title: Bidirectional regulation of human colonic smooth muscle contractility by tachykinin NK(2) receptors.
abstract: In this study, we attempted to clarify the mechanism of tachykinin-induced motor response in isolated smooth muscle preparations of the human colon. Fresh specimens of normal colon were obtained from patients suffering from colonic cancer. Using mucosa-free smooth muscle strips, smooth muscle tension with circular direction was monitored isometrically. Substance P (SP), neurokinin A (NKA), and neurokinin B (NKB) produced marked contraction. All of these contractions were inhibited by saredutant, a selective NK(2)-R antagonist, but not by CP122721, a selective NK(1)-R antagonist or talnetant, a selective NK(3)-R antagonist. βAla(8)-NKA(4-10) induced concentration-dependent contraction similar to NKA, but Sar(9)-Met(11)-SP and Met-Phe(7)-NKB did not cause marked contraction. Colonic contraction induced by βAla(8)-NKA(4-10) was completely blocked by saredutant, but not by atropine. Tetrodotoxin or N(G)-nitro-L-arginine methyl ester pretreatment significantly enhanced βAla(8)-NKA(4-10)-induced contraction. Immunohistochemical analysis showed that the NK(2)-R was expressed on the smooth muscle layers and myenteric plexus where it was also co-expressed with neuronal nitric oxide synthase in the myenteric plexus. These results suggest that the NK(2)-R is a major contributor to tachykinin-induced smooth muscle contraction in human colon and that the NK(2)-R-mediated response consists of an excitatory component via direct action on the smooth muscle and an inhibitory component possibly via nitric oxide neurons.
authors.affiliation: Inflammation Drug Discovery Unit, Pharmaceutical Research Division, Takeda Pharmaceutical Company Limited, Yodogawa-ku, Osaka 532-8686, Japan.
authors.forename: Akihiro
authors.initials: A
authors.lastname: Nakamura
authors.forename: Takahiro
authors.initials: T
authors.lastname: Tanaka
authors.forename: Akio
authors.initials: A
authors.lastname: Imanishi
authors.forename: Makiko
authors.initials: M
authors.lastname: Kawamoto
authors.forename: Masao
authors.initials: M
authors.lastname: Toyoda
authors.forename: Gaku
authors.initials: G
authors.lastname: Mizojiri
authors.forename: Yasuhiro
authors.initials: Y
authors.lastname: Tsukimi
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D001549:Benzamides / Q000494:pharmacology; D045744:Cell Line, Tumor; D003106:Colon / Q000033:anatomy & histology / Q000187:drug effects* / Q000502:physiology; D005260:Female; D006801:Humans; D066298:In Vitro Techniques; D007537:Isometric Contraction / Q000187:drug effects*; D008297:Male; D008875:Middle Aged; D009130:Muscle, Smooth / Q000187:drug effects* / Q000502:physiology; D064729:Neurokinin-1 Receptor Antagonists; D010880:Piperidines / Q000494:pharmacology; D011804:Quinolines / Q000494:pharmacology; D018040:Receptors, Neurokinin-1 / Q000819:agonists / Q000502:physiology; D018041:Receptors, Neurokinin-2 / Q000819:agonists / Q000037:antagonists & inhibitors / Q000502:physiology*; D018042:Receptors, Neurokinin-3 / Q000819:agonists / Q000037:antagonists & inhibitors / Q000502:physiology; D015320:Tachykinins / Q000494:pharmacology*
chemical_list: D001549:Benzamides; D064729:Neurokinin-1 Receptor Antagonists; D010880:Piperidines; D011804:Quinolines; D018040:Receptors, Neurokinin-1; D018041:Receptors, Neurokinin-2; D018042:Receptors, Neurokinin-3; D015320:Tachykinins; C106716:SB 223412; C073839:SR 48968; C099414:(2S,3S)-2-phenyl-3-((5-trifluoromethoxy-2-methoxy)benzylamino)piperidine