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Restoration of sarcolemmal nNOS is essential to normalize α‐adrenoceptor control of muscle blood flow in transgenic mdx mice
Author(s) -
Thomas Gail D,
Lai Yi,
Duan Dongsheng
Publication year - 2009
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.23.1_supplement.776.3
Subject(s) - endocrinology , medicine , sarcolemma , dystrophin , vasoconstriction , mdx mouse , skeletal muscle , duchenne muscular dystrophy , transgene , extensor digitorum longus muscle , genetically modified mouse , hindlimb , muscular dystrophy , minigene , biology , chemistry , gene , messenger rna , biochemistry , alternative splicing
Neuronal nitric oxide synthase (nNOS) is abundantly expressed in skeletal muscle, where it is localized to the sarcolemma via the dystrophin glycoprotein complex (DGC). We previously reported that nNOS‐derived NO blunts α‐adrenergic vasoconstriction in contracting muscle and that this protective effect is absent in boys with muscular dystrophy and in mdx mice in which mutations in the dystrophin gene disrupt the DGC and displace nNOS. We therefore hypothesized that restoration of sarcolemmal nNOS is essential to rescue the normal contraction‐induced attenuation of α‐adrenergic vasoconstriction. In the resting hindlimbs of transgenic mdx mice expressing minidystrophin genes that restore the DGC with (ΔH2‐R15) or without (ΔH2‐R19) restoring nNOS, intraarterial norepinephrine evoked similar decreases in femoral blood flow and vascular conductance. These constrictor responses were markedly attenuated by 81±3% in the contracting hindlimbs of the ΔH2‐R15 transgenics (p<0.05 vs. rest; n=8), but by only 16±4% in the ΔH2‐R19 transgenics (p>0.05 vs. rest; n=6) and by 10±5% in transgene negative littermates (n=3). Minigene expression yielded similar results in mdx4cv mice, which have a different dystrophin mutation and genetic background than mdx mice. These data indicate that recovery of sarcolemmal nNOS is essential to restore normal blood flow regulation in mdx skeletal muscle. Supported by the NIH and MDA.