Published online before print June 9, 2003, doi: 10.1161/01.CIR.0000072786.99163.FE
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(Circulation. 2003;107:2949.)
© 2003 American Heart Association, Inc.
Clinical Investigation and Reports |
Selective Impairment in Sympathetic Vasomotor Control With Norepinephrine Transporter Inhibition
From the Clinical Research Center, Helios Klinikum-Berlin, Franz Volhard Clinic, Medical Faculty of the Charité, Humboldt-University, Berlin (J.T., C.S., E.S., A.M.S., F.C.L., J.J.), and the Department of Psychiatry, Johannes Gutenberg University, Mainz (S.H.), Germany; and the Autonomic Dysfunction Service, Vanderbilt University, Nashville, Tenn (A.D.).
Correspondence to Jens Jordan, MD, Clinical Research Center, Haus 129, Franz-Volhard-Clinic, Humboldt University, Wiltbergstraße 50, 13125 Berlin, Germany. E-mail jordan{at}fvk-berlin.de
Background— Norepinephrine transporter (NET) inhibition increases the responsiveness to vasoactive medications and attenuates the response to sympathetic stimuli. The phenomenon may be a result of impaired regulation of sympathetic vasomotor tone.
Methods and Results— We studied the effects of the selective NET blocker reboxetine and placebo on baroreflex control of heart rate (HR) and sympathetic traffic in a randomized, double-blind, crossover manner in healthy subjects. Subjects ingested 8 mg reboxetine or placebo 12 hours and 1 hour before testing. ECGs were measured for HR, brachial and finger blood pressure (BP), and muscle sympathetic nerve activity (MSNA). Sympathetic and parasympathetic baroreflex slopes were determined by use of incremental phenylephrine and nitroprusside infusions. The dose to reach BP changes of 12.5 mm Hg was significantly lower during NET inhibition (0.25 versus 0.64 µg · kg-1 · min-1 phenylephrine and 0.40 versus 1.10 µg · kg-1 · min-1 nitroprusside, P<0.01). Baroreflex control of HR was similar (16 ms/mm Hg with placebo versus 14 ms/mm Hg with reboxetine) but reset to higher BP values. MSNA and sympathetically mediated low-frequency BP oscillations were profoundly reduced at baseline and failed to increase sufficiently during nitroprusside infusion. Reboxetine attenuated BP and MSNA responses to cold pressor testing.
Conclusions— NET inhibition profoundly and selectively reduces baroreflex control of sympathetic vasomotor tone and attenuates the responsiveness to sympathetic stimuli. The reduction in baroreflex buffering increases the sensitivity to vasoactive medications. Therefore, our findings represent a novel mechanism for drug interactions.
Key Words: nervous system, autonomic • baroreflex • antidepressive agents • receptors, adrenergic, alpha • catecholamines
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