title: PDE5 inhibition alleviates functional muscle ischemia in boys with Duchenne muscular dystrophy.
abstract: OBJECTIVE
  To determine whether phosphodiesterase type 5 (PDE5) inhibition can alleviate exercise-induced skeletal muscle ischemia in boys with Duchenne muscular dystrophy (DMD).
  
  
  METHODS
  In 10 boys with DMD and 10 healthy age-matched male controls, we assessed exercise-induced attenuation of reflex sympathetic vasoconstriction, i.e., functional sympatholysis, a protective mechanism that matches oxygen delivery to metabolic demand. Reflex vasoconstriction was induced by simulated orthostatic stress, measured as the decrease in forearm muscle oxygenation with near-infrared spectroscopy, and performed when the forearm muscles were rested or lightly exercised with rhythmic handgrip exercise. Then, the patients underwent an open-label, dose-escalation, crossover trial with single oral doses of tadalafil or sildenafil.
  
  
  RESULTS
  The major new findings are 2-fold: first, sympatholysis is impaired in boys with DMD-producing functional muscle ischemia-despite contemporary background therapy with corticosteroids alone or in combination with cardioprotective medication. Second, PDE5 inhibition with standard clinical doses of either tadalafil or sildenafil alleviates this ischemia in a dose-dependent manner. Furthermore, PDE5 inhibition also normalizes the exercise-induced increase in skeletal muscle blood flow (measured by Doppler ultrasound), which is markedly blunted in boys with DMD.
  
  
  CONCLUSIONS
  These data provide in-human proof of concept for PDE5 inhibition as a putative new therapeutic strategy for DMD.
  
  
  METHODS
  This study provides Class IV evidence that in patients with DMD, PDE5 inhibition restores functional sympatholysis.
authors.affiliation: From The Heart Institute (M.D.N., F.R., X.T., R.G.V.), and Department of Pediatrics (J.T.), Cedars-Sinai Medical Center, Los Angeles; Departments of Human Genetics (S.F.N.) and Pathology and Laboratory Medicine (S.F.N.), David Geffen School of Medicine at UCLA, Los Angeles; Department of Microbiology Immunology and Molecular Genetics (M.C.M.), David Geffen School of Medicine and College of Letters and Sciences, UCLA, Los Angeles; Department of Biomathematics (R.M.E.), and Department of Biostatistics, School of Public Health (R.M.E.), University of California, Los Angeles; and Pennsylvania Muscle Institute (H.L.S.), Department of Medicine, University of Pennsylvania, Philadelphia.
authors.forename: Michael D
authors.initials: MD
authors.lastname: Nelson
authors.affiliation: From The Heart Institute (M.D.N., F.R., X.T., R.G.V.), and Department of Pediatrics (J.T.), Cedars-Sinai Medical Center, Los Angeles; Departments of Human Genetics (S.F.N.) and Pathology and Laboratory Medicine (S.F.N.), David Geffen School of Medicine at UCLA, Los Angeles; Department of Microbiology Immunology and Molecular Genetics (M.C.M.), David Geffen School of Medicine and College of Letters and Sciences, UCLA, Los Angeles; Department of Biomathematics (R.M.E.), and Department of Biostatistics, School of Public Health (R.M.E.), University of California, Los Angeles; and Pennsylvania Muscle Institute (H.L.S.), Department of Medicine, University of Pennsylvania, Philadelphia.
authors.forename: Florian
authors.initials: F
authors.lastname: Rader
authors.affiliation: From The Heart Institute (M.D.N., F.R., X.T., R.G.V.), and Department of Pediatrics (J.T.), Cedars-Sinai Medical Center, Los Angeles; Departments of Human Genetics (S.F.N.) and Pathology and Laboratory Medicine (S.F.N.), David Geffen School of Medicine at UCLA, Los Angeles; Department of Microbiology Immunology and Molecular Genetics (M.C.M.), David Geffen School of Medicine and College of Letters and Sciences, UCLA, Los Angeles; Department of Biomathematics (R.M.E.), and Department of Biostatistics, School of Public Health (R.M.E.), University of California, Los Angeles; and Pennsylvania Muscle Institute (H.L.S.), Department of Medicine, University of Pennsylvania, Philadelphia.
authors.forename: Xiu
authors.initials: X
authors.lastname: Tang
authors.affiliation: From The Heart Institute (M.D.N., F.R., X.T., R.G.V.), and Department of Pediatrics (J.T.), Cedars-Sinai Medical Center, Los Angeles; Departments of Human Genetics (S.F.N.) and Pathology and Laboratory Medicine (S.F.N.), David Geffen School of Medicine at UCLA, Los Angeles; Department of Microbiology Immunology and Molecular Genetics (M.C.M.), David Geffen School of Medicine and College of Letters and Sciences, UCLA, Los Angeles; Department of Biomathematics (R.M.E.), and Department of Biostatistics, School of Public Health (R.M.E.), University of California, Los Angeles; and Pennsylvania Muscle Institute (H.L.S.), Department of Medicine, University of Pennsylvania, Philadelphia.
authors.forename: Jane
authors.initials: J
authors.lastname: Tavyev
authors.affiliation: From The Heart Institute (M.D.N., F.R., X.T., R.G.V.), and Department of Pediatrics (J.T.), Cedars-Sinai Medical Center, Los Angeles; Departments of Human Genetics (S.F.N.) and Pathology and Laboratory Medicine (S.F.N.), David Geffen School of Medicine at UCLA, Los Angeles; Department of Microbiology Immunology and Molecular Genetics (M.C.M.), David Geffen School of Medicine and College of Letters and Sciences, UCLA, Los Angeles; Department of Biomathematics (R.M.E.), and Department of Biostatistics, School of Public Health (R.M.E.), University of California, Los Angeles; and Pennsylvania Muscle Institute (H.L.S.), Department of Medicine, University of Pennsylvania, Philadelphia.
authors.forename: Stanley F
authors.initials: SF
authors.lastname: Nelson
authors.affiliation: From The Heart Institute (M.D.N., F.R., X.T., R.G.V.), and Department of Pediatrics (J.T.), Cedars-Sinai Medical Center, Los Angeles; Departments of Human Genetics (S.F.N.) and Pathology and Laboratory Medicine (S.F.N.), David Geffen School of Medicine at UCLA, Los Angeles; Department of Microbiology Immunology and Molecular Genetics (M.C.M.), David Geffen School of Medicine and College of Letters and Sciences, UCLA, Los Angeles; Department of Biomathematics (R.M.E.), and Department of Biostatistics, School of Public Health (R.M.E.), University of California, Los Angeles; and Pennsylvania Muscle Institute (H.L.S.), Department of Medicine, University of Pennsylvania, Philadelphia.
authors.forename: M Carrie
authors.initials: MC
authors.lastname: Miceli
authors.affiliation: From The Heart Institute (M.D.N., F.R., X.T., R.G.V.), and Department of Pediatrics (J.T.), Cedars-Sinai Medical Center, Los Angeles; Departments of Human Genetics (S.F.N.) and Pathology and Laboratory Medicine (S.F.N.), David Geffen School of Medicine at UCLA, Los Angeles; Department of Microbiology Immunology and Molecular Genetics (M.C.M.), David Geffen School of Medicine and College of Letters and Sciences, UCLA, Los Angeles; Department of Biomathematics (R.M.E.), and Department of Biostatistics, School of Public Health (R.M.E.), University of California, Los Angeles; and Pennsylvania Muscle Institute (H.L.S.), Department of Medicine, University of Pennsylvania, Philadelphia.
authors.forename: Robert M
authors.initials: RM
authors.lastname: Elashoff
authors.affiliation: From The Heart Institute (M.D.N., F.R., X.T., R.G.V.), and Department of Pediatrics (J.T.), Cedars-Sinai Medical Center, Los Angeles; Departments of Human Genetics (S.F.N.) and Pathology and Laboratory Medicine (S.F.N.), David Geffen School of Medicine at UCLA, Los Angeles; Department of Microbiology Immunology and Molecular Genetics (M.C.M.), David Geffen School of Medicine and College of Letters and Sciences, UCLA, Los Angeles; Department of Biomathematics (R.M.E.), and Department of Biostatistics, School of Public Health (R.M.E.), University of California, Los Angeles; and Pennsylvania Muscle Institute (H.L.S.), Department of Medicine, University of Pennsylvania, Philadelphia.
authors.forename: H Lee
authors.initials: HL
authors.lastname: Sweeney
authors.affiliation: From The Heart Institute (M.D.N., F.R., X.T., R.G.V.), and Department of Pediatrics (J.T.), Cedars-Sinai Medical Center, Los Angeles; Departments of Human Genetics (S.F.N.) and Pathology and Laboratory Medicine (S.F.N.), David Geffen School of Medicine at UCLA, Los Angeles; Department of Microbiology Immunology and Molecular Genetics (M.C.M.), David Geffen School of Medicine and College of Letters and Sciences, UCLA, Los Angeles; Department of Biomathematics (R.M.E.), and Department of Biostatistics, School of Public Health (R.M.E.), University of California, Los Angeles; and Pennsylvania Muscle Institute (H.L.S.), Department of Medicine, University of Pennsylvania, Philadelphia. Ronald.Victor@cshs.org.
authors.forename: Ronald G
authors.initials: RG
authors.lastname: Victor
mesh_terms: D000293:Adolescent; D002243:Carbolines / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics / Q000494:pharmacology*; D002648:Child; D015444:Exercise / Q000502:physiology; D005542:Forearm / Q000098:blood supply / Q000000981:diagnostic imaging; D006801:Humans; D007511:Ischemia / Q000188:drug therapy* / Q000209:etiology; D008297:Male; D018482:Muscle, Skeletal / Q000098:blood supply / Q000187:drug effects / Q000503:physiopathology; D020388:Muscular Dystrophy, Duchenne / Q000150:complications / Q000188:drug therapy* / Q000503:physiopathology; D058986:Phosphodiesterase 5 Inhibitors / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics / Q000494:pharmacology*; D010879:Piperazines / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics / Q000494:pharmacology*; D011687:Purines / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics / Q000494:pharmacology; D000068677:Sildenafil Citrate; D019265:Spectroscopy, Near-Infrared; D013450:Sulfones / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics / Q000494:pharmacology*; D013564:Sympathetic Nervous System / Q000187:drug effects / Q000503:physiopathology*; D000068581:Tadalafil; D014463:Ultrasonography; D014661:Vasoconstriction / Q000187:drug effects / Q000502:physiology
chemical_list: D002243:Carbolines; D058986:Phosphodiesterase 5 Inhibitors; D010879:Piperazines; D011687:Purines; D013450:Sulfones; D000068581:Tadalafil; D000068677:Sildenafil Citrate