(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

Duchenne muscular dystrophy (DMD) is a lethal genetic disease. Patients with DMD suffer progressive wasting of skeletal and cardiac muscles. They lack dystrophin, which is normally localized at the inner side of the sarcolemma of muscle and connects the intracellular cytoskeletal network of F-actin with laminin molecules in the extracellular matrix via dystroglycan complexes [1,2]. There is some evidence suggesting that dystrophin protects the plasma membrane in muscles from mechanical damage when the muscles contract [3,4] and further that it anchors the neural nitric oxide synthase [5,6], though the exact role of dystrophin is still unclear. Dystrophin-deficient (mdx) muscle exhibits a high calcium (Ca) content [7][8][9], though it is not certain whether this is a cause or a result of the degeneration of mdx muscle.Pharmaceutical therapies have been tested on patients with DMD, and various therapeutic aspects have been examined in animal models. Among the drugs tested, glucocorticoids such as prednisone and deflazacort appear to be efficacious for the treatment of mdx muscle [10][11][12]. Many antioxidants show no beneficial effects on mdx muscle despite the susceptibility of mdx muscle to oxidative stress [13][14][15]. Recently, we showed that, in male mdx mice, a zinc-carnosine complex (Z-103) that exhibits antioxidative activity and is currently being used clinically as an anti-ulcer agent [16,17] reduces fatigability of the whole animal concomitantly by reducing hypertrophy, degeneration, and fatigability of fast muscle [18]. Since, however, the clinical phenotype of the mdx mouse is much milder than that of human patients, it is important to test Z-103 using animals with a severe clinical phenotype. Though it is known that some mutant dogs (e.g., golden retriever muscular dystrophy) show a quite similar phenotype to human DMD, those animals are unavailable because of their sterility [2].During the course of studying mdx mice, we noticed that the mice became progressively more fragile as inbreeding proceeded. In the present study, we used Japanese Journal of Physiology, 52, 449-456, 2002 Key words: carnosine, EDL muscle, fatigue, muscular dystrophy, zinc. Abstract:The effect of zinc-carnosine complex (Z-103) on muscle function in dystrophin-deficient (mdx) mice was examined using several different courses of repetitive administration. Z-103 at a dose of 100 mg/kg increased the load resistant time (LRT), during which an animal bearing a load holds himself upright on a wire net, in mdx mice when administered at an age of less than about 4 months. The effect of Z-103 on LRT was independent of sex when given by intraperitoneal (I.P.) administration between 4 and 8 weeks of age. Administration of Z-103 from the age of 4 to 9 weeks had no significant effect on wet weight, magnitude or rate of rise of twitch force, or rate of decay of twitch force over time with twitch elicited by 0.5 Hz of electricity in the extensor digitorum longus muscle or calcium content in the gastrocnemius muscle, while it increased th...

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