The effect of ONO-3708, a novel TxA2 receptor antagonist, on U-46619-induced contraction of guinea pig and human tracheal strips in vitro and on bronchoconstriction in guinea pigs in vivo.

The effect of (9, 11), (11, 12)-didedoxa-9 alpha, 11-alpha-dimethylmethano-11,12-methano-13,14-dihydro-13-aza-14-oxo -15-cyclo-pentyl-16, 17, 18, 19, 20-pentanor-15-epi-TxA2 (ONO-3708) on 9,11-methanoepoxy-prostaglandin H2 (U-46619)-induced contraction of airway smooth muscle in the guinea pigs and human in vitro and bronchoconstriction in guinea pigs in vivo was investigated. In in vitro experiments, ONO-3708 inhibited the U-46619-induced contraction of isolated guinea pig and human tracheal smooth muscle in a dose related fashion (guinea pig; pA2=7.78, human; pA2 = 7.43). The contractions of guinea pig tracheal muscle caused by histamine and leukotriene D4 (LTD4) were not inhibited by ONO-3708. In in vivo experiments, intravenous injection of ONO-3708 at doses between 1 and 20 mg/kg inhibited the U-46619-induced increase of airway insufflation pressure as measured by Konzett-Rössler method. In addition, ONO-3708 inhibited the U-46619-induced increase in airway reactivity to acetylcholine. These data suggest that ONO-3708 has possible therapeutic utility for asthma in which TxA2 participates.