We tested the hypotheses that 1) there is an age-associated decrease in arterial alpha-adrenergic responsiveness and 2) there is upregulation of this response during suppression of sympathetic nervous system (SNS) activity. We measured forearm blood flow (FABF) by plethysmography during brachial artery infusions of the alpha-adrenergic agonist norepinephrine (NE) and the nonadrenergic agonist angiotensin II (ANG II) in 15 young and 14 older healthy human subjects. Among the old (O) relative to the young (Y) we identified greater plasma NE levels (Y: 1.29 +/- 0.07 nM vs. O: 2.14 +/- 0.17 nM; P = 0.0001); a decrease in NE-mediated reduction in FABF [analysis of variance (ANOVA) P = 0.04]; and, in contrast, no difference in ANG II-mediated reduction in FABF (ANOVA P = 0.43). In the nine older subjects studied during guanadrel (G) to suppress SNS activity, we identified decreased plasma NE levels [placebo (P): 2.11 +/- 0.24 nM vs. G: 1.09 +/- 0.09 nM; P = 0.002], increased NE-mediated FABF response (ANOVA P = 0.01), and no difference in FABF response to ANG II (ANOVA: P = 0.69) compared with P. We conclude that there is appropriate desensitization of arterial alpha-adrenergic responsiveness among the older relative to the young subjects that is specific for the alpha-adrenergic system. Among the older subjects there is homologous upregulation of this response when SNS activity is suppressed.