Bidirectional Regulation of Human Colonic Smooth Muscle Contractility by Tachykinin NK2 Receptors

DOI Web Site 2 Citations 51 References
  • Nakamura Akihiro
    Inflammation Drug Discovery Unit, Pharmaceutical Research Division, Takeda Pharmaceutical Company Limited, Japan
  • Tanaka Takahiro
    Inflammation Drug Discovery Unit, Pharmaceutical Research Division, Takeda Pharmaceutical Company Limited, Japan
  • Imanishi Akio
    Exploratory Research Center, Pharmaceutical Research Division, Takeda Pharmaceutical Company Limited, Japan
  • Kawamoto Makiko
    Exploratory Research Center, Pharmaceutical Research Division, Takeda Pharmaceutical Company Limited, Japan
  • Toyoda Masao
    Department of Surgery, Saiseikai-Nakatsu Hospital, Japan
  • Mizojiri Gaku
    Department of Surgery, Saiseikai-Nakatsu Hospital, Japan
  • Tsukimi Yasuhiro
    Inflammation Drug Discovery Unit, Pharmaceutical Research Division, Takeda Pharmaceutical Company Limited, Japan

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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 NK2-R antagonist, but not by CP122721, a selective NK1-R antagonist or talnetant, a selective NK3-R antagonist. βAla8-NKA(4-10) induced concentration-dependent contraction similar to NKA, but Sar9-Met11-SP and Met-Phe7-NKB did not cause marked contraction. Colonic contraction induced by βAla8-NKA(4-10) was completely blocked by saredutant, but not by atropine. Tetrodotoxin or NG-nitro-L-arginine methyl ester pretreatment significantly enhanced βAla8-NKA(4-10)–induced contraction. Immunohistochemical analysis showed that the NK2-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 NK2-R is a major contributor to tachykinin-induced smooth muscle contraction in human colon and that the NK2-R–mediated response consists of an excitatory component via direct action on the smooth muscle and an inhibitory component possibly via nitric oxide neurons.

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