Alteration of eicosanoid production in the sensitized guinea pig lung by CS-518.
The effects of CS-518 (sodium 2-(1-imidazolylmethyl)-4,5-dihydrobenzo [b]thiophene-6-carboxylate), a thromboxane A2 synthase inhibitor, on changes in arachidonic acid metabolism were investigated in the lung of actively sensitized guinea pigs. Antigen challenge enhanced the production of thromboxane A2 as well as histamine and peptide leukotrienes in lung fragments. Exogenous leukotriene D4 also stimulated significant thromboxane A2 production in the non-sensitized lung in vitro. CS-518 was effective in preventing the thromboxane A2 production induced by either antigen or leukotriene D4, and the IC50 values were 90 and 7.5 ng/ml (320 and 27 nM), respectively. CS-518 markedly potentiated the production of prostaglandin E2 and I2 with slight inhibition of leukotriene formation, but indomethacin significantly stimulated leukotriene production. When CS-518 was administered orally, it induced long-lasting inhibition of thromboxane A2 production and potentiation of prostaglandin I2 production in guinea pig lung. Thus, CS-518 not only inhibited thromboxane production but also improved the change in arachidonic acid metabolism in the guinea pig bronchoalveolar tissue during allergic reaction in vivo as well as in vitro, which suggests amelioration of the asthmatic condition.
Itoh
K
K
Biological Research Laboratories, Sankyo Co., Ltd., Tokyo, Japan.
Satoh
Y
Y
Hisamoto
M
M
Yamamura
N
N
Mukaiyama
O
O
Yamaguchi
T
T
Ikeda
T
T
Matsuda
K
K
D000284:Administration, Oral; D000818:Animals; D016718:Arachidonic Acid / Q000378:metabolism; D015777:Eicosanoids / Q000096:biosynthesis* / Q000378:metabolism; D006168:Guinea Pigs; D006632:Histamine / Q000096:biosynthesis; D007213:Indomethacin / Q000494:pharmacology; D008168:Lung / Q000187:drug effects* / Q000276:immunology / Q000378:metabolism; D008297:Male; D010047:Ovalbumin / Q000276:immunology; D011453:Prostaglandins / Q000096:biosynthesis; D011863:Radioimmunoassay; D013189:SRS-A / Q000096:biosynthesis / Q000494:pharmacology; D013876:Thiophenes / Q000494:pharmacology*; D013928:Thromboxane A2 / Q000096:biosynthesis; D013930:Thromboxane-A Synthase / Q000037:antagonists & inhibitors*; D014611:Vaccination
D015777:Eicosanoids; D011453:Prostaglandins; D013189:SRS-A; D013876:Thiophenes; C055806:RS 5186; D016718:Arachidonic Acid; D013928:Thromboxane A2; D006632:Histamine; D010047:Ovalbumin; D013930:Thromboxane-A Synthase; D007213:Indomethacin