title: Daikenchuto (TU-100) ameliorates colon microvascular dysfunction via endogenous adrenomedullin in Crohn's disease rat model.
abstract: BACKGROUND
  Daikenchuto (TU-100), a traditional Japanese medicine, has been reported to up-regulate the adrenomedullin (ADM)/calcitonin gene-related peptide (CGRP) system, which is involved in intestinal vasodilatation. The microvascular dysfunction of the intestine in Crohn's disease (CD), due to down-regulation of the ADM/CGRP system, is etiologically related to the recurrence of CD. Therefore, we investigated the vasodilatory effect of TU-100 in a CD rat model.
  
  
  METHODS
  Colitis was induced by the rectal instillation of 2,4,6-trinitrobenzenesulfonic acid (TNBS) in rats. Laser Doppler blood flowmetry was used to measure colonic blood flow. ADM, CGRP, and their receptors in the ischemic colon were measured by reverse transcription polymerase chain reaction (RT-PCR) and enzyme immunoassays. Additionally, we determined whether the intestinal epithelial cell line IEC-6 released ADM in response to TU-100.
  
  
  RESULTS
  TU-100 increased blood flow in ischemic segments of the colon but not in hyperemic segments. Pretreatment with an antibody to ADM abolished the vasodilatory effect of TU-100. CGRP levels and βCGRP mRNA expression were decreased in the ischemic colon, while protein and mRNA levels of ADM were unchanged. Hydroxy α-sanshool, the main constituent of TU-100, was the most active component in improving blood flow. Additionally, both TU-100 and hydroxy α-sanshool enhanced the release of ADM from IEC-6 cells.
  
  
  CONCLUSIONS
  In the ischemic colon, endogenous βCGRP, but not ADM, was decreased. Thus, it was concluded that TU-100 ameliorated microvascular dysfunction by the up-regulation of endogenous ADM in the CD rat model. TU-100 may be a possible therapeutic agent for gastrointestinal ischemia-related diseases including CD.
authors.affiliation: Division of Gastroenterologic and General Surgery, Department of Surgery, Asahikawa Medical University, 2-1 Midorigaoka-Higashi, Asahikawa, Hokkaido 078-8510, Japan. kono@asahikawa-med.ac.jp
authors.forename: Toru
authors.initials: T
authors.lastname: Kono
authors.forename: Yuji
authors.initials: Y
authors.lastname: Omiya
authors.forename: Yoshiki
authors.initials: Y
authors.lastname: Hira
authors.forename: Atsushi
authors.initials: A
authors.lastname: Kaneko
authors.forename: Shinichi
authors.initials: S
authors.lastname: Chiba
authors.forename: Tatsuya
authors.initials: T
authors.lastname: Suzuki
authors.forename: Masamichi
authors.initials: M
authors.lastname: Noguchi
authors.forename: Tsuyoshi
authors.initials: T
authors.lastname: Watanabe
mesh_terms: D053607:Adrenomedullin / Q000235:genetics / Q000378:metabolism*; D000577:Amides / Q000302:isolation & purification / Q000494:pharmacology; D000818:Animals; D015740:Calcitonin Gene-Related Peptide / Q000235:genetics / Q000378:metabolism; D002460:Cell Line; D003092:Colitis / Q000188:drug therapy* / Q000473:pathology; D003106:Colon / Q000098:blood supply / Q000187:drug effects / Q000473:pathology; D003424:Crohn Disease / Q000188:drug therapy* / Q000473:pathology; D004195:Disease Models, Animal; D007413:Intestinal Mucosa / Q000187:drug effects / Q000378:metabolism; D008297:Male; D055806:Microvessels; D005894:Panax; D010936:Plant Extracts / Q000737:chemistry / Q000494:pharmacology*; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D014302:Trinitrobenzenesulfonic Acid / Q000633:toxicity; D015854:Up-Regulation / Q000187:drug effects; D014664:Vasodilation / Q000187:drug effects; D032106:Zanthoxylum; D030521:Zingiberaceae
chemical_list: D000577:Amides; D010936:Plant Extracts; D012333:RNA, Messenger; C121414:dai-kenchu-to; D053607:Adrenomedullin; C100574:sanshool; D014302:Trinitrobenzenesulfonic Acid; D015740:Calcitonin Gene-Related Peptide