EFFECTS OF ENDOTHELIN-B ANTAGONIST RES-701-1 ON ENDOTHELIN-INDUCED CONTRACTILE RESPONSES IN-VIVO AND IN-VITRO IN GUINEA-PIGS

The effects of an endothelin (ET)-receptor B-specific antagonist, RES- 701-1, on ET-induced contraction of guinea-pig trachea and on ET-induc ed 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 ET(B)-specific agonist sarafot oxin S6c (pK(B) = 6.10). In the epithelium-intact tracheal preparation , RES-701-1 (1 x 10(-5) M) inhibited the ET-3-induced contraction (pK( B) = 5.27), but enhanced the ET-1-induced contraction significantly an d shifted the concentration-response curve to the left. The maximal re sponses of ET-1 and ET-3-induced contraction were augmented by epithel ium removal by 1.5 and 1.8-fold, respectively. Against ET-3-induced co ntraction in the tracheal preparation without epithelium, RES-701-1 (0 .3-10 x 10(-6) M) antagonized the contraction in a concentration-depen dent manner (pA(2) = 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 epitheliu m. 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 bronchoconstrict ion in anaesthetized guinea-pigs pretreated with propranolol (1.0 mg k g(-1)). When administered intravenously, RES-701-1 (0.3 or 10 mg kg(-1 )) showed significant reduction in both phases of bronchoconstriction induced by ET-3. As in the case of ET-l-induced bronchoconstriction, R ES-701-1 augmented the sustained phase although a significant reductio n 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.