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J Appl Physiol (August 23, 2002). doi:10.1152/japplphysiol.00033.2002
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Articles in PresS, published online ahead of print August 23, 2002
J Appl Physiol, 10.1152/jap.00033.2002
Submitted on January 15, 2002
Accepted on July 22, 2002

Autonomic Control Following Blockade of the Norepinephrine Transporter: A Model of Orthostatic Intolerance

Robert P Carson1, Andre Diedrich1, and David Robertson1*

1 Autonomic Dysfunction Center, Vanderbilt University, Nashville, TN, USA

* To whom correspondence should be addressed. E-mail: david.robertson{at}mcmail.vanderbilt.edu.

Orthostatic Intolerance (OI) is a debilitating syndrome characterized by tachycardia on assumption of upright posture. The norepinephrine transporter (NET) has been implicated in a genetic form of the disorder. We assessed the combined central and peripheral effects of pharmacologic NET blockade on cardiovascular regulation and baroreflex sensitivity in rats. Norepinephrine 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 norepinephrine (NE) metabolite, dihydroxyphenylserine (DHPG) relative to NE, all consistent with observations in human NET deficiency. Spectral analysis revealed a dramatic decrease in LF spectral power after DMI, 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 brainstem 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.




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