Orthostatic intolerance is a debilitating syndrome characterized by tachycardia 
on assumption of upright posture. The norepinephrine (NE) transporter (NET) has 
been implicated in a genetic form of the disorder. We assessed the combined 
central and peripheral effects of pharmacological NET blockade on cardiovascular 
regulation and baroreflex sensitivity in rats. NE reuptake was blocked 
chronically in female Sprague-Dawley rats by the NET antagonist desipramine 
(DMI). Treated animals demonstrated an elevated supine heart rate, reduced 
tyramine responsiveness, and a reduced plasma ratio of the intraneuronal NE 
metabolite dihydroxyphenylglycol relative to NE, all of which are consistent 
with observations in human NET deficiency. Spectral analysis revealed a dramatic 
decrease in low-frequency spectral power after DMI that was consistent with 
decreased sympathetic outflow. Stimulation of the baroreflex with the 
vasodilator nitroprusside revealed an attenuated tachycardia in DMI-treated 
animals. This indicated that the DMI-induced sympathoinhibitory effects of 
increased NE in the brain stem predominates over the functional elevation of NE 
stimulation of peripheral targets. Thus attenuated baroreflex function and 
reduced sympathetic outflow may contribute to the orthostatic intolerance of 
severe NET deficiency.