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Influence of regional differences in ET A and ET B receptor subtype proportions on endothelin‐1‐induced contractions in porcine isolated trachea and bronchus
Author(s) -
Goldie Roy G.,
D'Aprile Angela C.,
Cvetkovski Robert,
Rigby Paul J.,
Henry Peter J.
Publication year - 1996
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.1476-5381.1996.tb15252.x
Subject(s) - bronchus , contraction (grammar) , endothelin receptor , endothelin 1 , respiratory tract , endocrinology , medicine , endothelin 3 , carbachol , muscle contraction , receptor , respiratory system , antagonist , chemistry , biology , endothelins , anatomy , respiratory disease , lung
1 Quantitative autoradiographic studies were conducted to determine the distributions and densities of ET A and ET B binding site subtypes in porcine tracheal and bronchial smooth muscle. In addition, the roles of ET A and ET B receptors in endothelin‐1‐mediated contraction of these tissues were assessed. 2 Quantitative autoradiographic studies revealed that both ET A and ET B binding sites for [ 125 I]‐ endothelin‐1 were present in both bronchial and tracheal airway smooth muscle. However, the proportions of these sites were markedly different at these two levels within the respiratory tract. In tracheal smooth muscle, the proportions of ET A and ET B sites were 30± 1% and 70±1% respectively, whereas in bronchial smooth muscle, these proportions were virtually reversed, being 73±2% and 32±8% respectively. 3 Endothelin‐1 induced concentration‐dependent contraction of porcine tracheal and bronchial airway smooth muscle. Endothelin‐1 had similar potency (concentration producing 30% of the maximum carbachol contraction, C max ) in trachea (22 nM; 95% confidence limits (c.l.), 9–55 nM; n = 9) and bronchus (22 nM; c.l., 9–55 nM; n = 6). Endothelin‐1 also produced comparable maximal contractions in trachea (59±5% C max; n = 9) and bronchus (65 ± 4% C max , n = 6). 4 In trachea, endothelin‐1 induced contractions were not significantly inhibited by either the ET A receptor‐selective antagonist, BQ‐123 (3 μ m ) or the ET B receptor‐selective antagonist, BQ‐788 (1 μ m ). However, in the combined presence of BQ‐123 and BQ‐788, the concentration‐effect curve to endothelin‐ 1 was shifted to the right by 3.7 fold ( n = 8; P = 0.01). 5 In bronchus, concentration‐effect curves to endothelin‐1 were shifted to the right by BQ‐123 (3 μ m ; 4.3 fold; P <0.05), but not by BQ‐788 (1 μ m ). In the presence of both antagonists, concentration‐effect curves to endothelin‐1 were shifted by at least 6.7 fold ( n = 6; P = 0.01). 6 Sarafotoxin S6c induced contraction in both tissue types, although the maximum contraction was greater in trachea (53 ± 7% C max; n = 6) than in bronchus (21 ± 5% C max; n = 6). BQ‐788 (1 μ m ) markedly reduced sarafotoxin S6c potency in both trachea and bronchus (e.g. by 50 fold in trachea; c.l., 14–180; n = 6; P < 0.05). 7 These data demonstrate that the proportions of functional endothelin receptor subtypes mediating contraction of airway smooth muscle to endothelin‐1, vary significantly at different levels in the porcine respiratory tract.