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 pD₂ value (7.16_±₀.09, n_=₆) was significantly increased in the presence of peptidase inhibitors (thiorfan 1_μm , captopril 1_μm , bestatin 1_μm ) (pD₂_=₇.75_±₀.09, n_=₆). Indomethacin (5_μm ) did not appear to influence the ET_B-agonist pD₂ value (6.92_+₀.11, n_=₆) but potentiated its maximal response significantly (67.23_±₄.81% vs. 53.37_±₄.80%). 2 ?The concentration-response curve for the contractile response to IRL 1620 (pD₂=7.83__₀.01, n=16); was reproducible, although not completely, since the second curve to this selective ET_B agonist was shifted significantly to the right (pD₂_=₇.34_±₀.09, n_=_16) and a decrease in the maximal response was observed (20.0_±₂.0%). 3 ?BQ 788, a selective antagonist for ET_B receptors, employed in concentrations ranging from 1.5 to 150_n m , caused a dose-dependent shift to the right of the concentration-response curve to IRL 1620, with a pIC₅₀ value of 8.11_±₀.03; this action was not influenced by adding enzyme inhibitors (pIC₅₀_=₈.17_±₀.29). 4 ?Our data show that IRL 1620 undergoes a hydrolytic metabolism in guinea-pig bronchial preparations, which could influence the calculation of the pD₂. Pretreatment of the tissue with peptidase inhibitors and indomethacin is consequently significant in the evaluation of IRL 1620 activity, while it does not influence the action of the antagonist, BQ 788.