title: Effect of sildenafil on skeletal and cardiac muscle in Becker muscular dystrophy.
abstract: OBJECTIVE
  Patients with Becker muscular dystrophy (BMD) and Duchenne muscular dystrophy lack neuronal nitric oxide synthase (nNOS). nNOS mediates physiological sympatholysis, thus ensuring adequate blood supply to working muscle. In mice lacking dystrophin, restoration of nNOS effects by a phosphodiesterase 5 (PDE5) inhibitor (sildenafil) improves skeletal and cardiac muscle performance. Sildenafil also improves blood flow in patients with BMD. We therefore hypothesized that sildenafil would improve blood flow, maximal work capacity, and heart function in patients with BMD.
  
  
  METHODS
  A randomized, double-blind, placebo-controlled crossover design with two 4-week periods of treatment, separated by 2-week washout was used. We assessed brachial artery blood flow during maximal handgrip exercise, 6-minute walk test, maximal oxidative capacity, and life quality; cardiac function was evaluated by magnetic resonance imaging (MRI) at rest and during maximal handgrip exercise. Muscle nNOS and PDE5 were tested with Western blotting in 5 patients.
  
  
  RESULTS
  Sixteen patients completed all skeletal muscle evaluations, and 13 completed the cardiac MRI investigations. Sildenafil had no effect on any of the outcome parameters. No serious adverse effects were recorded. PDE5 and nNOS were deficient in 5 of 5 biopsies.
  
  
  CONCLUSIONS
  Despite positive evidence from animal models of dystrophinopathy and physiological findings in patients with BMD, this double-blind, placebo-controlled clinical study showed no effect of sildenafil on blood flow, maximal work capacity, and heart function in adults with BMD. This discrepancy may be explained by a significant downregulation of PDE5 in muscle.
authors.affiliation: Neuromuscular Research Unit and Department of Neurology, Rigshospitalet, University Hospital Glostrup, University of Copenhagen, Copenhagen, Denmark.
authors.forename: Nanna
authors.initials: N
authors.lastname: Witting
authors.forename: Christina
authors.initials: C
authors.lastname: Kruuse
authors.forename: Bo
authors.initials: B
authors.lastname: Nyhuus
authors.forename: Kira P
authors.initials: KP
authors.lastname: Prahm
authors.forename: Gulsenay
authors.initials: G
authors.lastname: Citirak
authors.forename: Stine J
authors.initials: SJ
authors.lastname: Lundgaard
authors.forename: Sebastian
authors.initials: S
authors.lastname: von Huth
authors.forename: Niels
authors.initials: N
authors.lastname: Vejlstrup
authors.forename: Ulrich
authors.initials: U
authors.lastname: Lindberg
authors.forename: Thomas O
authors.initials: TO
authors.lastname: Krag
authors.forename: John
authors.initials: J
authors.lastname: Vissing
mesh_terms: D000328:Adult; D000704:Analysis of Variance; D054706:Cyclic Nucleotide Phosphodiesterases, Type 5 / Q000378:metabolism; D004311:Double-Blind Method; D005260:Female; D005500:Follow-Up Studies; D018737:Hand Strength / Q000502:physiology; D006801:Humans; D008124:Locomotion / Q000187:drug effects; D008279:Magnetic Resonance Imaging; D008297:Male; D018482:Muscle, Skeletal / Q000187:drug effects* / Q000378:metabolism; D020388:Muscular Dystrophy, Duchenne / Q000188:drug therapy* / Q000473:pathology*; D009206:Myocardium / Q000473:pathology*; D052248:Nitric Oxide Synthase Type I / Q000378:metabolism; D010879:Piperazines / Q000627:therapeutic use*; D011687:Purines / Q000627:therapeutic use; D012039:Regional Blood Flow / Q000187:drug effects; D000068677:Sildenafil Citrate; D013450:Sulfones / Q000627:therapeutic use*; D014665:Vasodilator Agents / Q000627:therapeutic use*; D055815:Young Adult
chemical_list: D010879:Piperazines; D011687:Purines; D013450:Sulfones; D014665:Vasodilator Agents; D000068677:Sildenafil Citrate; C496320:NOS1 protein, human; D052248:Nitric Oxide Synthase Type I; D054706:Cyclic Nucleotide Phosphodiesterases, Type 5