title: Effects of endothelin B antagonist RES-701-1 on endothelin-induced contractile responses in-vivo and in-vitro in guinea-pigs.
abstract: The effects of an endothelin (ET)-receptor B-specific antagonist, RES-701-1, on ET-induced contraction of guinea-pig trachea and on ET-induced bronchoconstriction in anaesthetized guinea-pigs were investigated. In the epithelium-removed tracheal preparation, 1 x 10(-5) M RES-701-1 inhibited contractions induced by the ETB-specific agonist sarafotoxin S6c (pKB = 6.10). In the epithelium-intact tracheal preparation, RES-701-1 (1 x 10(-5) M)inhibited the ET-3-induced contraction (pKB = 5.27), but enhanced the ET-1-induced contraction significantly and shifted the concentration-response curve to the left. The maximal responses of ET-1- and ET-3-induced contraction were augmented by epithelium removal by 1.5 and 1.8-fold, respectively. Against ET-3-induced contraction in the tracheal preparation without epithelium, RES-701-1 (0.3-10 x 10(-6)M) antagonized the contraction in a concentration-dependent manner (pA2 = 5.9). On the other hand, RES-701-1 (1 x 10(-5)M) did not affect ET-1-evoked responses in the trachea without epithelium. The intravenous administration of ET-1 (1.5 nmol/kg-1) or ET-3 (1.5 nmol/kg-1) evoked a biphasic, fast and sustained bronchoconstriction in anaesthetized guinea-pigs pretreated with propranolol (1.0 mg/kg-1). when administered intravenously, RES-701-1 (0.3 or 1.0 mg/kg-1) showed significant reduction in both phases of bronchoconstriction induced by ET-3. As in the case of ET-1-induced bronchoconstriction, rES-701-1 augmented the sustained phase although a significant reduction of the fast phase was observed. These results indicate that RES-701-1 can inhibit the ET-3 induced airway responses not only in-vitro but also in-vivo.
authors.affiliation: Pharmaceutical Research Laboratories, Kyowa Hakko Kogyo Co., Ltd., Shizuoka, Japan.
authors.forename: T
authors.initials: T
authors.lastname: Ikemura
authors.forename: K
authors.initials: K
authors.lastname: Ohmori
authors.forename: T
authors.initials: T
authors.lastname: Tanaka
authors.forename: Y
authors.initials: Y
authors.lastname: Matsuda
authors.forename: S
authors.initials: S
authors.lastname: Kitamura
mesh_terms: D000818:Animals; D016084:Bronchoconstriction / Q000187:drug effects*; D004305:Dose-Response Relationship, Drug; D065128:Endothelin Receptor Antagonists; D019332:Endothelin-1 / Q000633:toxicity; D019334:Endothelin-3 / Q000633:toxicity; D004848:Epithelium / Q000187:drug effects / Q000502:physiology; D006168:Guinea Pigs; D066298:In Vitro Techniques; D008297:Male; D009119:Muscle Contraction / Q000187:drug effects; D009130:Muscle, Smooth / Q000187:drug effects*; D010456:Peptides, Cyclic / Q000494:pharmacology*; D011433:Propranolol / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D017466:Receptors, Endothelin / Q000502:physiology; D014132:Trachea / Q000187:drug effects* / Q000378:metabolism; D014662:Vasoconstrictor Agents / Q000633:toxicity; D014757:Viper Venoms / Q000633:toxicity
chemical_list: D065128:Endothelin Receptor Antagonists; D019332:Endothelin-1; D019334:Endothelin-3; D010456:Peptides, Cyclic; D017466:Receptors, Endothelin; D014662:Vasoconstrictor Agents; D014757:Viper Venoms; C057354:sarafotoxins s6; C087120:RES 701-1; D011433:Propranolol; C072247:cyclo(Trp-Asp-Pro-Val-Leu)