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Selective Norepinephrine Reuptake Inhibition as a Human Model of Orthostatic Intolerance
Abstract
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.
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“Iatrogenic inhibition of the norepinephrine transporter has also been shown to engender a POTS-like state, increase upright heart rate, and exacerbate symptoms in POTS patients (46-49).”
From Postural orthostatic tachycardia syndrome: mechanisms and new therapies (2020) · cites this paper as [48]
In the citing paper
“Administration of reboxetine, a norepinephrine transporter inhibitor, to healthy controls provoked hemodynamic changes consistent with POTS (48).”
From Postural orthostatic tachycardia syndrome: mechanisms and new therapies (2020) · cites this paper as [48]
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Metadata
- Authors
- Schroeder, C., Tank, J., Boschmann, M., Diedrich, A., Sharma, A. M., Biaggioni, I., Luft, F. C., & Jordan, J.
- Affiliations
- Vanderbilt University (US)
- 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.
- Venue
- Circulation
- Published
- 2002-01-22
- Volume
- 105
- Issue
- 3
- Pages
- 347-353
- ISSN
- 0009-7322 (ISSN-L)
- 1524-4539
- OpenAlex
- W2053706211
- Cited by
- 127
- References
- 32
- Citations by year
- 2025: 2 · 2024: 7 · 2023: 4 · 2022: 2 · 2021: 3 · 2020: 2 · 2019: 2 · 2018: 5 · 2017: 3 · 2016: 7 · 2015: 2 · 2014: 5 · 2013: 8 · 2012: 6
- FWCI
- 10.16
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Circulation (publishedVersion)
- PubMed (publishedVersion)
- MDC Repository (Max-Delbrueck-Center for Molecular Medicine) (submittedVersion)
- Funders
- Deutsche Forschungsgemeinschaft
- Topics
- Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Cardiovascular Syncope and Autonomic Disorders
- Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Heart Rate Variability and Autonomic Control
- Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Cardiac electrophysiology and arrhythmias
- Keywords
- norepinephrine transporter, norepinephrine reuptake inhibition, reboxetine, orthostatic intolerance, vasovagal reaction, heart rate, blood pressure, phenylephrine sensitivity, cold pressor test, head-up tilt, handgrip test
- MeSH terms
- Reboxetine, Adrenergic Agonists, Adult, Autonomic Nervous System, Biological Transport, Blood Pressure, Double-Blind Method, Female, Heart Rate, Humans, Isoproterenol, Male, Morpholines, Norepinephrine, Phenylephrine, Posture, Reflex, Syndrome, Tachycardia, Baroreflex, Cross-Over Studies, Tilt-Table Test, Adrenergic Uptake Inhibitors
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