The DOI matches its Crossref record; 35 of the 35 references it cites were found in a registry or an index; 2 of the 19 sources its claims cite were checked for support.
Orthostatic Intolerance and Tachycardia Associated with Norepinephrine-Transporter Deficiency
Open accessAbstract
BACKGROUND: Orthostatic intolerance is a syndrome characterized by lightheadedness, fatigue, altered mentation, and syncope and associated with postural tachycardia and plasma norepinephrine concentrations that are disproportionately high in relation to sympathetic outflow. We tested the hypothesis that impaired functioning of the norepinephrine transporter contributes to the pathophysiologic mechanism of orthostatic intolerance. METHODS: In a patient with orthostatic intolerance and her relatives, we measured postural blood pressure, heart rate, plasma catecholamines, and systemic norepinephrine spillover and clearance, and we sequenced the norepinephrine-transporter gene and evaluated its function. RESULTS: The patient had a high mean plasma norepinephrine concentration while standing, as compared with the mean (+/-SD) concentration in normal subjects (923 vs. 439+/-129 pg per milliliter [5.46 vs. 2.59+/-0.76 nmol per liter]), reduced systemic norepinephrine clearance (1.56 vs. 2.42+/-0.71 liters per minute), impairment in the increase in the plasma norepinephrine concentration after the administration of tyramine (12 vs. 56+/-63 pg per milliliter [0.07 vs. 0.33+/-0.37 pmol per liter]), and a disproportionate increase in the concentration of plasma norepinephrine relative to that of dihydroxyphenylglycol. Analysis of the norepinephrine-transporter gene revealed that the proband was heterozygous for a mutation in exon 9 (encoding a change from guanine to cytosine at position 237) that resulted in more than a 98 percent loss of function as compared with that of the wild-type gene. Impairment of synaptic norepinephrine clearance may result in a syndrome characterized by excessive sympathetic activation in response to physiologic stimuli. The mutant allele in the proband's family segregated with the postural heart rate and abnormal plasma catecholamine homeostasis. CONCLUSIONS: Genetic or acquired deficits in norepinephrine inactivation may underlie hyperadrenergic states that lead to orthostatic intolerance.
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TL;DR
In a woman with orthostatic intolerance and her identical twin, the authors found evidence of impaired norepinephrine reuptake, including a heterozygous Ala457Pro mutation in the norepinephrine transporter gene that nearly abolished transporter function. The mutation tracked with higher standing heart rates and plasma norepinephrine and lower DHPG:norepinephrine ratios in relatives, suggesting a hyperadrenergic mechanism for some orthostatic intolerance.
Key findings
- The proband had a standing plasma norepinephrine concentration of 923 pg/mL versus 439±129 pg/mL in normal subjects, reduced systemic norepinephrine clearance of 1.56 versus 2.42±0.71 L/min, and a blunted plasma norepinephrine rise after tyramine of 12 versus 56±21 pg/mL.
- Plasma DHPG:norepinephrine ratios were low in the proband and her twin compared with normal subjects: supine 3.06 and 2.41 versus 5.52, and upright 1.05 and 1.17 versus 3.44.
- The proband was heterozygous for a G237C mutation in exon 9 of the norepinephrine transporter gene, producing Ala457Pro; expressed mutant transporter showed 2 percent or less of wild-type uptake activity, corresponding to more than 98 percent loss of function.
- The mother and four siblings were heterozygous for the mutation; heterozygous relatives had significantly higher standing heart rates and upright plasma norepinephrine concentrations and significantly lower DHPG:norepinephrine ratios, but none had the full syndrome. The mutation was absent in 254 unrelated persons.
Methods
- Case-family study of a 33-year-old proband with orthostatic intolerance, her identical twin, nine siblings, and their mother; clinical measurements included supine and upright blood pressure, heart rate, plasma catecholamines, tyramine challenge, and tritiated norepinephrine infusion with nitroprusside to assess spillover and clearance.
- Genetic and functional work included sequencing of norepinephrine-transporter gene exons, expression of wild-type and Ala457Pro cDNA in Chinese-hamster-ovary cells for tritiated norepinephrine uptake, and allele-specific oligonucleotide hybridization for genotyping.
- Comparisons used 10 normal subjects for blood pressure, heart rate, and catecholamines, 9 for tyramine response, and 8 for norepinephrine spillover and clearance; paired and unpaired t-tests were used with two-sided P values.
Limitations
- The paper states that the Ala457Pro mutation was not found in 254 unrelated persons and does not explain all cases of orthostatic intolerance; heterozygous relatives showed some abnormalities but none had the full syndrome, so other genetic or environmental factors likely contributed.
- Evident from the text: the study is very small, centered on one proband and her twin with limited family and normal comparison groups, and lacks independent replication.
- The functional evidence comes from heterologous cell expression rather than patient tissue, and the case-family design limits generalizability.
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Claims the paper makes
45 Own result · 21 Own interpretation · 11 No full text of the sources · 2 No basis given · 1 Supported · 1 Couldn’t confirm · 1 Not checked yet · 1 Own method · accuracy not yet measured
The cited sources that could be checked couldn’t confirm or dispute this claim.
In the paper
“A deficiency of the norepinephrine transporter may explain several of the clinical findings in patients with this disorder: the high heart rate in the supine position, the high plasma concentration of norepinephrine in association with the relatively low plasma concentration of dihydroxyphenylglycol, the impaired response of norepinephrine to tyramine, 13 the reduced systemic clearance of norepine”
§ OR THOSTATIC INTOLERANCE AND TACHYCARDIA ASSOCIATED WITH NOREPINEPHRINE-TRANSPOR TER DEFICIENCY ORTHOSTATIC INTOLERANCE AND TACHYCARDIA ASSOCIATED WITH NOREPINEPHRINE-TRANSPORTER DEFICIENCY > DISCUSSION
What the sources say
- Not checked — no full text of the sourcecites [13] Jacob G, 1999, Circulation source
- Could not verifycites [27] Furlan R, 1998, Circulation sourceExperimental — accuracy not yet measured
The Autonomic Control section reports elevated supine norepinephrine and tachycardia, but proposes a possible central nervous system abnormality rather than a norepinephrine-transporter deficiency. Searches for transporter deficiency, tyramine, and dihydroxyphenylglycol found no passage in our copy addressing the claimed explanation. (LLM, conf=0.76)
hedgedconditionalSingle case- Asserted: passes — The authors put it forward as true.
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In the paper
“Norepinephrine clearance did not change appreciably after the nitroprusside infusion in either the proband (1.76 liters per minute) or the normal subjects (2.31±0.68liters per minute).”
§ OR THOSTATIC INTOLERANCE AND TACHYCARDIA ASSOCIATED WITH NOREPINEPHRINE-TRANSPOR TER DEFICIENCY ORTHOSTATIC INTOLERANCE AND TACHYCARDIA ASSOCIATED WITH NOREPINEPHRINE-TRANSPORTER DEFICIENCY > Spillover and Clearance of Systemic Norepinephrine
plainSingle case- Asserted: passes — The authors put it forward as true.
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A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“In the proband and her twin, the plasma concentrations of dihydroxyphenylglycol, an intraneuronal metabolite of norepinephrine, 9 were low in relation to the plasma norepinephrine concentrations (ratio of dihydroxyphenylglycol to norepinephrine in the supine position, 3.06 in the proband and 2.41 in her twin, vs. 5.52 in the normal subjects; ratio in the upright position, 1.05 in the proband and 1”
§ OR THOSTATIC INTOLERANCE AND TACHYCARDIA ASSOCIATED WITH NOREPINEPHRINE-TRANSPOR TER DEFICIENCY ORTHOSTATIC INTOLERANCE AND TACHYCARDIA ASSOCIATED WITH NOREPINEPHRINE-TRANSPORTER DEFICIENCY > Autonomic Responses
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In the paper
“Direct sequence analysis of the norepinephrinetransporter gene in the proband revealed no divergence from previously published sequences 14,18 in exons 1 through 8 and exons 10 through 15.”
§ OR THOSTATIC INTOLERANCE AND TACHYCARDIA ASSOCIATED WITH NOREPINEPHRINE-TRANSPOR TER DEFICIENCY ORTHOSTATIC INTOLERANCE AND TACHYCARDIA ASSOCIATED WITH NOREPINEPHRINE-TRANSPORTER DEFICIENCY > Identification of a Functional Missense Mutation in the Norepinephrine-Transporter Gene
What the sources say
plainSingle case- Asserted: passes — The authors put it forward as true.
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A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“We evaluated a patient and her identical twin, both of whom had symptoms typical of orthostatic intolerance”
§ OR THOSTATIC INTOLERANCE AND TACHYCARDIA ASSOCIATED WITH NOREPINEPHRINE-TRANSPOR TER DEFICIENCY ORTHOSTATIC INTOLERANCE AND TACHYCARDIA ASSOCIATED WITH NOREPINEPHRINE-TRANSPORTER DEFICIENCY > Conclusions
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A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“reduced systemic norepinephrine clearance (1.56 vs. 2.42±0.71liters per minute)”
- Also stated in: § Spillover and Clearance of Systemic Norepinephrine · plain
“norepinephrine clearance in the proband was less than half that in the normal subjects (1.56 vs. 2.42±0.71liters per minute).”
§ OR THOSTATIC INTOLERANCE AND TACHYCARDIA ASSOCIATED WITH NOREPINEPHRINE-TRANSPOR TER DEFICIENCY ORTHOSTATIC INTOLERANCE AND TACHYCARDIA ASSOCIATED WITH NOREPINEPHRINE-TRANSPORTER DEFICIENCY > Results
plainSingle case- Asserted: passes — The authors put it forward as true.
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- Also stated in: § Spillover and Clearance of Systemic Norepinephrine · plain
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“The patient had a high mean plasma nor- epinephrine concentration while standing, as compared with the mean (±SD) concentration in normal subjects (923 vs. 439±129 pg per milliliter [5.46 vs. 2.59±0.76nmol per liter])”
§ OR THOSTATIC INTOLERANCE AND TACHYCARDIA ASSOCIATED WITH NOREPINEPHRINE-TRANSPOR TER DEFICIENCY ORTHOSTATIC INTOLERANCE AND TACHYCARDIA ASSOCIATED WITH NOREPINEPHRINE-TRANSPORTER DEFICIENCY > Results
plaincorrelationalSingle case- Asserted: passes — The authors put it forward as true.
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A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Analysis of the norepinephrine-transporter gene revealed that the proband was heterozygous for a mutation in exon 9 (encoding a change from guanine to cytosine at position 237)”
- Also stated in: § T ABLE 1. B LOOD P RESSURE , H EART R ATE , AND P LASMA C ATECHOLAMINE C ONCENTRATIONS IN THE P ROBAND , H ER T WIN S ISTER , AND 10 U · plain
“The proband was heterozygous for both the C154A and the G237C polymorphisms (Fig. 2A).”
§ OR THOSTATIC INTOLERANCE AND TACHYCARDIA ASSOCIATED WITH NOREPINEPHRINE-TRANSPOR TER DEFICIENCY ORTHOSTATIC INTOLERANCE AND TACHYCARDIA ASSOCIATED WITH NOREPINEPHRINE-TRANSPORTER DEFICIENCY > Results
plainSingle case- Asserted: passes — The authors put it forward as true.
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- Also stated in: § T ABLE 1. B LOOD P RESSURE , H EART R ATE , AND P LASMA C ATECHOLAMINE C ONCENTRATIONS IN THE P ROBAND , H ER T WIN S ISTER , AND 10 U · plain
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“The arterial plasma norepinephrine concentration at rest was slightly higher in the proband than in the normal subjects (280 pg per milliliter [1.66 nmol per liter] vs. 204±51 pg per milliliter [1.21±0.30nmol per liter]).”
§ OR THOSTATIC INTOLERANCE AND TACHYCARDIA ASSOCIATED WITH NOREPINEPHRINE-TRANSPOR TER DEFICIENCY ORTHOSTATIC INTOLERANCE AND TACHYCARDIA ASSOCIATED WITH NOREPINEPHRINE-TRANSPORTER DEFICIENCY > Spillover and Clearance of Systemic Norepinephrine
plaincorrelationalSingle case- Asserted: passes — The authors put it forward as true.
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A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“impairment in the increase in the plasma norepinephrine concentration after the administration of tyramine (12 vs. 56±63 pg per milliliter [0.07 vs. 0.33± 0.37 pmol per liter])”
- Also stated in: § Response to Tyramine · plain
“In the proband, the same dose of tyramine increased systolic blood pressure by 18 mm Hg but increased the plasma norepinephrine concentration by only 12 pg per milliliter (0.07 nmol per milliliter).”
§ OR THOSTATIC INTOLERANCE AND TACHYCARDIA ASSOCIATED WITH NOREPINEPHRINE-TRANSPOR TER DEFICIENCY ORTHOSTATIC INTOLERANCE AND TACHYCARDIA ASSOCIATED WITH NOREPINEPHRINE-TRANSPORTER DEFICIENCY > Results
plainSingle case- Asserted: passes — The authors put it forward as true.
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- Load-bearing: passes — The paper’s conclusions depend on it.
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- Also stated in: § Response to Tyramine · plain
- It may state two separate claims as one. 11
- Probably not a substantial claim. 2
Every source the paper cites for this claim was checked and supports it.
In the paper
“The dihydroxyphenylglycol then enters the circulation and can serve as a marker of norepinephrine uptake and monoamine oxidase activity 9 (Fig. 4).”
§ OR THOSTATIC INTOLERANCE AND TACHYCARDIA ASSOCIATED WITH NOREPINEPHRINE-TRANSPOR TER DEFICIENCY ORTHOSTATIC INTOLERANCE AND TACHYCARDIA ASSOCIATED WITH NOREPINEPHRINE-TRANSPORTER DEFICIENCY > DISCUSSION
What the sources say
- Supportedcites [9] source
The Introduction (p. 1) identifies DHPG as a norepinephrine metabolite present in human plasma. The Conclusions (p. 7) link plasma DHPG to neuronal norepinephrine uptake, and the DHPG/NE ratio discussion (p. 7) predicts a changed DHPG response when either uptake or monoamine oxidase is blocked. The paper presents this as information obtained from DHPG measured alongside norepinephrine, rather than as a standalone measure of enzyme activity. (LLM, conf=0.86)
plaincorrelational- Asserted: passes — The authors put it forward as true.
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It may state two separate claims as one.
- Supported
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“In the normal subjects, the mean (±SD) systolic blood pressure increased by 19±2 mm Hg and the mean plasma norepinephrine concentration increased by 56 ±21 pg per milliliter (0.33±0.12 nmol per liter) in response to 3 mg of tyramine.”
§ OR THOSTATIC INTOLERANCE AND TACHYCARDIA ASSOCIATED WITH NOREPINEPHRINE-TRANSPOR TER DEFICIENCY ORTHOSTATIC INTOLERANCE AND TACHYCARDIA ASSOCIATED WITH NOREPINEPHRINE-TRANSPORTER DEFICIENCY > Response to Tyramine
plaindirect- Asserted: passes — The authors put it forward as true.
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It may state two separate claims as one.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“The proband and her twin sister had normal autonomic reflexes, but their blood pressure and heart rate were variable (Fig. 1).”
§ OR THOSTATIC INTOLERANCE AND TACHYCARDIA ASSOCIATED WITH NOREPINEPHRINE-TRANSPOR TER DEFICIENCY ORTHOSTATIC INTOLERANCE AND TACHYCARDIA ASSOCIATED WITH NOREPINEPHRINE-TRANSPORTER DEFICIENCY > Autonomic Responses
plain- Asserted: passes — The authors put it forward as true.
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It may state two separate claims as one.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Their heart rates while supine were slightly but not significantly greater than those of their family members with the wild-type genotype, but their heart rates while standing were significantly higher (Fig. 3A and 3B).”
§ OR THOSTATIC INTOLERANCE AND TACHYCARDIA ASSOCIATED WITH NOREPINEPHRINE-TRANSPOR TER DEFICIENCY ORTHOSTATIC INTOLERANCE AND TACHYCARDIA ASSOCIATED WITH NOREPINEPHRINE-TRANSPORTER DEFICIENCY > Segregation of the Ala457Pro Mutation with a Phenotype
plain- Asserted: passes — The authors put it forward as true.
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It may state two separate claims as one.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Likewise, plasma norepinephrine concentrations in the supine position were somewhat higher and plasma norepinephrine concentrations in the upright position were significantly higher in the heterozygous family members than in those with the normal genotype (Fig. 3C and 3D).”
§ OR THOSTATIC INTOLERANCE AND TACHYCARDIA ASSOCIATED WITH NOREPINEPHRINE-TRANSPOR TER DEFICIENCY ORTHOSTATIC INTOLERANCE AND TACHYCARDIA ASSOCIATED WITH NOREPINEPHRINE-TRANSPORTER DEFICIENCY > Segregation of the Ala457Pro Mutation with a Phenotype
plaincorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
The paper states this without a source or data behind it here, so there is nothing to check it against. The quote shows it is in the paper.
In the paper
“In contrast, the Ala457Pro mutation renders the transporter nonfunctional and segregates with altered heart-rate regulation and altered norepinephrine metabolism.”
§ OR THOSTATIC INTOLERANCE AND TACHYCARDIA ASSOCIATED WITH NOREPINEPHRINE-TRANSPOR TER DEFICIENCY ORTHOSTATIC INTOLERANCE AND TACHYCARDIA ASSOCIATED WITH NOREPINEPHRINE-TRANSPORTER DEFICIENCY > DISCUSSION
plaincorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“In Chinese-hamster-ovary cells that had been transiently transfected with cDNA encoding the human norepinephrine transporter, uptake of tritiated norepinephrine was 10 times that in vector-transfected cells, whereas in cells transfected with cDNA encoding the Ala457Pro mutation in the norepinephrine transporter, the uptake was 2 percent or less (Fig. 2D).”
§ OR THOSTATIC INTOLERANCE AND TACHYCARDIA ASSOCIATED WITH NOREPINEPHRINE-TRANSPOR TER DEFICIENCY ORTHOSTATIC INTOLERANCE AND TACHYCARDIA ASSOCIATED WITH NOREPINEPHRINE-TRANSPORTER DEFICIENCY > T ABLE 1. B LOOD P RESSURE , H EART R ATE , AND P LASMA C ATECHOLAMINE C ONCENTRATIONS IN THE P ROBAND , H ER T WIN S ISTER , AND 10 U
plaindirect- Asserted: passes — The authors put it forward as true.
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It may state two separate claims as one.
In the paper
“Approximately 80 to 90 percent of the norepinephrine released into many synapses is cleared by this mechanism, and the remaining 10 to 20 percent spills over into the circulation or extraneuronal tissue.8”
§ OR THOSTATIC INTOLERANCE AND TACHYCARDIA ASSOCIATED WITH NOREPINEPHRINE-TRANSPOR TER DEFICIENCY ORTHOSTATIC INTOLERANCE AND TACHYCARDIA ASSOCIATED WITH NOREPINEPHRINE-TRANSPORTER DEFICIENCY > Conclusions
What the sources say
- Not checked — no full text of the sourcecites [8] Esler M, 1990, Physiol Rev source
plaindirect- Asserted: passes — The authors put it forward as true.
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It may state two separate claims as one.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“The reduced DHPG concentration in the neuron results in lower concentrations of this metabolite in the plasma and, consequently, a ratio of plasma DHPG to plasma norepinephrine that is lower than normal.”
§ OR THOSTATIC INTOLERANCE AND TACHYCARDIA ASSOCIATED WITH NOREPINEPHRINE-TRANSPOR TER DEFICIENCY ORTHOSTATIC INTOLERANCE AND TACHYCARDIA ASSOCIATED WITH NOREPINEPHRINE-TRANSPORTER DEFICIENCY > DISCUSSION
plaindirect- Asserted: passes — The authors put it forward as true.
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It may state two separate claims as one.
- Rests on an assumption: DHPG diffuses out of the neuron into the circulation.
What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“All samples of genomic DNA were coded before genotype analysis in order to preserve the anonymity of the subjects.”
§ OR THOSTATIC INTOLERANCE AND TACHYCARDIA ASSOCIATED WITH NOREPINEPHRINE-TRANSPOR TER DEFICIENCY ORTHOSTATIC INTOLERANCE AND TACHYCARDIA ASSOCIATED WITH NOREPINEPHRINE-TRANSPORTER DEFICIENCY > Genotyping of Ala457Pro Alleles
plain- Asserted: passes — The authors put it forward as true.
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- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Because acute pharmacologic blockade of the norepinephrine transporter causes a decrease in sympathetic outflow, 33 one would expect a decrease in sympathetic tone with a deficiency of the norepinephrine transporter.”
§ OR THOSTATIC INTOLERANCE AND TACHYCARDIA ASSOCIATED WITH NOREPINEPHRINE-TRANSPOR TER DEFICIENCY ORTHOSTATIC INTOLERANCE AND TACHYCARDIA ASSOCIATED WITH NOREPINEPHRINE-TRANSPORTER DEFICIENCY > DISCUSSION
hedgedconditional- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“In persons with norepinephrine-transporter deficiency, the release of norepinephrine into the synaptic space is normal, but because of the decreased activity of the norepinephrine transporter, less than 80 percent of norepinephrine is taken up into the neuron that released it, so that the spillover into the circulation is greater than 20 percent.”
§ OR THOSTATIC INTOLERANCE AND TACHYCARDIA ASSOCIATED WITH NOREPINEPHRINE-TRANSPOR TER DEFICIENCY ORTHOSTATIC INTOLERANCE AND TACHYCARDIA ASSOCIATED WITH NOREPINEPHRINE-TRANSPORTER DEFICIENCY > DISCUSSION
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
- Rests on an assumption: Approximately 80 percent of norepinephrine in the synaptic space is taken up by the norepinephrine transporter into the neuron that released it, and approximately 20 percent spills over into the circulation.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Because the substitution of proline disrupts alpha-helical secondary structures that are supported by alanine residues, this mutation may disrupt the transport of norepinephrine.”
§ OR THOSTATIC INTOLERANCE AND TACHYCARDIA ASSOCIATED WITH NOREPINEPHRINE-TRANSPOR TER DEFICIENCY ORTHOSTATIC INTOLERANCE AND TACHYCARDIA ASSOCIATED WITH NOREPINEPHRINE-TRANSPORTER DEFICIENCY > DISCUSSION
hedgedconditionalSingle case- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
The paper relies on this without support.
The in vitro loss of norepinephrine transport caused by the Ala457Pro mutation reflects impaired norepinephrine clearance in the patients.
“nephrine transport was greatly diminished by the Ala457Pro mutation.”
The paper relies on this without support.
Under normal conditions, norepinephrine is released from vesicles in the neuron into the synaptic space, where it can interact with presynaptic and postsynaptic alpha- and beta-adrenergic receptors.
“Under normal conditions, norepinephrine is released from vesicles in the neuron into the synaptic space, where it can interact with presynaptic and postsynaptic a-and b-adrenergic receptors.”
The paper relies on this without support.
Approximately 80 percent of norepinephrine in the synaptic space is taken up by the norepinephrine transporter into the neuron that released it, and approximately 20 percent spills over into the circulation.
“Approximately 80 percent of the norepinephrine in the synaptic space is taken up by the norepinephrine transporter into the neuron that released it, and approximately 20 percent spills over into the circulation.”
The paper relies on this without support.
Norepinephrine taken up by the neuron that released it is preferentially converted to DHPG by monoamine oxidase; some is repackaged into synaptic vesicles.
“Norepinephrine taken up by the neuron that released it is preferentially converted to dihydroxyphenylglycol (DHPG) by monoamine oxidase; some is repackaged into the synaptic vesicles.”
The paper relies on this without support.
DHPG diffuses out of the neuron into the circulation.
“DHPG diffuses out of the neuron into the circulation.”
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?
The source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
In the citing paper
“Many patients with POTS have increased sympathetic nervous system tone measured with direct nerve recordings 5 or biochemically with an elevated plasma norepinephrine on standing 6–8.”
From Propranolol Decreases Tachycardia and Improves Symptoms in the Postural Tachycardia Syndrome: Less Is More (2009) · cites this paper as [8]
Experimental — accuracy not yet measuredThe source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
In the citing paper
“With 1 notable exception of a particular mutation causing POTS in members of a single family, 37 no evidence supports a monogenic cause of POTS.”
From Diagnosis and management of postural orthostatic tachycardia syndrome (2022) · cites this paper as [37]
Experimental — accuracy not yet measuredIn the citing paper
“A very rare form of hyperadrenergic POTS is caused by a loss-of-function mutation in the gene for the norepinephrine transporter (NET) [54].”
From Postural tachycardia syndrome: beyond orthostatic intolerance (2015) · cites this paper as [54]
In the citing paper
“While many conditions, such as mast cell activation disorders (9), Ehlers-Danlos syndrome (10, 11), deconditioning (12), and genetic mutations of norepinephrine transporters (13), coexist with POTS, their downstream effects also funnel into these three principal pathophysiologic mechanisms.”
From Postural orthostatic tachycardia syndrome: mechanisms and new therapies (2020) · cites this paper as [13]
In the citing paper
“Shannon et al. (13) discovered a single missense mutation (ALA457Pro) in the norepinephrine transporter gene ( SLC6A2 ) that resulted in a 98% loss of function in the transporter and was present in two identical twins with POTS.”
From Postural orthostatic tachycardia syndrome: mechanisms and new therapies (2020) · cites this paper as [13]
In the citing paper
“Each twin had normal levels of supine plasma norepinephrine (269 pg/ml and 199 pg/ml), but standing plasma norepinephrine exceeded 900 pg/ml.”
From Postural orthostatic tachycardia syndrome: mechanisms and new therapies (2020) · cites this paper as [13]
In the citing paper
“Alteration of norepinephrine metabolism, congenital or iatrogenic, is another well-described cause of hyperadrenergic POTS.”
From Postural orthostatic tachycardia syndrome: mechanisms and new therapies (2020) · cites this paper as [13]
In the citing paper
“One of the twins even became hypertensive with standing (13).”
From Postural orthostatic tachycardia syndrome: mechanisms and new therapies (2020) · cites this paper as [13]
In the citing paper
“In certain cases, it may be possible to recognize key endophenotypes (13, 73, 79).”
From Postural orthostatic tachycardia syndrome: mechanisms and new therapies (2020) · cites this paper as [13]
In the citing paper
“A loss of function single point mutation in the NET gene SLC6A2 was identified in one family with orthostatic tachycardia”
From Postural tachycardia syndrome – Diagnosis, physiology, and prognosis (2018) · cites this paper as Shannon et al., 2000
In the citing paper
“In a subgroup of these patients, a rare mutation of norepinephrine-transporter gene was found, resulting in reduced synaptic norepinephrine reuptake and excessive sympathetic activation [56].”
From Postural orthostatic tachycardia syndrome: clinical presentation, aetiology and management (2019) · cites this paper as [56]
In the citing paper
“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.”
From Phenotypic Evidence of Faulty Neuronal Norepinephrine Reuptake in Essential Hypertension (2000) · cites this paper as [9]
In the citing paper
“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”
From Phenotypic Evidence of Faulty Neuronal Norepinephrine Reuptake in Essential Hypertension (2000) · cites this paper as [9]
In the citing paper
“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.”
From Phenotypic Evidence of Faulty Neuronal Norepinephrine Reuptake in Essential Hypertension (2000) · cites this paper as [9]
In the citing paper
“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”
From Phenotypic Evidence of Faulty Neuronal Norepinephrine Reuptake in Essential Hypertension (2000) · cites this paper as [9]
In the citing paper
“It should be kept in mind that sinus tachycardia paroxysms may be due to anxiety as in panic disorder44 (epinephrine-mediated), norepinephrine reuptake inhibition45 (a very rare condition; norepinephrine-mediated) or drug intake (e.g. beta-agonists in asthma).”
From Sinus Tachycardia: a Multidisciplinary Expert Focused Review (2022) · cites this paper as [45]
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.
Rated major: it would touch a result — a value a result rests on, reported and recomputed p-values on opposite sides of the significance level, two passages that conflict with no sign which is right, or a cited work retracted before this paper was published.
In the paper
§ OR THOSTATIC INTOLERANCE AND TACHYCARDIA ASSOCIATED WITH NOREPINEPHRINE-TRANSPOR TER DEFICIENCY ORTHOSTATIC INTOLERANCE AND TACHYCARDIA ASSOCIATED WITH NOREPINEPHRINE-TRANSPORTER DEFICIENCY > Results
“12 vs. 56±63 pg per milliliter”
§ OR THOSTATIC INTOLERANCE AND TACHYCARDIA ASSOCIATED WITH NOREPINEPHRINE-TRANSPOR TER DEFICIENCY ORTHOSTATIC INTOLERANCE AND TACHYCARDIA ASSOCIATED WITH NOREPINEPHRINE-TRANSPORTER DEFICIENCY > Response to Tyramine
“the mean plasma norepinephrine concentration increased by 56 ±21 pg per milliliter”
Rated major: it would touch a result — a value a result rests on, reported and recomputed p-values on opposite sides of the significance level, two passages that conflict with no sign which is right, or a cited work retracted before this paper was published.
In the paper
§ OR THOSTATIC INTOLERANCE AND TACHYCARDIA ASSOCIATED WITH NOREPINEPHRINE-TRANSPOR TER DEFICIENCY ORTHOSTATIC INTOLERANCE AND TACHYCARDIA ASSOCIATED WITH NOREPINEPHRINE-TRANSPORTER DEFICIENCY > Segregation of the Ala457Pro Mutation with a Phenotype
“The mother and four siblings (including the twin sister) were heterozygous for the mutant allele (Fig. 2E).”
§ OR THOSTATIC INTOLERANCE AND TACHYCARDIA ASSOCIATED WITH NOREPINEPHRINE-TRANSPOR TER DEFICIENCY ORTHOSTATIC INTOLERANCE AND TACHYCARDIA ASSOCIATED WITH NOREPINEPHRINE-TRANSPORTER DEFICIENCY > DISCUSSION
“the proband and nine family members (three family members with the Ala457Pro mutation and six with the normal genotype)”
Rated major: it would touch a result — a value a result rests on, reported and recomputed p-values on opposite sides of the significance level, two passages that conflict with no sign which is right, or a cited work retracted before this paper was published.
In the paper
§ OR THOSTATIC INTOLERANCE AND TACHYCARDIA ASSOCIATED WITH NOREPINEPHRINE-TRANSPOR TER DEFICIENCY ORTHOSTATIC INTOLERANCE AND TACHYCARDIA ASSOCIATED WITH NOREPINEPHRINE-TRANSPORTER DEFICIENCY > Results
“0.33± 0.37 pmol per liter”
§ OR THOSTATIC INTOLERANCE AND TACHYCARDIA ASSOCIATED WITH NOREPINEPHRINE-TRANSPOR TER DEFICIENCY ORTHOSTATIC INTOLERANCE AND TACHYCARDIA ASSOCIATED WITH NOREPINEPHRINE-TRANSPORTER DEFICIENCY > Response to Tyramine
“0.33±0.12 nmol per liter”
Rated minor: it would not touch a result — a value no result rests on, a p-value that stays on the same side of the significance level, or a conflict that is clerical, resolved elsewhere in the paper, or outside its own findings.
In the paper
“norepinephrine clearance in the proband was less than half that in the normal subjects (1.56 vs. 2.42±0.71liters per minute)”
§ OR THOSTATIC INTOLERANCE AND TACHYCARDIA ASSOCIATED WITH NOREPINEPHRINE-TRANSPOR TER DEFICIENCY ORTHOSTATIC INTOLERANCE AND TACHYCARDIA ASSOCIATED WITH NOREPINEPHRINE-TRANSPORTER DEFICIENCY > Spillover and Clearance of Systemic Norepinephrine
Reported 0.5 · recomputed 0.644628
Rated minor: it would not touch a result — a value no result rests on, a p-value that stays on the same side of the significance level, or a conflict that is clerical, resolved elsewhere in the paper, or outside its own findings.
In the paper
§ OR THOSTATIC INTOLERANCE AND TACHYCARDIA ASSOCIATED WITH NOREPINEPHRINE-TRANSPOR TER DEFICIENCY ORTHOSTATIC INTOLERANCE AND TACHYCARDIA ASSOCIATED WITH NOREPINEPHRINE-TRANSPORTER DEFICIENCY > DISCUSSION
“This change from cytosine to guanine results in a change from alanine to proline at amino acid position 457 (Ala457Pro).”
§ OR THOSTATIC INTOLERANCE AND TACHYCARDIA ASSOCIATED WITH NOREPINEPHRINE-TRANSPOR TER DEFICIENCY ORTHOSTATIC INTOLERANCE AND TACHYCARDIA ASSOCIATED WITH NOREPINEPHRINE-TRANSPORTER DEFICIENCY > T ABLE 1. B LOOD P RESSURE , H EART R ATE , AND P LASMA C ATECHOLAMINE C ONCENTRATIONS IN THE P ROBAND , H ER T WIN S ISTER , AND 10 U
“a missense mutation in which guanine was replaced by cytosine at position 237 (G237C)”
Rated minor: it would not touch a result — a value no result rests on, a p-value that stays on the same side of the significance level, or a conflict that is clerical, resolved elsewhere in the paper, or outside its own findings.
In the paper
§ OR THOSTATIC INTOLERANCE AND TACHYCARDIA ASSOCIATED WITH NOREPINEPHRINE-TRANSPOR TER DEFICIENCY ORTHOSTATIC INTOLERANCE AND TACHYCARDIA ASSOCIATED WITH NOREPINEPHRINE-TRANSPORTER DEFICIENCY > Response to Tyramine
“increased the plasma norepinephrine concentration by only 12 pg per milliliter (0.07 nmol per milliliter)”
§ OR THOSTATIC INTOLERANCE AND TACHYCARDIA ASSOCIATED WITH NOREPINEPHRINE-TRANSPOR TER DEFICIENCY ORTHOSTATIC INTOLERANCE AND TACHYCARDIA ASSOCIATED WITH NOREPINEPHRINE-TRANSPORTER DEFICIENCY > Identification of a Functional Missense Mutation in the Norepinephrine-Transporter Gene
“To convert values for plasma norepinephrine to nanomoles per liter, multiply by 0.005911.”
Citations
Cites
Expression cloning of a cocaine-and antidepressant-sensitive human noradrenaline transporter
Pacholczyk, T., Blakely, R. D., & Amara, S. G. (1991) · Nature · doi:10.1038/350350a0 · Cited by 933
Self-citationOverflow of catecholamine neurotransmitters to the circulation: source, fate, and functions
Esler, M., Jennings, G., Lambert, G., Meredith, I., Horne, M., & Eisenhofer, G. (1990) · Physiological Reviews · doi:10.1152/physrev.1990.70.4.963 · Cited by 794
Idiopathic postural orthostatic tachycardia syndrome: An attenuated form of acute pandysautonomia?
Schondorf, R., & Low, P. A. (1993) · Neurology · doi:10.1212/wnl.43.1_part_1.132 · Cited by 548
Molecular Physiology of Norepinephrine and Serotonin Transporters
Blakely, R. D., De Felice, L. J., & Hartzell, H. C. (1994) · Journal of Experimental Biology · doi:10.1242/jeb.196.1.263 · Cited by 404
Self-citationADLER‐GRASCHINSKY, E., & LANGER, S. Z. (1975) · British Journal of Pharmacology · doi:10.1111/j.1476-5381.1975.tb07328.x · Cited by 335
Postural tachycardia syndrome (POTS)
Lamotte, G., & Low, P. A. (2023) · Elsevier eBooks · doi:10.1016/b978-0-323-85492-4.00118-6 · Cited by 301
Plasma dihydroxyphenylglycol and the intraneuronal disposition of norepinephrine in humans.
Goldstein, D. S., Eisenhofer, G., Stull, R., Folio, C. J., Keiser, H. R., & Kopin, I. J. (1988) · Journal of Clinical Investigation · doi:10.1172/jci113298 · Cited by 245
Chronic Orthostatic Intolerance: A Disorder With Discordant Cardiac and Vascular Sympathetic Control
Furlan, R., Jacob, G., Snell, M., Robertson, D., Porta, A., Harris, P., & Mosqueda-Garcia, R. (1998) · Circulation · doi:10.1161/01.cir.98.20.2154 · Cited by 229
Self-citationEffects of volume loading and pressor agents in idiopathic orthostatic tachycardia
Jacob, G., Shannon, J. R., Black, B., Biaggioni, I., Mosqueda-Garcia, R., Robertson, R. M., & Robertson, D. (1997) · Circulation · doi:10.1161/01.cir.96.2.575 · Cited by 206
Self-citationHypocapnia and Cerebral Hypoperfusion in Orthostatic Intolerance
Novak, V., Spies, J. M., Novak, P., McPhee, B. R., Rummans, T. A., & Low, P. A. (1998) · Stroke · doi:10.1161/01.str.29.9.1876 · Cited by 191
Research works printed but not linked: 6
- Low PA, 1995, Neurology, 45, S19
- Apparsundaram S, 1998, J Pharmacol Exp Ther, 287, 733
- Davis D, 1987, Circ Res, 61, I87
- Tung CS, 1983, J Pharmacol Exp Ther, 227, 484
- Esler MD, 1991, Am J Physiol, 260, R817
- Shannon JR, 1998, Circulation, 98, I
Cited by
Sorted by citations
Items 101–200 of 595
Postural Orthostatic Tachycardia Syndrome: Prevalence, Pathophysiology, and Management
Zadourian, A., Doherty, T. A., Swiatkiewicz, I., & Taub, P. R. (2018) · Drugs · doi:10.1007/s40265-018-0931-5 · Cited by 90
“Within the primary hyperadrenergic subtype, there is a loss-of-function mutation that causes a norepinephrine transporter (NET) deficiency [33].”
BackgroundBurnweit, C. A., Zerpa, J., Nahmad, M., Lankau, C. A., Weinberger, M., Malvezzi, L., Smith, L., Shapiro, T., & Thayer, K. (2004) · Journal of Pediatric Surgery · doi:10.1016/j.jpedsurg.2003.11.037 · Cited by 92
Disorders of the Autonomic Nervous System
Chelimsky, T. C., Robertson, D. M., & Chelimsky, G. G. (2012) · Elsevier eBooks · doi:10.1016/b978-1-4377-0434-1.00102-x · Cited by 87
Self-citationCastéra, L., Nègre, I., Samii, K., & Buffet, C. (2001) · The American Journal of Gastroenterology · doi:10.1111/j.1572-0241.2001.03776.x · Cited by 84
Paradoxical Effect of Sibutramine on Autonomic Cardiovascular Regulation
Birkenfeld, A. L., Schroeder, C., Boschmann, M., Tank, J., Franke, G., Luft, F. C., Biaggioni, I., Sharma, A. M., & Jordan, J. (2002) · Circulation · doi:10.1161/01.cir.0000036370.31856.73 · Cited by 85
Self-citationHahn, M. K., Mazei‐Robison, M. S., & Blakely, R. (2005) · Molecular Pharmacology · doi:10.1124/mol.105.011270 · Cited by 86
“1) (Halushka et al., 1999; Runkel et al., 2000; Shannon et al., 2000; Iwasa et al., 2001; Hahn et al., 2003).”
BackgroundInfluentialSelf-citationEsler, M. (2001) · American Journal of Hypertension · doi:10.1016/s0895-7061(01)02081-7 · Cited by 84
Jordan, J., Ricci, F., Hoffmann, F., Hamrefors, V., & Fedorowski, A. (2020) · Hypertension · doi:10.1161/hypertensionaha.120.14340 · Cited by 89
Self-citationSmall-fiber neuropathy with cardiac denervation in postural tachycardia syndrome
Haensch, C., Tosch, M., Katona, I., Weis, J., & Isenmann, S. (2014) · Muscle & Nerve · doi:10.1002/mus.24245 · Cited by 79
“However, NET dysfunction is rare.(37) Moreover, decreased (albeit slightly) innervation of the skin encourages the view that we have identified a partial sympathetic dysfunction.”
BackgroundRobertson, S. D., Matthies, H. J. G., Owens, W. A., Sathananthan, V., Christianson, N. S. B., Kennedy, J. P., Lindsley, C. W., Daws, L. C., & Galli, A. (2010) · Journal of Neuroscience · doi:10.1523/jneurosci.0126-10.2010 · Cited by 82
“…plays a pivotal role in controlling global noradrenergic tone, and its aberrant regulation has the capacity to impact mental health (Ganguly et al., 1986; Klimek et al., 1997; Rumantir et al., 2000; Shannon et al., 2000; Hahn et al., 2003, 2005, 2008, 2009; Kim et al., 2006; Haenisch et al., 2008).”
BackgroundThe neuronal noradrenaline transporter, anxiety and cardiovascular disease
Esler, M., Alvarenga, M. E., Pier, C., Richards, J., El‐Osta, A., Barton, D., Haikerwal, D., Kaye, D. M., Schlaich, M. P., Guo, L. J., et al. (2006) · Journal of Psychopharmacology · doi:10.1177/1359786806066055 · Cited by 78
Sympathetic Nerve Activity in Response to Hypotensive Stress in the Postural Tachycardia Syndrome
Bonyhay, I., & Freeman, R. L. (2004) · Circulation · doi:10.1161/01.cir.0000147280.90339.e9 · Cited by 78
Clozapine-Induced Cardiovascular Side Effects and Autonomic Dysfunction: A Systematic Review
Yuen, J. W. Y., Kim, D. D., Procyshyn, R. M., White, R. F., Honer, W. G., & Barr, A. M. (2018) · Frontiers in Neuroscience · doi:10.3389/fnins.2018.00203 · Cited by 79
“…Masuo et al., 2003; Schlaich et al., 2004), left ventricular hypertrophy (Zoccali Frontiers in Neuroscience | www.frontiersin.org 6 April 2018 | Volume 12 | Article 203 et al., 2002; Schlaich et al., 2003) and postural tachycardia (Shannon et al., 2000; Goldstein et al., 2002; Mayer et al., 2006).”
BackgroundOrthostatic intolerance in pediatrics
Stewart, J. M. (2002) · The Journal of Pediatrics · doi:10.1067/mpd.2002.122727 · Cited by 77
Wilson, K. E., Welbury, R. R., & Girdler, N. M. (2002) · Anaesthesia · doi:10.1046/j.1365-2044.2002.02784.x · Cited by 77
Urwin, R., Bennetts, B., Wilcken, B. M., Lampropoulos, B., Beumont, P. J. V., Clarke, S., Russell, J. D., Tanner, S. L., & Nunn, K. (2002) · Molecular Psychiatry · doi:10.1038/sj.mp.4001080 · Cited by 76
Choline transporter gene variation is associated with attention-deficit hyperactivity disorder
English, B. A., Hahn, M. K., Gizer, I., Mazei-Robison, M., Steele, A., Kurnik, D., Stein, M., Waldman, I., & Blakely, R. (2009) · Journal of Neurodevelopmental Disorders · doi:10.1007/s11689-009-9033-8 · Cited by 65
“Although other coding variants in neurotransmitter transporters are known to act dominantly that could be explained by dominantnegative interactions [66–68], similar information is not yet available for the CHT Val89 variant.”
BackgroundSelf-citationClemow, D. B., & Bushe, C. (2015) · Journal of Psychopharmacology · doi:10.1177/0269881115602489 · Cited by 79
“Thus, the extent of NET blockade (reduced neuronal uptake) can be readily determined by using the cerebral spinal fluid (CSF), plasma, or urine DHPG:norepinephrine ratio as a specific biomarker for NET blockade (Bieck and Potter, 2005; Shannon et al., 2000; Vincent et al., 2004).”
BackgroundA review of postural orthostatic tachycardia syndrome
Carew, S., ́Connor, M. O., Cooke, J., Conway, R. P., Sheehy, C. M., Costelloe, Á., & Lyons, D. (2008) · EP Europace · doi:10.1093/europace/eun324 · Cited by 73
“Genetic A gene mutation encoding the NA transporter protein has been described in patients with POTS phenotype.(18) This protein normally allows reuptake of NA from the synaptic cleft.”
BackgroundPreemptive Analgesia at the Crossroad
Kissin, I. (2005) · Anesthesia & Analgesia · doi:10.1213/01.ane.0000144429.39988.9b · Cited by 76
Vašků, A., Goldbergová, M. P., Hollá, L. I., et al. (2004) · Matrix Biology · doi:10.1016/j.matbio.2003.10.004 · Cited by 72
Inhibition of the Norepinephrine Transporter by the Venom Peptide χ-MrIA
Sharpe, I. A., Palant, E., Schroeder, C. I., Kaye, D. M., Adams, D. J., Alewood, P. F., & Lewis, R. J. (2003) · Journal of Biological Chemistry · doi:10.1074/jbc.m213030200 · Cited by 72
Splanchnic-mesenteric capacitance bed in the postural tachycardia syndrome (POTS)
Tani, H., Singer, W., McPhee, B. R., Opfer-Gehrking, T. L., Haruma, K., Kajiyama, G., & Low, P. A. (2000) · Autonomic Neuroscience · doi:10.1016/s1566-0702(00)00205-8 · Cited by 71
Baroreflex control of muscle sympathetic nerve activity in postural orthostatic tachycardia syndrome
Muenter Swift, N., Charkoudian, N., Dotson, R. M., Suarez, G. A., & Low, P. A. (2005) · American Journal of Physiology-Heart and Circulatory Physiology · doi:10.1152/ajpheart.01243.2004 · Cited by 70
“transporter function was identified and shown to track with orthostatic tachycardia among members of an individual family ( 36 ).”
BackgroundJordan, J., Shannon, J. R., Diedrich, A., Black, B. K., & Robertson, D. (2002) · Hypertension · doi:10.1161/hy1201.097202 · Cited by 69
Self-citationPhysiological Genomics of Antidepressant Targets: Keeping the Periphery in Mind
Blakely, R. (2001) · Journal of Neuroscience · doi:10.1523/jneurosci.21-21-08319.2001 · Cited by 69
“…regulation of these transporters, particularly the antidepressant-sensitive norepinephrine (NE) transporters (NETs) and serotonin (5-HT) transporters (SERTs), I am puzzled that only a single, validated coding polymorphism has been identified that supports a clinical syndrome (Shannon et al., 2000).”
BackgroundInfluentialSelf-citationSelective Impairment in Sympathetic Vasomotor Control With Norepinephrine Transporter Inhibition
Tank, J., Schroeder, C., Diedrich, A., Szczech, E., Haertter, S., Sharma, A. M., Luft, F. C., & Jordan, J. (2003) · Circulation · doi:10.1161/01.cir.0000072786.99163.fe · Cited by 66
“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.”
BackgroundSelf-citationOrthostatic Intolerance: A Disorder of Young Women
Ali, Y. S., Daamen, N., Jacob, G., Jordan, J., Shannon, J. R., Biaggioni, I., & Robertson, D. (2000) · Obstetrical & Gynecological Survey · doi:10.1097/00006254-200004000-00025 · Cited by 64
Self-citationA comparison of oral midazolam and nitrous oxide sedation for dental extractions in children
Wilson, K. E., Girdler, N. M., & Welbury, R. R. (2006) · Anaesthesia · doi:10.1111/j.1365-2044.2006.04835.x · Cited by 67
Familial orthostatic tachycardia due to norepinephrine transporter deficiency
ROBERTSON, D., FLATTEM, N., TELLIOGLU, T., CARSON, R., GARLAND, E., SHANNON, J. R., JORDAN, J., JACOB, G., BLAKELY, R. D., & BIAGGIONI, I. (2001) · Annals of the New York Academy of Sciences · doi:10.1111/j.1749-6632.2001.tb03703.x · Cited by 64
Self-citationEffects of Norepinephrine Reuptake Inhibition on Postural Tachycardia Syndrome
Green, E. A., Raj, V., Shibao, C. A., Biaggioni, I., Black, B. K., Dupont, W. D., Robertson, D., & Raj, S. R. (2013) · Journal of the American Heart Association · doi:10.1161/jaha.113.000395 · Cited by 64
“The first indication that altered NET activity was implicated in the hyperadrenergic state observed in POTS came from the study of a 33-year-old female with a 20-year history of orthostatic tachycardia (among other symptoms of orthostatic intolerance).(32) In response to upright posture, she experienced a 4-fold incre…”
BackgroundSelf-citationHorvath, G., Sutto, Z., Torbati, A., Conner, G., Salathe, M., & Wanner, A. (2003) · American Journal of Physiology - Lung cellular and Molecular Physiology · doi:10.1152/ajplung.00054.2003 · Cited by 66
Wyller, V. B., Saul, J. P., Walløe, L., & Thaulow, E. (2007) · European Journal of Applied Physiology · doi:10.1007/s00421-007-0634-1 · Cited by 63
“In a detailed study of adult POTS-patients, Jacob et al. found reduced norepinephrine reuptake in the sympathetic synapse (Jacob et al. 1999), and a mutation in the norepinephrine reuptake protein was indeed documented in a pair of twins suVering from POTS (Shannon et al. 2000).”
Keller, N. R., Diedrich, A., Appalsamy, M., Tuntrakool, S., Lonce, S., Finney, C., Caron, M. G., & Robertson, D. (2004) · Circulation · doi:10.1161/01.cir.0000141804.90845.e6 · Cited by 62
Self-citationLimb venous compliance in patients with idiopathic orthostatic intolerance and postural tachycardia
Freeman, R., Lirofonis, V., Farquhar, W. B., & Risk, M. (2002) · Journal of Applied Physiology · doi:10.1152/japplphysiol.00817.2001 · Cited by 61
“Pathophysiological mechanisms proposed to explain the tachycardia and symptoms of orthostatic intolerance include hypovolemia (7), cardiac 2-adrenoreceptor supersensitivity, impaired clearance of synaptic norepinephrine (28), baroreflex dysfunction (6), and selective sympathetic denervation affecting predominantly the…”
BackgroundPostural Tachycardia Syndrome in Children and Adolescents
Jarjour, I. T. (2013) · Seminars in Pediatric Neurology · doi:10.1016/j.spen.2013.01.001 · Cited by 61
Cardiac hypertrophy in neonatal nephrectomized rats: the role of the sympathetic nervous system
Ghosh, S. S., Krieg, R. J., Sica, D. A., Wang, R., Fakhry, I., & Gehr, T. W. B. (2008) · Pediatric Nephrology · doi:10.1007/s00467-008-0978-8 · Cited by 61
“The increase in NE in this patient was due to decreased clearance of NE [18], which also reflects that decreased NET can result in increased circulating catecholamines.”
BackgroundInfluentialSubstrate Binding Stoichiometry and Kinetics of the Norepinephrine Transporter
Schwartz, J. W., Novarino, G., Piston, D. W., & DeFelice, L. J. (2005) · Journal of Biological Chemistry · doi:10.1074/jbc.m412923200 · Cited by 60
Acetylcholinesterase Inhibition in Patients With Orthostatic Intolerance
Singer, W., Opfer-Gehrking, T. L., Nickander, K. K., Hines, S. M., & Low, P. A. (2006) · Journal of Clinical Neurophysiology · doi:10.1097/01.wnp.0000229946.01494.4c · Cited by 60
“Antiganglionic antibodies have been described in some patients with OI, and a norepinephrine transporter deficiency has been described in one family (Shannon et al., 2000; Vernino et al., 2000).”
BackgroundCerebral Autoregulation in Orthostatic Intolerance
Schondorf, R., Benoit, J., & Stein, R. D. (2001) · Annals of the New York Academy of Sciences · doi:10.1111/j.1749-6632.2001.tb03702.x · Cited by 58
Mendelian Forms of Human Hypertension and Mechanisms of Disease
Luft, F. C. (2003) · Clinical Medicine & Research · doi:10.3121/cmr.1.4.291 · Cited by 57
Sinus Tachycardia: a Multidisciplinary Expert Focused Review
Mayuga, K. A., Fedorowski, A., Ricci, F., Gopinathannair, R., Dukes, J. W., Gibbons, C., Hanna, P., Sorajja, D., Chung, M., Benditt, D., et al. (2022) · Circulation: Arrhythmia and Electrophysiology · doi:10.1161/circep.121.007960 · Cited by 59
Lin, Z., Canales, J. J., Björgvinsson, Þ., Thomsen, M., Qu, H., Liu, Q., Torres, G. E., & Caine, S. B. (2011) · Progress in molecular biology and translational science · doi:10.1016/b978-0-12-385506-0.00001-6 · Cited by 61
Sympathetic dysfunction in vasovagal syncope and the postural orthostatic tachycardia syndrome
Lambert, É., & Lambert, G. W. (2014) · Frontiers in Physiology · doi:10.3389/fphys.2014.00280 · Cited by 56
“The first indication that altered NET activity was implicated in the hyperadrenergic state observed in POTS came from the study of a 33-year-old female with a 20-year history of POTS (Shannon et al., 2000).”
BackgroundContemporary dental photography: selection and application.
Terry, D. A., Snow, S. R., & McLaren, E. A. (2008) · PubMed · Cited by 57
Epigenetic Modification of the Norepinephrine Transporter Gene in Postural Tachycardia Syndrome
Bayles, R., KN, H., Lambert, E., Baker, E. K., Agrotis, A., Guo, L., Jowett, J. B. M., Esler, M., Lambert, G., & El-Osta, A. (2012) · Arteriosclerosis, Thrombosis, and Vascular Biology · doi:10.1161/atvbaha.111.244343 · Cited by 56
“Direct sequence analysis of the SLC6A2 gene has been performed in many patients, but to date a loss of function coding region mutation of the SLC6A2 gene has been found in 1 family kindred only.(6,22) Extensive analysis of SLC6A2 gene polymorphisms in the present study identified no genotype that could explain a dysfu…”
BackgroundInfluentialZhao, Y., & Sun, L. S. (2008) · Journal of Clinical Neuroscience · doi:10.1016/j.jocn.2007.11.007 · Cited by 56
Bauman, P. A., & Blakely, R. (2002) · Archives of Biochemistry and Biophysics · doi:10.1016/s0003-9861(02)00232-1 · Cited by 56
Self-citationMayer, A. F., Schroeder, C., Heusser, K., Tank, J., Diedrich, A., Schmieder, R. E., Luft, F. C., & Jordan, J. (2006) · Hypertension · doi:10.1161/01.hyp.0000225424.13138.5d · Cited by 55
Self-citationNeuronal and hormonal perturbations in postural tachycardia syndrome
Mar, P. L., & Raj, S. R. (2014) · Frontiers in Physiology · doi:10.3389/fphys.2014.00220 · Cited by 52
Bhat, S., El‐Kasaby, A., Freissmuth, M., & Sučić, S. (2020) · Pharmacology & Therapeutics · doi:10.1016/j.pharmthera.2020.107785 · Cited by 53
Neurotransmitter transporters: why dance with so many partners?
González, M. I. (2003) · Current Opinion in Pharmacology · doi:10.1016/j.coph.2003.09.004 · Cited by 52
“As might be expected, recent studies are starting to associate polymorphisms or mutations with a variety of diseases, including orthostatic intolerance, autism and stressinduced depression [1,2 ,3] (for reviews, see [4,5 ]).”
BackgroundLeitch, J., Anderson, K., Gambhir, S., Millar, K., Robb, N. D., McHugh, S., & Kenny, G. N. C. (2004) · Anaesthesia · doi:10.1111/j.1365-2044.2004.03761.x · Cited by 53
Marques, F. Z., Eikelis, N., Bayles, R., Lambert, É., Straznicky, N. E., Hering, D., Esler, M., Head, G. A., Barton, D. A., Schlaich, M. P., et al. (2016) · Molecular Psychiatry · doi:10.1038/mp.2016.40 · Cited by 51
Grubb, B. P., Kanjwal, M. Y., & KOSINSKI, D. J. (2001) · Journal of Interventional Cardiac Electrophysiology · doi:10.1023/a:1009845521949 · Cited by 51
“This concept was recently con®rmed in a brilliant paper by Robertson's group at Vanderbilt, where the exact genes responsible for this disorder were isolated in one severely affected family [21].”
Vagal and Sympathetic Function in Neuropathic Postural Tachycardia Syndrome
Jacob, G., Diedrich, L., Sato, K., Brychta, R. J., Raj, S. R., Robertson, D., Biaggioni, I., & Diedrich, A. (2019) · Hypertension · doi:10.1161/hypertensionaha.118.11803 · Cited by 51
Self-citationFarhan, H., Freissmuth, M., & Sitte, H. H. (2006) · Handbook of experimental pharmacology · doi:10.1007/3-540-29784-7_12 · Cited by 49
“Amphetamines differ in their affinities for monoamine transporters: for instance, d-amphetamine predominantly targets DAT while MDMA acts mainly on SERT ( Seiden et al. 1993; Green et al. 2003).”
BackgroundSympathetic Activation in Adipose Tissue and Skeletal Muscle of Hypertensive Rats
Cabassi, A., Vinci, S., Cantoni, A. M., Quartieri, F., Moschini, L., Cavazzini, S., Cavatorta, A., & Borghetti, A. (2002) · Hypertension · doi:10.1161/hy0202.103471 · Cited by 49
Sinus tachyarrhythmias and the specific bradycardic agents: a marriage made in heaven?
Yusuf, S., & Camm, A. J. (2003) · Journal of Cardiovascular Pharmacology and Therapeutics · doi:10.1177/107424840300800202 · Cited by 48
“In certain cases of this form of POTS, the basic abnormality responsible is a defective norepinephrine-transporter mechanism (109).”
BackgroundMazei‐Robison, M. S., & Blakely, R. (2005) · Neuropharmacology · doi:10.1016/j.neuropharm.2005.08.012 · Cited by 47
Self-citationEshragh, J. L., Dhruva, A., Paul, S. M., Cooper, B. A., Mastick, J., Hamolsky, D., Levine, J. D., Miaskowski, C. A., & Kober, K. M. (2016) · Journal of Pain and Symptom Management · doi:10.1016/j.jpainsymman.2016.08.004 · Cited by 48
“Mutations in the SLCA2 gene are associated with orthostatic intolerance, a syndrome that includes fatigue as a significant symptom.(114,116) In addition, polymorphisms in the SLCA2 gene were associated with major depression, a condition that includes fatigue as a major symptom.”
Effects of graded LBNP on MSNA and interstitial norepinephrine
Khan, M. H., Sinoway, L. I., & MacLean, D. A. (2002) · American Journal of Physiology-Heart and Circulatory Physiology · doi:10.1152/ajpheart.00412.2001 · Cited by 47
SLC6 Transporter Folding Diseases and Pharmacochaperoning
Freissmuth, M., Stockner, T., & Sucic, S. (2017) · Handbook of experimental pharmacology · doi:10.1007/164_2017_71 · Cited by 42
Cardiovascular effects of xenon and nitrous oxide in patients during fentanyl‐midazolam anaesthesia*
Goto, T., Hanne, P., Ishiguro, Y., Ichinose, F., Niimi, Y., & Morita, S. (2004) · Anaesthesia · doi:10.1111/j.1365-2044.2004.03900.x · Cited by 47
Miranda, N. A., Boris, J. R., Kouvel, K., & Stiles, L. E. (2018) · Neurology Report · doi:10.1097/npt.0000000000000231 · Cited by 47
Norepinephrine transporter inhibition prevents tilt-induced pre-syncope
Schroeder, C., Birkenfeld, A. L., Mayer, A. F., Tank, J., Diedrich, A., Luft, F. C., & Jordan, J. (2006) · Journal of the American College of Cardiology · doi:10.1016/j.jacc.2006.04.073 · Cited by 45
Self-citationKanjwal, K., Saeed, B., Karabin, B., Kanjwal, Y., & Grubb, B. P. (2011) · Cardiology Journal · doi:10.5603/cj.2011.0008 · Cited by 46
“Beta-blockers and centrally acting sympatholytics like clonidine, by counteracting the excess norepinephrine either by decreasing the centrally mediated release or by receptor blockage, may result in a substantial decline in norepinephrine mediated effects [1, 2, 8, 15, 16].”
BackgroundStress-Related Programming of Autonomic Imbalance: Role in Allergy and Asthma
Wright, R. J. (2012) · Chemical immunology/Fortschritte der Allergielehre/Progress in allergy/Chemical immunology and allergy · doi:10.1159/000336496 · Cited by 45
Goldstein, D. S., & Cheshire, W. P. (2017) · Clinical Autonomic Research · doi:10.1007/s10286-017-0425-7 · Cited by 46
Adam, B., Liebregts, T., & Holtmann, G. (2007) · Nature Clinical Practice Gastroenterology & Hepatology · doi:10.1038/ncpgasthep0717 · Cited by 44
“Synaptic levels of norepinephrine are modulated by the norepinephrine transporter (also known as the sodium-dependent noradrenaline transporter), and in one family it has been shown that a mutation in SLC6A2 , the gene that encodes the norepinephrine transporter, is associated with autonomic dysfunction”
BackgroundMárquez, M. F., Urias, K., Hermosillo, A. G., JARDON, J., Iturralde-Torres, P., Colín, L., Nava, S., & CARDENAS, M. (2005) · EP Europace · doi:10.1016/j.eupc.2005.05.004 · Cited by 45
“Recently, a mutation resulting in a deficiency of the noradrenaline transporter was found in a family with postural orthostatic tachycardia syndrome, a disease associated with postural syncope [12].”
BackgroundSubcellular localization of the antidepressant-sensitive norepinephrine transporter
Matthies, H. J. G., Han, Q., Shields, A. D., Wright, J., Moore, J. L., Winder, D. G., Galli, A., & Blakely, R. (2009) · BMC Neuroscience · doi:10.1186/1471-2202-10-65 · Cited by 43
“NET dysfunction has been linked to attention, mood and cardiovascular disorders [17-25].”
BackgroundSelf-citationLiao, Y., & Du, J. (2020) · Neuroscience Bulletin · doi:10.1007/s12264-020-00497-4 · Cited by 46
“In addition, a mutation of the SLC6A2 gene encoding the NE transporter has been found in some patients showing significant sympathetic activation because of the decreased reuptake of synaptic NE [61].”
BackgroundMathias, C. J. (2002) · Clinical Medicine · doi:10.7861/clinmedicine.2-3-237 · Cited by 42
Tabara, Y., Kohara, K., & Miki, T. (2002) · Journal of Hypertension · doi:10.1097/00004872-200204000-00022 · Cited by 43
Phenotypical evidence for a gender difference in cardiac norepinephrine transporter function
Schroeder, C., Adams, F., Boschmann, M., Tank, J., Haertter, S., Diedrich, A., Biaggioni, I., Luft, F. C., & Jordan, J. (2004) · American Journal of Physiology-Regulatory, Integrative and Comparative Physiology · doi:10.1152/ajpregu.00689.2003 · Cited by 42
“(6; 16; 17; 30) Interestingly, in a family with genetic NET dysfunction, two women reported severe symptoms of orthostatic intolerance.(28) Even if the gender difference were explained by a difference in counter regulation rather than a difference in NET function, the contribution of NET to cardiovascular regulation i…”
Self-citationChiari I malformation as a cause of orthostatic intolerance symptoms: a media myth?
Garland, E. M., & Robertson, D. (2001) · The American Journal of Medicine · doi:10.1016/s0002-9343(01)00922-6 · Cited by 40
Self-citationThe value of autonomic testing in postural tachycardia syndrome
Al-Shekhlee, A., Lindenberg, J. R., Hachwi, R. N., & Chelimsky, T. C. (2005) · Clinical Autonomic Research · doi:10.1007/s10286-005-0282-7 · Cited by 41
“Since headache and gastrointestinal symptoms constitute the main clinical difference between the two groups, it is reasonable to ask whether POTS-AN group may in fact represent a group with inherited dysautonomia [ 10 ].”
BackgroundFunctional Gene Variation in the Human Norepinephrine Transporter
Kim, C., Waldman, I. D., Blakely, R., & Kim, K. (2008) · Annals of the New York Academy of Sciences · doi:10.1196/annals.1417.023 · Cited by 41
Self-citationCognitive impairments associated with CFS and POTS
Shanks, L., Jason, L. A., Evans, M. A., & Brown, A. A. (2013) · Frontiers in Physiology · doi:10.3389/fphys.2013.00113 · Cited by 41
Tellioğlu, T., & Robertson, D. (2001) · Expert Reviews in Molecular Medicine · doi:10.1017/s1462399401003878 · Cited by 41
Self-citationSavchenko, V. L., Sung, U., & Blakely, R. (2003) · Molecular and Cellular Neuroscience · doi:10.1016/s1044-7431(03)00235-5 · Cited by 41
Self-citationAutonomic Dysfunction in Cardiology: Pathophysiology, Investigation, and Management
Arnold, A. C., Ng, J., Lei, L. Y., & Raj, S. R. (2017) · Canadian Journal of Cardiology · doi:10.1016/j.cjca.2017.09.008 · Cited by 42
“Endurance exercise training reduces orthostatic tachycardia, improves quality of life, and restores blood volume, stroke volume, and left ventricular mass in POTS.56 Acute blood volume expansion with intravenous saline (1-2 L) may improve orthostatic tachycardia and symptoms in POTS.57 While useful for rescue during a…”
InfluentialFischer, F. P., Kasture, A. S., Hummel, T., & Sučić, S. (2022) · Frontiers in Molecular Biosciences · doi:10.3389/fmolb.2022.834498 · Cited by 40
“A 33-year-old woman suffering from the autonomic disorder orthostatic intolerance was found to harbor a heterozygous A457P point mutation in the SLC6A2 gene (Shannon et al., 2000).”
BackgroundNorepinephrine Transporter Gene Variation Modulates Acute Response to d-Amphetamine
Dlugos, A. M., Freitag, C. M., Hohoff, C., McDonald, J. M., Cook, E. H., Deckert, J., & de Wit, H. (2007) · Biological Psychiatry · doi:10.1016/j.biopsych.2006.09.031 · Cited by 40
Nitrous oxide-oxygen or oral midazolam for pediatric outpatient sedation
Hulland, S. A., Freilich, M. M., & Sándor, G. K. B. (2002) · Oral Surgery Oral Medicine Oral Pathology Oral Radiology and Endodontology · doi:10.1067/moe.2002.124763 · Cited by 40
Deficient vesicular storage: A common theme in catecholaminergic neurodegeneration
Goldstein, D. S., Holmes, C. S., Sullivan, P., Mash, D. C., Sidransky, E., Stefani, A., Kopin, I. J., & Sharabi, Y. (2015) · Parkinsonism & Related Disorders · doi:10.1016/j.parkreldis.2015.07.009 · Cited by 39
Li, H., Wang, Y., Liu, P., Chen, Y., Feng, X., Tang, C., Du, J., & Jin, H. (2016) · Pediatric Cardiology · doi:10.1007/s00246-016-1436-1 · Cited by 40
Cerebral autoregulation is preserved in postural tachycardia syndrome
Schondorf, R., Benoit, J., & Stein, R. (2005) · Journal of Applied Physiology · doi:10.1152/japplphysiol.00225.2005 · Cited by 38
“Various abnormalities have been described, including the presence of an attenuated autonomic neuropathy (25, 43), increased cardiac norepinephrine spillover (19), impaired norepinephrine transporter (45), or reduced vagal cardiac baroreflex sensitivity (14).”
BackgroundConfounders of Vasovagal Syncope
Nwazue, V. C., & Raj, S. R. (2012) · Cardiology Clinics · doi:10.1016/j.ccl.2012.09.003 · Cited by 39
Roles of catechol neurochemistry in autonomic function testing
Goldstein, D. S., & Cheshire, W. P. (2018) · Clinical Autonomic Research · doi:10.1007/s10286-018-0528-9 · Cited by 38
“Attenuation of the plasma norepinephrine response to tyramine was part of the discovery process leading to identification of POTS from inherited NET deficiency [110].”
Postural Orthostatic Tachycardia Syndrome (POTS): An Update for Clinical Practice
Sebastian, S. A., Co, E. L., Panthangi, V., Jain, E., Ishak, A., Shah, Y., Vasavada, A. M., & Padda, I. (2022) · Current Problems in Cardiology · doi:10.1016/j.cpcardiol.2022.101384 · Cited by 41
Sympathetic control of the circulation in hypertension: lessons from autonomic disorders
Biaggioni, I. (2003) · Current Opinion in Nephrology & Hypertension · doi:10.1097/00041552-200303000-00008 · Cited by 38
Self-citationStewart, J. M. (2012) · Expert Review of Cardiovascular Therapy · doi:10.1586/erc.12.139 · Cited by 38
Neurocirculatory Abnormalities in Chronic Orthostatic Intolerance
Goldstein, D. S., Eldadah, B. A., Holmes, C. S., Pechnik, S., Moak, J. P., & Sharabi, Y. (2005) · Circulation · doi:10.1161/01.cir.0000155613.20376.ca · Cited by 38
“nephrine spillover)? (3) In COI, do the hemodynamic find-”
BackgroundNorepinephrine transporter expression and function in noradrenergic cell differentiation
Sieber‐Blum, M., & Ren, Z. (2000) · Springer eBooks · doi:10.1007/978-1-4615-4351-0_8 · Cited by 38
Neukirchen, M., Hipp, J., Schaefer, M. S., Brandenburger, T., Bauer, I., Winterhalter, M., Kienbaum, P., & Werdehausen, R. (2012) · British Journal of Anaesthesia · doi:10.1093/bja/aes303 · Cited by 37
Energy landscape of LeuT from molecular simulations
Gür, M., Zomot, E., Cheng, M. H., & Bahar, İ. (2015) · The Journal of Chemical Physics · doi:10.1063/1.4936133 · Cited by 36
NET silencing by let-7i in postural tachycardia syndrome
Khan, A. W., Ziemann, M., Corcoran, S. J., Kaipananickal, H., Okabe, J., Rafehi, H., Maxwell, S., Esler, M., & El‐Osta, A. (2017) · JCI Insight · doi:10.1172/jci.insight.90183 · Cited by 37
“While the etiology remains largely unknown, faulty neuronal reuptake of the sympathetic nervous system signaling neurotransmitter norepinephrine (NE) has been implicated (1).”
BackgroundSung, U., Jennings, J. L., Link, A. J., & Blakely, R. (2005) · Biochemical and Biophysical Research Communications · doi:10.1016/j.bbrc.2005.05.165 · Cited by 37
Self-citation
Metadata
- Authors
- Shannon, J. R., Flattem, N. L., Jordan, J., Jacob, G., Black, B. K., Biaggioni, I., Blakely, R. D., & Robertson, D.
- Affiliations
- Vanderbilt University (US)
- Venue
- New England Journal of Medicine
- Publisher
- Massachusetts Medical Society
- Published
- 2000-02-24
- Volume
- 342
- Issue
- 8
- Pages
- 541-549
- ISSN
- 0028-4793 (ISSN-L)
- 1533-4406
- OpenAlex
- W2133465432
- Cited by
- 594
- References
- 34
- Citations by year
- 2026: 4 · 2025: 9 · 2024: 14 · 2023: 9 · 2022: 17 · 2021: 13 · 2020: 22 · 2019: 17 · 2018: 18 · 2017: 15 · 2016: 22 · 2015: 11 · 2014: 15 · 2013: 23 · 2012: 16
- FWCI
- 49.25
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- New England Journal of Medicine (publishedVersion)
- PubMed (publishedVersion)
- MDC Repository (Max-Delbrueck-Center for Molecular Medicine) (acceptedVersion)
- Funders
- National Heart, Lung, and Blood Institute (P01HL056693)
- National Institute of Mental Health (MH 58921, R01MH058921)
- National Center for Research Resources (RR00095)
- 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
- orthostatic intolerance, postural orthostatic tachycardia syndrome, norepinephrine transporter, plasma norepinephrine, norepinephrine clearance, hyperadrenergic state, sympathetic hyperactivity, plasma catecholamines, dihydroxyphenylglycol, loss-of-function mutations
- MeSH terms
- Adult, Amino Acid Sequence, Base Sequence, Blood Pressure, Carrier Proteins, Female, Heart Rate, Humans, Male, Methoxyhydroxyphenylglycol, Molecular Sequence Data, Norepinephrine, Pedigree, Posture, Syncope, Tachycardia, Sequence Homology, Amino Acid, Mutation, Missense, Symporters, Norepinephrine Plasma Membrane Transport Proteins
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