Possible site of action of TAK-637, a tachykinin NK(1) receptor antagonist, on the micturition reflex in guinea pigs.
TAK-637((aR,9R)-7-[3,5-bis(trifluoromethyl)benzyl]-8,9,10, 11-tetrahydro-9-methyl-5-(4-methylphenyl)-7H-[1,4]diazocino[2,1-g] [1,7]naphthyridine-6,13-dione) is a novel tachykinin NK(1) receptor antagonist that has been shown to inhibit the micturition reflex in guinea pigs. The aim of this study was to clarify its mechanism of action in guinea pigs. TAK-637 inhibited the spinal vesico-vesical reflex induced by electrical stimulation of the proximal cut end of the pelvic nerve in spinal animals, but not bladder contractions induced by electrical stimulation of the distal cut end of the nerve. Furthermore, TAK-637 had no effect on carbachol- or electrical field stimulation-induced contractions of isolated bladder muscle strips in an organ bath, whereas drugs used for abnormally frequent micturition inhibited both contractions. These results suggest that TAK-637 inhibits the micturition reflex by acting, at least in part, on the spinal cord, and its mechanism of action clearly differs from those of antimuscarinics or spasmolytics.
Pharmaceutical Research Division, Takeda Chemical Industries Ltd., 2-17-85, Jusohonmachi, Yodogawa-ku, 532-8686, Osaka, Japan. kamo_izumi@takeda.co.jp
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Kamo
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Imai
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Okanishi
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D000818:Animals; D001285:Atropine / Q000494:pharmacology; D001559:Benzhydryl Compounds / Q000494:pharmacology; D001561:Benzilates / Q000494:pharmacology; D002217:Carbachol / Q000494:pharmacology; D003408:Cresols / Q000494:pharmacology; D003714:Denervation; D004305:Dose-Response Relationship, Drug; D004558:Electric Stimulation; D006168:Guinea Pigs; D006801:Humans; D066298:In Vitro Techniques; D008297:Male; D008333:Mandelic Acids / Q000494:pharmacology; D009119:Muscle Contraction / Q000187:drug effects; D009287:Naphthyridines / Q000494:pharmacology*; D010388:Pelvis / Q000294:innervation; D010665:Phenylpropanolamine; D012018:Reflex / Q000187:drug effects*; D000068737:Tolterodine Tartrate; D001743:Urinary Bladder / Q000187:drug effects* / Q000294:innervation / Q000502:physiology; D001745:Urinary Bladder Diseases / Q000503:physiopathology
D001559:Benzhydryl Compounds; D001561:Benzilates; D003408:Cresols; D008333:Mandelic Acids; D009287:Naphthyridines; D010665:Phenylpropanolamine; C015586:propiverine; D000068737:Tolterodine Tartrate; D001285:Atropine; D002217:Carbachol; C005419:oxybutynin; C403052:TAK 637