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.
Nagai
H
H
Department of Pharmacology, Gifu Pharmaceutical University, Japan.
Tsuji
F
F
Inagaki
N
N
Kitagaki
K
K
Fukutomi
O
O
Koda
A
A
Daikoku
M
M
D019796:15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; D000109:Acetylcholine / Q000494:pharmacology; D000818:Animals; D016084:Bronchoconstriction / Q000187:drug effects*; D006168:Guinea Pigs; D006632:Histamine / Q000494:pharmacology; D006801:Humans; D008297:Male; D009119:Muscle Contraction / Q000187:drug effects*; D009130:Muscle, Smooth / Q000187:drug effects; D011450:Prostaglandin Endoperoxides, Synthetic / Q000494:pharmacology; D011982:Receptors, Prostaglandin / Q000037:antagonists & inhibitors*; D017482:Receptors, Thromboxane; D012119:Respiration / Q000187:drug effects; D013189:SRS-A / Q000378:metabolism / Q000494:pharmacology; D013928:Thromboxane A2 / Q000031:analogs & derivatives* / Q000037:antagonists & inhibitors / Q000494:pharmacology; D014132:Trachea / Q000187:drug effects*
D011450:Prostaglandin Endoperoxides, Synthetic; D011982:Receptors, Prostaglandin; D017482:Receptors, Thromboxane; D013189:SRS-A; D013928:Thromboxane A2; D019796:15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; D006632:Histamine; C049855:ONO 3708; D000109:Acetylcholine