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Mechanism of Rho-kinase-mediated Ca2+-independent contraction in aganglionic smooth muscle in a rat model of Hirschsprung’s disease

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Abstract

Purpose

Lack of ganglion cells is the main cause of bowel movement disorder in Hirschsprung’s disease. Because smooth muscle is the primary organ, the properties of intestinal smooth muscle need to be investigated. We therefore investigated the reactivity of the contractile system and the mechanism of contraction in aganglionic intestinal smooth muscle.

Methods

Colonic smooth muscle strips from endothelin-B receptor gene-deficient [EDNRB(−/−)] rats were loaded with the Ca2+ indicator dye fura-PE3/AM and changes in fluorescence intensity were monitored. The intracellular calcium concentration ([Ca2+]i) and force development in the strips were measured simultaneously.

Results

The force induced by 10 μM substance P (SP) was higher than that induced by 60 mM K+ depolarization (control), whereas [Ca2+]i elevation induced by 10 μM SP was less than that induced by 60 mM K+ in all segments. Pretreatment with the Rho-kinase inhibitor Y-27632 inhibited force development more strongly in EDNRB(−/−) aganglionic segments than in EDNRB(+/+) ganglionic segments. However, [Ca2+]i was higher in EDNRB(−/−) aganglionic segments than in EDNRB(+/+) ganglionic segments.

Conclusions

The Ca2+-independent pathway involving Rho-kinase was hyperactivated in EDNRB(−/−) aganglionic segments. This phenomenon is assumed to compensate for Ca2+ channel downregulation and Ca2+-dependent contraction. From a clinical point of view, the motility of aganglionic intestine would be controllable with the control of Ca2+-independent contraction before definitive operations in Hirschsprung’s disease.

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Acknowledgment

This study was supported in part by a grant-in-aid for scientific research from the Ministry of Education, Culture, Sports, Science and Technology, Japan.

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Authors and Affiliations

  1. Department of Pediatric Surgery, Reproductive and Developmental Medicine, Faculty of Medical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-Ku, Fukuoka, 812-8582, Japan

    Junko Akiyoshi, Satoshi Ieiri, Takanori Nakatsuji & Tomoaki Taguchi

  2. Department of Advanced Medicine and Innovative Technology, Kyushu University Hospital, Fukuoka, Japan

    Satoshi Ieiri

Authors
  1. Junko Akiyoshi
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  2. Satoshi Ieiri
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  3. Takanori Nakatsuji
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  4. Tomoaki Taguchi
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Correspondence to Satoshi Ieiri.

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Akiyoshi, J., Ieiri, S., Nakatsuji, T. et al. Mechanism of Rho-kinase-mediated Ca2+-independent contraction in aganglionic smooth muscle in a rat model of Hirschsprung’s disease. Pediatr Surg Int 25, 955–960 (2009). https://doi.org/10.1007/s00383-009-2461-4

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  • DOI: https://doi.org/10.1007/s00383-009-2461-4

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