title: Effects of Ro 47-0203 on endothelin-1 and sarafotoxin S6c-induced contractions of human bronchus and guinea-pig trachea.
abstract: 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.
authors.affiliation: Department of Inflammation/Autoimmune Diseases, Roche Pharmaceuticals, Hoffmann-La Roche Inc., Nutley, NJ 07110-1199, USA.
authors.forename: P R
authors.initials: PR
authors.lastname: Gater
authors.forename: M A
authors.initials: MA
authors.lastname: Wasserman
authors.forename: L M
authors.initials: LM
authors.lastname: Renzetti
mesh_terms: D000328:Adult; D000368:Aged; D000818:Animals; D000077300:Bosentan; D001980:Bronchi / Q000187:drug effects; D004347:Drug Interactions; D019332:Endothelin-1 / Q000494:pharmacology*; D005260:Female; D006168:Guinea Pigs; D006801:Humans; D066298:In Vitro Techniques; D008297:Male; D008875:Middle Aged; D009119:Muscle Contraction / Q000187:drug effects*; D009130:Muscle, Smooth / Q000187:drug effects; D010456:Peptides, Cyclic / Q000494:pharmacology; D017466:Receptors, Endothelin / Q000187:drug effects*; D013449:Sulfonamides / Q000494:pharmacology*; D014132:Trachea / Q000187:drug effects; D014757:Viper Venoms / Q000494:pharmacology*
chemical_list: D019332:Endothelin-1; D010456:Peptides, Cyclic; D017466:Receptors, Endothelin; D013449:Sulfonamides; D014757:Viper Venoms; C057354:sarafotoxins s6; D000077300:Bosentan; C072247:cyclo(Trp-Asp-Pro-Val-Leu)