[Effects of Y-20811, a specific thromboxane A2 synthetase inhibitor, on chemical mediator-induced bronchoconstriction in guinea pigs].
We investigated the effects of Y-20811 on chemical mediator-induced bronchoconstriction and the release of chemical mediators into lung perfusion fluid during arachidonic acid (AA)-induced bronchoconstriction in guinea pigs. Y-20811 (0.01-1 mg/kg, i.v.), like acetylsalicylic acid or indomethacin, dose-dependently suppressed arachidonic acid- and LTD4-induced bronchoconstriction, and it (1 mg/kg, i.v.) also inhibited PAF-induced bronchoconstriction in guinea pigs. However, at a dose of 1 mg/kg, i.v., it was inactive against the bronchoconstriction induced by histamine, serotonin and acetylcholine in guinea pigs. Y-20811 (0.3-10 mg/kg) administered orally also prevented the LTD4-induced bronchoconstriction in a dose-dependent manner. This protective effect of Y-20811 (10 mg/kg, p.o.) persisted for at least 24 hr. Y-20811 (10 mg/kg, p.o.) also inhibited antigen-induced bronchoconstriction in guinea pigs passively sensitized with anti-ovalbumin guinea pig serum and pretreated with mepyramine. In the perfused and ventilated guinea pig lungs, Y-20811 inhibited AA-induced bronchoconstriction, decreased the release of TXA2 (estimated as TXB2) and increased the release of PGE2 into the perfused lung fluid, significantly (TXB2 and PGE2 were measured by HPLC). Therefore, Y-20811 suppressed various stimulant-induced bronchoconstrictions through the decrease of TXA2 production and the increase of PGE2 production. Thus, Y-20811 should prove useful as an anti-asthmatic drug.
Kagoshima
M
M
Yoshitomi Pharmaceutical Industries, Ltd., Fukuoka, Japan.
Tomomatsu
N
N
Fukuda
T
T
Mikashima
H
H
Terasawa
M
M
D000818:Animals; D016718:Arachidonic Acid; D001095:Arachidonic Acids / Q000037:antagonists & inhibitors; D016084:Bronchoconstriction / Q000187:drug effects*; D003864:Depression, Chemical; D015232:Dinoprostone / Q000096:biosynthesis; D004305:Dose-Response Relationship, Drug; D005260:Female; D006168:Guinea Pigs; D007093:Imidazoles / Q000494:pharmacology*; D008168:Lung / Q000378:metabolism; D013189:SRS-A / Q000037:antagonists & inhibitors; D013928:Thromboxane A2 / Q000096:biosynthesis*; D013930:Thromboxane-A Synthase / Q000037:antagonists & inhibitors*
D001095:Arachidonic Acids; D007093:Imidazoles; D013189:SRS-A; C049966:Y 20811; D016718:Arachidonic Acid; D013928:Thromboxane A2; D013930:Thromboxane-A Synthase; D015232:Dinoprostone