Reflex sympathetic responses to physiologic stress are known to be modulated by afferent sensory mechanisms. However, the potential influence of baseline sympathetic tone on these reflex-mediated responses is unclear. To test the hypothesis that the resting level of muscle sympathetic nerve activity (MSNA) influences reflex-mediated changes in MSNA in normal man, MSNA, blood pressure (BP), central venous pressure (CVP), and heart rate (HR) was measured in 38 normal subjects at rest and during deactivation of cardiopulmonary baroreceptors (CPBR) with lower body negative pressure (LBNP; 0 to -15 mmHg). A cold pressor test (CPT) also was performed in 25 subjects. Incremental LBNP decreased CVP (from 5.8 +/- 0.4 to 2.1 +/- 0.4 mmHg) without altering BP or HR, and increased in MSNA burst frequency (from 22.5 +/- 1.4 to 30.2 +/- 1.4 bursts/min). There was no significant correlation between levels of MSNA and any haemodynamic parameter at rest. There was a significant inverse correlation between CPBR sympathetic gain (CPBRSG, slope of the regression line correlating percentage change in MSNA (bursts/min) per mmHg decrease in CVP during non-hypotensive LBNP) and resting MSNA (r = -0.72, p < 0.0001). A significant inverse correlation was also observed between MSNA responses to the CPT (expressed as percentage change in burst frequency from control) and the resting MSNA (r = -0.63, p = 0.008). Sixteen subjects were restudied 3 weeks to 14 months later to determine reproducibility of measurements; resting BP and CVP, HR, and MSNA levels were not different between the two sessions, as was CPBRSG. In ten of these 16 subjects, in whom the CPT was repeated the MSNA response also was not significantly different. These studies demonstrate an inverse relationship between resting MSNA and both cardiopulmonary baroreflex sensitivity and sympathetic neural responses to the non-baroreflex mediated cold pressor stimulus. These findings suggest that resting levels of sympathetic neural activity influence reflex-mediated changes in muscle sympathetic nerve activity.