Background The postural tachycardia syndrome is a common disorder that is characterized by chronic orthostatic symptoms and a dramatic increase in heart rate on standing, but that does not involve orthostatic hypotension. Several lines of evidence indicate that this disorder may result from sympathetic denervation of the legs. Methods We measured norepinephrine spillover (the rate of entry of norepinephrine into the venous circulation) in the arms and legs both before and in response to exposure to three stimuli (the cold pressor test, sodium nitroprusside infusion, and tyramine infusion) in 10 patients with the postural tachycardia syndrome and in 8 age- and sex-matched normal subjects. Results At base line, the mean (±SD) plasma norepinephrine concentration in the femoral vein was lower in the patients with the postural tachycardia syndrome than in the normal subjects (135±30 vs. 215±55 pg per milliliter [0.80±0.18 vs. 1.27±0.32 nmol per liter], P=0.001). Norepinephrine spillover in the arms increased to a similar extent in the two groups in response to each of the three stimuli, but the increases in the legs were smaller in the patients with the postural tachycardia syndrome than in the normal subjects (0.001 ±0.09 vs. 0.12±0.12 ng per minute per deciliter of tissue [0.006±0.53 vs. 0.71 ±0.71 nmol per minute per deciliter] with the cold pressor test, P=0.02; 0.02±0.07 vs. 0.23±0.17 ng per minute per deciliter [0.12±0.41 vs. 1.36±1.00 nmol per minute per deciliter] with nitroprusside infusion, P=0.01; and 0.008± 0.09 vs. 0.19±0.25 ng per minute per deciliter [0.05± 0.53 vs. 1.12±1.47 nmol per minute per deciliter] with tyramine infusion, P=0.04). Conclusions The neuropathic postural tachycardia syndrome results from partial sympathetic denervation, especially in the legs. (C) 2000, Massachusetts Medical Society.