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- Title
Treatment with a Nitric Oxide-Donating NSAID Alleviates Functional Muscle Ischemia in the Mouse Model of Duchenne Muscular Dystrophy.
- Authors
Thomas, Gail D.; Jianfeng Ye; De Nardi, Claudio; Monopoli, Angela; Ongini, Ennio; Victor, Ronald G.
- Abstract
In patients with Duchenne muscular dystrophy (DMD) and the standard mdx mouse model of DMD, dystrophin deficiency causes loss of neuronal nitric oxide synthase (nNOSm) from the sarcolemma, producing functional ischemia when the muscles are exercised. We asked if functional muscle ischemia would be eliminated and normal blood flow regulation restored by treatment with an exogenous nitric oxide (NO)-donating drug. Beginning at 8 weeks of age, mdx mice were fed a standard diet supplemented with 1% soybean oil alone or in combination with a low (15 mg/kg) or high (45 mg/kg) dose of HCT 1026, a NO-donating nonsteroidal anti-inflammatory agent which has previously been shown to slow disease progression in the mdx model. After 1 month of treatment, vasoconstrictor responses to intra-arterial norepinephrine (NE) were compared in resting and contracting hindlimbs. In untreated mdx mice, the usual effect of muscle contraction to attenuate NE-mediated vasoconstriction was impaired, resulting in functional ischemia: NE evoked similar decreases in femoral blood flow velocity and femoral vascular conductance (FVC) in the contracting compared to resting hindlimbs (ΔFVC contraction/DFVC rest = 0.8860.03). NE-induced functional ischemia was unaffected by low dose HCT 1026 (ΔFVC ratio = 0.92±0.04; P>0.05 vs untreated), but was alleviated by the high dose of the drug (ΔFVC ratio = 0.22±0.03; P>0.05 vs untreated or low dose). The beneficial effect of high dose HCT 1026 was maintained with treatment up to 3 months. The effect of the NO-donating drug HCT 1026 to normalize blood flow regulation in contracting mdx mouse hindlimb muscles suggests a putative novel treatment for DMD. Further translational research is warranted.
- Subjects
INGESTION; FORCE &; energy; PREDATION; CARNIVOROUS animals; FORAGING behavior; NITROGEN; PROTEINS
- Publication
PLoS ONE, 2012, Vol 7, Issue 11, p1
- ISSN
1932-6203
- Publication type
Article
- DOI
10.1371/journal.pone.0049350