In Duchenne muscular dystrophy (DMD), skeletal muscle failure is the prominent manifestation, although disorders such as gastric dilatation and intestinal pseudo-obstruction have also been reported (Barohn et al., 1988). In an animal model of DMD, the mdx mouse, gastric and colonic tissue show functional alterations and deranged motility similar to those reported clinically. These differences have been attributed to impaired nitric oxide (NO) production (Baccari et al., 2000; Mulè et al., 2001). This study examined ontogenic differences in cholinergic muscarinic receptor-mediated contractile responses and sensitivity to both endogenous and exogenous NO in tissue obtained from mdx and normal (C57BL/10SnJ) mice.

Normal and mdx mutant male mice (5 - 30g) of ages relating to well-characterised phases in the pathology of the mdx mouse were used. These were termed pre-, mid- and post-muscle degeneration and related to 7±2 days, 31±4 days and 160±14 days of age respectively. Concentration-response curves were obtained to acetylcholine (ACh; 1 nM-30 mM). In addition the relaxant properties of the tissues following pre-contraction with carbachol (0.4 µM) were also determined in response to either the NO synthase substrate L-arginine (L-arg; 1 mM) or the NO donor glyceryl trinitrate (GTN; 40 µM) in the absence and presence of N-nitro-L-arginine methyl ester (L-NAME, 1 mM). The relaxant effect of GTN alone was also investigated. Data were compared using Student’s t-test. No significant difference between the EC₅₀ concentrations for ACh or relaxant responses to GTN in mdx and normal tissues were observed in any of the age groups. However, L-NAME significantly reduced the relaxant response to L-arg in both tissues from normal animals of all age groups, and also in the pre and post-muscle degeneration age group in mdx animals (P<0.05) (see Table 1).

Table 1 : L-NAME on % relaxation response to L-arg. Data=mean ± s.e.mean (n=5-6), * P<0.05, ** P<0.01

These data suggest that deranged G.I. motility in mdx fundic and colonic tissue is unlikely a consequence of differences in either responsiveness to ACh or NO but may reflect changes in endogenous NO production. This agrees with existing data suggesting that NO production is impaired in muscle from mdx animals due to possible alterations in the dystrophin associated protein complex to which nNOS is bound.

Baccari M.C. et al., (2000). Neurosci. Lett., 282, 105-108.
Barohn R.J. et al., (1988), N. Engl. J. Med., 319, 15-18.
Mulè F. et al., (2001). Am. J. Physiol., 281, G1264-1270.