Although previous studies in both animals and humans have suggested that cardiac baroreceptors modulate reflex sympathetic vasoconstriction during exercise, more recent studies in conscious animals have not supported this view. To further test this concept in humans, we measured sympathetic nerve discharge with intraneural microelectrodes while we used static handgrip to activate the exercise pressor reflex and nonhypotensive lower-body negative pressure (LBNP) to selectively unload the cardiac baroreflex. In nine healthy subjects, we measured blood pressure, heart rate, central venous pressure, and muscle sympathetic nerve activity (MSNA) from the peroneal nerve (resting leg) during 2 minutes of static handgrip at 20% and 30% of maximal voluntary contraction (MVC) alone and in combination with LBNP at -5 mm Hg. Handgrip alone (exercise reflex) at 20% and 30% MVC caused graded increases in MSNA. LBNP alone (cardiac reflex) did not alter blood pressure or heart rate but decreased central venous pressure by 2.5 +/- 0.1 mm Hg (mean +/- SEM, p less than 0.05) and increased MSNA by 92 +/- 22% over the control value. Most important, handgrip performed during LBNP (interaction of reflexes) caused increases in MSNA that were comparable with the increases during handgrip alone: +114 +/- 32% versus +175 +/- 89% at 20% MVC and +328 +/- 101% versus +431 +/- 110% at 30% MVC (handgrip plus LBNP vs. handgrip alone, p greater than 0.1). Pressor and heart rate responses to handgrip also were unaffected by LBNP. In five additional experiments, comparable findings were obtained when the LBNP was superimposed on handgrip rather than handgrip being superimposed on LBNP. In conclusion, this study provides direct evidence in humans that nonhypotensive LBNP does not augment muscle sympathetic outflow during static handgrip and challenges the concept of an important interaction between cardiac baroreceptor and exercise pressor reflexes during this form of exercise.