Adenosine increases heart rate and sympathetic nerve activity reflexively in conscious humans through several mechanisms. The purpose of this study was to assess the relative contributions of arterial baroreceptor unloading, carotid chemoreceptor stimulation, and other adenosine-sensitive afferent nerves to these responses. In 12 healthy men, the effect on blood pressure, heart rate (HR), and muscle sympathetic nerve activity (MSNA; peroneal nerve) of lower body negative pressure (LBNP; -15 mmHg (1 mmHg = 133.3 Pa)) was compared with the effect of intravenous adenosine (35, 70, and l40 micrograms.kg-1.min-1). In eight subjects, the highest dose was reinfused during 100% oxygen to suppress arterial chemoreceptors. Blood pressure reductions during LBNP and adenosine (140 micrograms.kg-1.min-1) were similar. HR did not change significantly during LBNP (+2 +/- 2 beats/min; mean +/- SE) but increased at the highest adenosine dose (+25 +/- 3 beats/min; p < 0.05). MSNA increased significantly (p < 0.05) during both interventions (+255 +/- 82 and +247 +/- 58 units/100 beats for adenosine and LBNP, respectively), and there was no difference in the MSNA response to these two stimuli (p > 0.1). Oxygen inhibited adenosine-induced increases in HR and MSNA (from +305 +/- 99 to +198 +/- 75 units/100 beats and from +26 +/- 4 to +18 +/- 3 beats/min; p < 0.05 for both comparisons). The MSNA response to these combined stimuli was similar to that observed during LBNP. In contrast, the residual HR response (+18 +/- 3 beats/min) was significantly greter than the response to LBNP (+2 +/- 2 beats/min; p < 0.05). These data indicate that arterial baroreceptor unloading cannot account for the marked adenosine-induced increase in HR, but may be sufficient to explain its effect on MSNA. The effect of 100% oxygen confirms that stimulation of carotid chemoreceptors accounts for approximately one-third of the HR and MSNA response to adenosine. However, other mechanisms, such as stimulation of adenosine-sensitive afferent nerves in other vascular beds, are involved in the HR and possibly the MSNA response.