Exercise is a potent stimulus to activate the sympathetic nervous system. Previous work suggests that metabolite-sensitive muscle afferents are activated near the point of fatigue, and, when activated, they determine the muscle sympathetic nerve activity (MSNA) response to isometric forearm exercise. Yet, studies using a more prolonged rhythmic exercise paradigm suggest that the sympathetic nervous system can be activated in a more graded fashion. The purpose of this study was to determine whether metaboreceptor stimulation would also be responsible for MSNA responses to prolonged rhythmic isotonic forearm exercise. Subjects (n = 16) performed rhythmic isotonic forearm exercise at 25% maximal voluntary contraction for 30 min as we measured MSNA (microneurography). We observed progressive increases in MSNA with a peak increase of 161 units from a baseline value of 180 units. We also performed posthandgrip circulatory arrest (PHG-CA) in nine of these subjects. This maneuver isolates the metaboreceptor contribution to MSNA. During PHG-CA, delta MSNA values were not different from those observed during a freely perfused recovery period (n = 7). We also compared MSNA responses during the rhythmic paradigm with those seen during a static protocol at 40% of maximal voluntary contraction in five subjects. The two types of exercise caused similar increases in MSNA, but only the static paradigm was associated with a sustained MSNA response during PHG-CA. Finally, 31P-nuclear magnetic resonance was used to evaluate muscle metabolic responses during rhythmic and static forearm exercise (n = 6). Static exercise caused muscle acidosis and an increase in H2PO4-, whereas rhythmic exercise had no effect on muscle metabolism.(ABSTRACT TRUNCATED AT 250 WORDS)