Role of peptidase and cyclooxygenase inhibitors in the guinea-pig bronchial response to the synthetic endothelin ETB agonist IRL 1620 and antagonist BQ-788

1 In isolated guinea-pig bronchial preparations the selective endothelin ET B agonist, IRL 1620 caused a concentration-dependent contraction. The pD(2) value (7.16 +/- 0.09, n = 6) was significantly increased in the presence o f peptidase inhibitors (thiorfan 1 mu M, captopril 1 mu M, bestatin 1 mu M) (pD(2) = 7.75 +/- 0.09, n = 6). Indomethacin (5 mu M) did not appear to in fluence the ETB-agonist pD(2) value (6.92 + 0.11, n = 6) but potentiated it s maximal response significantly (67.23 +/- 4.81% vs. 53.37 +/- 4.80%). 2 The concentration-response curve for the contractile response to IRL 1620 (pD(2) = 7.83 +/- 0.01, (n) under bar = 16); was reproducible, although no t completely, since the second curve to this selective ETB agonist was shif ted significantly to the right (pD(2) = 7.34 +/- 0.09, n = 16) and a decrea se in the maximal response was observed (20.0 +/- 2.0%). 3 BQ 788, a selective antagonist for ETB receptors, employed in concentrati ons ranging from 1.5 to 150 nM, caused a dose-dependent shift to the right of the concentration-response curve to IRL 1620, with a pIC(50) value of 8. 11 +/- 0.03; this action was not influenced by adding enzyme inhibitors (pI C(50) = 8.17 +/- 0.29). 4 Our data show that IRL 1620 undergoes a hydrolytic metabolism in guinea-p ig bronchial preparations, which could influence the calculation of the pD( 2). Pretreatment of the tissue with peptidase inhibitors and indomethacin i s consequently significant in the evaluation of IRL 1620 activity, while it does not influence the action of the antagonist, BQ 788.