Acute phosphodiesterase inhibition improves functional muscle ischemia in patients with Becker muscular dystrophy

Abstract

Loss of sarcolemmal nitric oxide synthase (nNOS) engenders ischemia of exercising dystrophin‐deficient muscles of mdx mice and boys with Duchenne muscular dystrophy. We tested if muscle ischemia also occurs in Becker muscular dystrophy (BMD), a milder disease often caused by dystrophin mutations involving the nNOS binding site, and is improved by tadalafil, a phosphodiesterase (PDE5A) inhibitor that enhances cGMP/NO signaling. We measured reflex vasoconstriction (decreased forearm muscle oxygenation [ΔHb02, near infrared spectroscopy] during lower body negative pressure [LBNP]) at rest and during rhythmic handgrip (HG) in 5 male controls (Ctrls) and 10 men with BMD who underwent a placebo‐controlled cross‐over trial of single‐dose (20 mg) tadalafil. At baseline, HG greatly attenuated vasoconstriction in Ctrls (ΔHb02:−393±89 vs. −91±40 units, p<.01; rest vs. HG) but caused no attenuation in BMD (−381±45 vs. − 374±46). Tadalafil markedly improved ischemia in BMD (ΔHb02:− 439±70 vs. −230±54, rest vs. HG; p=0.014) whereas placebo had no effect. These data provide the first evidence in man that PDE5A inhibition can improve blood flow regulation in dystrophin‐deficient skeletal muscle. Funded by MDA 201149.

Microvascular response to exercise varies along the length of the tibialis anterior muscle

“…A lower regional perfusion and slower microvascular response to exercise could be of importance for pathologies where the muscle's ability to adequately match the oxygen demand during activity is impaired and where regional differences in disease progression have been observed, such as in Duchenne and Becker muscular dystrophies. 29 , 30 , 31 , 32 , 33 One might argue that regions with inherently lower perfusion and exercise response are especially vulnerable to impairments due to a pathology, which might result in a heterogeneous disease progression within the muscle. To assess the clinical implication of regional differences in microvascular response to exercise, it would be interesting to relate these differences to damage because of impairments in oxygen supply.…”

“…Most studies using ASL in muscle have only reported data from a single slice with the implicit assumption that muscle perfusion is homogeneous. 1,[3][4][5][6] Recent literature, however, has reported proximodistal differences in perfusion-related parameters and oxidative capacity, measured by IVIM, T 2 *, and 31 P MRS. 7,8 Proximodistal differences could be relevant for pathological situations, such as diabetes and peripheral artery disease, 9,10 because it can be argued that muscle regions with inherently lower perfusion or slower microvascular response to exercise are more vulnerable when perfusion is impaired as result of a disease. Therefore, covering larger imaging volumes is of great interest when assessing microvascular response to exercise.…”