The role of enzyme and substrate dependence in NO‐mediated vascular dysfunction with aging

The typical aging process results in arterial dysfunction, often attributed to a fall in nitric oxide (NO) bioavailability. The diminished efficacy of the enzyme responsible for NO production, endothelial nitric oxide synthase (eNOS), and the required substrate, extracellular L‐arginine, may play a role in age‐related vascular dysfunction. Supplementation of tetrahydrobiopterin (BH4), a cofactor which recouples eNOS, and chronic supplementation of L‐Citrulline (L‐Cit), which increases plasma L‐arginine, may both increase NO bioavailability. Therefore, this study sought to evaluate the role of increased eNOS activity or L‐arginine concentration alone, and the combination of both, in the NO‐mediated vascular dysfunction associated with advancing age. Eight old subjects (73 ± 6 yr) received BH4 (100 mg per kg wt) acutely and underwent a 7 day supplementation of L‐Citrulline (6 g per day). Vascular function was assessed with: brachial artery flow mediated dilation (FMD: %) and passive leg movement (PLM: blood flow ΔPeak and AUC). Assessments were performed with and without BH4, both before and after L‐Citrulline supplementation (Ctrl; BH4; L‐Cit; L‐Cit + BH4). PLM ΔPeak increased ≈35% and ≈27% in the BH4 and L‐Cit + BH4 conditions, respectively (p< 0.05). PLM AUC increased ≈114% (p< 0.05) in the L‐Cit + BH4 condition. No significant intervention‐induced changes in FMD were detected. Thus, age‐induced vascular dysfunction, as measured by PLM which is likely more NO mediated than FMD, appears to belimited to a greater degree by eNOS function than eNOS substrate. However, the combination of improved eNOS coupling with increased eNOS substrate results in the greatest enhancement in vascular function in this population. This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal .