This Article Full Text Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Schroeder, C. Articles by Jordan, J. Search for Related Content PubMed PubMed Citation Articles by Schroeder, C. Articles by Jordan, J. Related Collections Cardiovascular Pharmacology Autonomic, reflex, and neurohumoral control of circulation

(Circulation. 2002;105:347.)
© 2002 American Heart Association, Inc.

Clinical Investigation and Reports

Selective Norepinephrine Reuptake Inhibition as a Human Model of Orthostatic Intolerance

Christoph Schroeder, MD; Jens Tank, MD; Michael Boschmann, MD; Andre Diedrich, MD; Arya M. Sharma, MD; Italo Biaggioni, MD; Friedrich C. Luft, MD; Jens Jordan, MD

From the Clinical Research Center (C.S., J.T., A.M.S., F.C.L., J.J.), HELIOS Klinkum-Berlin, Franz Volhard Clinic, Medical Faculty of the Charité, Humboldt-University, Berlin, Germany; German Institute of Human Nutrition (M.B.), Potsdam, Germany; and Autonomic Dysfunction Service (A.D., I.B.), Vanderbilt University, Nashville, Tenn.

Correspondence to Jens Jordan, MD, Clinical Research Center, Haus 129, Franz-Volhard-Clinic, Humboldt University, Wiltbergstr. 50, 13125 Berlin, Germany. Email jordan{at}fvk-berlin.de

Background— Observations in patients with functional mutations of the norepinephrine transporter (NET) gene suggest that impaired norepinephrine uptake may contribute to idiopathic orthostatic intolerance.

Methods and Results— We studied the effect of the selective NET blocker reboxetine and placebo in a randomized, double-blind, crossover fashion on cardiovascular responses to cold pressor testing, handgrip testing, and a graded head-up tilt test (HUT) in 18 healthy subjects. In a subset, we determined isoproterenol and phenylephrine sensitivities. Subjects ingested 8 mg reboxetine or placebo 12 hours and 1 hour before testing. In the supine position, heart rate was 65±2 bpm with placebo and 71±3 bpm with reboxetine. At 75° HUT, heart rate was 84±3 and 119±4 bpm with placebo and with reboxetine (P<0.0001). Mean arterial pressure was 85±2 with placebo and 91±2 mm Hg with reboxetine while supine (P<0.01) and 88±2 mm Hg and 90±3 mm Hg at 75° HUT. Blood pressure responses to cold pressor and handgrip testing were attenuated with reboxetine. Reboxetine increased the sensitivity to the chronotropic effect of isoproterenol and the pressor effect of phenylephrine. Vasovagal reactions occurred in 9 subjects on placebo and in 1 subject on reboxetine.

Conclusions— Selective NET blockade creates a phenotype that resembles idiopathic orthostatic intolerance. This observation supports the hypothesis that disordered norepinephrine uptake mechanisms can contribute to human cardiovascular disease. Our study also suggests that NET inhibition might be useful in preventing vasovagal reactions.

Key Words: autonomic • baroreflex • adrenoreceptors • catecholamines • syncope

This article has been cited by other articles:

				V Raj, K L Haman, S R Raj, D Byrne, R D Blakely, I Biaggioni, D Robertson, and R C Shelton Psychiatric profile and attention deficits in postural tachycardia syndrome J. Neurol. Neurosurg. Psychiatry, March 1, 2009; 80(3): 339 - 344. [Abstract] [Full Text] [PDF]

				S. Carew, M. O. Connor, J. Cooke, R. Conway, C. Sheehy, A. Costelloe, and D. Lyons A review of postural orthostatic tachycardia syndrome Europace, January 1, 2009; 11(1): 18 - 25. [Abstract] [Full Text] [PDF]

				E. Lambert, N. Eikelis, M. Esler, T. Dawood, M. Schlaich, R. Bayles, F. Socratous, A. Agrotis, G. Jennings, G. Lambert, et al. Altered Sympathetic Nervous Reactivity and Norepinephrine Transporter Expression in Patients With Postural Tachycardia Syndrome Circ Arrhythmia Electrophysiol, June 1, 2008; 1(2): 103 - 109. [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]

				A K Agarwal, R Garg, A Ritch, and P Sarkar Postural orthostatic tachycardia syndrome Postgrad. Med. J., July 1, 2007; 83(981): 478 - 480. [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]

				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]

				S. Vincent, P. R. Bieck, E. M. Garland, C. Loghin, F. P. Bymaster, B. K. Black, C. Gonzales, W. Z. Potter, and D. Robertson Clinical Assessment of Norepinephrine Transporter Blockade Through Biochemical and Pharmacological Profiles Circulation, June 29, 2004; 109(25): 3202 - 3207. [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. 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]

				L. E. Rasmussen and O. A. Nedergaard Effects of Reboxetine on Sympathetic Neuroeffector Transmission in Rabbit Carotid Artery J. Pharmacol. Exp. Ther., September 1, 2003; 306(3): 995 - 1002. [Abstract] [Full Text] [PDF]

				J. Tank, C. Schroeder, A. Diedrich, E. Szczech, S. Haertter, A. M. Sharma, F. C. Luft, and J. Jordan Selective Impairment in Sympathetic Vasomotor Control With Norepinephrine Transporter Inhibition Circulation, June 17, 2003; 107(23): 2949 - 2954. [Abstract] [Full Text] [PDF]

				M. Bechir, C. Binggeli, R. Corti, R. Chenevard, L. Spieker, F. Ruschitzka, T. F. Luscher, and G. Noll Dysfunctional Baroreflex Regulation of Sympathetic Nerve Activity in Patients With Vasovagal Syncope Circulation, April 1, 2003; 107(12): 1620 - 1625. [Abstract] [Full Text] [PDF]

				R. P. Carson, A. Diedrich, and D. Robertson Autonomic control after blockade of the norepinephrine transporter: a model of orthostatic intolerance J Appl Physiol, December 1, 2002; 93(6): 2192 - 2198. [Abstract] [Full Text] [PDF]

				A. L. Birkenfeld, C. Schroeder, M. Boschmann, J. Tank, G. Franke, F. C. Luft, I. Biaggioni, A. M. Sharma, and J. Jordan Paradoxical Effect of Sibutramine on Autonomic Cardiovascular Regulation Circulation, November 5, 2002; 106(19): 2459 - 2465. [Abstract] [Full Text] [PDF]

				M. Boschmann, C. Schroeder, N. J. Christensen, J. Tank, G. Krupp, I. Biaggioni, S. Klaus, A. M. Sharma, F. C. Luft, and J. Jordan Norepinephrine Transporter Function and Autonomic Control of Metabolism J. Clin. Endocrinol. Metab., November 1, 2002; 87(11): 5130 - 5137. [Abstract] [Full Text] [PDF]

				D. S. Goldstein, C. Holmes, S. M. Frank, R. Dendi, R. O. Cannon III, Y. Sharabi, M. D. Esler, and G. Eisenhofer Cardiac Sympathetic Dysautonomia in Chronic Orthostatic Intolerance Syndromes Circulation, October 29, 2002; 106(18): 2358 - 2365. [Abstract] [Full Text] [PDF]