Published online before print June 9, 2003, doi: 10.1161/01.CIR.0000072786.99163.FE
| |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
(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
 |
Abstract |
|---|
 Top Abstract IntroductionMethodsResultsDiscussionReferences |
|---|
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
|
Introduction |
|---|
|
TopAbstractIntroductionMethodsResultsDiscussionReferences |
|---|
Approximately 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 norepinephrine. 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 |
|---|
|
TopAbstractIntroductionMethodsResultsDiscussionReferences |
|---|
Subjects
We studied 12 healthy control subjects (11 men, 1 woman; age, 32±6 years; body mass index, 24±3 kg/m2). Written informed 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 µm; shaft diameter, 200 µm) 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
After instrumentation and recording of a stable baseline for ≥30 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 double-blind 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 µg · 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 ß-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.
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 |
|---|
|
TopAbstractIntroductionMethodsResultsDiscussionReferences |
|---|
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 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 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).
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 µg · kg-1 · min-1 with reboxetine and 0.64 µg · kg-1 · min-1 with placebo (P<0.01). The nitroprusside dose that decreased SBP 12.5 mm Hg was 0.40 µg · kg-1 · min-1 with reboxetine and 1.10 µg · 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 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 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. Reboxetine profoundly reduced low-frequency oscillations of SBP even during nitroprusside infusions.
|
|
Response to Propranolol
Complete ß-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 |
|---|
|
TopAbstractIntroductionMethodsResultsDiscussionReferences |
|---|
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 baroreflex-mediated 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 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.
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.
|
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-Delbrueck-Center of Molecular Medicine.
Received January 13, 2003; accepted March 7, 2003.
|
References |
|---|
|
TopAbstractIntroductionMethodsResultsDiscussionReferences |
|---|
1. James WP, Astrup A, Finer N, et al. Effect of sibutramine on weight maintenance after weight loss: a randomised trial. STORM Study Group Sibutramine Trial of Obesity Reduction and Maintenance. Lancet. 2000; 356: 2119–2125.[CrossRef][Medline] [Order article via Infotrieve]
2. Rumantir MS, Kaye DM, Jennings GL, et al. Phenotypic evidence of faulty neuronal norepinephrine reuptake in essential hypertension. Hypertension. 2000; 36: 824–829.
3. Shannon JR, Flattem N, Jordan J, et al. Orthostatic intolerance and tachycardia associated with norepinephrine transporter deficiency. N Engl J Med. 2000; 342: 541–549.
4. Schroeder C, Tank J, Boschmann M, et al. Selective norepinephrine reuptake inhibition as a human model of orthostatic intolerance. Circulation. 2002; 105: 347–353.
5. Kahan T, Hjemdahl P, Dahlof C. Relationship between the overflow of endogenous and radiolabelled noradrenaline from canine blood perfused gracilis muscle. Acta Physiol Scand. 1984; 122: 571–582.[Medline] [Order article via Infotrieve]
6. Esler MD, Wallin G, Dorward PK, et al. Effects of desipramine on sympathetic nerve firing and norepinephrine spillover to plasma in humans. Am J Physiol. 1991; 260: R817–R823.[Medline] [Order article via Infotrieve]
7. Birkenfeld AL, Schroeder C, Boschmann M, et al. Paradoxical effect of sibutramine on autonomic cardiovascular regulation. Circulation. 2002; 106: 2459–2465.
8. Jordan J, Tank J, Shannon JR, et al. Baroreflex buffering and susceptibility to vasoactive drugs. Circulation. 2002; 105: 1459–1464.
9. Tank J, Diedrich A, Schroeder C, et al. Limited effect of systemic ß-blockade on sympathetic outflow. Hypertension. 2001; 38: 1377–1381.
10. Boschmann M, Schroeder C, Christensen NJ, et al. Norepinephrine transporter function and autonomic control of metabolism. J Clin Endocrinol Metab. 2002; 87: 5130–5137.
11. Tank J, Baevski RM, Fender A, et al. Reference values of indices of spontaneous baroreceptor reflex sensitivity. Am J Hypertens. 2000; 13: 268–275.[CrossRef][Medline] [Order article via Infotrieve]
12. Tank J, Jordan J, Diedrich A, et al. Genetic influences on baroreflex function in normal twins. Hypertension. 2001; 37: 907–910.
13. Wong EH, Sonders MS, Amara SG, et al. Reboxetine: a pharmacologically potent, selective, and specific norepinephrine reuptake inhibitor. Biol Psychiatry. 2000; 47: 818–829.[CrossRef][Medline] [Order article via Infotrieve]
14. Goldstein DS, Eisenhofer G, Stull R, et al. Plasma dihydroxyphenylglycol and the intraneuronal disposition of norepinephrine in humans. J Clin Invest. 1988; 81: 213–220.[Medline] [Order article via Infotrieve]
15. Furlan R, Porta A, Costa F, et al. Oscillatory patterns in sympathetic neural discharge and cardiovascular variables during orthostatic stimulus. Circulation. 2000; 101: 886–892.
16. Eisenhofer G, Saigusa T, Esler MD, et al. Central sympathoinhibition and peripheral neuronal uptake blockade after desipramine in rabbits. Am J Physiol. 1991; 260: R824–R832.[Medline] [Order article via Infotrieve]
17. Montano N, Ruscone TG, Porta A, et al. Power spectrum analysis of heart rate variability to assess the changes in sympathovagal balance during graded orthostatic tilt [see comments]. Circulation. 1994; 90: 1826–1831.
18. Malliani A, Pagani M, Lombardi F, et al. Cardiovascular neural regulation explored in the frequency domain. Circulation. 1991; 84: 482–492.
19. Furlan R, Jacob G, Snell M, et al. Chronic orthostatic intolerance: a disorder with discordant cardiac and vascular sympathetic control. Circulation. 1998; 98: 2154–2159.
20. Jordan J, Shannon JR, Black B, et al. Malignant vagotonia due to selective baroreflex failure. Hypertension. 1997; 30: 1072–1077.
21. Robertson D, Hollister AS, Carey EL, et al. Increased vascular beta2-adrenoreceptor responsiveness in autonomic dysfunction. J Am Coll Cardiol. 1984; 3: 850–856.[Abstract]
22. Jordan J, Shannon JR, Biaggioni I, et al. Contrasting actions of pressor agents in severe autonomic failure. Am J Med. 1998; 105: 116–124.[CrossRef][Medline] [Order article via Infotrieve]
23. Mohring J, Glanzer K, Maciel JJ, et al. Greatly enhanced pressor response to antidiuretic hormone in patients with impaired cardiovascular reflexes due to idiopathic orthostatic hypotension. J Cardiovasc Pharmacol. 1980; 2: 367–376.[Medline] [Order article via Infotrieve]
24. Jordan J, Shannon JR, Pohar B, et al. Contrasting effects of vasodilators on blood pressure and sodium balance in the hypertension of autonomic failure. J Am Soc Nephrol. 1999; 10: 35–42.
25. Page IH, McCubbin JW. Buffer reflexes, tolerance to ganglioplegics and their relationship to enhanced pressor responsiveness. Am J Physiol. 1959; 197: 217–222.
26. Haas E, Goldblatt H. Effects of various ganglionic blocking agents on blood pressure and on activity of pressor agents. J Physiol. 1960; 198: 1023–1028.
27. Shannon JR, Jordan J, Black B, et al. Uncoupling of the baroreflex by NN-cholinergic blockade in dissecting the components of cardiovascular regulation. Hypertension. 1998; 32: 101–107.
This article has been cited by other articles:
 |
|
 |
|
  J. Tank, K. Heusser, A. Diedrich, D. Hering, F. C. Luft, A. Busjahn, K. Narkiewicz, and J. Jordan Influences of Gender on the Interaction between Sympathetic Nerve Traffic and Central Adiposity J. Clin. Endocrinol. Metab., December 1, 2008; 93(12): 4974 - 4978. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 I. Moldovanova, C. Schroeder, G. Jacob, C. Hiemke, A. Diedrich, F. C. Luft, and J. Jordan Hormonal Influences on Cardiovascular Norepinephrine Transporter Responses in Healthy Women Hypertension, April 1, 2008; 51(4): 1203 - 1209. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. Strempel, C. Schroeder, R. Hemmersbach, A. Boese, J. Tank, A. Diedrich, M. Heer, F. C. Luft, and J. Jordan Norepinephrine transporter inhibition alters the hemodynamic response to hypergravitation J Appl Physiol, March 1, 2008; 104(3): 756 - 760. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 C. Torp-Pedersen, I. Caterson, W. Coutinho, N. Finer, L. Van Gaal, A. Maggioni, A. Sharma, W. Brisco, R. Deaton, G. Shepherd, et al. Cardiovascular responses to weight management and sibutramine in high-risk subjects: an analysis from the SCOUT trial Eur. Heart J., December 1, 2007; 28(23): 2915 - 2923. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. Tank, K. Heusser, A. Diedrich, R. J. Brychta, F. C. Luft, and J. Jordan Yohimbine Attenuates Baroreflex-Mediated Bradycardia in Humans Hypertension, November 1, 2007; 50(5): 899 - 903. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
C. Shibao, S. R. Raj, A. Gamboa, A. Diedrich, L. Choi, B. K. Black, D. Robertson, and I. Biaggioni Norepinephrine Transporter Blockade With Atomoxetine Induces Hypertension in Patients With Impaired Autonomic Function Hypertension, July 1, 2007; 50(1): 47 - 53. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
K. Heusser, S. Engeli, J. Tank, A. Diedrich, S. Wiesner, J. Janke, F. C. Luft, and J. Jordan Sympathetic Vasomotor Tone Determines Blood Pressure Response to Long-Term Sibutramine Treatment J. Clin. Endocrinol. Metab., April 1, 2007; 92(4): 1560 - 1563. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 C. Schroeder, A. L. Birkenfeld, A. F. Mayer, J. Tank, A. Diedrich, F. C. Luft, and J. Jordan Norepinephrine Transporter Inhibition Prevents Tilt-Induced Pre-Syncope J. Am. Coll. Cardiol., August 1, 2006; 48(3): 516 - 522. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. F. Mayer, C. Schroeder, K. Heusser, J. Tank, A. Diedrich, R. E. Schmieder, F. C. Luft, and J. Jordan Influences of Norepinephrine Transporter Function on the Distribution of Sympathetic Activity in Humans Hypertension, July 1, 2006; 48(1): 120 - 126. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A. M. Sharma Does pharmacologically induced weight loss improve cardiovascular outcome? Sibutramine pharmacology and the cardiovascular system Eur. Heart J. Suppl., November 1, 2005; 7(suppl_L): L39 - L43. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 C. Schroeder, S. Vernino, A. L. Birkenfeld, J. Tank, K. Heusser, A. Lipp, T. Benter, C. Lindschau, R. Kettritz, F. C. Luft, et al. Plasma exchange for primary autoimmune autonomic failure. N. Engl. J. Med., October 13, 2005; 353(15): 1585 - 1590. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. Tank, A. Diedrich, E. Szczech, F. C. Luft, and J. Jordan Baroreflex Regulation of Heart Rate and Sympathetic Vasomotor Tone in Women and Men Hypertension, June 1, 2005; 45(6): 1159 - 1164. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 N. R. Keller, A. Diedrich, M. Appalsamy, S. Tuntrakool, S. Lonce, C. Finney, M. G. Caron, and D. Robertson Norepinephrine Transporter-Deficient Mice Exhibit Excessive Tachycardia and Elevated Blood Pressure With Wakefulness and Activity Circulation, September 7, 2004; 110(10): 1191 - 1196. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 T. Kawada, T. Miyamoto, K. Uemura, K. Kashihara, A. Kamiya, M. Sugimachi, and K. Sunagawa Effects of neuronal norepinephrine uptake blockade on baroreflex neural and peripheral arc transfer characteristics Am J Physiol Regulatory Integrative Comp Physiol, June 1, 2004; 286(6): R1110 - R1120. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
C. Schroeder, F. Adams, M. Boschmann, J. Tank, S. Haertter, A. Diedrich, I. Biaggioni, F. C. Luft, and J. Jordan Phenotypical evidence for a gender difference in cardiac norepinephrine transporter function Am J Physiol Regulatory Integrative Comp Physiol, May 1, 2004; 286(5): R851 - R856. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. Tank, A. Diedrich, E. Szczech, F. C. Luft, and J. Jordan {alpha}-2 Adrenergic Transmission and Human Baroreflex Regulation Hypertension, May 1, 2004; 43(5): 1035 - 1041. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. Woolard, T. Bennett, W. R. Dunn, D. J. Heal, S. Aspley, and S. M. Gardiner Acute Cardiovascular Effects of Sibutramine in Conscious Rats J. Pharmacol. Exp. Ther., March 1, 2004; 308(3): 1102 - 1110. [Abstract] [Full Text] [PDF]
|
|
| |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||