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Eur J Pharmacol. 1996 May 23;304(1-3):123-8.

Effects of Ro 47-0203 on endothelin-1 and sarafotoxin S6c-induced contractions of human bronchus and guinea-pig trachea.

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Department of Inflammation/Autoimmune Diseases, Roche Pharmaceuticals, Hoffmann-La Roche Inc., Nutley, NJ 07110-1199, USA.


Endothelin exerts a variety of biological effects in the lung which indicate that this peptide may have a role in the pathophysiology of a number of pulmonary diseases. In this study, the endothelin receptors on the human bronchus were compared with those on the guinea-pig trachea using the novel, non-peptide antagonist Ro 47-0203 (4-tert-butyl-N-[6-(2-hydroxy-ethoxy)-5-(2-methoxy-phenoxy)-2,2' -bipyrimidin-4-yl]-benzenesulphonamide, non-selective for endothelin ETA over endothelin ETB receptor) and the peptide antagonist BQ123 (cyclo(-D-Val-Leu-D-Trp-D-Asp-Pro), endothelin ETA receptor selective). On the human bronchus and guinea-pig trachea, the concentration-effect curve for endothelin-1 was shifted to the right by Ro 47-0203 (100 microM) with concentration ratios of 28.2 +/- 6.8 and 39.5 +/- 13.9, respectively but lower concentrations of the antagonist had no effect. Although the concentration-effect curve for sarafotoxin S6c on the human bronchus was shifted to the right by Ro 47-0203 (30 and 100 microM, concentration ratio: 6.88 +/- 1.72 and 69.7 +/- 17.2, respectively), equivalent degrees of inhibition could be obtained on guinea-pig trachea with lower concentrations of antagonist (10 and 30 microM, concentration ratio: 6.90 +/- 1.58 and 75.8 +/- 14.1 respectively). The lack of effect of BQ123 (10 microM) and the high concentrations of Ro 47-0203 needed to show antagonism indicate that endothelin receptors on both tissues are probably the endothelin ETB subtype. Although the antagonism by Ro 47-0203 is not classically competitive, the greater effect of Ro 47-0203 against sarafotoxin S6c on the guinea-pig trachea may reflect a difference between the endothelin ETB receptors on these tissues.

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