To ascertain whether increased sympathetic nervous system activity may contribute to the attenuation of prazosin's effect on congestive heart failure, we measured plasma norepinephrine levels in 10 patients with severe heart failure before and after chronic prazosin therapy. Norcpinephrine levels were increased in eight of 10 patients while supine (145 +/- 133 pg/mL; after, 481 +/- 376 pg/mL; P < 0.01); levels measured in five patients while upright were also increased (before, 351 +/- 238 pg/mL; after, 651 +/- 258 pg/mL; P < 0.05). Left ventricular ejection fraction measured by gated blood pool scan was increased from 16.9% +/- 8.1% to 25.4% +/- 11.3% (N = 10, P < 0.01). Mean systemic blood pressure and heart rate were unchanged. Increased plasma norepinephrine levels may attenuate prazosin's vasodilator action in heart failure. The cause of the increase in norepinephrine levels is unclear and warrants further study.