Prostaglandins released from blood vessels modulate vascular tone, and inhibition of their production during exogenous infusions of catecholamines causes increased venoconstriction. To determine the influence of prostaglandin production on venoconstriction during physiological stimuli known to cause sympathetic activation, and to assess its importance in chronic heart failure (CHF), we studied 11 normal subjects (62 ± 4 yr) and 14 patients with CHF (64 ± 2 yr, left ventricular ejection fraction 23 ± 1%, New York Heart Association classes II and III) (means ± SE). Dorsal hand vein distension was measured during mental arithmetic (MA), cold pressor test (CPT), and lower body negative pressure (LBNP; 10 and 40 mmHg), with saline infusion in one hand and local indomethacin (cyclooxygenase inhibitor) infusion (3 µg/min) in the other. Acetylcholine (0.01-1 nmol/min) dilated veins preconstricted with PGF₂ in normals but, consistent with endothelial dysfunction, barely did so in CHF patients (P = 0.001). Nonendothelial venodilation to sodium nitroprusside (0.3-10 nmol/min) was not different between normals and CHF patients. Resting venous norepinephrine levels were higher in CHF patients (2,812 ± 420 pmol/l) than normals (1,418 ± 145 pmol/l, P = 0.007). In normals, indomethacin caused increased venoconstriction to MA (from 4.9 ± 1.5 to 19.2 ± 4.5%, P = 0.022) and CPT (from 2.9 ± 3.8 to 17.6 ± 4.2%, P = 0.007). In CHF, indomethacin caused increased venoconstriction to MA (from 6.6 ± 3.9% to 19.0 ± 4.5%, P = 0.014), CPT (from 9.6 ± 2.1% to 20.1 ± 3.7%, P = 0.001), and 40 mmHg LBNP (from 10.7 ± 3.0% to 23.2 ± 3.8%, P = 0.041). Control responses for all tests were not different between normals and CHF patients. The effects of indomethacin on venoconstriction to MA and CPT were not different between normals and CHF patients, but venoconstriction to 40 mmHg LBNP was accentuated in CHF patients (P = 0.036). Inhibition of prostaglandins by indomethacin significantly enhances hand vein constriction to physiological stimuli in both normals and CHF patients, although a differential effect exists for LBNP.