We determined the influences of breathing-induced changes in intrathoracic and intravascular pressures, central respiratory drive, and pulmonary vagal feedback on the within-breath variation in skeletal muscle sympathetic nerve activity (MSNA) in humans. MSNA (peroneal microneurography), arterial blood pressure (Finapres finger monitor), and tidal volume (VT) were recorded continuously in six normal subjects and four heart-lung transplant patients during: 1) spontaneous air breathing; 2) increased FICO2; 3) voluntary augmentation of VT with and without inspiratory resistance; and 4) positive pressure, passive mechanical ventilation. During conditions 3 and 4, which were performed under isocapnic conditions with a high MSNA background (either high resting activity or nonhypotensive lower body suction), subjects breathed at control or elevated VT with normal or prolonged inspiratory time (TI); breathing frequency was 12 breaths per minute. During control breathing in normal subjects there was a distinct within-breath pattern of MSNA, with approximately 70% of the activity occurring during low lung volumes (initial half of inspiration and latter half of expiration). This within-breath variation of MSNA was potentiated with increased VT breathing (> 85% of activity occurring during low lung volumes; p < 0.05 versus control breathing) and was similar during the voluntary and CO2-induced hyperpneas. MSNA decreased progressively and markedly from onset to late inspiration; fell slightly further, reaching its nadir at end-inspiration/onset-expiration; and rose sharply during mid-late expiration. Only the nadir of MSNA was associated with any change in arterial pressure. Resistive breathing, especially at elevated VT, caused a fall in arterial pressure and increased respiratory drive during inspiration, yet MSNA still declined as lung volume increased. Normal within-breath modulation of MSNA also was observed during control and elevated VT induced via positive pressure with passive ventilation, which reversed lung inflation/deflation-induced intrathoracic pressure changes and reduced or removed respiratory motor output. During control breathing in transplant patients the specific within-breath pattern of MSNA was somewhat different than that of the normal subjects, but on average, the overall low lung volume to high lung volume MSNA ratio was similar to normal subjects. In contrast to the normal subjects, however, there was no potentiation of the within-breath variation of MSNA with elevated tidal breathing. These findings indicate that during normal levels of tidal breathing most of the respiratory phase influence on muscle sympathetic outflow observed in normal conscious humans is independent of baroreceptor-sensed fluctuations in intrathoracic or intravascular pressures and of lung inflation-stimulated vagal afferent activity.(ABSTRACT TRUNCATED AT 400 WORDS)