Treatment with a Nitric Oxide-Donating NSAID Alleviates Functional Muscle Ischemia in the Mouse Model of Duchenne Muscular Dystrophy

作者: Gail D. Thomas , Jianfeng Ye , Claudio De Nardi , Angela Monopoli , Ennio Ongini

DOI: 10.1371/JOURNAL.PONE.0049350

关键词: DystrophinVasoconstrictionMuscle contractionDuchenne muscular dystrophyInternal medicineEndocrinologySurgerySarcolemmamdx mouseMedicineNitric oxideIschemiaGeneral Biochemistry, Genetics and Molecular BiologyGeneral Agricultural and Biological SciencesGeneral Medicine

摘要: In patients with Duchenne muscular dystrophy (DMD) and the standard mdx mouse model of DMD, dystrophin deficiency causes loss neuronal nitric oxide synthase (nNOSμ) from sarcolemma, producing functional ischemia when muscles are exercised. We asked if muscle would be eliminated normal blood flow regulation restored by treatment an exogenous (NO)-donating drug. Beginning at 8 weeks age, mice were fed a diet supplemented 1% soybean oil alone or in combination low (15 mg/kg) high (45 dose HCT 1026, NO-donating nonsteroidal anti-inflammatory agent which has previously been shown to slow disease progression model. After 1 month treatment, vasoconstrictor responses intra-arterial norepinephrine (NE) compared resting contracting hindlimbs. untreated mice, usual effect contraction attenuate NE-mediated vasoconstriction was impaired, resulting ischemia: NE evoked similar decreases femoral velocity vascular conductance (FVC) hindlimbs (ΔFVC contraction/ΔFVC rest = 0.88±0.03). NE-induced unaffected 1026 ratio 0.92±0.04; P>0.05 vs untreated), but alleviated drug 0.22±0.03; P<0.05 dose). The beneficial maintained up 3 months. normalize hindlimb suggests putative novel for DMD. Further translational research is warranted.

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