Premium
Inorganic Nitrate and Nitrite Restore Functional Sympatholysis in Dystrophin‐deficient Mdx Mice
Author(s) -
Li Liang,
Thomas Gail
Publication year - 2015
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.29.1_supplement.831.8
Subject(s) - nitrite , duchenne muscular dystrophy , chemistry , xanthine oxidase , dystrophin , nitric oxide , mdx mouse , medicine , endocrinology , sarcolemma , pharmacology , vasoconstriction , nitrate , biochemistry , skeletal muscle , enzyme , organic chemistry
Conventional nitric oxide (NO) production by the muscle‐specific isoform of neuronal NO synthase (nNOSμ) is greatly reduced in the dystrophin‐deficient muscles of mdx mice and of patients with Duchenne muscular dystrophy (DMD). This loss of NO signaling renders the diseased muscles susceptible to ischemia during exercise due to unopposed sympathetic vasoconstriction. We therefore asked if NO‐dependent functional sympatholysis could be restored in the contracting muscles of mdx mice using an alternate reductive pathway to generate NO from inorganic nitrate or nitrite. Norepinephrine (NE) evoked similar decreases in femoral vascular conductance (FVC) in the resting and contracting hindlimbs of untreated mdx mice, indicating functional muscle ischemia (ΔFVC contraction/rest: 0.85 ± 0.06, n = 15). After treatment with a single ip dose of nitrate or nitrite, NE evoked smaller decreases in FVC in the contracting versus resting hindlimbs, demonstrating restored sympatholysis (ΔFVC contraction/rest: nitrate‐4 mg/kg, 0.50 ± 0.06; nitrate‐8 mg/kg, 0.26 ± 0.07; and nitrite‐0.2 mg/kg, 0.33 ± 0.07; n = 5 each). The beneficial effect of nitrite was prevented by co‐administration of carboxy‐PTIO to scavenge NO (n = 3), allopurinol to inhibit xanthine oxidase (n = 4) or raloxifene to inhibit aldehyde oxidase (n = 4). These findings indicate that the alternative nitrate‐nitrite‐NO pathway may be exploited to overcome reduced nNOSμ‐NO signaling and improve blood flow regulation in the dystrophic muscles of mdx mice. Supported by DoD W81XWH‐12‐1‐0256 and NIH AR056551.