Orthostatic Intolerance and Tachycardia Associated with Norepinephrine-Transporter Deficiency
John R. Shannon, M.D., Nancy L. Flattem, B.S., Jens Jordan, M.D., Giris Jacob, M.D., D.Sc., Bonnie K. Black, B.S.N., Italo Biaggioni, M.D., Randy D. Blakely, Ph.D., and David Robertson, M.D.
Background Orthostatic intolerance is a syndrome characterizedby lightheadedness, fatigue, altered mentation, and syncopeand associated with postural tachycardia and plasma norepinephrineconcentrations that are disproportionately high in relationto sympathetic outflow. We tested the hypothesis that impairedfunctioning of the norepinephrine transporter contributes tothe 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 wesequenced the norepinephrine-transporter gene and evaluatedits function.
Results The patient had a high mean plasma norepinephrine concentrationwhile standing, as compared with the mean (±SD) concentrationin normal subjects (923 vs. 439±129 pg per milliliter[5.46 vs. 2.59±0.76 nmol per liter]), reduced systemicnorepinephrine clearance (1.56 vs. 2.42±0.71 liters perminute), impairment in the increase in the plasma norepinephrineconcentration after the administration of tyramine (12 vs. 56±63pg per milliliter [0.07 vs. 0.33± 0.37 pmol per liter]),and a disproportionate increase in the concentration of plasmanorepinephrine relative to that of dihydroxyphenylglycol. Analysisof the norepinephrine-transporter gene revealed that the probandwas heterozygous for a mutation in exon 9 (encoding a changefrom guanine to cytosine at position 237) that resulted in morethan a 98 percent loss of function as compared with that ofthe wild-type gene. Impairment of synaptic norepinephrine clearancemay result in a syndrome characterized by excessive sympatheticactivation in response to physiologic stimuli. The mutant allelein the proband's family segregated with the postural heart rateand abnormal plasma catecholamine homeostasis.
Conclusions Genetic or acquired deficits in norepinephrine inactivationmay underlie hyperadrenergic states that lead to orthostaticintolerance.
Orthostatic intolerance is a syndrome characterized by adrenergicsymptoms that occur when an upright posture is assumed: theheart rate increases by at least 30 beats per minute, withoutorthostatic hypotension.1 Most patients with orthostatic intoleranceare women between the ages of 20 and 50 years old.2 This syndrome,first described by Da Costa3 more than 100 years ago, has beencalled soldier's heart,4 neurocirculatory asthenia,5 and themitral valve prolapse syndrome.6 It is similar to the chronicfatigue syndrome in many respects.7
Most attempts to explain the physiologic and biochemical abnormalitiesassociated with orthostatic intolerance have focused on an increasedrelease of norepinephrine in response to the change from a supineto an upright position. An alternative explanation is that thereis an abnormality in the clearance of norepinephrine from thesynaptic cleft. The primary mechanism of inactivation of norepinephrinein the synapse is uptake into the neuron by the norepinephrinetransporter. Approximately 80 to 90 percent of the norepinephrinereleased into many synapses is cleared by this mechanism, andthe remaining 10 to 20 percent spills over into the circulationor extraneuronal tissue.8 It is noteworthy that drugs that inhibitthe norepinephrine transporter (e.g., cocaine, amphetamines,and tricyclic antidepressants) cause features typical of orthostaticintolerance (tachycardia, orthostatic symptoms, and high plasmacatecholamine concentrations).
We evaluated a patient and her identical twin, both of whomhad symptoms typical of orthostatic intolerance, and in bothfound clinical and laboratory signs of disordered uptake ofnorepinephrine. Because the norepinephrine transporter has apivotal role in norepinephrine uptake at the synaptic cleft,we determined whether the impaired uptake of norepinephrinein these patients could have been caused by a mutation in thegene that encodes the norepinephrine transporter.
Methods
The proband was a 33-year-old woman with a 20-year history ofexertional and orthostatic tachycardia, dyspnea, difficultyconcentrating, and syncope. Her blood pressure had varied substantiallyafter each of three cesarean sections, with values as high as210/180 mm Hg. Treatment with beta-adrenergic–antagonistdrugs, compression stockings, and fludrocortisone was ineffective.Implantation of a dual-chamber pacemaker decreased the frequencyof the syncope, but the symptoms of orthostatic intolerancepersisted. An echocardiogram revealed slight mitral regurgitationand possible mitral-valve prolapse. The proband's identicaltwin also had a history of mitral-valve prolapse as well astachycardia and syncope that were worsened by exertion and anupright posture.
The study was approved by the Vanderbilt University investigationalreview board, and all subjects, including family members, gavewritten informed consent.
Clinical Studies
The proband and her twin were admitted to the General ClinicalResearch Center at Vanderbilt University Medical Center. Useof all medications had been discontinued two weeks before admission.For three days, the women were given a caffeine-free, low-monoaminediet containing 150 mmol of sodium per day and 70 mmol of potassiumper day. Urine was then collected for 24 hours for measurementof catecholamines and catecholamine metabolites. After an overnightfast, the women's blood pressure, heart rate, and plasma catecholamineswere measured while they were supine and after 30 minutes ofstanding. Plasma and urine catecholamines were measured by high-performanceliquid chromatography.9,10 Testing of autonomic reflexes wasperformed as previously described.11 In the proband, brachialblood pressure and plasma norepinephrine were measured beforeand at the time of maximal blood pressure after the injectionof a 3-mg bolus of tyramine. Systemic spillover and clearanceof norepinephrine before and during baroreflex-mediated sympatheticactivation, induced by the administration of sodium nitroprusside(Ohmeda, Liberty Corner, N.J.), were measured in the probandduring continuous monitoring of intraarterial blood pressureand heart rate, as follows. Tritiated norepinephrine was infusedintravenously at a rate of 1 µCi per minute after theadministration of a loading dose of 25 µCi per minute,as previously described,12,13 and plasma norepinephrine andthe specific activity of tritiated norepinephrine were measured.13Nitroprusside was then infused into a contralateral antecubitalvein. When the systolic blood pressure had decreased by 20 mmHg (at a rate of 1.2 µg of nitroprusside per kilogramof body weight per minute), the measurements were repeated.
Blood pressure, heart rate, and plasma catecholamine concentrationsin the proband and her twin sister were compared with thosein 10 unrelated normal subjects recruited from a pool of normalvolunteers; the sisters' plasma catecholamine responses aftertyramine administration were compared with those in 9 unrelatednormal subjects; and their norepinephrine spillover and clearancewere compared with those in 8 unrelated normal subjects.
Blood samples were obtained from the proband, her nine siblings,and her mother for DNA analysis. In the mother and all the siblingsexcept for one sister, blood pressure and heart rate were determinedin the supine position and after 5 minutes of standing, andplasma catecholamines were measured after the subjects had beensupine for 20 minutes and then after they had been standingfor 30 minutes.
Detection of Mutations
Amplification and sequencing were performed at the VanderbiltCenter for Molecular Neuroscience DNA Sequencing Core. GenomicDNA was isolated from venous blood with the PureGene DNA ExtractionKit (Gentra Systems, Minneapolis), and the exons of the humannorepinephrine-transporter gene (SLC6A2; McKusick no. 16397014)were amplified with the use of the polymerase chain reactionand sense and antisense primers (the sequences of oligonucleotidesused for the exonic polymerase chain reaction and the conditionsfor amplification are available on request). The amplified products(60 ng per aliquot) were directly sequenced with fluorescentdideoxynucleotide chain terminators (AmpliTaq FS, Perkin ElmerApplied Biosystems, Foster City, Calif.) on an automated DNAsequencer (ABI 310, Perkin Elmer Applied Biosystems).
Functional Analysis of the Identified Mutation
DNA encoding a human norepinephrine transporter with alaninereplaced by proline at position 457 (Ala457Pro) was createdwith the use of a kit (QuikChange Site-Directed MutagenesisKit, Stratagene, La Jolla, Calif.) with the oligonucleotides5'CCTTCAGTACTTTCCTTCTCCCCCTGTTCTGCATAACCAAG3' and 5'CTTGGTTATGCAGAACAGGGGGAGAAGGAAAGTACTGA-AGG3'.The underlined bases are those that were introduced to createa mutation in which guanine was replaced by cytosine at position237 (G237C) or to introduce a ScaI restriction site that couldbe used to identify mutant plasmids. Amplified DNA was clonedinto a construct (pcDNA3, Invitrogen, Carlsbad, Calif.) containingwild-type human norepinephrine-transporter complementary DNA(cDNA) in which a silent mutation, or one that does not resultin a change in amino acid (in this case, leucine at position438), had previously been introduced to create a unique AflII restriction site and thus facilitate subcloning of the mutatedsequence back into the wild-type construct. The subcloned regionwas sequenced with the norepinephrine-transporter oligonucleotides5'CATTCT-GGGCTGTTGTGT3' and 5'GTGGTTGTGGTCAGCATCATC3'. DNA frommultiple isolates of mutant clones was purified (Qiagen, SantaClarita, Calif.) to test the effect of the Ala457Pro mutationon transporter activity.
Wild-type norepinephrine transporter, norepinephrine transporterwith the Ala457Pro mutation, and pcDNA3 plasmids were transientlytransfected into Chinese-hamster-ovary cells (American TypeCulture Collection, Rockville, Md.) with the use of lipofectamine.The cells were assayed for tritiated norepinephrine-transporteractivity (20 nmol per liter) 72 hours after transfection, aspreviously described.15
Genotyping of Ala457Pro Alleles
Allele-specific oligonucleotide hybridization was used to testfor the presence of the Ala457Pro mutation, with hybridizationof 5'CCTTCTCGCCCTGTT3' to the wild-type allele and hybridizationof 5'CCTTCTCCCCCTGTT3' to the mutant allele. The underlinedbases are those used to identify the single-nucleotide polymorphismin the mutant allele. All samples of genomic DNA were codedbefore genotype analysis in order to preserve the anonymityof the subjects. Genotypes were then used to associate genotypeswith phenotypes.
Statistical Analysis
Paired and unpaired t-tests were used to compare clinical findingsbetween the groups of subjects and within each group beforeand after exposure to various stimuli. Data were analyzed withPrism software (GraphPad Software, San Diego, Calif.). All Pvalues are two-sided.
Results
Autonomic Responses
The proband and her twin sister had normal autonomic reflexes,but their blood pressure and heart rate were variable (Figure 1).Their blood pressure, heart rate, and plasma catecholamineconcentrations in the supine and upright positions and thosein the unrelated normal subjects13 are shown in Table 1. Inthe proband and her twin, the plasma concentrations of dihydroxyphenylglycol,an intraneuronal metabolite of norepinephrine,9 were low inrelation to the plasma norepinephrine concentrations (ratioof dihydroxyphenylglycol to norepinephrine in the supine position,3.06 in the proband and 2.41 in her twin, vs. 5.52 in the normalsubjects; ratio in the upright position, 1.05 in the probandand 1.17 in her twin, vs. 3.44 in the normal subjects). Urinaryexcretion of norepinephrine was high in both the proband andher twin (435 and 125 µg per 24 hours [2.57 and 0.74 µmolper 24 hours], respectively; normal value, <90 µg per24 hours [0.53 µmol per 24 hours]).
Figure 1. Continuous Recordings of Blood Pressure and Heart Rate in the Proband and Her Twin Sister.
Beat-by-beat recordings of blood pressure as determined by photoplethysmography and continuous recordings of heart rate show spontaneous increases of up to 50 mm Hg in blood pressure and 25 beats per minute in heart rate in the proband and her twin sister. In the proband, a 75-degree tilt increased the variation in blood pressure and heart rate.
Table 1. Blood Pressure, Heart Rate, and Plasma Catecholamine Concentrations in the Proband, Her Twin Sister, and 10 Unrelated Normal Subjects.
Response to Tyramine
After it is taken up into neurons by the norepinephrine transporter,tyramine has a hypertensive effect caused by the release ofnorepinephrine.16,17 In the normal subjects, the mean (±SD)systolic blood pressure increased by 19±2 mm Hg and themean plasma norepinephrine concentration increased by 56 ±21pg per milliliter (0.33±0.12 nmol per liter) in responseto 3 mg of tyramine. In the proband, the same dose of tyramineincreased systolic blood pressure by 18 mm Hg but increasedthe plasma norepinephrine concentration by only 12 pg per milliliter(0.07 nmol per milliliter).
Spillover and Clearance of Systemic Norepinephrine
The arterial plasma norepinephrine concentration at rest wasslightly higher in the proband than in the normal subjects (280pg per milliliter [1.66 nmol per liter] vs. 204±51 pgper milliliter [1.21±0.30 nmol per liter]). This increasewas due primarily to a decrease in the rate of removal of norepinephrinefrom the circulation (norepinephrine clearance): although therate at which norepinephrine entered the circulation (norepinephrinespillover) was lower in the proband than in the normal subjects(436 vs. 514±277 ng per minute [2.58 vs. 3.04±1.64nmol per minute]), norepinephrine clearance in the proband wasless than half that in the normal subjects (1.56 vs. 2.42±0.71liters per minute). During the infusion of nitroprusside, norepinephrinespillover increased to 1072 ng per minute (6.34 nmol per minute)in the proband but only to 745±212 ng per minute (4.40±1.25nmol per minute) in the normal subjects. Norepinephrine clearancedid not change appreciably after the nitroprusside infusionin either the proband (1.76 liters per minute) or the normalsubjects (2.31±0.68 liters per minute).
Identification of a Functional Missense Mutation in the Norepinephrine-Transporter Gene
The combination in the proband of a low ratio of plasma dihydroxyphenylglycolto norepinephrine, a blunted response of plasma norepinephrineto tyramine, and a decreased plasma norepinephrine clearancesuggested a potential defect in the norepinephrine transporter.The presence of similar findings in her twin sister suggesteda genetic origin.
Direct sequence analysis of the norepinephrine-transporter genein the proband revealed no divergence from previously publishedsequences14,18 in exons 1 through 8 and exons 10 through 15.However, two novel polymorphisms were identified in exon 9:a silent polymorphism in which cytosine was replaced by adenineat position 154 (C154A) and a missense mutation in which guaninewas replaced by cytosine at position 237 (G237C) (position numbersrefer to the GenBank sequence for exon 9). The proband was heterozygousfor both the C154A and the G237C polymorphisms (Figure 2A).The G237C mutation results in a change from alanine to proline(Ala457Pro) within a highly conserved region of transmembranedomain 9 (Figure 2B and Figure 2C).
Figure 2. Evaluation of the Norepinephrine-Transporter (NET) Mutation.
DNA sequencing of the norepinephrine-transporter gene (Panel A) identified both cytosine (C) and guanine (G) (arrows) at position 237 of exon 9 in both the sense (top) and antisense (bottom) DNA strands, indicating heterozygosity at this locus. This change from cytosine to guanine results in a change from alanine to proline at amino acid position 457 (Ala457Pro). The Ala457Pro mutation is in transmembrane domain 9 of the norepinephrine transporter (Panel B). S-S denotes a disulfide bond, and Ph canonical sites for protein phosphorylation. Transmembrane domain 9 is highly conserved among the related murine and bovine norepinephrine transporters and the frog epinephrine transporter (ET) (Panel C). Shading indicates areas of homology among species. The asterisk denotes the site of mutation. As compared with the wild-type norepinephrine transporter, the transporter with the Ala457Pro mutation results in impairment of mean norepinephrine uptake in transiently transfect-ed Chinese-hamster-ovary cells (Panel D). I bars indicate 1 SD. Panel E is a schematic diagram of the hybridization study and shows the presence of the mutant (P, for proline) and wild-type (A, for alanine) alleles. Panel F shows a pedigree of the proband. P (for proline) denotes the mutant allele and A (for alanine) the wild-type allele. Circles denote female family members, and squares male family members. The slash denotes a deceased family member, and the arrow indicates the proband.
Heterologous expression of the wild-type norepinephrine-transportergene and human cDNA encoding the Ala457Pro mutation revealedthat norepinephrine transport was greatly diminished by theAla457Pro mutation. In Chinese-hamster-ovary cells that hadbeen transiently transfected with cDNA encoding the human norepinephrinetransporter, uptake of tritiated norepinephrine was 10 timesthat in vector-transfected cells, whereas in cells transfectedwith cDNA encoding the Ala457Pro mutation in the norepinephrinetransporter, the uptake was 2 percent or less (Figure 2D). Multipleclones were tested, and in another cell line (LLC-PK1, providedby M. Hahn), all the clones were devoid of transport activity(data not shown).
Segregation of the Ala457Pro Mutation with a Phenotype
The proband's mother and eight of the proband's siblings weregenotyped by allele-specific oligonucleotide hybridization.The mother and four siblings (including the twin sister) wereheterozygous for the mutant allele (Figure 2E). Their heartrates while supine were slightly but not significantly greaterthan those of their family members with the wild-type genotype,but their heart rates while standing were significantly higher(Figure 3A and Figure 3B). Likewise, plasma norepinephrine concentrationsin the supine position were somewhat higher and plasma norepinephrineconcentrations in the upright position were significantly higherin the heterozygous family members than in those with the normalgenotype (Figure 3C and Figure 3D). Finally, the ratios of dihydroxyphenylglycolto norepinephrine in plasma in both the supine and upright positionswere significantly lower in those who were heterozygous forthe mutation than in the other family members (Figure 3E andFigure 3F).
Figure 3. Heart Rate and Plasma Catecholamine Concentrations in the Proband and Her Family in the Supine and Upright Positions.
Heart rate, plasma concentrations of norepinephrine, and the ratio of its intraneuronal metabolite, dihydroxyphenylglycol (DHPG), to norepinephrine were determined in the proband and nine family members (three family members with the Ala457Pro mutation and six with the normal genotype). In the supine position, the heart rate in the family members with the mutation was similar to that in those without the mutation. However, in the upright position, the heart rate and plasma norepinephrine concentrations were significantly higher in those with the mutation than in those without it. Plasma norepinephrine concentrations in the supine position were somewhat higher in the family members with the mutation than in the others. The ratio of the plasma DHPG concentration to the plasma norepinephrine concentration was significantly lower in both the supine and the upright positions in those with the mutation, a finding consistent with impairment of norepinephrine uptake. Each point represents one subject, and the horizontal lines represent the mean values. To convert plasma norepinephrine values to nanomoles per liter, multiply by 0.005911. P values are for the comparison between family members with the Ala457Pro mutation and those with the normal genotype.
Discussion
The deficiency in norepinephrine transport in the proband andseveral members of her family was the result of a functionalmutation in the gene encoding the norepinephrine transporter.Previously detected coding polymorphisms in this gene have noreported effect on norepinephrine transport.19 In contrast,the Ala457Pro mutation renders the transporter nonfunctionaland segregates with altered heart-rate regulation and alterednorepinephrine metabolism. The proband had a defect in norepinephrineuptake. Her heart rate while supine was about 10 beats per minutefaster than the mean value for age-matched normal subjects20and rose substantially when she stood. This change in heartrate was accompanied by an increase in the plasma norepinephrineconcentration to almost four times its value in the supine position.These changes may have been caused by either an increase inthe release (spillover) of norepinephrine or a decrease in itsclearance.8,21 The blunting of the increase in plasma norepinephrinein the proband in response to the administration of tyramineand her low systemic norepinephrine clearance suggest that theuptake of norepinephrine was impaired. The abnormal relationbetween plasma concentrations of dihydroxyphenylglycol and norepinephrineprovides further evidence of impaired norepinephrine uptake.Some of the norepinephrine taken up into neurons by the norepinephrinetransporter reaches the vesicles, where it is stored for laterrelease, but much of it is converted to dihydroxyphenylglycolby monoamine oxidase.8 The dihydroxyphenylglycol then entersthe circulation and can serve as a marker of norepinephrineuptake and monoamine oxidase activity9 (Figure 4). The relativelylow ratios of dihydroxyphenylglycol to norepinephrine in plasmain the proband and her twin sister indicate that norepinephrinetransport in these women was impaired.
Figure 4. Neuronal Metabolism of Norepinephrine in Persons with Norepinephrine-Transporter Deficiency.
Under normal conditions, norepinephrine is released from vesicles in the neuron into the synaptic space, where it can interact with presynaptic and postsynaptic - and ß-adrenergic receptors. 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. 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. DHPG diffuses out of the neuron into the circulation. 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. In addition, more norepinephrine is available for interaction with the adrenergic receptors in the synaptic space. Because of the decreased uptake of norepinephrine, the production of DHPG is decreased. 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.
These findings in both the proband and her identical twin stronglysuggested the presence of an abnormality in the norepinephrine-transportergene, which has been mapped to chromosome 16q.22 Analysis ofthis gene in the proband revealed a missense mutation that resultedin the replacement of an alanine residue with a proline residuein a highly conserved transmembrane region of the transporter.Because the substitution of proline disrupts alpha-helical secondarystructures that are supported by alanine residues, this mutationmay disrupt the transport of norepinephrine. Functional analysisof the proband's mutant norepinephrine transporter demonstratedthat it had 2 percent or less of the activity of the transporterencoded by the wild-type gene.
The pathophysiologic features of orthostatic intolerance havebeen thought to be due to a primary23 or secondary23,24,25,26activation of sympathetic outflow. A deficiency of the norepinephrinetransporter may explain several of the clinical findings inpatients with this disorder: the high heart rate in the supineposition, the high plasma concentration of norepinephrine inassociation with the relatively low plasma concentration ofdihydroxyphenylglycol, the impaired response of norepinephrineto tyramine,13 the reduced systemic clearance of norepinephrine,13and the disparity between the changes in heart rate and plas-manorepinephrine concentrations and the change in muscle sympathetic-nerveactivity in the upright position.27 In many patients with orthostaticintolerance, the disproportionately greater increase in heartrate than in diastolic pressure in the upright posture13 mayalso be explained by a deficiency of the norepinephrine transporter.The noradrenergic synaptic clefts in the heart are approximatelythree times as narrow as the synaptic clefts in the vasculature,28making the removal of norepinephrine from the synapses in theheart far more dependent on the activity of the norepinephrinetransporter than is removal from synapses in the vascular beds.29Therefore, a decrease in transporter activity could result ina disproportionately greater effect on heart rate than on bloodpressure, as is observed in patients with orthostatic intolerance.
Impairment of the norepinephrine transporter in the centralnervous system may also contribute to the phenotype. Norepinephrinereleased in the brain can either increase30,31 or decrease32sympathetic outflow. Because acute pharmacologic blockade ofthe norepinephrine transporter causes a decrease in sympatheticoutflow,33 one would expect a decrease in sympathetic tone witha deficiency of the norepinephrine transporter. Yet in the probandand in many other patients with orthostatic intolerance, centralsympathetic tone seems to be increased.34,35 This paradoxicalincrease may represent the sum of the effects of partial inhibitionof norepinephrine transport at multiple sites in the centralnervous system.
The Ala457Pro mutation does not explain all cases of orthostaticintolerance. The mutation was not present in any of 254 unrelatedpersons, including normal subjects, patients with hypertension,and other patients with orthostatic intolerance (data not shown).Furthermore, in the current study, family members who had themutation also had some of the physiologic and biochemical abnormalitiesdetected in the proband and her twin sister, but none had thefull-blown syndrome. Thus, other genetic or environmental factorsmust have contributed to the phenotype in the two affected women.
In conclusion, the identification of defective norepinephrinetransport in patients with orthostatic intolerance suggestsa previously unrecognized mechanism in some patients with thisclinical problem.
Supported in part by grants from the National Institutes ofHealth (MH58921, to Dr. Blakely; PO1 HL56693, to Dr. Robertson;and RR00095, to Drs. Robertson and Shannon), the National Aeronauticsand Space Administration (NAS 9 19483, to Drs. Robertson andBiaggioni), and the Nathan Blaser Shy–Drager ResearchProgram of Vanderbilt University.
We are indebted to Drs. Graeme Eisenhofer, Bojan Pohar, RogelioMosqueda-Garcia, Raffaello Furlan, R. Andrew Gaffney, Rose MarieRobertson, and Jack Alexander of Red Wing, Minnesota, and toDorothea Boemer for their contributions to this study.
Source Information
From the Autonomic Dysfunction Center (J.R.S., J.J., G.J., B.K.B., I.B., D.R.) and the Center for Molecular Neuroscience (N.L.F., R.D.B.), Departments of Medicine, Pharmacology, and Neurology, Vanderbilt University, Nashville.
Address reprint requests to Dr. Robertson at the General Clinical Research Center, AA3228 MCN, Vanderbilt University, Nashville, TN 37232-2195, or at david.robertson{at}mcmail.vanderbilt.edu.
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Previous
- and ß-adrenergic receptors. 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. 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. DHPG diffuses out of the neuron into the circulation. 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. In addition, more norepinephrine is available for interaction with the adrenergic receptors in the synaptic space. Because of the decreased uptake of norepinephrine, the production of DHPG is decreased. 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.