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Induction by endothelin‐1 of epithelium‐dependent relaxation of guinea‐pig trachea in vitro : role for nitric oxide
Author(s) -
Filep János G.,
Battistini Bruno,
Sirois Pierre
Publication year - 1993
Publication title -
british journal of pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.432
H-Index - 211
eISSN - 1476-5381
pISSN - 0007-1188
DOI - 10.1111/j.1476-5381.1993.tb13620.x
Subject(s) - carbachol , nitric oxide , trachealis muscle , thromboxane a2 , endocrinology , guinea pig , contraction (grammar) , stimulation , medicine , chemistry , endothelin 1 , thromboxane , prostacyclin , endothelin receptor , respiratory epithelium , receptor , respiratory system , platelet , charybdotoxin
1 The purpose of the present experiments was to study the underlying mechanisms responsible for the relaxant action of endothelin‐1 (ET‐1) in the guinea‐pig trachea in vitro . 2 In tracheal strips precontracted (60–70% of the maximum) with carbachol, ET‐1 (1–100 n m ) evoked slowly developing concentration‐dependent relaxations. Preincubation of the tissues with the thromboxane A 2 /prostaglandin H 2 receptor antagonist, BM 13505 (5 μ m ) significantly potentiated the relaxant response to ET‐1. 3 Removal of the epithelium changed the response of precontracted tracheal preparations to ET‐1 from a relaxation to a sustained contraction. 4 ET‐1‐induced relaxations were abolished by methylene blue (10 μ m ) and were almost completely attenuated by oxyhaemoglobin (5 μ m ) and N G ‐monomethyl‐ l ‐arginine ( l ‐NMMA, 100 μ m ), an inhibitor of nitric oxide synthesis, but were not altered by indomethacin (10 μ m ). 5 In tracheal strips under passive tension, ET‐1 (1–100 n m ) elicited dose‐dependent contractions. The sensitivity of tissues to ET‐1 was significantly enhanced by removal of the epithelium (apparent EC 50 values were 28.1 ± 4.1 and 12.5 ± 0.8 n m in intact and rubbed trachea, respectively, n = 7, P < 0.01). 6 Preincubation of intact tracheal strips with methylene blue, oxyhaemoglobin or l ‐NMMA did not mimic the effect of epithelium removal on ET‐1‐induced contractions. 7 There was a concentration‐dependent increase in thromboxane A 2 but not in PGE 2 and prostacyclin release from intact tracheal strips following stimulation with ET‐1 (5–100 n m ). 8 These results show that ET‐1 exerts a dual action on guinea‐pig isolated trachea: it evokes contractions at low resting tone, whereas it induces relaxations at higher resting tone. The relaxant action of ET‐1 may be mediated by nitric oxide released from epithelial cells and resultant activation of smooth muscle guanylate cyclase.