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Norepinephrine Transporter Blockade in Neurogenic Orthostatic Hypotension

ABSTRACT:

The clinical picture of autonomic failure is dominated by disabling orthostatic hypotension. Recent developments in the understanding of the underlying pathophysiology of the discrete clinical forms of autonomic failure have revealed that participants with multiple system atrophy (MSA) are characterized by impairment of central autonomic pathways crucial for autonomic cardiovascular control, but have intact peripheral postganglionic noradrenergic fibers. Participants with MSA have peripheral residual sympathetic tone that is no longer modulated by central autonomic centers and is not under baroreflex control and, therefore, cannot be harnessed to improve their orthostatic hypotension. On the other hand, participants with pure autonomic failure (PAF) and with Parkinson' s disease (PD) are characterized by neurodegeneration and loss of peripheral noradrenergic fibers, as evidenced by low levels of plasma norepinephrine and absent cardiac uptake of labeled catechols. Pharmacological inhibition of the norepinephrine transporter (NET) is an example of an approach that can take advantage of the participants' own residual sympathetic tone. NET inhibition will increase synaptic norepinephrine that is tonically released in MSA participants by preventing its reuptake. This should result in an increase in blood pressure.

This is a longitudinal study of 50 participants, age 18-80 years with neurogenic orthostatic hypotension associated with impaired reflexes. The purpose of this study is to determine if the magnitude of the pressor response to atomoxetine at study entry, will be useful as a biomarker to differentiate those participants that will ultimately be shown to have pre-ganglionic (central) lesions (MSA) with those shown to have post ganglionic (peripheral) lesions (PAF and PD).

PROVIDER: phs001595 | dbGaP |

REPOSITORIES: dbGaP

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			Action	DRS
	GapExchange_phs001595.v1.p1.xml	Xml
	dbGaPEx2.1.5.xsd	Other
	phs001595.v1-Documents.zip	Other
	Study_Report.phs001595.ARD_6103.v1.p1.MULTI.pdf	Pdf
	manifest_phs001595.ARD_6103.v1.p1.c1.GRU-IRB-PUB.pdf	Pdf

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Norepinephrine Transporter Blockade in Neurogenic Orthostatic Hypotension

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