies of ET receptor antagonists depend upon the ET agonist.