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

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 0.5 g, 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 (BaCl 2 ) 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 BaCl 2 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.