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CLINICAL RESEARCH: AUTONOMIC FUNCTION

Norepinephrine Transporter Inhibition Prevents Tilt-Induced Pre-Syncope

Christoph Schroeder, MD^_*, Andreas L. Birkenfeld, MD^_*, Antje F. Mayer^_*, Jens Tank, MD^_*, Andre Diedrich, MD, PhD, Friedrich C. Luft, MD^_* and Jens Jordan, MD^_*,_*

^_* Franz-Volhard Clinical Research Center, Medical Faculty of the Charité and HELIOS Klinikum, Berlin, Germany
Autonomic Dysfunction Service, Vanderbilt University, Nashville, Tennessee.

Manuscript received January 25, 2006; revised manuscript received March 10, 2006, accepted April 10, 2006.

^_* Reprint requests and correspondence: Dr. Jens Jordan, Franz-Volhard Clinical Research Center, Charité Campus Buch, Wiltbergstr. 50, Haus 129, 13125 Berlin, Germany. (Email: jordan{at}fvk.charite-buch.de).

OBJECTIVES: We tested the hypothesis that pharmacological norepinephrine reuptake transporter (NET) inhibition delays the onset of head-up tilt-induced presyncope in healthy subjects.

BACKGROUND: Treatment of neurally mediated syncope is unsatisfactory. In a previous study in a small number of healthy subjects, pharmacologic NET inhibition delayed the onset of head-up tilt-induced pre-syncope.

METHODS: We combined data sets from 3 substudies comprising 51 healthy subjects without a history of syncope. In a double-blind, randomized, cross-over fashion, subjects underwent 2 head-up tilt tests, once with placebo and once with a NET inhibitor (sibutramine or reboxetine). Tilt testing was prematurely ended when pre-syncopal symptoms such as dizziness, nausea, or visual disturbances occurred together with a decrease in blood pressure and/or heart rate.

RESULTS: The mean tolerated tilt test duration was 29 ± 2 min with placebo and 35 ± 1 min with NET inhibition (p = 0.001). The odds ratio for premature abortion of head-up tilt testing was 0.22 (95% confidence interval 0.09 to 0.55, p < 0.001) in favor of NET inhibition. Norepinephrine reuptake transporter inhibition elicited a pressor response and increased upright heart rate.

CONCLUSIONS: In healthy subjects, NET inhibition prevents tilt-induced neurally mediated (pre)syncope. Therefore, NET inhibition may be a worthwhile target of drug intervention for larger trials in highly symptomatic patients with neurally mediated syncope.

Abbreviations and Acronyms   DHPG = dihydroxyphenylglycol   HR = heart rate   NET = norepinephrine reuptake transporter

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