Recent studies have shown a lack of an increase in muscle sympathetic nerve activity (MSNA) during leg exercise. Experiments using isometric knee extension (IKE) have shown a biphasic response in MSNA with a decrease during the 1st min and a return of MSNA to control levels during the 2nd min of IKE. Moreover, MSNA was not augmented during postexercise muscle ischemia (PEMI) of the exercising leg, suggesting that the muscle metaboreflex may have not been engaged in these experiments. The purpose of the present study was 1) to examine MSNA during IKE performed to fatigue to determine whether MSNA could be increased with leg exercise and 2) to determine whether increases in MSNA during fatiguing IKE were associated with an augmented MSNA response during PEMI. IKE was initially performed to fatigue at 30% of maximal voluntary contraction in the sitting position (n = 7; trial 1). IKE elicited a marked increase in mean arterial pressure and heart rate (P < 0.01). Total MSNA (burst frequency x mean burst amplitude; units) in the contralateral leg increased 96 +/- 40% (P < 0.01) above control levels during the final 30 s of IKE (207 +/- 23 s). Subjects (n = 8) then performed IKE to fatigue followed by PEMI (trial 2). MSNA in the contralateral leg increased 107 +/- 50% (P < 0.01) above control levels during the final 30 s of IKE (169 +/- 12 s) and remained significantly elevated during PEMI (83 +/- 40% above control), indicating that the muscle metaboreflex was engaged during fatiguing IKE.(ABSTRACT TRUNCATED AT 250 WORDS)