Effect of sildenafil on skeletal and cardiac muscle in Becker muscular dystrophy
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Effect of sildenafil on skeletal and cardiac muscle in Becker muscular dystrophy. / Witting, Nanna; Kruuse, Christina ; Nyhuus, Bo; Prahm, Kira P; Citirak, Gulsenay; Lundgaard, Stine J; von Huth, Sebastian; Vejlstrup, Niels; Lindberg, Ulrich; Krag, Thomas O; Vissing, John.
I: Annals of Neurology, Bind 76, Nr. 4, 10.2014, s. 550–557.Publikation: Bidrag til tidsskrift › Tidsskriftartikel › Forskning › fagfællebedømt
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TY - JOUR
T1 - Effect of sildenafil on skeletal and cardiac muscle in Becker muscular dystrophy
AU - Witting, Nanna
AU - Kruuse, Christina
AU - Nyhuus, Bo
AU - Prahm, Kira P
AU - Citirak, Gulsenay
AU - Lundgaard, Stine J
AU - von Huth, Sebastian
AU - Vejlstrup, Niels
AU - Lindberg, Ulrich
AU - Krag, Thomas O
AU - Vissing, John
N1 - © 2014 American Neurological Association.
PY - 2014/10
Y1 - 2014/10
N2 - 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.INTERPRETATION: 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.
AB - 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.INTERPRETATION: 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.
KW - Adult
KW - Analysis of Variance
KW - Cyclic Nucleotide Phosphodiesterases, Type 5
KW - Double-Blind Method
KW - Female
KW - Follow-Up Studies
KW - Hand Strength
KW - Humans
KW - Locomotion
KW - Magnetic Resonance Imaging
KW - Male
KW - Muscle, Skeletal
KW - Muscular Dystrophy, Duchenne
KW - Myocardium
KW - Nitric Oxide Synthase Type I
KW - Piperazines
KW - Purines
KW - Regional Blood Flow
KW - Sulfones
KW - Vasodilator Agents
KW - Young Adult
U2 - 10.1002/ana.24216
DO - 10.1002/ana.24216
M3 - Journal article
C2 - 25042931
VL - 76
SP - 550
EP - 557
JO - Annals of Neurology
JF - Annals of Neurology
SN - 0364-5134
IS - 4
ER -
ID: 136682780