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1 Department of Integrative Physiology, University of Colorado-Boulder, Boulder, Colorado, United States
2 Integrative Physiology, University of Colorado, Boulder, Colorado, United States
* To whom correspondence should be addressed. E-mail: seals{at}colorado.edu.
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 (NO) by endothelial NO-synthase (eNOS), 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 NO synthesis, and enhancing FMD in older humans. To test this hypothesis, we measured FMD in 10 younger (21±1 years) and 12 older healthy men and women (60±years) following infusion of vehicle or vehicle+L-arginine. Baseline FMD in the older subjects was only ~60% of that in the younger subjects (P=0.002). L-arginine did not significantly increase FMD in either group despite ~20-fold increases in plasma L-arginine concentration (P<0.0001 vs. control). Protein expression in vascular endothelial cells showed that ADMA was not different in the younger and older subjects. Endothelium-independent vasodilation was not different between age groups or conditions. We conclude that increasing plasma concentrations of L-arginine does not significantly improve brachial artery FMD in older subjects and does not restore the age-associated loss of FMD. Together with the endothelial ADMA protein expression data, these findings suggest that competitive inhibition of L-arginine binding sites on eNOS by ADMA is not an important mechanism contributing to impaired FMD with aging in healthy humans.
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