The Effect of e-, i-, and n-Nitric Oxide Synthase Inhibition on Colonic Motility in Normal and Muscular Dystrophy (Mdx) Mice

Abstract

(5 µM) reduced the magnitude of local, rhythmic contractions (LC) paced by the interstitial cells of Cajal (ICC), but 1,3-PBIT (50 µM) increased their magnitude. There was no difference in the effect of spermine and 1,3-PBIT on the LC between mdx and control colon. The results suggest an inhibition of MMC by high concentrations of e-, i-, and n-NOS inhibitors, modulation of ICC activity by e-NOS, and greater susceptibility of MMC to n-NOS inhibition in the mdx proximal than in the control colon, which is very likely because of a deficit in n-NOS in the mdx smooth muscle affecting the MMC pacemaker. A deficit in the effect of mdx smooth muscle n-NOS on an MMC pacemaker may be the origin of diarrhea or constipation in human DMD. Japanese Journal of Physiology Vol. 54, [555][556][557][558][559][560][561][562][563][564][565][566] 2004 Abstract: To explore the origin of diarrhea or constipation in human Duchenne muscular dystrophy (DMD), the effect of the inhibition of e-, i-, and n-nitric oxide synthase (NOS) on the motility of proximal and distal segments of colon of muscular dystrophy (mdx) and control mice was studied. The frequency of migrating motor complexes (MMC) was higher in the proximal than in the distal segments in mdx colon (0.56 vs. 0.25 cpm) and in the control colon (0.7 vs. 0.25 cpm), and there was no difference when mdx was compared to control segments. High concentrations of NOS inhibitors, including 1,3-PBIT dihydrobromide (1,3-PBIT) and spermine, inhibited MMC. The dose of spermine required to inhibit MMC was lower for the proximal mdx colon than for the distal mdx or control colon. In the presence of tetrodotoxin, spermine (1 mM) and 1,3-PBIT

In vivo neutralization of IL‐6 receptors ameliorates gastrointestinal dysfunction in dystrophin‐deficient mdx mice

“…Our findings of slower transit and reduced defecation in mdx mice exposed to an anxiogenic environment is unlikely to reflect less sensitivity to the stressor in this mouse model but is consistent with slowed GI transit previously reported in mdx mice . These mice have also been reported to have diarrhea or constipation, but we did not observe differences in water content or stool consistency in this study. Moreover, the thickness of the mucosal layer was similar in WT and mdx colons, which supports intact colonic absorpto‐secretory function in the absence of dystrophin.…”

“…Although, the most apparent physical symptoms of DMD are related to progressive physical disability and immobility, loss of dystrophin from smooth muscle is associated with gastrointestinal (GI) disturbances, such as nausea and vomiting, dilation of the small intestine and colon, delayed gastric emptying, hypo‐motility, chronic constipation, and in severe cases, pseudo‐obstruction . Some of these GI symptoms including slowed colonic transit times, altered GI motility, and diarrhea or constipation are recapitulated in the dystrophin‐deficient mdx mouse model of DMD.…”

Modulatory effect of intestinal polyamines and trace amines on the spontaneous phasic contractions of the isolated ileum and colon rings of mice

“…As described in circular preparations of the small intestine, but not in the longitudinal ones [41], TTX raised the basal tone of ileum rings maintaining similar spontaneous motility, and only a slight decrease in the amplitude, but not on the frequency of contractions, was observed. This toxin did not modify the basal tone of the colon rings, but decreased the amplitude and increased the frequency of the phasic contractions, as reported in longitudinal preparations [21]. These demonstrated the influence of tonic neural control on spontaneous motility, which might involve the sympathetic and parasympathetic nervous system.…”

“…They were studied with regard to their effects on the epithelial absorption of nutrients [8], and their potential effect in inflammatory bowel diseases [38] and colon cancer adenomas [12]. Polyamines have also been reported to modulate gastrointestinal smooth muscle contractions [13,14,39] and spontaneous motility [20,21,40], based mainly on longitudinal preparations.…”

“…Extracellular exposure to polyamines relaxed most of the vascular and non-vascular smooth muscles studied [18,19]. This includes the inhibitory effect on guinea-pig gastric smooth muscle [20] and colon [21] motility, although an increase of isometric tension and the facilitation of carbachol-induced contractions in mice ileum has also been reported [14]. …”