Tadalafil‐sensitive impairment in muscle blood flow during exercise in Duchenne Muscular Dystrophy

Abstract

Out‐of‐frame mutations in the dystrophin gene cause Duchenne muscular dystrophy (DMD)—a devastating X‐linked muscle wasting disease for which there is no treatment other than corticosteroids. In DMD, loss of the cytoskeletal protein dystrophin impairs sarcoelmmal targeting of nNOS, which is the main source of skeletal muscle‐derived nitric oxide (NO). We previously showed that loss of nNOS impairs the normal exercise‐induced attenuation of reflex vasoconstriction in dystrophic skeletal muscle, thus implicating a putative vascular component to the pathogenesis of DMD. Here we present data on a second phenotype, that muscle blood flow (BF, measured by Doppler ultrasound of the brachial artery) fails to increase normally during mild rhythmic handgrip exercise in 6 boys with DMD (7–13 years of age) compared with 8 age‐matched male controls (Ctrls): ΔBF:+13±5% vs. +81±10%, respectively (p<.05). Moreover, we show that the phosphodiesterase 5 inhibitor Tadalafil, restores active hyperemia in boys with DMD in a dose‐dependent manner: 0.5 mg/kg, +56±13%; 1.0 mg/kg, +72+18% These data significantly advance the vascular hypothesis of DMD and implicate PDE5 inhibition as a putative therapeutic treatment option.Support: Parent Project Muscular Dystrophy, Heart and Stroke Foundation of Canada (MN)