Background: Inter-individual variability in sympathetic nerve activity (SNA) has provided important insight into integrative mechanisms contributing to blood pressure regulation in humans. In younger individuals, higher levels of SNA are balanced by lower levels of cardiac output and less adrenergic responsiveness to a given amount of noradrenaline. Older people tend to have higher SNA and higher blood pressure, but some mechanisms may act to protect older individuals against excessive pressor effects of SNA, including decreased adrenergic responsiveness compared to younger people. In the present study, we tested the hypothesis that in young men, SNA would have a restraining effect on peripheral vasodilator responsiveness, whereas in older men this phenomenon would not exist. Methods: 12 older men (age, mean ± SEM; 64 ± 2 yrs) and 14 young men participated (age; 24 ± 2 yrs) participated in this study. Muscle sympathetic nerve activity (MSNA; peroneal microneurography), arterial blood pressure (BP; brachial intra-arterial catheter) and forearm blood flow (venous occlusion plethysmography) were measured during 5 minutes of supine quiet rest and in response to incremental intra-arterial infusion of sodium nitroprusside (NTP; 0.5, 1.0 and 2.0 μg/100 ml/min) and acetylcholine (ACH; 2, 4 and 8 μg/100 ml forearm volume/min). Results: Systolic BP, mean BP and MSNA were higher in older (140 ± 3 mmHg; 89 ± 4 mmHg; 34 ± 2 bursts/100 heart beats) compared to young men (128 ± 2 mmHg; 80 ± 2 mmHg; 64 ± 3 bursts/100 heart beats). Baseline forearm vascular resistance (FVR) was similar in older and younger men. There was an inverse relationship of MSNA to the change in FVR in response to 1 0 μg/100 ml forearm volume/min of NTP and 4 8 μg/100 ml forearm volume/min ACH in younger men (r = 0.80; r =0.73, respectively; P<0.05). However, there was no such relationship observed in older men (r = 0.32, r = 0.30, respectively). Conclusions: In young men, high resting MSNA appears to limit endothelial dependant and non-endothelial dependant vasodilation. However, this apparent restraining effect of MSNA does not exist in older men. A decrease in vascular alpha-adrenergic receptor sensitivity that occurs with age may explain these findings. The lack of a restraining effect of high MSNA on forearm vasodilation may partially protect healthy older men against the detrimental effects of high MSNA on the vasculature.