Effects of CS-518, a thromboxane synthase inhibitor, on the asthmatic response.
The anti-asthmatic effects of CS-518 (sodium 2-(1-imidazolylmethyl)-4,5-dihydrobenzo[b]thiophene-6-carboxylate) , a specific thromboxane A2 (TXA2) synthase inhibitor, were investigated in the ovalbumin-sensitized guinea pig asthmatic model. Although CS-518 slightly inhibited (about 25%) whole bronchoconstriction, it significantly inhibited the antigen-induced bronchoconstriction mediated by slow-reacting substance of anaphylaxis (SRS-A), which was not reduced by chlorpheniramine, a histamine H1 antagonist. On the other hand, indomethacin, a cyclooxygenase inhibitor, potentiated the SRS-A-mediated constriction. CS-518 strongly, and indomethacin slightly, suppressed the leukotriene D4-induced bronchoconstriction. CS-518 clearly inhibited the antigen-induced airway hyperresponsiveness, but this compound had no effect on the airway hyperresponsiveness induced by U-46619, a TXA2-mimetic agent, and propranolol. These results suggest that CS-518 suppresses the development of bronchoconstriction and airway hyperresponsiveness in asthmatic models by inhibition of TXA2 synthesis with the concomitant increase in bronchodilating prostaglandins such as prostaglandin E2 and prostaglandin I2.
Yamaguchi
T
T
Biological Research Laboratories, Sankyo Co., Ltd., Tokyo, Japan.
Mukaiyama
O
O
Itoh
K
K
Satoh
Y
Y
Terada
A
A
Iizuka
Y
Y
D019796:15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; D000818:Animals; D001249:Asthma / Q000139:chemically induced / Q000503:physiopathology*; D016535:Bronchial Hyperreactivity / Q000503:physiopathology; D016084:Bronchoconstriction / Q000187:drug effects; D002744:Chlorpheniramine / Q000494:pharmacology; D004195:Disease Models, Animal; D006168:Guinea Pigs; D007213:Indomethacin / Q000494:pharmacology; D008297:Male; D008689:Methacrylates / Q000494:pharmacology; D010047:Ovalbumin / Q000276:immunology; D011433:Propranolol / Q000494:pharmacology; D011450:Prostaglandin Endoperoxides, Synthetic / Q000494:pharmacology; D013189:SRS-A / Q000037:antagonists & inhibitors / Q000494:pharmacology; D013876:Thiophenes / Q000494:pharmacology*; D013928:Thromboxane A2 / Q000502:physiology; D013930:Thromboxane-A Synthase / Q000037:antagonists & inhibitors*; D014662:Vasoconstrictor Agents / Q000494:pharmacology
D008689:Methacrylates; D011450:Prostaglandin Endoperoxides, Synthetic; D013189:SRS-A; D013876:Thiophenes; D014662:Vasoconstrictor Agents; C055806:RS 5186; D002744:Chlorpheniramine; D013928:Thromboxane A2; D019796:15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; D010047:Ovalbumin; D011433:Propranolol; D013930:Thromboxane-A Synthase; C034364:ozagrel; D007213:Indomethacin