Treatment of Hypotensive Patients Having a Unique Pattern of Autonomic Symptoms
Phase: PHASE2
Conditions: Autonomic Nervous System Diseases, Orthostatic Hypotension, Dopamine Beta-Hydroxylase Deficiency, Orthostatic Intolerance
Sponsor: Vanderbilt University

April 4, 2002 
 
 
 
Treatment of Orthostatic Hypotension 
 
NCT00581477 
 
Protocol and Statistical Analysis Plan 
 
November 14, 2003 

 
2
CLINICAL RESEARCH CENTER 
VANDERBILT UNIVERSITY 
PROJECT PROPOSAL #1288 
 
 
Project Title: The Treatment of Orthostatic Hypotension  
The Treatment of Orthostatic Hypotension 
 
Project Number:   
 
 
 
IRB Approval Number:  030750 
 
IRB Approval Date: November 14, 2003  
 
Principal Investigator: 
David Robertson, M.D., Professor of Medicine, Pharmacology and  
Neurology  
 
Co-Investigator(s): 
 
Emily Garland, Ph.D., Division of Clinical Pharmacology 
 
 
 
 
Paula Yamhure, RN, Division of Cardiology 
 
 
 
 
Italo Biaggioni, MD, Departments of Medicine and Pharmacology 
 
 
 
 
Satish Raj, MD, Division of Clinical Pharmacology 
 
 
 
 
Bonnie Black, RN, Division of Cardiology 
 
 
 
 
Indu Taneja, MD, Division of Clinical Pharmacology 
 
HYPOTHESIS 
We propose that a systematic trial of medications in patients presenting with a unique and chronic 
constellation of symptoms of autonomic dysfunction will provide us with information on the 
pathophysiology of their condition and assist us in optimizing their treatment. 
 
SPECIFIC AIMS 
To give a single dose of one or more drugs to determine the effect on orthostatic hypotension in a group 
of patients with autonomic dysfunction of unknown pathophysiology.  Depending on the results of these 
single-dose trials, we might subsequently do 5-day trials and chronic (approximately 2 months) trials. 
 
 
BACKGROUND AND SIGNIFICANCE 
Norepinephrine (NE) and epinephrine (E) are critical determinants of blood pressure. Moreover, they are 
also involved in the regulation of autonomic outflow in the brainstem and spinal cord. In the periphery, 
NE is pressor, but within the central nervous system (CNS) it often depresses sympathetic outflow, 
resulting in a fall in blood pressure.  Thus, any factor that alters the synthesis of these catecholamines 
can perturb blood pressure at several interacting levels. Tyrosine hydroxylase [(tyrosine to L-
dihydroxyphenylalanine (DOPA)] is the rate-limiting step in NE synthesis under almost all 
circumstances. DOPA decarboxylase converts DOPA to dopamine (DA).  Dopamine-ß-hydroxylase 
(DBH) converts DA to NE.  Loss of DBH leads to an inability of the neuron to synthesize NE, resulting 
in a buildup of DA.   
 
In 1986, we, and independently, colleagues in Rotterdam, reported a syndrome in which patients have a 
congenital absence of the DBH enzyme. Results of a battery of biochemical and physiological tests in 
DBH-deficient patients helped us to identify the pathophysiology of these patients and enabled us to 
design an effective treatment. 
 
Occasionally, patients present to the Autonomic Dysfunction Center with a unique constellation of 

 
3
symptoms of autonomic dysfunction so that they do not fit into a diagnostic category (Orthostatic 
Intolerance, Pure Autonomic Failure, Multiple System Atrophy, Baroreflex Failure).  Some of these 
patients have severe orthostatic hypotension and resemble those with DBH deficiency, but they do not 
have the extreme plasma levels of DA.  We propose that medication trials in these patients will assist us 
in optimizing their treatment.  Evaluation will be undertaken under controlled conditions with 
medication and dietary restrictions and will consist primarily of orthostatic blood pressure and heart rate 
measurements and plasma catecholamine determinations. 
 
Participants will first take part in a study designed to provide information on the pathophysiology of 
their autonomic problems (The Pathophysiology of Orthostatic Hypotension, IRB#030752, CRC 
approval pending).  Results from this study will help us determine which drug(s) to administer in the 
proposed protocol. 
 
PRELIMINARY STUDIES 
Once the pathophysiology of DBH deficiency was understood, we were able to rapidly develop a 
specific and effective therapy. Consistent with DOPA and DA reducing blood pressure, the 
administration of a tyrosine hydroxylase inhibitor, such as metyrosine, raises blood pressure in DBH-
deficient individuals. The pressor effect appears to correlate with the metyrosine-associated reduction in 
plasma DA and DOPA levels and also urinary DA levels. DOPS, or Droxidopa INN:(-)-threo-3-(3, 4-
dihydroxyphenyl)-L-serine, is structurally closely related to NE, but has an additional COOH group.  It 
can be pumped up into the noradrenergic nerves and converted into NE by L-aromatic amino-acid 
decarboxylase without requiring DBH.  L-DOPS has been used effectively in the treatment of patients 
with complete DBH deficiency.  It might also improve the blood pressure in patients that have profound 
orthostatic hypotension but do not appear to have complete DBH deficiency.   
 
EXPERIMENTAL DESIGN AND METHODS 
Participants in this study are patients with hypotension, who have undergone evaluation as part of our 
“The Pathophysiology of Orthostatic Hypotension” protocol (IRB#030752, CRC approval pending).  
Based on the results of these studies, we will administer medication which we believe might improve 
their symptoms.  We will first test a single dose of one or more drugs with monitoring for 24 hours.  A 
drug or drugs effective at preventing an orthostatic fall in blood pressure might then be tested in a 5-day 
crossover trial with comparison of effects to placebo.  Based on the results of the 5-day trial, a patient 
might then be given a 2-month trial of the drug, with periodic admissions to the GCRC for assessment of 
symptoms. The period of time needed to complete this study will depend on the number of medications 
tested.   
 
Drug withdrawal 
Participants must remain off any medications that could affect blood pressure for three days prior to and 
during study.  This includes not only their usual scheduled medications, but also other drugs that might 
be taken intermittently. If their symptoms are severe enough that they or their physician have concerns 
that their symptoms may worsen, they may be admitted to the hospital for observation during this 
portion of the study.  While they are an inpatient on the GCRC, their general condition, blood pressure 
and heart rate will be checked regularly to reduce any risk. 
 
Urine pregnancy test 
We will perform a urine pregnancy test every time female participants are admitted to the hospital for 
this study.   
 
Diet 

 
4
We will ask study participants to eat a standard diet with no caffeine, 150-mEq/day sodium, 70 mEq 
potassium, and no substances that interfere with catecholamine synthesis, release or assay for three days 
prior to and during testing. 
 
24-Hour Urine Collection 
Participants will collect their urine for 24 hours every time they are admitted to the hospital for this 
study. The urine will be analyzed for sodium, potassium, creatinine,and  catecholamines. 
 
Orthostatic vital signs 
Orthostatic vital signs will be measured several times a day.  This testing consists of blood pressure and 
heart rate measured while patients are lying down and then repeated after standing quietly for 5 minutes, 
using the Dinamap. 
 
Single-dose drug trials 
Participants will be admitted to the Vanderbilt Clinical Research Center the evening prior to the study. 
In the morning, the patients will be seated or in bed for a 30 min baseline period of blood pressure and 
heart rate monitoring.  The medication will be given by mouth, and blood pressure and heart rate will be 
monitored every 10-15 minutes for the first hour, using a Dinamap. Orthostatic vital signs will be taken 
after 1, 2, 3, 4, 8, and 12 hours.  Fifteen ml of blood will be collected through a saline lock during 
baseline and after 2, 4, and 8 hours while in the supine and standing positions to measure 
catecholamines (total of 4 samples lying down and 4 samples upright).  Aldosterone will also be 
measured in blood collected during baseline and at one other timepoint, depending on the duration of the 
drug effect (total of 2 samples lying down and 2 samples upright). A second blood sample will be 
collected with the aldosterone and an aliquot of plasma frozen for possible analysis of plasma renin 
activity. Urine will be collected from 0-7 hours, 7-12 hours and 12-24 hours for measurement of 
catecholamines.  Depending on how well the drug is tolerated and the degree of improvement in 
orthostatic vital signs and symptoms following the drug, another single-dose drug trial might be 
scheduled 48 hours after the first or the patient might be asked to start a 5-day trial of the drug at that 
time.   If they are not scheduled for another trial at this time, they can be discharged.  The medications 
include domperidone, metyrosine, L-DOPS, alpha-methyldopa, L-dopa, carbidopa, atomoxetine, and 
placebo.   
 
 
 
 
 
Single-dose trial 
Time 
Days 3,2  
pre-study 
Day 
1 
pre-study 
                                   Study Day  
 
 
 
0 hr 
1 hr 
2 hr 3 hr 4 hr 8 hr 12 
hr 
24 
hr 
Drug/diet 
restriction 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Urine collection  
X 
X 
X 
X 
X 
X 
X 
X 
X 
Admission 
to 
GCRC 
 
X 
 
 
 
 
 
 
 
 
Pregnancy test 
 
X 
 
 
 
 
 
 
 
 
Drug 
administration 
 
 
X 
 
 
 
 
 
 
 
Blood sample 
 
 
X 
 
 
 
X 
X 
X 
 
Vital signs 
 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
5-Day drug trials 
Once the appropriate dose has been decided, we will conduct a single-blinded crossover trial.  
Depending on where they live and the severity of their symptoms, participants might be able to go home 

 
5
for part of this study.  However, after 4 days on the drug (or placebo), they will be admitted to the 
GCRC.  They will be supine and NPO after midnight.  In the morning, we will do a Posture Study to 
determine the effectiveness of the treatment.  Before breakfast, we will draw 15 ml of blood while they 
are supine and another 15 ml after they have stood for 30 minutes to measure catecholamines and 
aldosterone.  A second blood sample will be collected with the aldosterone and an aliquot of plasma 
frozen for possible analysis of plasma renin activity. We will monitor blood pressure and heart rate 
during this study, using a Dinamap. Standing time will be determined, and the participants will be asked 
about their symptoms periodically during the study.  For at least three days following this testing, 
participants will take no medication.  They will then start a 5-day regimen of the medication, if they 
previously took the placebo, or placebo, if they previously took the medication. They will not be told 
whether they are taking active drug or placebo.  The Posture Study will be repeated in the GCRC after 
the second 5-day period.   
 
 
 
 
 
 
 
 
5-day trial 
Time 
Day 
3  
pre-
study 
Days 
1,2 
pre-
study 
Study 
day 0   
Study 
days 
1,2,3 
Study 
day 4 
Study 
day 5 
Study 
days 
6,7 
Study 
day 8 
Study days 
9,10,11 
Study day 
12 
Study day 
13 
Drug/diet 
restriction 
X 
X 
X 
X X X X 
X 
X 
X 
X 
X 
X X 
X 
 
X 
Urine 
collection 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
X 
 
Admission to 
GCRC 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
X 
 
Pregnancy 
test 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Drug/placebo 
administration 
 
 
X 
X X X X 
 
 
 
X 
X 
X X 
X 
 
Posture 
study/Blood 
sample 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
X 
Vital signs 
 
 
 
 
 
 
X 
X 
 
 
 
 
 
 
X 
X 
 
Depending on the results of the 5-day trial, participants will be given a longterm trial of a drug.  At the 
initiation of treatment, and after two weeks, four weeks, and eight weeks of drug, they will be evaluated 
by a posture study, 24-hour urine collection and assessment of their symptoms.  The dose of the 
medication will be adjusted after two and four weeks of treatment if there has been insufficient 
improvement in blood pressure (able to stand with< 20 mmHg decrease in systolic blood pressure) or 
symptoms.   
 
 
 
 
 
 
Chronic trial 
Days 
-3,-2 
-1 
0 
1-10 
11,12 
13 
14 
15-24 25,26 
27 
28 
29-52 
53,54 
55 
56 
Restrict diet 
X 
X 
X 
 
X 
X 
X 
 
X 
X 
X 
 
X 
X 
X 
Collect urine   
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
Admit 
to 
GCRC 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
Pregnancy 
test 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
Take Drug  
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Posture 
study/ Collect 
blood 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
Vital signs 
 
X 
X 
 
 
X 
X 
 
 
X 
X 
 
X 
X 
X 
Adjust 
dosage 
 
 
 
 
 
 
X 
 
 
 
X 
 
 
 
 

 
6
 
 
BIOSTATISTICS 
Statistical analyses will be performed on a personal computer with the statistical package SPSS for 
Windows (Version 10.0, SPSS, Chicago). Some paired comparisons (Paired t-test, Wilcoxon signed-
rank test, repeated measures ANOVA, Friedman ANOVA by ranks) might be needed to compare 
treatment responses within a subject. 
 
Protection of Human Subjects: 
   
POPULATION:   
The conduct of these studies will involve approximately 25 human subjects. Subjects will include 
patients with severe orthostatic hypotension and other autonomic symptoms who do not meet criteria for 
one of our standard diagnoses.  Potential study participants will first take part in “The Pathophysiology 
of Orthostatic Hypotension” (IRB #030752, CRC approval pending). Results from that study will 
provide information on the pathophysiology of the autonomic disorder and might suggest which 
medication(s) might be an effective treatment. Subjects will range in age from 18-70 and be non-
smokers, drug-free, able to give informed consent, and free of pulmonary, renal, hematopoietic, hepatic 
and cardiac disease.  Exclusion criteria for the study include smoking, pregnancy, medications affecting 
the autonomic nervous system, any chronic illness, and anemia (Hct<35). 
 
RESEARCH MATERIALS:  
Research materials include blood, urine, and data.  The blood will be analyzed for catecholamines, renin 
and aldosterone. Urine will be analyzed for catecholamines, sodium, potassium, and creatinine.  
 
RECRUITMENT OF SUBJECTS:  
We will recruit patients from those referred to the physicians of the Autonomic Dysfunction Center at 
Vanderbilt who have participated in “The Pathophysiology of Orthostatic Hypotension” (IRB #030752, 
CRC approval pending). In each instance, the investigator will describe the complete protocol to the 
prospective participant.  The subjects will then be given a written informed consent form that has been 
approved by the Vanderbilt Institutional Review Board.  The subject will be given adequate time to read 
the consent form, ask questions, and if satisfied by the responses, sign the form.  Consent or refusal to 
participate in this study will not affect medical care.  No modifications or waiver of the elements of 
consent have been authorized, nor will any be necessary in the execution of this study. 
 
POTENTIAL RISKS:   
Blood drawing and insertion of venous catheters are uncomfortable and may cause bruising, bleeding, 
permanent damage to the vessel and in rare instance, infection.  The risk of bleeding can be prevented by 
tight compression of the site.  Experienced personnel will place all intravascular lines using sterile 
technique.   
 
Consuming a sodium- and caffeine-controlled diet might not be to the subject’s taste preferences. If a 
subject drinks caffeinated beverages regularly and stops caffeine intake suddenly, he/she might have 
headaches and fatigue for a few days.  These symptoms can be avoided by cutting down gradually on 
the amount of caffeine in the diet. 
 
Stopping medications might cause a temporary worsening of symptoms for patients.  Careful monitoring 
of blood pressure and heart rate will permit immediate attention and termination of the protocol when 
necessary. 
 
Collection of urine can be inconvenient. 

 
7
 
The seated oral medical trials are tedious and boring because they require being seated for an extended 
period of time while blood pressure is monitored.     
 
When any medication is used in testing, there is a small risk of an unforeseeable life-threatening allergic 
reaction.  Side effects associated with specific medications are listed below.  Side effects are listed as 
common, uncommon, and rare.   
 
Domperidone – common: dry mouth, abdominal cramps, diarrhea. Uncommon: loss of balance 
or muscle control, swelling of mouth, increased breast milk flow, headache, hives, hot flashes. 
Rare: pounding or racing heart beat, swelling of extremities, change in appetite, constipation, 
dizziness. 
 
-Methyldopa – common: weakness, distention of lower abdomen, constipation, swelling of the 
lower extremities, fever and depression, anxiety, nightmares, being sleepy or drowsy, headache 
and dry mouth.  Uncommon:  dizziness, gas, diarrhea, chest pain, stuffiness of the nose, low 
blood pressure on standing, low heart rate, nausea or vomiting, abnormal liver function tests.  
Serious or life-threatening: extremely rare reactions are fatal liver damage and fatal inflammation 
to the heart. 
 
Carbidopa – only reported to have adverse effects when it is given with the drug levodopa for 
Parkinson’ s disease.  Common adverse events with the carbidopa-levodopa combination include 
dyskinesias and nausea.  Less common adverse effects are psychotic episodes, depression and 
dementia. 
 
Metyrosine – common: drowsiness, diarrhea, drooling, trembling and shaking of hands and 
fingers; trouble speaking. Uncommon: decreased sexual ability in men, dry mouth, nausea, 
vomiting, stuffy nose, anxiety, confusion, hallucinations, mental depression.  Rare or life-
threatening: crystalluria (the excretion of crystals in the urine resulting in urine retention), black, 
tarry stools, unusual bleeding or bruising, muscle spasms, painful urination, pinpoint red spots on 
skin, restlessness, shortness of breath, shuffling walk, skin rash and itching, swelling of feet or 
lower legs, tic-like movements 
 
L-Dopa (levodopa) – common: abdominal pain, dry mouth, loss of appetite, nightmares, gas, 
abnormal thoughts, agitation, anxiety, clumsiness, difficulty swallowing, dizziness, excessive 
watering of mouth, nausea and vomiting, uncontrolled body movements.  Uncommon: Chest 
pain, mood or mental changes, discoloration of sweat or urine, constipation, diarrhea, flushed 
skin, headache, hiccups, increased sweating, muscle twitching, trouble sleeping, blurred vision, 
difficult urination, dilated pupils, dizziness or lightheadedness when getting up from a lying or 
sitting position, double vision, fast or pounding heartbeat, hot flushes, mental depression, skin 
rash, weight gain or loss. Rare: back or leg pain, black tarry stools, chills, convulsions, fever, 
high blood pressure, loss of appetite, swelling of feet or lower legs 
 
Atomoxetine – common: headache, nausea, sleepiness, trouble sleeping, anxiety, dry mouth, loss 
of appetite, dizziness, constipation, flushed or warm sensation, rash. Uncommon: loose stools, 
excessive energy, excitement, stomache ache, fluttering sensation in chest, abnormal heart 
rhythm sensations, tingling, vomiting, aching muscles. Rare: abnormal blood tests, such as 
abnormal liver function tests 
 
L-DOPS – The use of L-DOPS is under investigation and is not approved by the FDA.  We have 
used it for many years in a small population of patients that lack dopamine-beta-hydroxylase, the 

 
8
enzyme that converts dopamine to norepinephrine.  The initial dose is low and adjusted to treat 
low blood pressure without adverse effects.  It is possible that there may be some side effects.  
The following rare side effects have been reported: increased blood pressure, nausea, headache, 
hallucination, anorexia, increased liver enzymes, dizziness/lightheadedness, heart fluttering, 
thirst, nervousness, stomachache, vomiting, abdominal pain, chest pain, and fatigue. 
 
Placebo – The placebo is a pill or capsule that does not contain active ingredient.  It should 
therefore have no side effects. 
 
 
PROTECTION:  
Monitoring of vital signs will help minimize potential risks.  All information will be kept strictly 
confidential. 
 
BENEFITS:  
We guarantee no direct benefits to the study participants.  Results of this study will improve our 
understanding of autonomic dysfunction and might lead to important advances in the management of 
these diseases. 
 
DATA SAFETY MONITORING PLAN 
Data from subjects enrolled in this study will be reviewed on a bi-monthly basis by the P.I.and at least 
one co-investigator. Any adverse event of a serious or greater nature will be reviewed immediately with 
the P.I.  Emily Garland, Ph.D. will be responsible for tracking adverse events in this study. 
 
The adverse event will be described with the following information: description of the event; outcome of 
the event; duration of the event; relationship to study procedure; requirement, if any, for treatment or 
intervention; and outcome. 
 
Adverse events will be graded according to the following scale: 
 
0 = No adverse event or within normal limits 
 
1 = Mild adverse event (transient and mild in nature, and no treatment is necessary) 
2 = Moderate adverse event (some intervention and treatment are necessary, but participant 
completely recovers 
3 = Severe adverse event (an event that results in hospitalization, disability, or death or is life-
threatening) 
 
The investigator will state his opinion on whether there is a reasonable possibility that the event or 
experience is related to a procedure performed as part of this study. 

 
9
JUSTIFICATION FOR GCRC UTILIZATION  
 
The following GCRC services are necessary for conducting this scientific study: 
 
Inpatient/Outpatient Support:Approximately 25 patients will be studied over the five years.  The length 
of stay and number of admissions will depend on the number of medication trials performed with each 
patient. A research  nurse will be needed to draw blood  and monitor blood pressure during 
pharmacological testing, to document pulse and blood pressure during orthostatic vital signs, to perform 
posture studies, and to assist with urine collections, as well as for general patient care. 
 
Biostatistical Support: Although we do not anticipate doing any data analysis, review by the GCRC 
biostatistician is requested, as well as assistance with any unforeseen data analysis. 
 
Informatics Support: Review by the Informatics specialist and access to data from the Core Lab is 
required. 
 
Core Lab Utilization: The Core Lab is needed for plasma and urine catecholamine analysis and urinary 
sodium, potassium and creatinine. 
 
Nursing Support: Nursing support will be needed for blood draws, urine collections, posture studies, and 
medication studies. 
 
Nutrition Services Utilization: We will ask patients to eat a standard diet with no caffeine and 150 mEq 
sodium, 70 mEq potassium while in the hospital for these procedures.  We might ask them to restrict 
their diet for up to three days prior to admission.   
 
 
OTHER SUPPORT 
 
84 urine pregnancy tests are needed. 
700 plasma aldosterone and 50 plasma renin analyses are requested, as well as processing of 650 
aliquots of plasma to be frozen for possible future analysis of plasma renin activity. 

 
10 
Gender/Minority Mix 
 
This study does not exclude research participants by race or gender and includes research participants 
aged 18 – 70 years old.  We expect the overall distribution of participants to be even across gender and 
ethnic groups. 
 
Table I – National Figures for Mix of Study Population 
 
 
Am. 
Indian 
Alaskan  
Native 
Asian 
Pacific  
Islander 
Black, 
of 
H
Origin 
Hispanic White, 
of 
H
Origin 
Other 
Total 
Male 
0.4 
1.4 
5.7 
4.3 
36.9 
* 
48.7 
Female 
0.4 
1.4 
6.0 
4.5 
38.8 
* 
51.1 
Total 
0.8 
2.8 
11.7 
8.8 
75.7 
* 
99.8 
* negligible in this context.        Note: Rounding errors led to totals different from 100%. 
 
 
Table II – Tennessee Figures for Mix of Study Population 
 
 
Am. 
Indian 
Alaskan  
Native 
Asian 
Pacific  
Islander 
Black, 
of 
H
Origin 
Hispanic White, 
of 
H
Origin 
Other 
Total 
Male 
0.1 
0.5 
7.4 
0.4 
39.9 
* 
48.3 
Female 
0.1 
0.5 
8.0 
0.4 
42.8 
* 
51.8 
Total 
0.2 
1.0 
15.4 
0.8 
82.7 
* 
100.1 
* negligible in this context.        Note: Rounding errors led to totals different from 100%. 
 
 
Table III – Anticipated Enrollment – Actual Patient Numbers 
 
Am. 
Indian 
Alaskan  
Native 
Asian 
Pacific  
Islander 
Black, 
of 
H
Origin 
Hispanic White, 
of 
H
Origin 
Other 
Total 
Male 
0 
0 
2 
1 
10 
0 
13 
Female 
0 
0 
2 
0 
10 
0 
12 
Total 
0 
0 
4 
1 
20 
0 
25 
 
 
 
 

 
11 
REFERENCES 
 
Man in 't Veld AJ, Boomsma F, Lenders J, Meiracker Avd, Julien C, Tulen J et al. Patients with 
congenital dopamine b-hydroxylase deficiency. A lesson in catecholamine physiology. Am J Hypertens 
1988;1:231-38. 
Man in 't Veld AJ, Boomsma F, Moleman P, Schalekamp MA. Congenital dopamine-b-hydroxylase 
deficiency: A novel orthostatic syndrome. Lancet 1987;1:183-87. 
Man in 't Veld AJ, Boomsma F, van den Meiracker AH, Julien C, Lenders J, Schalekamp MA. d,l-threo-
3,4-dihydroxyphenylserine restores sympathetic control and cures orthostatic hypotension in dopamine 
beta-hydroxylase deficiency. J.Hypertens.Suppl. 1988;6:S547-S549. 
Man in 't Veld AJ, Boomsma F, van den Meiracker AH, Schalekamp MA. Effect of unnatural 
noradrenaline precursor on sympathetic control and orthostatic hypotension in dopamine-beta-
hydroxylase deficiency. Lancet 1987;2:1172-75. 
Robertson D. Genetics and molecular biology of hypotension. Curr Opin Nephrol Hypertens 1994;3:13-
24. 
Robertson D, Biaggioni I, Ertl AC, Robertson RM, Diedrich A, Blakely RD et al. Orthostatic 
intolerance: emerging genetic and environmental etiologies. J.Gravit.Physiol. 1999;6:51-54. 
Robertson D, Goldberg MR, Hollister AS, Onrot J, Wiley R, Thompson JG et al. Isolated failure of 
autonomic noradrenergic neurotransmission: Evidence for impaired beta-hydroxylation of dopamine. 
N.Engl.J.Med. 1986;314:1494-97. 
Robertson D, Haile V, Perry SE, Robertson RM, Phillips JA, Biaggioni I. Dopamine beta-hydroxylase 
deficiency. A genetic disorder of cardiovascular regulation. Hypertension 1991;18:1-8. 
Robertson D, Hale N. Genetic diseases of hypotension. Adv.Pharmacol. 1998;42:61-5.:61-65. 
Robertson D, Hollister AS,  Biaggioni I. Dopamine-b-hydroxylase deficiency and cardiovascular 
control, In: Laragh JH, Brenner BM, editors. Hypertension Pathophysiology, Diagnosis and 
Management. New York: Raven Press, Ltd.; 1990. p. 749-59. 
van den Meiracker AH, Boomsma F, Man in 't Veld AJ. Dopamine-b-Hydroxylase Deficiency, In: 
Robertson D, Low PA, Polinsky RJ, editors. Primer on the Autonomic Nervous System. San Diego, CA: 
Academic Press, Inc.; 1996. p. 205-08.