title: Impaired flow-mediated dilation with age is not explained by L-arginine bioavailability or endothelial asymmetric dimethylarginine protein expression.
abstract: Aging is associated with a decline in vascular endothelial function, manifesting in part as impaired flow-mediated arterial dilation (FMD), but the underlying mechanisms are uncertain. Impaired FMD may be mediated in part by a decrease in synthesis of nitric oxide by endothelial nitric oxide synthase, and in clinical populations this has been attributed to competitive inhibition of l-arginine binding sites by asymmetric dimethylarginine (ADMA). If this mechanism is involved in the age-associated decline in FMD, increasing l-arginine concentration may swing the competitive balance in favor of l-arginine binding, restoring nitric oxide synthesis, and enhancing FMD in older humans. To test this hypothesis, we measured FMD (brachial ultrasound) in 10 younger (21 +/- 1 yr) and 12 older healthy men and women (60 +/- 2 yr) following infusion of vehicle or vehicle + l-arginine. Baseline FMD in the older subjects was only approximately 60% of that in the younger subjects (P = 0.002). l-Arginine did not significantly increase FMD in either group despite 23-fold (older) and 19-fold (younger) increases in plasma l-arginine concentrations (P < 0.0001 vs. control). Protein expression (immunofluorescence) in vascular endothelial cells showed that ADMA and the enzyme isoform that controls its degradation, dimethylarginine dimethylaminohydrolase II, were not different in the younger and older subjects. Endothelium-independent vasodilation (sublingual nitroglycerine) was not different between age groups or conditions. We conclude that acutely increasing plasma concentrations of l-arginine do not significantly improve brachial artery FMD in healthy older subjects and thus does not restore the age-associated loss of FMD. Together with the finding that endothelial cell ADMA protein expression was not increased in older adults, these findings suggest that competitive inhibition of l-arginine binding sites on endothelial nitric oxide synthase by ADMA is not an important mechanism contributing to impaired conduit artery endothelium-dependent dilation with aging in healthy humans.
authors.affiliation: Department of Integrative Physiology, 354 UCB, Univ. of Colorado, Boulder, CO 80309, USA.
authors.forename: Phillip E
authors.initials: PE
authors.lastname: Gates
authors.forename: Meghan L
authors.initials: ML
authors.lastname: Boucher
authors.forename: Annemarie E
authors.initials: AE
authors.lastname: Silver
authors.forename: Kevin D
authors.initials: KD
authors.lastname: Monahan
authors.forename: Douglas R
authors.initials: DR
authors.lastname: Seals
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000375:Aging / Q000378:metabolism* / Q000502:physiology*; D000581:Amidohydrolases / Q000378:metabolism; D001120:Arginine / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000097:blood / Q000378:metabolism / Q000493:pharmacokinetics*; D001682:Biological Availability; D001916:Brachial Artery / Q000502:physiology; D002339:Carotid Arteries / Q000502:physiology; D004730:Endothelium, Vascular / Q000378:metabolism; D005260:Female; D006801:Humans; D007262:Infusions, Intravenous; D008297:Male; D008875:Middle Aged; D009569:Nitric Oxide / Q000378:metabolism; D018384:Oxidative Stress / Q000502:physiology; D012039:Regional Blood Flow / Q000502:physiology; D014664:Vasodilation / Q000502:physiology*
chemical_list: D009569:Nitric Oxide; C018524:N,N-dimethylarginine; D001120:Arginine; D000581:Amidohydrolases; C059999:dimethylargininase