Selective impairment in sympathetic vasomotor control with norepinephrine transporter inhibition.
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.


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 microg x kg(-1) x min(-1) phenylephrine and 0.40 versus 1.10 microg x kg(-1) x 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.
Tank
Jens
J
Clinical Research Center, Helios Klinikum-Berlin, Franz Volhard Clinic, Medical Faculty of the Charité, Humboldt-University, 13125 Berlin, Germany.
Schroeder
Christoph
C
Diedrich
Andre
A
Szczech
Elke
E
Haertter
Sebastian
S
Sharma
Arya M
AM
Luft
Friedrich C
FC
Jordan
Jens
J
D018759:Adrenergic Uptake Inhibitors / Q000494:pharmacology*; D000319:Adrenergic beta-Antagonists / Q000494:pharmacology; D000328:Adult; D017704:Baroreflex / Q000187:drug effects; D001794:Blood Pressure / Q000187:drug effects; D018592:Cross-Over Studies; D004305:Dose-Response Relationship, Drug; D004311:Double-Blind Method; D004347:Drug Interactions; D004562:Electrocardiography / Q000187:drug effects; D005260:Female; D006339:Heart Rate / Q000187:drug effects; D006801:Humans; D008297:Male; D009025:Morpholines / Q000494:pharmacology*; D050484:Norepinephrine Plasma Membrane Transport Proteins; D000077593:Reboxetine; D012016:Reference Values; D013564:Sympathetic Nervous System / Q000187:drug effects* / Q000503:physiopathology; D027981:Symporters / Q000037:antagonists & inhibitors*; D014662:Vasoconstrictor Agents / Q000494:pharmacology; D014665:Vasodilator Agents / Q000494:pharmacology; D014666:Vasomotor System / Q000187:drug effects* / Q000503:physiopathology
D018759:Adrenergic Uptake Inhibitors; D000319:Adrenergic beta-Antagonists; D009025:Morpholines; D050484:Norepinephrine Plasma Membrane Transport Proteins; C493227:SLC6A2 protein, human; D027981:Symporters; D014662:Vasoconstrictor Agents; D014665:Vasodilator Agents; D000077593:Reboxetine