We tested the hypothesis that sympathoadrenal activity in humans is low during spaceflight and that this effect can be simulated by head down bed rest (HDBR). Platelet norepinephrine and epinephrine were measured as indices of long-term changes in sympathoadrenal activity. Ten normal healthy subjects were studied before and during HDBR of 2 weeks duration, as well as during an ambulatory study period of a similar length. Platelet norepinephrine concentrations (half life=2 days) were studied in 5 cosmonauts, 2 weeks before launch, within 12 hours after landing following 11 to 12 days of flight and at least 2 weeks after return to earth. Due to the long half life of platelet norepinephrine, data obtained early after landing would still reflect the microgravity state. Platelet norepinephrine decreased markedly during HDBR (p<0.001), whereas there were no significant changes when subjects were ambulatory. Platelet epinephrine did not change during HDBR. During microgravity, platelet norepinephrine and epinephrine increased in 4 of the 5 cosmonauts. Platelet norepinephrine concentrations expressed in percentage of pre-flight and pre- HDBR values, respectively, were significantly different during microgravity as compared to HDBR (153±28% (mean±SEM) vs. 60±6%, p<0.004). Corresponding values for platelet epinephrine were also significant (293±85% vs. 90±12%, p<0.01). The mechanism of the platelet norepinephrine and epinephrine response during spaceflight flight is most likely related to the concomitant decrease in plasma volume. HDBR cannot be applied to simulate changes in sympathoadrenal activity during microgravity.