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Treatment with a nitric oxide‐donating NSAID counteracts functional muscle ischemia in dystrophin‐deficient mdx mice
Author(s) -
Thomas Gail D,
Monopoli Angela,
De Nardi Claudio,
Ongini Ennio,
Victor Ronald G
Publication year - 2012
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.26.1_supplement.1092.6
Subject(s) - duchenne muscular dystrophy , dystrophin , ischemia , nitric oxide , hindlimb , vasoconstriction , medicine , mdx mouse , endocrinology , vasodilation , sarcolemma , pharmacology , chemistry , anesthesia , skeletal muscle
The dystrophin‐deficient muscles of boys with Duchenne muscular dystrophy (DMD) and mdx mice, a model of DMD, are susceptible to ischemia during exercise due to loss of neuronal nitric oxide synthase (nNOS) from the sarcolemma. We hypothesized that treatment with a NO‐donating drug would compensate for nNOS deficiency and counteract functional muscle ischemia. We fed mdx mice a standard diet containing 1% soybean oil (vehicle) or a low (15 mg/kg) or high (45 mg/kg) dose of a NO‐releasing derivative of the NSAID flurbiprofen (n = 12/group). After 1 month of treatment, we compared vasoconstrictor responses to intra‐arterial norepinephrine (NE) in resting and contracting hindlimbs. In vehicle‐treated mice, the usual effect of muscle contraction to attenuate NE‐mediated vasoconstriction was impaired as shown by similar decreases in femoral vascular conductance in contracting vs resting hindlimbs (attenuation ratio = 0.88 ± 0.03). NE‐induced ischemia was also seen in the contracting hindlimbs of mice treated with low dose drug (0.92 ± 0.04; P > 0.05 vs vehicle), but was markedly attenuated in mice treated with high dose drug (0.22 ± 0.03; P < 0.05 vs vehicle or low dose). The beneficial effect of the high dose was maintained with treatment up to 3 months. These data demonstrate a robust anti‐ischemic effect of a NO‐donating drug in mdx mice and suggest a potential use in the treatment of DMD patients. Supported by NicOx, 801130.