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Chronic tadalafil treatment ameliorates functional muscle ischemia and exercise‐induced muscle injury in dystrophindeficient mdx mice
Author(s) -
Li Liang,
Zepeda Nancy,
Victor Ronald G,
Thomas Gail D
Publication year - 2013
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.27.1_supplement.943.19
Subject(s) - tadalafil , medicine , dystrophin , endocrinology , ischemia , duchenne muscular dystrophy , mdx mouse , creatine kinase , cgmp specific phosphodiesterase type 5 , hindlimb , contraction (grammar) , vasoconstriction , erectile dysfunction
The dystrophin‐deficient muscles of patients with Duchenne or Becker muscular dystrophy and mdx mice are susceptible to ischemia during exercise due to loss of sarcolemmal neuronal nitric oxide synthase (nNOS). We showed that functional muscle ischemia is alleviated in patients and mice by acute treatment with the phosphodiesterase 5A (PDE5A) inhibitor tadalafil to boost NO‐cGMP signaling in the diseased muscles. We now asked if this anti‐ischemic effect is sustained during chronic PDE5A inhibition. We fed mdx mice control or medicated diets (tadalafil, 4 mg/kg) for 3 months and then evaluated norepinephrine (NE)‐induced hindlimb vasoconstriction. NE evoked similar decreases in femoral vascular conductance (FVC) in resting and contracting hindlimbs of untreated mdx mice, indicating functional muscle ischemia (ΔFVC contraction/rest, 1.07 ± 0.13; n=10). NE‐induced ischemia was attenuated in tadalafil‐treated mice (ΔFVC contraction/rest, 0.61 ± 0.06; n=9; P<0.05 vs untreated) and was similar to C57BL10 controls (ΔFVC contraction/rest, 0.50 ± 0.08; n=10). Serum creatine kinase activity was elevated 6‐fold post‐exercise in untreated mice, but only 2.5‐fold in treated mice (P<0.05). These findings indicate that chronic PDE5A inhibition counteracts functional muscle ischemia in mdx mice, which may reduce injury of the vulnerable dystrophin‐deficient muscles during exercise. Supported by MDA, 158944.