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USA – no Experimental Biology, maior congresso de ciências básicas dos Estados Unidos, serão apresentados três trabalhos de um mesmo grupo que reforçam o papel das alterações vasculares na distrofia muscular de Duchenne. Estudos prévios demonstraram que há uma incapacidade dos portadores de distrofia de Becker em reduzir a vasocontrição reflexa desencadeada por exercícios. Nestes três trabalhos, dois em seres humanos e um em camundongos este efeito é novamente demonstrado. Além disso com o uso de inibidores da fosfodiesterase habitualmente utilizados em disfunção erétil, como o tadalafil ou sildenafil, a resposta vasoativa se recupera ao menos parcialmente. O resumo em inglês destes trabalhos pode ser lido aqui: a) (Experimental Biology, 2013) Phosphodiesterase 5 inhibition rescues functional sympatholysis in Duchenne Muscular Dystrophy We recently reported that functional sympatholysis (i.e., muscle contraction-induced attenuation of reflex vasoconstriction) is impaired in Becker Muscular dystrophy and rescued by phosphodiesterase (PDE)5 inhibition with tadalafil. However, tadalafil failed to rescue sympatholysis in one BMD patient with a rapidly progressive disease resembling Duchenne Muscular Dystrophy. Thus, we tested the ability of two different phosphodiesterase inhibitors, tadalafil and sildenafil, to rescue sympatholysis in DMD. In 6 boys with DMD (ages 7-13) and 8 healthy controls, we measured reflex vasoconstriction (decreased forearm muscle oxygenation [ΔHb02, near infrared spectroscopy] evoked by lower body negative pressure) at rest and during rhythmic handgrip exercise. First, we confirm that sympatholysis is impaired in DMD, because handgrip greatly attenuated vasoconstriction in controls (ΔHb02:-22±6 vs. -9±5 %, p<.05; rest vs. HG) but caused no attenuation in DMD (-17±2 vs. -15±3%). Then, in a randomized single dose (0.5 mg/kg) cross-over trial of tadalafil vs. sildenafil, we show that sympatholysis is rescued in DMD by either PDE5 inhibitor (tadalafil: -21±3 vs. -11±4; sildenafil, -22±4 vs. -12±3%; ΔHb02 rest vs. HG). PDE5 inhibition therefore constitutes a putative therapeutic treatment option for patients with either Becker or Duchenne Muscular Dystrophy. Support: Parent Project Muscular Dystrophy b) (Experimental Biology, 2013) Tadalafil-sensitive impairment in muscle blood flow during exercise in Duchenne Muscular Dystrophy 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) c) (Experimental Biology, 2013) Chronic tadalafil treatment ameliorates functional muscle ischemia and exercise-induced muscle injury in dystrophin- deficient mdx mice. Liang Li, Nancy Zepeda, Ronald G Victor, Gail D Thomas. The The dystrophin-deficient muscles of patients with Duchenne or Becker muscular dystrophy and mdx mice are susceptible to ischemia during exercise due to loss of sarcolemmal neuronal nitric oxide synthase (nNOS). We showed that functional muscle ischemia is alleviated in patients and mice by acute treatment with the phosphodiesterase 5A (PDE5A) inhibitor tadalafil to boost NO-cGMP signaling in the diseased muscles. We now asked if this anti-ischemic effect is sustained during chronic PDE5A inhibition. We fed mdx mice control or medicated diets (tadalafil, 4 mg/kg) for 3 months and then evaluated norepinephrine (NE)-induced hindlimb vasoconstriction. NE evoked similar decreases in femoral vascular conductance (FVC) in resting and contracting hindlimbs of untreated mdx mice, indicating functional muscle ischemia (ΔFVC contraction/rest, 1.07 ± 0.13; n=10). NE-induced ischemia was attenuated in tadalafil-treated mice (ΔFVC contraction/rest, 0.61 ± 0.06; n=9; P<0.05 vs untreated) and was similar to C57BL10 controls (ΔFVC contraction/rest, 0.50 ± 0.08; n=10). Serum creatine kinase activity was elevated 6-fold post-exercise in untreated mice, but only 2.5-fold in treated mice (P<0.05). These findings indicate that chronic PDE5A inhibition counteracts functional muscle ischemia in mdx mice, which may reduce injury of the vulnerable dystrophin-deficient muscles during exercise. Supported by MDA, 158944.
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