Contraction of human airway smooth muscle by endothelin-1 and IRL 1620: effect of bosentan

Abstract We have examined whether 4-tert-butyl- N -[6-(2-hydroxy-ethoxy)-5-(2-methoxy-phenoxy)-2,2′-bipyrimidin-4-yl]-benzenesulfonamide (bosentan; endothelin ET A/B receptor antagonist) and ( R )2-[( R )-2-[( S )-2-[[1-(hexahydro-1 H -azepinyl)]carbonyl] amino-4-methylpentanoil]amino-3-[3-(1-methyl-1 H -indoyl)]propionyl]amino-3-(2-pyridyl) propionic acid (FR 139317; endothelin ET A receptor antagonist) inhibit contractions of human airway smooth muscle induced by endothelin-1 or Suc-[Glu 9 ,Ala 11,15 ]enthothelin-1-(8–21) (IRL 1620; endothelin ET B receptor agonist). Endothelin-1 and IRL 1620 were equipotent. Bosentan and FR 139317 (each 10 μM) produced a small shift in response curves to endothelin-1 (1.6- and 1.5-fold, respectively). However, bosentan was more potent against contractions elicited by IRL 1620 (10 μM, 11.2-fold shift) suggesting that these agonists exhibit different kinetic interactions with endothelin receptors or implying an interaction with a novel endothelin ET B receptor subtype in human airways.