Characterization of the endothelin receptor subtype mediating epithelium-derived relaxant nitric oxide release from guinea-pig trachea

1 The endothelin (ET) receptor subtype that mediates niric oxide (NO)-dependent airway relaxation in tracheal tube preparations precontracted with carbachol and pretreated with indomethacin was investigated. The release of NO induced by ET from guinea-pig trachea using a recently developed porphyrinic microsensor was also measured. 2 ET-I (1 pM-100nM) contracted tracheal tube preparations pretreated with the NO-synthase inhibitor, L-NMMA, and relaxed, in an epithelium-dependent manner, preparations pretreated with the inactive enantiomer D-NMMA. The effect of L-NMMA was reversed by L-Arg, but not by D-Arg. 3 The selective ET(B) receptor agonists, IRL 1620 or sarafotoxin S6c, both (1 pM-100 nM) contracted tracheal tube preparations in a similar manner either after treatment with D-NMMA or with L-NMMA. In the presence of the ET(A) receptor antagonist, FR139317 (10 mu M), ET-I administration resulted in a contraction that was similar after either L-NMMA or D-NMMA. In the presence of the ETB receptor antagonist, BQ788 (1 mu M), ET-1 relaxed and contracted tracheas pretreated with D-NMMA and L-NMMA, respectively. 4 Exposure of tracheal segments to ET-1 (1-1000 nM) caused a concentration-dependent increase in NO release that was reduced by L-NMMA. IRL1620 (1 mu M) did not cause any significant NO release. FR139317 (10 mu M), but not, BQ788 (1 mu M), inhibited the NO release induced by ET-I. 5 These results demonstrate that in the isolated guinea-pig trachea activation of ET(B) receptors results in a contractile response, whereas activation of ET(A) receptors cause both a contraction, and an epithelium-dependent relaxation that is mediated by NO release.