Acetylcholine-related bowel dysmotility in homozygous mutant NCX/HOX11L.1-deficient (NCX−/−) mice—evidence that acetylcholine is implicated in causing intestinal neuronal dysplasia

Presented at the 55th Annual Meeting of the Section on Surgery of the American Academy of Pediatrics, New Orleans, Louisiana, October 31-November 2, 2003.
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Abstract

Background/purpose

Homozygous mutant Ncx/Hox11L.1-deficient (Ncx−/−) mice develop mega-ileo-ceco-colon (mega-ICC) with a caliber change in the proximal colon. The authors investigated the mechanism of intestinal dysmotility in these mice.

Methods

Five-week-old Ncx−/− mice with mega ICC were compared with age-matched BDF1 control mice. Jejunum, ileum, and colon were excised from all mice and 1.0-cm-long strips of each organ, each with a resting tension of 0.5g, were suspended in an organ bath filled with Tyrode’s solution at 37°C and bubbled with a mixture of 95% oxygen and 5% carbon dioxide. Contractile responses to acetylcholine chloride (ACh), histamine, serotonin, and barium chloride (BaCl2) were recorded isometrically.

Results

For ACh, Ncx−/− mice had decreased distal colon circular muscle contraction only at lower doses and decreased distal colon longitudinal muscle contraction for all doses compared with controls (P < .05 or P < .01). In the proximal colon, Ncx−/− mice had increased circular muscle contraction only at higher doses and decreased longitudinal muscle contraction only at lower doses compared with controls (P < .01 or P < .05). ACh did not affect jejunum, and there were no significant effects on ileum. There was no response to histamine and serotonin by any part of the bowel, and the response to BaCl2 was the same for both Ncx−/− mice and controls.

Conclusions

Only ACh differentially affected muscle contraction in Ncx−/− mice in the proximal and distal colon. Thus, ACh is implicated in causing the bowel dysmotility seen in Ncx−/− mice and human IND.

Section snippets

Drugs

The test drugs used were histamine, serotonin, acetylcholine chloride (ACh), and barium chloride (BaCl2). Histamine and serotonin were purchased from Sigma Chemical Co, St Louis, MO. ACh was provided as Ovisot Injection by Daiichi Pharmaceutical Co, Tokyo, Japan, and BaCl2 was provided by Wako Pure Chemicals, Osaka, Japan. All drugs were dissolved in distilled water before use.

Methods

(C57BL/6xDBA/2) F1 mice were purchased from Lapna SLC (Hamamatsu, Japan). Ncx−/− mice were created according to a

Results

For ACh, Ncx−/− mice had decreased distal colon circular muscle contraction only at lower doses (P < .05 or P < .01; Fig 1A α) and decreased distal colon longitudinal muscle contraction for all doses compared with controls (P < .05 or P < .01; Fig 1B α). In the proximal colon, Ncx−/− mice had increased circular muscle contraction only at higher doses (P < .05 or P < .01; Fig 1A β), and decreased longitudinal muscle contraction only at lower doses compared with controls (P < .05 or P < .01; Fig

Discussion

The motility of the intestine wall is controlled and affected by the enteric nervous system (ENS). The ENS and smooth muscles of the intestine constitute a neuromuscular unit, an important complex for normal bowel motility.7 Thus, motor activity of the alimentary tract is controlled by a careful balance of inhibitory and excitatory stimuli in a complex manner.3 The most common condition affecting bowel motility in infancy is HD, and although the incidence of IND has been reported to be similar

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