Prazosin was given for 10 to 14 days to eight hypertensive patients on a fixed intake of dietary salt. Except as limited by side effects, the dose was increased from 2 mg/day to a maximum dose of 24 mg/day. During treatment, when subjects were studied in supine and upright positions, mean arterial pressure (MAP) fell 6% and 12% (p<0.025 and p<0.005), heart rate rose 3% and 9% (p<0.05 and p<0.005), and plasma norepinephrine increased 95% and 107% (p<0.01 and p<0.001) over control. Daily excretion of the norepinephrine metabolites methoxyhydroxyphenyl glycol (MHPG) and vanillylmandelic acid (VMA) increased 42% and 17% (p<0.05 for each) during treatment. There were no changes in average body weight or plasma renin for the group, but patients whose body weight increased tended to show less reduction in blood pressure (correlation coefficient, r = 0.72, p<0.05) and smaller increases in heart rate (r = −0.73, p<0.05) during treatment with prazosin. These data suggest that expansion of extracellular fluid and activation of the sympathetic nervous system oppose the hemodynamic effects of prazosin.Clinical Pharmacology and Therapeutics(1981)29,7–11; doi:10.1038/clpt.19