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Acute phosphodiesterase inhibition improves functional muscle ischemia in patients with Becker muscular dystrophy
Author(s) -
Martin Elizabeth Anne,
Walker Ashley E,
Scott Bryan L,
Malott Teresa C,
Singh Nirmal,
Gurudevan Swaminatha V,
Johannes Jimmy,
Elashoff Robert M,
Thomas Gail D,
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.1092.7
Subject(s) - dystrophin , tadalafil , cgmp specific phosphodiesterase type 5 , medicine , duchenne muscular dystrophy , endocrinology , muscular dystrophy , ischemia , skeletal muscle , vasoconstriction , vasodilation , cardiology , sildenafil
Loss of sarcolemmal nitric oxide synthase (nNOS) engenders ischemia of exercising dystrophin‐deficient muscles of mdx mice and boys with Duchenne muscular dystrophy. We tested if muscle ischemia also occurs in Becker muscular dystrophy (BMD), a milder disease often caused by dystrophin mutations involving the nNOS binding site, and is improved by tadalafil, a phosphodiesterase (PDE5A) inhibitor that enhances cGMP/NO signaling. We measured reflex vasoconstriction (decreased forearm muscle oxygenation [ΔHb0 2 , near infrared spectroscopy] during lower body negative pressure [LBNP]) at rest and during rhythmic handgrip (HG) in 5 male controls (Ctrls) and 10 men with BMD who underwent a placebo‐controlled cross‐over trial of single‐dose (20 mg) tadalafil. At baseline, HG greatly attenuated vasoconstriction in Ctrls (ΔHb0 2 :−393±89 vs. −91±40 units, p<.01; rest vs. HG) but caused no attenuation in BMD (−381±45 vs. − 374±46). Tadalafil markedly improved ischemia in BMD (ΔHb0 2 :− 439±70 vs. −230±54, rest vs. HG; p=0.014) whereas placebo had no effect. These data provide the first evidence in man that PDE5A inhibition can improve blood flow regulation in dystrophin‐deficient skeletal muscle. Funded by MDA 201149.