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Abstract

Aging impairs ACh-induced dilation in skeletal muscle feed arteries: role of Akt-dependent phosphorylation of eNOS.

Meredith J. Luttrell1, John W. Seawright1, Daniel W. Trott1 and Christopher R. Woodman1,2

1. Dept. of Health and Kinesiology Texas A&M University, College Station, TX 77843

2. Dept of Veterinary Physiology and Pharmacology Texas A&M University, College Station, TX 77843

We tested the hypothesis that impaired nitric oxide (NO)-mediated, endothelium-dependent dilation in aged soleus muscle feed arteries (SFA) is due to an age-related decrement in PI3-kinase(PI3K)/protein kinase B (Akt)-dependent phosphorylation of endothelial NO synthase (eNOS) on serine residue 1177 (p-eNOSser1177). SFA from young (4 mo) and old (24 mo) Fischer 344 rats were cannulated for examination of endothelium-dependent vasodilator responses to acetylcholine (ACh). To determine the mechanism by which aging affected vasodilation to ACh, vasodilator responses were assessed in the absence and presence of Nw-nitro-L-arginine (L-NNA, to inhibit NOS), LY-294002 (to inhibit PI3K), or 1L6-hydroxymethyl-chiro-inositol-2-(R)-2-O-methyl-3-O-octadecyl-sn-glycerocarbonate (AktI, to inhibit Akt). Results indicate that ACh-induced vasodilation was significantly blunted in old SFA, whereas dilation to sodium nitroprusside (a NO donor) was not compromised. The age-group difference in ACh-induced dilation was abolished in the presence of L-NNA, LY-294002, or AktI. In a separate set of experiments, ACh-induced vasodilation was assessed in SFA from young and old rats. SFA were subsequently removed from the pipettes, snap frozen, and immunoblot analysis was used to assess p-AktSer473, p-eNOSser1177, total Akt and total eNOS protein content. ACh-induced vasodilation was blunted in old SFA; however, the p-AktSer473/Akt and p-eNOSser1177/eNOS ratios were similar in young and old SFA. Collectively, these results indicate that NO-mediated dilation is impaired in old SFA; however, the decrement in endothelial function is not due to reduced PI3K/Akt-dependent phosphorylation of eNOS on serine residue 1177.

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