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Daikenchuto (TU-100) ameliorates colon microvascular dysfunction via endogenous adrenomedullin in Crohn’s disease rat model

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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.

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Acknowledgments

This work was supported by a Grant-in-Aid for Scientific Research provided by the Ministry of Education, Culture, Sports, Science and Technology, Japan (No. 22591475). The authors thank Dr. Kazunori Hashimoto for supplying hydroxy α-sanshool. We are grateful to Dr. Masaru Sakaguchi and Mr. Yoshiyasu Satake for their skillful technical assistance. We also thank Drs. Masahiro Yamamoto, Shinichi Kasai, and Yoshio Kase for their helpful discussions.

Conflict of interest

The authors declare that they have no conflict of interest.

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Authors and Affiliations

  1. Division of Gastroenterologic and General Surgery, Department of Surgery, Asahikawa Medical University, 2-1 Midorigaoka-Higashi, Asahikawa, Hokkaido, 078-8510, Japan

    Toru Kono, Yuji Omiya, Atsushi Kaneko & Tatsuya Suzuki

  2. Department of Anatomy, Asahikawa Medical University, Asahikawa, Hokkaido, Japan

    Yoshiki Hira & Tsuyoshi Watanabe

  3. Division of Central Laboratory for Research and Education, Asahikawa Medical University, Asahikawa, Hokkaido, Japan

    Shinichi Chiba

  4. Tsumura Research Laboratories, Tsumura & Co., Ibaraki, Japan

    Yuji Omiya, Atsushi Kaneko & Masamichi Noguchi

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  1. Toru Kono
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Correspondence to Toru Kono.

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Kono, T., Omiya, Y., Hira, Y. et al. Daikenchuto (TU-100) ameliorates colon microvascular dysfunction via endogenous adrenomedullin in Crohn’s disease rat model. J Gastroenterol 46, 1187–1196 (2011). https://doi.org/10.1007/s00535-011-0438-2

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  • DOI: https://doi.org/10.1007/s00535-011-0438-2

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