Influence of regional differences in ETA and ETB receptor subtype proportions on endothelin-1-induced contractions in porcine isolated trachea and bronchus.

1. Quantitative autoradiographic studies were conducted to determine the distributions and densities of ETA and ETB binding site subtypes in porcine tracheal and bronchial smooth muscle. In addition, the roles of ETA and ETB receptors in endothelin-1-mediated contraction of these tissues were assessed. 2. Quantitative autoradiographic studies revealed that both ETA and ETB binding sites for [125I]-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 ETA and ETB 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, Cmax) 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% Cmax; n = 9) and bronchus (65 +/- 4% Cmax, n = 6). 4. In trachea, endothelin-1 induced contractions were not significantly inhibited by either the ETA receptor-selective antagonist, BQ-123 (3 microM) or the ETB receptor-selective antagonist, BQ-788 (1 microM). 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 microM; 4.3 fold; P < 0.05), but not by BQ-788 (1 microM). 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% Cmax; n = 6) than in bronchus (21 +/- 5% Cmax; n = 6). BQ-788 (1 microM) 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.