Short‐term naproxcinod treatment ameliorates functional muscle ischemia in dystrophin‐deficient mdx mice (1156.1)

Impaired nitric oxide (NO) signaling in the dystrophin‐deficient muscles of patients with Duchenne muscular dystrophy (DMD) and the mdx mouse model of DMD renders the diseased muscles susceptible to functional ischemia, which enhances both fatigue and exercise‐induced muscle injury. We therefore asked if short‐term treatment with naproxcinod, a NO‐donating naproxen, would prevent functional muscle ischemia and restore normal blood flow regulation in the exercising muscles of mdx mice. Norepinephrine (NE) evoked similar decreases in femoral vascular conductance (FVC) in resting and contracting hindlimbs of vehicle‐treated mdx mice, indicating functional muscle ischemia (ΔFVC contraction/rest: 0.93 ± 0.16, n=5). Naproxcinod (40 mg/kg, po) modestly reduced muscle ischemia when given as a single dose and markedly ameliorated it when treatment was extended to 1 wk (ΔFVC contraction/rest: 0.67 ± 0.18 and 0.39 ± 0.08, respectively; n=9 each), while treatment with equimolar naproxen was without effect (n=5). Daily treatment with a lower dose of naproxcinod (20 mg/kg) was equally effective in preventing functional ischemia in mdx and nNOS null mice (ΔFVC contraction/rest: 0.39 ± 0.05, n=10 and 0.31 ± 0.02, n=4, respectively). These findings suggest that naproxcinod’s ability to donate NO rather than inhibit cyclooxygenase is the main mechanism by which the drug improves muscle blood flow regulation in mdx mice. Grant Funding Source : Supported by DoD, W81XWH‐12‐1‐0256