Selective Impairment in Sympathetic Vasomotor Control
With Norepinephrine Transporter Inhibition
Jens Tank, MD; Christoph Schroeder, MD; Andre Diedrich, MD;
Elke Szczech; Sebastian Haertter, MD; Arya M. Sharma, MD; Friedrich C. Luft, MD; Jens Jordan, MD
Downloaded from http://circ.ahajournals.org/ by guest on June 17, 2017
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 ␮g · kg⫺1 · min⫺1
phenylephrine and 0.40 versus 1.10 ␮g · 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. (Circulation. 2003;
107:2949-2954.)
Key Words: nervous system, autonomic 䡲 baroreflex 䡲 antidepressive agents
䡲 receptors, adrenergic, alpha 䡲 catecholamines
A
pproximately 80% to 90% of released norepinephrine is
taken up again by postganglionic adrenergic neurons
through the norepinephrine transporter (NET) and repackaged or
metabolized. Most antidepressants, sibutramine,1 and illicit
drugs, such as cocaine, inhibit NET. Given the importance of
norepinephrine homeostasis in cardiovascular and metabolic
regulation and the widespread use of NET inhibitors, one would
expect a large body of literature on NET physiology. However,
the issue has been largely neglected. Clinical studies implicating
impaired norepinephrine uptake in the pathogenesis of essential
hypertension2 and orthostatic intolerance3,4 renewed interest in
NET physiology. A particular impetus was the recent description
of a family in which orthostatic intolerance segregated with a
functional NET gene mutation.3 When applied to isolated organs
or given intra-arterially in low doses, NET inhibitors increase
norepinephrine washout.5 Thus, one might expect that a decrease
in NET function exerts a profound increase in blood pressure
(BP) and heart rate (HR) through increased synaptic norepineph-
rine. Indeed, NET dysfunction or blockade is associated with
marked orthostatic tachycardia and increased upright plasma
norepinephrine concentrations.3,4 However, NET inhibition results in a profound decrease in basal sympathetic nerve traffic,
low-frequency oscillations in systolic BP (SBP), and systemic
norepinephrine spillover.4,6,7 Moreover, the pressor response to
sympathetic stimuli is strongly attenuated.4,7 Finally, NET inhibition substantially increases sensitivity to various vasoactive
drugs,4 which may be related to impaired baroreflex BP buffering.8 We tested the hypothesis that the paradoxical decrease in
sensitivity to sympathetic stimuli and hypersensitivity to vasoactive medications with NET inhibition are explained by a
selective impairment in sympathetic vasomotor regulation.
Methods
Subjects
We studied 12 healthy control subjects (11 men, 1 woman; age,
32⫾6 years; body mass index, 24⫾3 kg/m2). Written informed
Received January 13, 2003; accepted March 7, 2003.
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 [email protected]
© 2003 American Heart Association, Inc.
Circulation is available at http://www.circulationaha.org
DOI: 10.1161/01.CIR.0000072786.99163.FE
2949
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Circulation
June 17, 2003
consent was obtained before study entry. All studies were approved
by the institutional review board. Forty-eight hours before study,
volunteers received a diet free of substances that could interfere with
catecholamine measurements. We conducted 2 separate studies.
Instrumentation
Respiration and ECG were measured continuously (Cardioscreen,
Medis GmbH). Beat-by-beat BP (Finapres, Ohmeda) and brachial
arterial BP (Dinamap, Critikon) were determined. Muscle sympathetic nerve activity (MSNA) was recorded from the right peroneal
nerve. A unipolar tungsten electrode (uninsulated tip diameter, 1 to
5 ␮m; shaft diameter, 200 ␮m) was inserted into the muscle nerve
fascicles of the peroneal nerve at the fibular head for multiunit
recordings. Nerve activity was amplified with a total gain of
100 000, bandpass-filtered (0.7 to 2 kHz), and integrated.9
Acute Effect of NET Inhibition
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After instrumentation and recording of a stable baseline for ⱖ30
minutes, 6 healthy subjects (5 men, 1 woman; age, 36⫾2 years; body
mass index, 23⫾2 kg/m2) ingested 8 mg of the selective NET
inhibitor reboxetine (Edronax, Pharmacia Upjohn). Recordings were
continued for an additional 120 minutes. A cold pressor test was
performed by placing 1 hand in ice water (50% ice, 50% water) for
1 minute at baseline and every 30 minutes after reboxetine ingestion.
Blood samples were taken every 30 minutes. Plasma reboxetine
levels were determined by high-performance liquid chromatography
with column-switching and ultraviolet detection.
Crossover Study With NET Inhibition
Ten male subjects (age, 31⫾6 years; body mass index, 24⫾4 kg/m2)
ingested 8 mg reboxetine or matching placebo 12 hours and 1 hour
before the study as described previously.4,10 Studies with placebo
and with reboxetine were conducted on separate days in a doubleblind crossover manner after an overnight fast. After a stable
baseline had been reached, subjects underwent cold pressor testing.
Thereafter, incremental infusions of sodium nitroprusside and phenylephrine hydrochloride (0.2, 0.4, 0.8, and 1.6 ␮g · kg⫺1 · min⫺1 over
a period of 5 minutes) were given. The infusions were stopped after
the maximum dose had been given or after diastolic BP had changed
by ⬎15 mm Hg. After baseline values had returned, bolus injections
of propranolol were applied every 3 minutes (0.01, 0.02, 0.04, 0.06,
and 0.08 mg/kg) in incremental doses. Subjects received a total
intravenous 0.21-mg/kg propranolol dose within 15 minutes. Cold
pressor testing was repeated during ␤-blockade.
Data Acquisition and Analysis
Data were converted from analog to digital at 500 Hz using the
Windaq pro⫹ software (Dataq Instruments Inc). R-R intervals,
diastolic BP and SBP values, and respiration were defined offline for
the complete records using a program written by one of the authors
(A.D.) that is based on PV-wave software (Visual Numerics Inc).
MSNA bursts were identified after the integrated signal had been
filtered and the baseline defined according to following criteria: (1)
signal-to-noise ratio (set to 2.5), (2) tolerance limits of the skewness
of the rising and falling parts of the bursts, (3) latency limit, (4) burst
width limit (short duration⫽artifact, long duration⫽skin sympathetic
nerve activity or afferent activity), and (5) no preceding premature
beats.9
Spectral Analysis and Baroreflex Sensitivity
Pharmacological baroreflex sensitivity was determined from the
steepest part of the sigmoidal curve obtained during phenylephrine
and sodium nitroprusside infusions. HR and BP variability were
determined by use of spectral analysis, cross-spectral analysis, and
the transfer function between R-R intervals and SBP. Analysis was
performed for 5-minute segments during different baselines before
each intervention.11,12 To obtain reliable spectra during phenylephrine and sodium nitroprusside infusions, we used a sliding fast
Fourier transform algorithm (step, 60 seconds; window, 64 seconds).
Three minutes before the application of the next dose were averaged.
Figure 1. Reboxetine plasma concentrations, BP (SBP, diastolic
BP [DBP]), HR, and MSNA after reboxetine ingestion. Reboxetine plasma concentrations increased within 30 minutes after
ingestion and reached a maximum after 90 minutes (top).
Change in reboxetine plasma concentration was associated with
a moderate increase in SBP and HR (middle). Reboxetine profoundly reduced sympathetic vasomotor tone (MSNA) (bottom).
*P⬍0.05.
Statistics
All data are expressed as mean⫾SEM. Intraindividual differences
were compared by the paired t test or the Wilcoxon test. ANOVA
testing for repeated measures was used for multiple comparisons. A
value of P⬍0.05 was considered significant.
Results
Acute NET Inhibition
Changes in reboxetine plasma concentration over time are
illustrated in Figure 1 (top). The maximum of the reboxetine
plasma concentration was reached after ⬇90 minutes. BP was
124⫾6/72⫾5 mm Hg at baseline and increased to a maximum of 143⫾8/81⫾6 mm Hg 120 minutes after reboxetine
ingestion (P⬍0.01) (Figure 1, middle). HR increased from
Tank et al
Norepinephrine Transporter and Baroreflex Buffering
2951
supine position (P⬍0.01). Supine HR was 60⫾2 bpm with
placebo and 68⫾2 bpm with reboxetine. As in the acute
study, reboxetine attenuated the cold pressor response. During cold pressor testing, BP increased 13⫾3/12⫾2 mm Hg
with placebo and 6⫾3/3⫾2 mm Hg with reboxetine
(P⬍0.01). Reboxetine also blunted the handgrip response
(data not shown).
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Figure 2. Changes in cold pressor responsiveness before (0
minutes) and after reboxetine ingestion. Reboxetine profoundly
attenuated response of SBP (top) and sympathetic vasomotor
tone (MSNA) (bottom) to cold pressor testing. #P⬍0.05.
60⫾3 to 68⫾4 bpm (P⬍0.01) (Figure 1, middle). Resting
MSNA (normalized area under the burst) was 9.9⫾2.6
arbitrary units (AU) at baseline. Within 30 minutes of
reboxetine ingestion, MSNA started to decrease and reached
a minimum of 1.2⫾0.5 AU after 90 minutes (Figure 1,
bottom). The decrease in resting MSNA was associated with
a profound reduction in the cold pressor response (Figure 2,
top). Moreover, reboxetine substantially reduced the MSNA
increase during cold pressor testing (Figure 2, bottom).
MSNA recordings were maintained throughout the study in
all subjects.
Crossover Study With NET Inhibition
Resting BP and HR
BP was 118⫾4/66⫾2 mm Hg with placebo and 133⫾5/
73⫾3 mm Hg with reboxetine with the subject resting in the
Basal Sympathetic Nerve Activity
With placebo, MSNA recordings of good quality were
obtained in all subjects. Proper positioning of the neurography needle was tested by eliciting afferent nerve activity with
tapping on the innervated muscle, by inducing muscle twitching with internal stimulation, provoking MSNA bursts with
bolus injections of sodium nitroprusside or during inspiratory
breath-hold in all subjects. However, during reboxetine,
recordings with spontaneous, pulse-synchronous MSNA
bursts were recorded in only 5 subjects. Resting MSNA was
reduced profoundly with reboxetine (8.2⫾2.0 AU with placebo, 1.3⫾0.2 AU with reboxetine; P⬍0.01). Figure 3
illustrates representative BP and MSNA recordings with
placebo and reboxetine. In this individual, basal MSNA was
reduced profoundly with reboxetine but increased after nitroprusside bolus application.
Responses to Phenylephrine and Nitroprusside
Reboxetine substantially increased sensitivity to phenylephrine and nitroprusside (Figure 4, top). The phenylephrine
dose to increase BP 12.5 mm Hg was 0.25 ␮g · kg⫺1 · min⫺1
with reboxetine and 0.64 ␮g · kg⫺1 · min⫺1 with placebo
(P⬍0.01). The nitroprusside dose that decreased SBP
12.5 mm Hg was 0.40 ␮g · kg⫺1 · min⫺1 with reboxetine and
1.10 ␮g · kg⫺1 · min⫺1 with nitroprusside (P⬍0.01). The
maximal steepness of the baroreflex HR curves was similar
during placebo and during reboxetine (16⫾2 ms/mm Hg with
placebo versus 14⫾2 ms/mm Hg with reboxetine) (Figure 4,
middle). However, the baroreflex curves were reset to higher
BP values. The sympathetic baroreflex curve that was obtained in 4 subjects was remarkably distorted with reboxetine
(Figure 4, bottom). With placebo, MSNA increased properly
with nitroprusside and was suppressed with phenylephrine.
With reboxetine, MSNA was very low at baseline and did not
decrease further with phenylephrine. Nitroprusside lowered
Figure 3. Representative recordings of finger
BP and integrated MSNA (IMSNA) after placebo
(top) and reboxetine (bottom). Reboxetine virtually abolished MSNA. When BP was acutely
lowered with nitroprusside bolus application
(arrow), MSNA reappeared.
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June 17, 2003
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Figure 5. HR variability in low-frequency range (LF-RR) and
high-frequency range (HF-RR) and ratio between LFRR and
HFRR were plotted against BP during nitroprusside and phenylephrine infusions. Compared with placebo, reboxetine
decreased HR variability in both frequency ranges. During
reboxetine, LF/HF ratio increased excessively when BP was
lowered with nitroprusside.
high- and low-frequency ranges was reduced as BP was
lowered with nitroprusside. Reboxetine reduced HR variability in both frequency ranges independently of BP. However,
the ratio between HR variability in the low-frequency and
high-frequency ranges was increased with reboxetine. Rebox-
Figure 4. Top, Changes in BP with incremental infusion of
phenylephrine (phe) and nitroprusside (ntp) during placebo and
during reboxetine treatment. Reboxetine profoundly increased
sensitivity to vasoactive medications. Middle, Baroreflex HR
curves during placebo and during reboxetine treatment. Maximal slope and slope at operating point were similar during both
interventions. However, with reboxetine, baroreflex curve was
reset to higher BP values. Bottom, Sympathetic baroreflex curve
(MSNA) during placebo and during reboxetine (n⫽4). During
reboxetine, sympathetic activity failed to increase properly when
BP was lowered. #P⬍0.05.
BP but failed to increase MSNA properly. Only when BP was
markedly reduced did MSNA begin to increase.
We determined HR and BP variability at baseline and at
each infusion step. The variability data were plotted against
BP (Figures 5 and 6). With placebo, HR variability in the
Figure 6. BP variability in low-frequency range (LFSBP) was
plotted against BP during nitroprusside and phenylephrine infusions. Reboxetine reduced LFSBP profoundly at baseline. Moreover, LFSBP failed to increase when BP was lowered with nitroprusside. In contrast, during placebo, LFSBP increased
markedly with nitroprusside infusion.
Tank et al
Norepinephrine Transporter and Baroreflex Buffering
etine profoundly reduced low-frequency oscillations of SBP
even during nitroprusside infusions.
Response to Propranolol
Complete ␤-blockade with propranolol did not result in a
significant BP reduction during either placebo or reboxetine.
With placebo, R-R interval length was 962⫾32 ms before and
1060⫾38 ms with propranolol. With reboxetine, R-R interval
length was 878⫾40 ms before and 1003⫾35 ms with propranolol. Propranolol had no effect on the HR or BP response to cold
pressor testing during placebo or during reboxetine treatment.
Discussion
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We determined the effect of NET inhibition with reboxetine
on the regulation of sympathetic vasomotor control. Reboxetine is a highly selective NET inhibitor and does not bind to
muscarinic cholinergic receptors or adrenoceptors.13 Therefore, reboxetine provides a useful pharmacological tool to
selectively manipulate norepinephrine uptake in clinical studies.10 Reboxetine in the doses used in the present study
inhibits norepinephrine uptake sufficiently, as indicated by a
robust reduction in the ratio between venous dihydroxyphenylglycol and norepinephrine.10,14
We observed a substantial suppression in sympathetic
traffic with selective NET inhibition. NET inhibition may
influence both the discharge pattern of individual postganglionic neurons and the number of neurons that are recruited
simultaneously. Nonselective NET inhibition with desipramine also attenuates sympathetic traffic.6 These findings are
supported by the reduction in low-frequency SBP oscillations
(“Mayer waves”) in the present investigation and in previous
studies.4,7 Mayer waves are related to oscillations in sympathetic vasomotor discharge. They increase during sympathetic
stimulation.15 In healthy normotensive subjects, BP increases
with NET inhibition.4,6,7 Therefore, the decrease in sympathetic vasomotor tone could be caused by baroreflexmediated inhibition. If the inhibition of sympathetic tone
were mediated by the baroreflex, BP lowering would reverse
the effect. In any event, MSNA and low-frequency oscillations in SBP remained suppressed during nitroprusside infusion. Thus, the decrease in MSNA is not explained solely by
baroreflex-mediated inhibition.
Our findings are consistent with the idea that the decrease
in sympathetic vasomotor tone is largely explained by a direct
effect on the central nervous system. Stimuli that are normally followed by robust increases in BP, such as handgrip or
cold pressor testing, hardly elicit a response during NET
inhibition.4,7 Our study demonstrates that the phenomenon
can be explained in part by decreased responsiveness of
sympathetic vasomotor neurons. A reduction in sympathetic
activity was also observed in rabbits when desipramine was
applied locally to the brain.16 The reduction in sympathetic
activity is mediated at least in part by central nervous system
␣2-adrenoceptors.16
In addition to the effect of selective NET inhibition on
sympathetic vasomotor tone, we observed changes in HR
regulation. With NET inhibition, the baroreflex HR curve
was reset to higher BP values. The shape of the baroreflex
curve was maintained. Thus, at a given BP, HR is increased
2953
markedly during NET inhibition. The shift of the baroreflex
HR curve may contribute to the orthostatic tachycardia
observed in patients with NET deficiency3 and in individuals
treated with NET inhibitors.4,7 The change in HR regulation
was also reflected in the HR variability data. The change in
BP with NET inhibition makes the interpretation of HR
variability data difficult. Therefore, we plotted HR variability
data against BP during different infusion steps with nitroprusside and phenylephrine. NET inhibition resulted in a reduction in HR variability, particularly during nitroprusside infusion. The ratio of low-frequency to high-frequency
oscillations of the R-R interval, which is sometimes referred
to as sympathovagal balance,17,18 was increased during NET
inhibition. This finding is supported by studies using the
norepinephrine spillover technique. In these studies, NET
inhibition was shown to cause disproportional sympathetic
stimulation of the heart compared with the vasculature and
the kidney.6 This phenomenon was attributed primarily to the
fact that the heart is more dependent on NET to remove
norepinephrine from the synaptic cleft. Our study suggests
that the oscillatory component of sympathetic HR and vasomotor regulation is also shifted toward the heart. Thus, a
central nervous system mechanism may also contribute to the
disproportional stimulation of the heart with NET inhibition.
A similar mechanism has also been postulated in orthostatic
intolerance patients.19
We observed a major increase in the sensitivity to phenylephrine and nitroprusside infusions during selective NET
inhibition. Similarly, selective NET inhibition increases the
sensitivity to phenylephrine and nitroprusside bolus doses.4
Moreover, isoproterenol infusion exerts a marked depressor
response during NET inhibition but not during placebo
treatment.4 The depressor response during phase 2 of the
Valsalva maneuver is also increased during NET inhibition.4,7
Considering the different modes of action of all these stimuli,
it is not likely that the hypersensitivity can be explained
entirely by a change in vascular sensitivity. Instead, we
suggest that NET inhibition interferes with baroreflex BP
buffering. In patients with damage to the afferent baroreflex,
the sensitivity to phenylephrine and nitroprusside is increased
dramatically.20 Dysfunction of the efferent baroreflex arc
because of either neuronal degeneration (autonomic failure)21–24 or ganglionic blockade25–27 profoundly increases the
sensitivity to vasoactive medications. The baroreflex buffers
changes in BP through adjustment of HR and sympathetic
vasomotor tone.8 The hypersensitivity to vasoactive medications during NET inhibition cannot be explained by impaired
baroreflex HR control. Close to the operating point, the
steepness of the baroreflex HR curves was virtually identical
during placebo and during reboxetine. Our study suggests that
the decrease in baroreflex BP buffering is explained by a
selective decrease in baroreflex vasomotor control, because
MSNA and low-frequency BP failed to increase properly
during nitroprusside infusions. Our findings may explain in
part why BP tends to increase with acute NET inhibition even
though circulating norepinephrine and whole-body norepinephrine spillover decrease.6,7,10 The same amount of endogenous norepinephrine may elicit a greater pressor response in
the setting of impaired baroreflex buffering.
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Circulation
June 17, 2003
Our findings may have important clinical implications.
Pharmacological NET inhibition, which is widely applied in
clinical practice, not only suppresses resting sympathetic
vasomotor tone but also impairs the ability to respond to
sympathetic stimuli. We hypothesize that in conditions associated with high sympathetic vasomotor tone, NET inhibition
might lower resting sympathetic activity. Our study also
confirms previous studies suggesting that NET is important
not only in the regulation of overall sympathetic tone but also
in the distribution of sympathetic activity to different organs.6
NET inhibition selectively attenuates the efficiency of the
baroreflex to regulate sympathetic vasomotor tone. This
mechanism may contribute to orthostatic hypotension in the
elderly. Finally, the selective sympathetic baroreflex dysfunction sensitizes the cardiovascular system to vasoactive medications and represents a novel mechanism for drug
interactions.
Downloaded from http://circ.ahajournals.org/ by guest on June 17, 2017
Acknowledgments
This work was supported in part by Bundesministerium für Bildung
und Forschung und Deutsche Forschungsmunschaft grants. Dr Jordan is a recipient of a Helmholtz fellowship of the Max-DelbrueckCenter of Molecular Medicine.
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Selective Impairment in Sympathetic Vasomotor Control With Norepinephrine
Transporter Inhibition
Jens Tank, Christoph Schroeder, Andre Diedrich, Elke Szczech, Sebastian Haertter, Arya M.
Sharma, Friedrich C. Luft and Jens Jordan
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Circulation. 2003;107:2949-2954; originally published online June 9, 2003;
doi: 10.1161/01.CIR.0000072786.99163.FE
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