Ann Neurol. 2014 Jul 4. doi: 10.1002/ana.24216. [Epub ahead of print]

Effect of sildenafil on skeletal and cardiac muscle in Becker muscular dystrophy.

Witting N¹, Kruuse C, Nyhuus B, Prahm K, Citirak G, Lundgaard S, von Huth S, Vejlstrup N, Lindberg U, Krag T, Vissing J.

Abstract

Background:

Patients with Becker and Duchenne muscular dystrophies, (BMD and DMD) 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 wash-out was used. We assessed brachial artery blood flow during maximal handgrip exercise, six minute walk test, maximal oxidative capacity, life quality, and cardiac function was evaluated by MRI at rest and during maximal handgrip exercise. Muscle nNOS and PDE5 was tested with western blotting in 5 patients.

Findings:

Sixteen patients completed all skeletal muscle evaluations and 13 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 5/5 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 down-regulation of PDE5 in muscles.

ANN NEUROL 2014. © 2014 American Neurological Association.