[Pharmacological actions of S-145, a novel thromboxane A2 antagonist, in various smooth muscles].
Antagonistic actions of S-145 ((+-)-5(Z)-7-[3-endo[(phenylsulfonyl)amino]bicyclo[2.2.1] hept-2-exo-yl]heptenoic acid) against U-46619, a thromboxane A2 mimic, were studied using isolated thoracic aorta of the rat and the trachea, lung parenchyma and ileum of the guinea pig. S-145 as well as SQ-29548 and ONO-3708 inhibited the contraction of aorta induced by U-46619 in a concentration-dependent manner. The IC50 value of each compound was 1.4, 14.5 and 52.6 nM. S-145 also inhibited contractions of the aorta induced by high concentrations of PGE1, PGE2 and PGF2 alpha, but failed to affect the responses to K+, Ca2+, NE, 5-HT, and angiotensin II. Contractions of trachea and lung parenchyma of the guinea pig induced by U-46619 were concentration-dependently inhibited by S-145, but those induced by histamine and leukotriene D4 were not affected. Ileac contractions by PGE2 and PGF2 alpha were not inhibited by S-145. The (+)-isomer of S-145 was more potent and the (-)-isomer was less potent than S-145 for antagonistic action against U-46619. These results suggest that S-145 is a potent and specific antagonist to the thromboxane A2 receptor; and in the aorta, the thromboxane A2 receptor may respond to high concentrations of PGs.
Otani
K
K
Shionogi Research Laboratories, Shionogi & Co., Ltd., Osaka, Japan.
Shima
N
N
Doteuchi
M
M
D019796:15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; D000818:Animals; D001013:Aorta, Thoracic / Q000187:drug effects; D001643:Bridged Bicyclo Compounds / Q000494:pharmacology*; D001952:Bridged-Ring Compounds / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D005229:Fatty Acids, Monounsaturated / Q000494:pharmacology*; D006168:Guinea Pigs; D007082:Ileum / Q000187:drug effects; D066298:In Vitro Techniques; D008168:Lung / Q000187:drug effects; D008297:Male; D009130:Muscle, Smooth / Q000187:drug effects*; D011450:Prostaglandin Endoperoxides, Synthetic / Q000037:antagonists & inhibitors*; D051381:Rats; D011982:Receptors, Prostaglandin / Q000037:antagonists & inhibitors; D014132:Trachea / Q000187:drug effects
D001643:Bridged Bicyclo Compounds; D001952:Bridged-Ring Compounds; D005229:Fatty Acids, Monounsaturated; D011450:Prostaglandin Endoperoxides, Synthetic; D011982:Receptors, Prostaglandin; C056566:S 145; D019796:15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid