To test the hypothesis that the subcutaneous vascular constrictor response to an orthostatic stress in humans is augmented after exposure to microgravity, the following experiment was performed. Four male astronauts underwent a standardized stepwise lower body negative pressure (LBNP) profile 5 mo before and between 24 and 40 h after completion of the 10-day Spacelab D2 mission (STS-55). Forearm subcutaneous blood flow was continuously measured during LBNP by the 133Xe washout technique, and forearm subcutaneous vascular resistance (FSVR) was estimated by dividing mean arterial pressure by forearm subcutaneous blood flow. Relative to the pre-LBNP level, FSVR increased to 169 +/- 42 (P < 0.05), 176 +/- 12 (P < 0.05) and 158 +/- 27% during postflight LBNP of -11 (20 min), -23 (5 min), and -30 (7.5 min) mmHg, respectively. During the same LBNP levels of the same durations preflight, FSVR increased to 121 +/- 11 (not significant), 139 +/- 12 (P < 0.05), and 135 +/- 13% (P < 0.05), respectively. Thus, FSVR increased more promptly and, in three of the four subjects, was more pronounced during postflight than during preflight LBNP. In conclusion, the FSVR response was more prompt and tended to be accentuated after 1-2 days after exposure to 10 days of microgravity and could act as a defense mechanism to alleviate decreased orthostatic tolerance.