The purpose of the present study was to examine the effects of femoral arterial injections of adenosine on muscle sympathetic nerve activity (MSNA) under three different conditions. These conditions were adenosine injection alone, adenosine injection after phenylephrine infusion, and adenosine injection distal to a thigh cuff inflated to arrest the circulation. The arterial injection of adenosine alone resulted in a fourfold (255 +/- 18 U/min) increase above baseline (73 +/- 12 U/min; P < 0.05) in MSNA with an onset latency of 15.8 +/- 0.8 s from the time of injection. The systemic infusion of phenylephrine resulted in an increase (P < 0.05) in mean arterial pressure of approximately 10 mmHg and a decrease (P < 0.05) in heart rate of 8-10 beats/min compared with baseline values before phenylephrine infusion. After adenosine injection, the onset latency for the increase in MSNA was delayed to 19.2 +/- 2.1 s and the magnitude of increase was attenuated by approximately 50% (123 +/- 20 U/min) compared with adenosine injection alone (P < 0.05). When a cuff was inflated to 220 mmHg to arrest the circulation and adenosine was injected into the leg distal to the inflated cuff, there were no significant changes in MSNA or any of the other measured variables. However, on deflation of the cuff, there was a rapid increase (P < 0.05) in MSNA, with an onset latency of 9.1 +/- 0.9 s, and the magnitude of increase (276 +/- 28 U/min) was similar to that observed for adenosine alone. These data suggest that approximately 50% of the effects of exogenously administered adenosine are a result of baroreceptor unloading due to a drop in blood pressure. Furthermore, the finding that adenosine did not directly result in an increase in MSNA while it was trapped in the leg but that it needed to be released into the circulation suggests that adenosine does not directly stimulate thin fiber muscle afferents in the leg of humans. In contrast, it would appear that adenosine exerts its effects via some other chemically sensitive pool of afferents.