PDE5 inhibition alleviates functional muscle ischemia in boys with Duchenne muscular dystrophy
PDE5 inhibition alleviates functional muscle ischemia in boys with Duchenne muscular dystrophy
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DOI：
10.1212/wnl.0000000000000498
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发表时间：
2014-06-10
期刊：
影响因子：
9.9
通讯作者：
Victor, Ronald G.
中科院分区：
文献类型：
--
作者：
Nelson, Michael D.;Rader, Florian;Victor, Ronald G.
目的：探讨抑制磷酸二酯酶5(PDE5)能否减轻Duchenne肌营养不良症(DMD)患儿运动性骨骼肌缺血。方法：在10例Duchenne肌营养不良症(DMD)患儿和10名健康男性对照中，我们评估了运动引起的反射性交感血管收缩的减弱，即功能性交感神经溶解，这是一种将氧气供应与代谢需求相匹配的保护机制。通过模拟立位应激诱发反射性血管收缩，用近红外光谱分析测定前臂肌肉氧合能力的下降，并在前臂肌肉休息或轻微运动时进行有节奏的握力运动。然后，患者接受开放标签、剂量递增、交叉试验，单剂量口服他达拉非或西地那非。结果：主要新发现有两个方面：第一，产生DMD的功能性肌肉缺血的男孩的交感神经溶解功能受损-尽管当代背景治疗仅使用皮质类固醇或联合使用心脏保护药物。第二，用标准临床剂量的他达拉非或西地那非抑制PDE5以剂量依赖的方式缓解这种缺血。此外，抑制PDE5也使运动引起的骨骼肌血流量增加(多普勒超声测量)正常化，这种增加在患有DMD的男孩中明显减弱。结论：这些数据为抑制PDE5作为DMD新的治疗策略提供了人体内证据。证据分类：这项研究提供了DMD患者PDE5抑制可恢复功能性交感神经溶解的IV类证据。
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 forearmmuscles 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. Classification of evidence: This study provides Class IV evidence that in patients with DMD, PDE5 inhibition restores functional sympatholysis.