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Phosphodiesterase 5 inhibition rescues functional sympatholysis in Duchenne Muscular Dystrophy
Author(s) -
Nelson Michael,
Martin Elizabeth A.,
Tang Xiu,
Johannes Jimmy,
Lewis Joshua,
Gurudevan Swaminatha V.,
Nelson Stanley,
Miceli Carrie,
Victor Ronald G.
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.943.18
Subject(s) - duchenne muscular dystrophy , tadalafil , sildenafil , cgmp specific phosphodiesterase type 5 , medicine , muscular dystrophy , vasoconstriction , erectile dysfunction , mdx mouse , endocrinology , dystrophin
We recently reported that functional sympatholysis (i.e., muscle contraction‐induced attenuation of reflex vasoconstriction) is impaired in Becker Muscular dystrophy and rescued by phosphodiesterase (PDE)5 inhibition with tadalafil. However, tadalafil failed to rescue sympatholysis in one BMD patient with a rapidly progressive disease resembling Duchenne Muscular Dystrophy. Thus, we tested the ability of two different phosphodiesterase inhibitors, tadalafil and sildenafil, to rescue sympatholysis in DMD. In 6 boys with DMD (ages 7–13) and 8 healthy controls, we measured reflex vasoconstriction (decreased forearm muscle oxygenation [ΔHb02, near infrared spectroscopy] evoked by lower body negative pressure) at rest and during rhythmic handgrip exercise. First, we confirm that sympatholysis is impaired in DMD, because handgrip greatly attenuated vasoconstriction in controls (ΔHb02: −22±6 vs. −9±5 %, p<.05; rest vs. HG) but caused no attenuation in DMD (−17±2 vs. −15±3%). Then, in a randomized single dose (0.5 mg/kg) cross‐over trial of tadalafil vs. sildenafil, we show that sympatholysis is rescued in DMD by either PDE5 inhibitor (tadalafil: −21±3 vs. −11±4; sildenafil, −22±4 vs. −12±3%; ΔHb02 rest vs. HG). PDE5 inhibition therefore constitutes a putative therapeutic treatment option for patients with either Becker or Duchenne Muscular Dystrophy. Support: Parent Project Muscular Dystrophy