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Cited by 95Blood Pressure and Hypertension StudiesNeuroscience and Neuropharmacology ResearchReceptor Mechanisms and Signaling

Phenotypic Evidence of Faulty Neuronal Norepinephrine Reuptake in Essential Hypertension

Open access
Rumantir, Magdalena S., Kaye, David M., Jennings, Garry L., Vaz, Mario, Hastings, Jacqueline A., Esler, Murray D.·2000·Hypertension
DOI 10.1161/01.hyp.36.5.824
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Abstract

Abstract—Previous reports suggest that neuronal norepinephrine (NE) reuptake may be impaired in essential hypertension, perhaps because of dysfunction of the NE transporter, although the evidence is inconclusive. To further test this proposition, we applied phenotypically relevant radiotracer methodology, infusion of tritiated NE and quantification of NE metabolites, to 34 healthy lean subjects (body mass index <27.0 kg/m 2), 19 overweight (body mass index >28.0 kg/m 2) but otherwise healthy normotensive subjects, 13 untreated lean patients with essential hypertension, and 14 obesity-related hypertensives. Spillover of NE from the heart was increased in lean hypertensives only (mean±SD 33.4±20.6 versus 16.1±11.7 ng/min in lean normotensives,P<0.05), but this could have resulted from high cardiac sympathetic nerve firing rates, faulty NE reuptake, or both. The arterial plasma concentration of 3-methoxy-4-hydroxylphenylglycol, an extraneuronal metabolite of NE, was elevated in lean hypertensives only (3942±1068 versus 3055±888 pg/mL in healthy subjects,P<0.05). The fractional extraction of plasma tritiated NE in passage through the heart, determined on the basis of neuronal NE uptake, was reduced in lean essential hypertensives (0.65±0.19 versus 0.81±0.11 in healthy subjects,P<0.05). Cardiac release of the tritiated NE metabolite [3 H]dihydroxylphenylglycol, produced intraneuronally by monoamine oxidase after uptake of [3 H]NE by the transporter, was reduced in lean hypertensives only (992±1435 versus 4588±3189 dpm/min in healthy subjects,P<0.01) These findings suggest that neuronal reuptake of NE is impaired in essential hypertension. Through amplification of the neural signal, such a defect could constitute a neurogenic variant of essential hypertension. In obesity-related hypertension, there was no phenotypic evidence of NE transporter dysfunction.

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Written from the paper’s full text.

TL;DR

In lean essential hypertensives, cardiac norepinephrine spillover was increased and multiple indices of neuronal norepinephrine reuptake were reduced, suggesting faulty neuronal NE reuptake. The authors propose this defect could define a neurogenic variant of essential hypertension, whereas obesity-related hypertension showed no such phenotypic evidence.

Key findings

  • Cardiac NE spillover was increased in lean hypertensives only: 33.4±20.6 vs 16.1±11.7 ng/min in lean normotensives (P<0.05).
  • Arterial plasma MHPG, an extraneuronal NE metabolite, was elevated in lean hypertensives only: 3942±1068 vs 3055±888 pg/mL in healthy subjects (P<0.05).
  • Transcardiac fractional extraction of plasma tritiated NE was reduced in lean essential hypertensives: 0.65±0.19 vs 0.81±0.11 in healthy subjects (P<0.05).
  • Cardiac release of [³H]DHPG, formed intraneuronally after neuronal uptake of [³H]NE, was reduced in lean hypertensives only: 992±1435 vs 4588±3189 dpm/min in healthy subjects (P<0.01); no phenotypic evidence of NE transporter dysfunction was found in obesity-related hypertension.

Methods

  • Radiotracer methodology with infusion of tritiated NE and quantification of NE metabolites in 80 adults: 34 healthy lean subjects, 19 overweight normotensive subjects, 13 untreated lean patients with essential hypertension, and 14 obesity-related hypertensives.
  • Whole-body NE kinetics were measured in all 80 subjects; cardiac plasma NE kinetics were measured in 57 subjects via coronary sinus venous sampling. Indices included whole-body and cardiac NE spillover, arterial MHPG, plasma tritiated NE clearance, transcardiac fractional extraction of tritiated NE, and cardiac [³H]DHPG spillover.
  • Neurochemicals were measured by HPLC with electrochemical detection; results are mean±SD, with ANOVA or Mann-Whitney U tests and P<0.05 for significance.

Limitations

  • Stated by the authors: most participants were male, so whether findings apply equally to female hypertensive patients remains uncertain; possible laboratory alerting/anxiety and undetected dietary sodium restriction were considered but argued unlikely to explain the findings.
  • Stated by the authors: whole-body changes were proportionally less than cardiac changes and may reflect partial reuptake impairment plus the lesser importance of NE uptake in organs such as kidney and skeletal muscle; total NE spillover was 20% higher and total plasma NE clearance 18% lower in lean hypertensives but these did not reach significance (clearance P=0.059).
  • Evident from the text: this is a cross-sectional phenotypic study without direct measurement of sympathetic nerve firing or transporter gene mutation/functional testing in the studied cohort; the authors note that a future study coupling such neurochemical indices with transporter gene mutation screening and in vitro functional assessment is needed.

Model-written summary. Check it against the paper before relying on it.

Integrity signals

Registry

Crossref · 10.1161/01.hyp.36.5.824

Cites

Statistics

Nothing to recompute.

Claims the paper makes

0 of 37 cited sources checked · 0 supported · 0 flagged

  • Findingown data

    The ratio of plasma NE to DHPG was higher in lean hypertensives than in healthy controls (0.30 vs 0.20, P<0.01).

    “The ratio of the plasma concentration of NE to that of its intraneuronal metabolite DHPG, which provides a semiquantitative index of whole body NE neuronal reuptake, 8,15 was higher in lean hypertensives than in healthy controls (0.30 versus 0.20, PϽ0.01, Figure 3).”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [8]

      Not checked in the free run.

    • cites [15] source

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  • Findingown data

    The mean plasma concentration of NE was 45% higher in lean hypertensive subjects than in lean healthy volunteers.

    “The mean plasma concentration of NE was 45% higher in lean hypertensive subjects than in lean healthy volunteers (PϽ0.05)(Table 2)”
    Quote in the paperSubstantial claim
  • Findingown data

    Heart rates in both lean and obese hypertensive groups were elevated compared with normotensive subjects.

    “Heart rates in both lean and obese hypertensive groups were elevated compared with those of normotensive subjects (Table 1).”
    Quote in the paperNot a substantial claim
  • Findingown data

    Cardiac NE spillover was significantly higher in lean than in obese hypertensives.

    “Cardiac NE spillover was significantly higher in lean than in obese hypertensives (PϽ0.05, Figure 3).”
    Quote in the paperSubstantial claim
  • Findingown data

    In lean patients with essential hypertension, the arterial plasma concentration of MHPG is elevated compared with healthy subjects.

    “The arterial plasma concentration of 3-methoxy-4hydroxylphenylglycol, an extraneuronal metabolite of NE, was elevated in lean hypertensives only (3942Ϯ1068 versus 3055Ϯ888 pg/mL in healthy subjects, PϽ0.05).”
    • Also stated in: § Results · plain
      “The concentration in arterial plasma of the extraneuronal NE metabolite MHPG was elevated in lean hypertensives only (3942Ϯ1068 pg/mL) compared with that in healthy subjects (3056Ϯ888 pg/mL) (Table 2).”
    Quote in the paperSubstantial claim
    • Rests on an assumption: MHPG is an extraneuronal metabolite of NE.
  • May combine two claims. 12
  • Classified as probably not a substantial claim. 8
  • The quote only partly states this claim. 1

  • May combine two claims.

    Findingown data

    The arterial plasma concentration of [3H]DHPG was 28% lower in lean hypertensives than in healthy lean volunteers, but the difference was not statistically significant (P=0.09).

    “The arterial plasma concentration of [ 3 H]DHPG was 28% lower in lean hypertensives than in healthy lean volunteers (Pϭ0.09, Figure 4) and lower still in both obese experimental groups; in the latter cases, this may be attributable to the somewhat lower tritiated NE infusion rates (Table 1).”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    The total NE spillover rate was 20% higher in lean hypertensive subjects than in lean healthy volunteers, but the difference was not statistically significant.

    “the total NE spillover rate was 20% higher (difference not statistically significant) (Figure 3).”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    Typical neurochemical consequences of neuronal NE reuptake impairment are facilitation of NE spillover, reduced NE plasma clearance, and altered NE metabolite pattern.

    “Typical neurochemical consequences of neuronal NE reuptake impairment are facilitation of NE spillover from sympathetic nerves to plasma, reduced clearance of NE from plasma for the body as a whole and by individual organs, and alteration in the pattern of NE metabolites due to reduction in neuronal metabolism and augmentation of extraneuronal metabolism.5,7,8,11,12,15”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [5] source

      Not checked in the free run.

    • cites [7]

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    • cites [8]

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  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims. The quote only partly states this claim.

    Premisecitation

    The cardinal diagnostic features of postural tachycardia syndrome are exaggerated reflex increases in heart rate and plasma NE concentration with standing, attributable in the reported kindred to the NE transporter fault.

    “The cardinal diagnostic features of this condition are exaggerated reflex increases in heart rate and plasma NE concentration with standing, 9 attributable in the kindred reported although not in the majority of patients with the condition to the NE transporter fault.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [9] source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Near-total absence of activity of the neuronal NE transporter was reported in a family kindred with postural tachycardia syndrome due to a missense mutation of the NE transporter gene.

    “Near-total absence of activity of the neuronal NE transporter was recently reported in a family kindred with the postural tachycardia syndrome, in which a missense mutation of the NE transporter gene has been identified.9”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [9] source

      Not checked in the free run.

  • May combine two claims.

    Study design and conductcitation

    Undetected dietary sodium restriction is unlikely to explain the observed reduction in NE reuptake and increase in cardiac NE spillover, because sodium depletion increases renal but not cardiac NE spillover and increases neuronal NE uptake.

    “This is unlikely, because available evidence indicates that in humans, sodium depletion increases renal, but not cardiac, NE spillover 12 and actually increases neuronal NE uptake.6”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [12] source

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    • cites [6]

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  • May combine two claims.

    Study design and conductown data

    Most participants were male, and whether the findings apply equally to female hypertensive patients remains uncertain.

    “The first is the possible relevance of sex, in that most participating subjects were male, and although it is not our experience, an influence of sex on sympathetic function and catecholamine metabolism has been described.16 Whether our findings apply equally to female hypertensive patients remains uncertain.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [16]

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Study design and conductown data

    Lean hypertensive patients had a higher mean BMI than lean normotensive subjects (25.1 vs 23.1 kg/m2, P<0.05).

    “All lean hypertensive patients had a BMI of Ͻ27 kg/m 2 , but overall BMI was higher than that in lean subjects with normal blood pressure, with mean values of 25.1 and 23.1 kg/m 2 , respectively (PϽ0.05).”
    Quote in the paperNot a substantial claim

  • Classified as probably not a substantial claim.

    Premisecitation

    A missense mutation of the NE transporter gene in a family kindred with postural tachycardia syndrome causes the exaggerated reflex increase in heart rate with standing.

    “We were encouraged in this line of thinking by the recent description of a missense mutation of the NE transporter gene in a family kindred with the postural tachycardia syndrome 9 in whom the exaggerated reflex increase in heart rate with standing, which is a cardinal feature of the disorder, was due to the NE transporter fault.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [9] source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S4 (based).

    Premisenone given

    The disposition of NE after its release is more dependent on neuronal reuptake in the heart than in all other organs.

    “We thought that because the disposition of NE after its release is more dependent on neuronal reuptake in the heart than in all other organs, 8 incomplete grades of impairment of NE transporter function would be most likely to be phenotypically evident there.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [8]

      Not checked in the free run.

  • May combine two claims.

    Interpretationcitation

    It remains credible that a defect in neuronal NE reuptake could cause hypertension, because postural tachycardia syndrome involves a regional sympathetic neuropathy that might modify the translation of a neuronal reuptake defect into blood pressure elevation.

    “Probably so, given that there is evidence of an associated regional sympathetic neuropathy that involves multiple sites.including the legs and kidneys (but not the heart).in the postural tachycardia syndrome, 19 which might be expected to modify the translation of a neuronal reuptake defect into blood pressure elevation.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [19] source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    In a substantial proportion of patients, essential hypertension is neurogenic, with high rates of NE spillover from the heart and kidneys.

    “Available evidence indicates that in a substantial proportion of patients, essential hypertension is neurogenic, with documentation of high rates of spillover of norepinephrine (NE) from the heart and kidneys. 1”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [1] source

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    The lack of significant whole-body changes in lean hypertensives could result from partial impairment of neuronal NE reuptake and from the lesser importance of NE uptake in organs such as kidneys and skeletal muscle compared with the heart.

    “This could have resulted from a partial impairment of neuronal NE reuptake, suggested by a comparison with total NE plasma clearance values reported when reuptake is totally absent (plasma clearance 25% to 40% reduced), 8,11 but it probably also reflects the lesser importance of NE uptake to overall NE disposition in organs such as the kidneys and skeletal muscle (compared with the heart), which m”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [8]

      Not checked in the free run.

    • cites [11] source

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    • cites [12] source

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  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Study design and conductown data

    The neurochemical measurements had intra-assay coefficients of variation of 4.6% for plasma NE, 5.0% for MHPG, 3.9% for DHPG, 5.3% for 3H-labeled NE, and 8.2% for [3H]DHPG; within-day coefficients of variation for total and cardiac NE spillover were 5.9% and 6.2%.

    “Intra-assay coefficients of variation were 4.6% for plasma NE at a concentration of 200 pg/mL, 5.0% for MHPG at a concentration of 1000 pg/mL, 3.9% for DHPG at a concentration of 1000 pg/mL, 5.3% for 3 H-labeled NE at a concentration of 600 dpm/mL, and 8.2% for [ 3 H]DHPG at a concentration of 40 to 100 dpm/mL.”
    • Also stated in: § Retest Reliability of the Measures · plain
      “Within-day coefficients of variation for total and cardiac NE spillover under resting conditions are 5.9% and 6.2%.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [14]

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    Screening identified 13 DNA sequence variants of the NE transporter gene, of which 5 were interpreted as missense substitutions.

    “Screening of a mixed population of blood bank donors and psychiatric patients (with schizophrenia and bipolar affective disorder) recently lead to the identification of 13 DNA sequence variants of the NE transporter gene, of which 5 were interpreted as missense substitutions.21”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [21]

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    The transporter gene mutation in the postural tachycardia syndrome kindred differs from the 5 previously identified missense substitutions and is associated with almost total absence of transporter activity.

    “The transporter gene mutation recently described in the postural tachycardia syndrome kindred differs from the 5 identified earlier and is associated with almost total absence of transporter activity.9”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [9] source

      Not checked in the free run.

16 of 16

  • The paper relies on this without support.

    The higher BMI in lean hypertensive patients compared with lean normotensive subjects does not account for the observed differences in cardiac NE kinetics.

    “All lean hypertensive patients had a BMI of Ͻ27 kg/m 2 , but overall BMI was higher than that in lean subjects with normal blood pressure, with mean values of 25.1 and 23.1 kg/m 2 , respectively (PϽ0.05).”

  • The paper relies on this without support.

    If a genetic fault involving the NE transporter were present in obesity-related hypertension, it would produce phenotypic evidence of NE transporter dysfunction.

    “In obesity-related hypertension, there was no phenotypic evidence of NE transporter dysfunction.”

  • The paper relies on this without support.

    MHPG is an extraneuronal metabolite of NE.

    “The arterial plasma concentration of 3-methoxy-4hydroxylphenylglycol, an extraneuronal metabolite of NE, was elevated in lean hypertensives only (3942Ϯ1068 versus 3055Ϯ888 pg/mL in healthy subjects, PϽ0.05).”
3 of 3

Claims other papers make about this one

Each is checked against this paper’s own text: does it say what the citing paper says it does?

Self-check

Percentages, sums and reported differences re-computed from the paper’s own numbers.

Each contradiction between two passages listed here was confirmed by an independent check.

  • Healthy-subject MHPG mean differs between abstract and Table 2

    Minor

    The abstract reports a healthy-subject MHPG mean of 3055 pg/mL, while Table 2 and the Results report 3056 pg/mL.

1 of 1

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References 22 · Cited by 95

Research works printed but not linked: 1

  1. 10.1161/hyp.31.1.64 · DOI

Authors
Rumantir, M. S., Kaye, D. M., Jennings, G. L., Vaz, M., Hastings, J. A., & Esler, M. D.
Affiliations
  • The Alfred Hospital (AU)
  • From the Baker Medical Research Institute and Alfred Baker Medical Unit of the Alfred Hospital, Melbourne, Australia. Dr Vaz’s present address is Department of Physiology, St John’s Medical College, Bangalore, India.
ORCID
Venue
Hypertension
Publisher
Ovid Technologies (Wolters Kluwer Health)
Published
2000-11
Volume
36
Issue
5
Pages
824-829
ISSN
  • 0194-911X (ISSN-L)
  • 1524-4563
DOI
10.1161/01.hyp.36.5.824
OpenAlex
W2140595638
Cited by
95
References
22
Citations by year
2025: 2 · 2024: 3 · 2023: 1 · 2021: 4 · 2020: 1 · 2019: 2 · 2018: 6 · 2017: 1 · 2016: 4 · 2015: 1 · 2014: 4 · 2013: 4 · 2012: 4
FWCI
5.70
Type
journal article
Language
en
Open access
Locations
  • Hypertension (publishedVersion)
  • PubMed (publishedVersion)
Funders
  • Medical Research Council
  • National Health and Medical Research Council
  • National Medical Research Council
Topics
  • Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Blood Pressure and Hypertension Studies
  • Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Receptor Mechanisms and Signaling
Keywords
essential hypertension, norepinephrine uptake, cardiac sympathetic activity, neurogenic hypertension, obesity-related hypertension
MeSH terms
Adolescent, Adult, Aged, Female, Heart, Humans, Hypertension, Male, Middle Aged, Myocardium, Neurons, Norepinephrine, Obesity, Phenotype, Sympathetic Nervous System, Thinness

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