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Decreased sympathetic neuronal uptake in idiopathic orthostatic hypotension.

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Decreased Sympathetic Neuronal Uptake
in Idiopathc Orthostatic Hypotension
Ronald J. Polinsky, MD,* David S. Goldstein, MD, PhD,t Robert T. Brown, MD," Harry R. Keiser, MD,?
and Irwin J. Kopin, MD$
The disappearance rates from plasma of intravenously administered levo-norepinephrine (I-NE), dextro-norepinephrine (d-NE), and isoproterenol (ISO) were measured in normal subjects and in patients with either multiplesystem atrophy (MSA) or idiopathic orthostatic hypotension (IOH). The two isomers, 1-NE and d-NE, were removed at
similar rates in all groups. In normal subjects, the d and 1 isomers of norepinephrine were cleared more rapidly than
ISO. In patients with IOH, the initial rates of disappearance of the NE isomers from plasma were slower than normal
and similar to the rate for IS0 disappearance. Plasma NE levels, NE clearance, and the apparent release rate of NE into
plasma from sympathetic neurons were significantly lower in patients with IOH than in normal subjects. Only the
apparent NE secretion rate was related to the baseline plasma NE level. Sympathetic neuronal dysfunction in IOH is
attended by a reduction in the clearance of NE. The very low plasma NE levels, in association with the striking
reduction in NE clearance, suggest that in IOH there is a marked decrease in NE release. NE clearance and apparent
NE secretion rate are normal in MSA, consistent with a central nervous system dysfunction in regulating the sympathetic nervous system. Neuronal uptake of NE in humans does not appear to be stereoselective.
Polinsky RJ, Goldstein DS, Brown RT, Keiser HR, Kopin IJ: Decreased sympathetic neuronal uptake
in idiopathic orthostatic hypotension. Ann Neurol 18.48-53, 1985
Sympathetic neuronal dysfunction may result from primary degeneration of the peripheral autonomic nervous system or from a deficit in regulation of the sympathetic outflow from the central nervous system.
Idiopathic orthostatic hypotension (IOH) occurs as a
pure or isolated form of progressive autonomic failure in the absence of peripheral neuropathy or
nonautonomic neurological signs (31. In multiplesystem atrophy (MSA) the autonomic dysfunction is
attended by central nervous system neurological disorders (17). Patients with MSA manifest signs of
olivopontocerebellar atrophy or striatonigral degeneration, or both. Although the clinical manifestations of
autonomic dysfunction are similar in these two disorders, IOH and MSA can be differentiated on the basis
of biochemical measurements and pharmacological responses (151. Norepinephrine (NE) is the neurotransmitter released at most peripheral sympathetic nerve
endings. The action of released NE is terminated
primarily by uptake into the sympathetic nerves. However, a portion of the released catecholamine escapes
into the plasma (11. Plasma levels of NE correlate with
direct electrophysiological measurement of sympathetic nerve activity (181. Thus, plasma NE levels can
be used as an indirect index of sympathetic function.
Clinical studies have provided additional justification
for the use of plasma NE levels in this determination.
After sympathectomy there is a decrease in the plasma
NE level in venous effluent blood from the affected
limb (141. Autonomic neuropathy also causes a reduction in plasma NE levels (51. Patients with IOH have
low supine plasma NE levels in contrast to normal
supine levels in MSA patients [16, 191. Neither group
shows an adequate increase in their plasma NE levels
upon standing. These findings suggest that the sympathetic nervous system dysfunction in IOH involves directly the more peripheral portions of the system
whereas in MSA the deficit appears to constitute a lack
of activation by the central nervous system of a relatively intact peripheral sympathetic nervous system.
The level of plasma NE is determined by the balance between the rates of its spillover into plasma and
its removal from the circulation. Several processes affect NE release, reuptake, or metabolism, and subsequent removal of NE from plasma (Fig 1). Although
neuronal uptake does not appear to be stereoselective,
studies in animals and of tissue preparations indicate
that uptake into synaptic vesicles andor NE metabolism by monoamine oxidase favors the naturally occurring levo-isomer [G, 111.Thus differences in the disap-
From the 'Medical Neurology Branch and SNeuroimmunology
Branch, National Institute of Neurological and Communicative Disorders and Stroke, and the t Hyperrension-Endocrine Branch, National Heart, Lung, and Blood Institute, Bethesda, MD 20205.
Received Aug 13, 1984, and in revised form Dec 4. Accepted for
publication Dec 8, 1984.
Address reprint
D,. pollnsky, National Insrltutes of
Health, Building 10, Room 5N-236, 9000 Rockville Pike,
Bethesda, MD 20205.
NORADRENERGIC NEURON
SYNAPTIC CLEFT
Clinical Characteristics and Plusma Norepinephrine Lezlels
of Control Subjects and Patients with Orthostatic Hypotension
~
Patient No.
1
2
3
4
5
6
7
8
9
Fig I . A peripheral noradrenergic neuron. (NE = norepinephrine; I S 0 = isoproterenol;M A 0 = monoamine oxidase;
COMT = catechol-ortho-methyltransferase.)
pearance rates of levo-norepinephrine (1-NE) and dextro-norepinephrine (d-NE) reflect stereospecificity in
vesicular uptake and/or metabolism of NE. Isoprotereno1 (ISO), however, is not taken up by sympathetic
neurons 141. A comparison of the plasma disappearance rates of NE and I S 0 provides a means for assessing rieuronal catecholamine uptake. We studied the
disappearance of intravenously administered, radioactively labeled catecholamines in patients with progressive autonomic failure in order to further characterize
t h e sympathetic nervous system deficit.
Methods
All patients were admitted to the Clinical Center of the
National Institutes of Health for evaluation of orthostatic
hypocension. A detailed medical history, neurological examination, blood studies, electrocardiogram, and chest x-ray
study were performed prior to this investigation. Medications were discontinued for a minimum of one week before
the sixdy, but diet was unrestricted. The clinical characteristics of the subjects included in this study are listed in the
Table. A clinical diagnosis of IOH or MSA was established
using criteria that have been described previously 1161. The
signs of autonomic dysfunction included orthostatic hypotension, decreased sinus arrhythmia, severe constipation, neurogenic bladder, reduced thermoregulatory sweating, and impotence (males). None of the patients had evidence of
peripheral neuropathy or signs suggestive of a systemic disorder associated with autonomic dysfunction. In addition to
chronic autonomic failure, patients with MSA had neurological signs indicating nonautonomic central nervous system
involvement (rigidity, bradykinesia, tremor, incoordination,
ataxia, d ysarthria, emotional lability, frontal release signs, Babinski's reflex). The duration of illness in IOH patients
ranged from 5 to 23 years but was less than 7 years for
patients with MSA. TweIve control subjects volunteered as
part of the N I H normal volunteer program and ranged in
age from 25 to 73. All had normal findings on physical exam-
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
~-
Age, Sex
Diagnosis
Baseline Plasma
NE (pgiml)
50, F
40, M
39, F
41, M
46, M
73, F
71, M
44, F
37, M
25, F
34, M
25, M
34, F
43, M
62, M
60, F
69, M
61, M
58, F
71, F
36, F
73, M
68, M
42, F
63, F
66, M
52, F
64, F
76, F
CON
CON
CON
CON
CON
CON
CON
CON
CON
CON
CON
CON
MSA
MSA
MSA
MSA
MSA
MSA
IOH
IOH
IOH
IOH
IOH
IOH
IOH
IOH
IOH
IOH
IOH
199
257
132
138
177
386
131
22 1
274
179
131
203
222
519
555
81
27 1
133
60
86
67
5
68
20
14
16
25
25
243
-
= norepinephrine; CON = control; MSA = multiple-system
disorder; IOH = idiopathic orthostatic hypotension;F = female; M
= male.
NE
ination as well as routine blood and urine testing. In particular, blood pressure in all control subjects was less than 1401
90 and there were no symptoms or signs of any medical
illness at the time of the study. Family history was negative
for hypertension. All subjects gave informed consenr for the
procedures in accordance with N I H guidelines.
Radioactive Catecholamine Infusion
Tritiated 1-NE (3H-1-NE) and I S 0 (3H-ISO)were purchased
from New England Nuclear Corp, Boston, MA and d-NE
labeled with carbon-14 ('*C-d-NE) was obtained from
Amersham Corp, Boston, MA. The minimum specific activity of the tritiated compounds used for these infusions was 5
Ci/mmole; the '*C-d-NE had a specific activity of 33 mCil
mmole. It was necessary to administer labeled compounds
with high specific activity so that tracer amounts without
significant pharmacological effects could b e detected. Each of
the radiolabeled catecholamines was tested for purity and
prepared for human use by the N I H radiopharrnacy. The
Polinsky et al: Neuronal Norepinephrine Uptake
49
compounds were diluted into a convenient volume of sterile
buffer and aliquoted into separate vials, each containing 50
pCi jH-I-NE, 50 pCi 3H-IS0, or 10 pCi 14C-d-NE. These
vials were stored at - 70°C until use.
All subjects were studied in the morning following an
overnight fast or after a light breakfast. An intravenous needle or catheter was inserted into an arm vein for blood sampling and another placed in a vein of the opposite arm for the
infusion. The subjects were kept supine during the entire
procedure. Blood pressure was measured every 5 minutes
during the test; the electrocardiogram was monitored
throughout the infusion.
A baseline blood sample was taken after a minimum of 20
minutes following insertion of the needles. A solution (65
ml) of D5W containing 50 pCi 'H-I-NE, 10 pCi I4C-d-NE,
and 50 pCi 3H-IS0 was infused intravenously over twenty
minutes using an IMED volumetric infusion pump set at a
rate of 180 mVhr. Blood samples were obtained at 1, 3, 5,
10, and 15 minutes and at the end of infusion (usually between 18.5 and 20 minutes). After the infusion was stopped,
blood samples were taken at 1, 2, 3, 5, 10, and 20 minutes.
Blood samples were collected into chilled heparinized tubes
and kept on ice until centrifuged at - 4°C. After centrifugation, the plasma was removed and kept frozen at -70°C
until the time of assay.
Analysis of Caterbolamines
All samples from a given patient were analyzed on the same
day, along with an aliquot of the infusate. Plasma NE and
I S 0 levels were determined using a modification of a previously described method which couples high-performance liquid chromatography (HPLC) with electrochemical detection
[lo). After thawing and centrifugation, 1 or 2 ml of plasma
was made alkaline by the addition of 400 ~1 of Tris-EDTA
buffer at p H 8.6, and about 1 ng N-methyldopamine and 2
ng I S 0 were added as internal standards. About 10 mg of
acid-washed alumina was added, and after 20 minutes of
vigorous mechanical shaking the tubes were centrifuged and
the supernatants were removed. The alumina was washed
twice with water. Catecholamines were eluted from the
alumina by adding 100 PI of either 0.1 M perchloric acid or
0.2 M acetic acid, then mixed thoroughly on a vortex mixer
for about 15 seconds.
NE and I S 0 in 90 p1 of the acid eluate were separated by
HPLC on a Microbondapak C18 reverse phase column. The
mobile phase, consisting of sodium acetate, EDTA, heptanesulfonic acid, and acetonitrile, flowed at a rate of 1 mY
min. A potential of 0.5 V was applied to the glassy carbon
electrode and the sensitivity of the detector was set at 1
nanoamps/V. Under these assay conditions, 15 to 20 pgiml
of plasma N E could be detected easily. Plasma N E levels
were calculated from the peak heights on the chromatogram
after correction for recovery of the internal standard. Recovery of catecholamines was approximately 70% and was not
different for either I S 0 or N-methyldopamine.
3H and I4C Determinations
The 3H and I4C contents of the plasma catecholamine peaks
were quantified by liquid scintillation spectrometry. Effluent
was collected from the detector outlet into separate glass
vials when the NE and I S 0 peaks appeared. It was necessary
50 Annals of Neurology Vol 18 No 1 July 1985
to use a longer collection interval for the I S 0 peak because it
was wider and the radioactivity trailed. More than 95% of
the radioactivity was present in a 90-second collection interval for the N E whereas two successive 90-second aliquots
were required to obtain a similar recovery of the I S 0
radioactivity. After addition of 10 ml of liquid scintillation
counting fluid (Aquasol), radioactivity in each vial was assayed by counting for 100 minutes. Background 'H and 14C
activity was determined by counting the effluent collected
during the N E and I S 0 peaks from the preinfusion baseline
blood sample. The appropriate background counts per minute (cpm) was subtracted from the NE and I S 0 peak cpm in
each sample. jH counts were adjusted for the crossover of
14C into the 3H window using ['4C]toluene as the standard.
The crossover ratio (3H channel cpm/'*C channel cpm) for
I4C was used to subtract a percentage of I4C cpm from the
'H cpm registered for each sample. The results were expressed as c p d m l of plasma by correcting the data for recovery and volume of plasma extracted.
Data Anulyszs
The N E clearance and apparent NE release rate were calculated as previously described {7]. Since the endogenous
plasma I-NE levels were not altered during the steady-state
portion of the infusion, it was possible to use the baseline
plasma I-NE levels to calculate the N E release rate. Statistical
significance of differences in mean plasma levels, clearances,
and release rates of N E among IOH patients, MSA patients,
and control subjects was determined using a one-way analysis
of variance. The pooled variance was used to assess the
significance of differences between group pairs as indicated
by the f value. A p value less than 0.05 defined statistical
significance.
The rates of decline in radiolabeled plasma catecholamine
levels were determined by calculating the slope resulting
from exponential regression of the appropriate c p d m l and
time during the first 5 minutes after stopping the infusion.
Differences in the initial rates of plasma catecholamine disappearance were examined by using a statistical method for
comparing two regression models [ 12).
Results
The mean ( + standard error of the mean) baseline
plasma NE level in IOH patients (57.2 -+ 13.7 pg/ml)
was significantly lower @ < 0.005) than in control
subjects (202.3 5 21.8 pg/ml) or MSA patients (296.8
k 80.8 pgiml). A steady-state level of labeled catecholamines was achieved between 10 and 15 minutes
after the infusion was started. After stopping the infusion, the declines in 3H-I-NE and 14C-d-NE were
biphasic with an initial rapid decline lasting 5 minutes
followed by a slower phase. Neither blood pressure
nor heart rate was altered significantly during the infusion procedure in control subjects or either patient
group.
In control subjects, the initial rates of decline in
plasma levels of 'H-1-NE and 14C-d-NE in the 5 minutes immediately after stopping the infusion were not
significantly different. Radiolabeled I S 0 levels in
0
0
CONTROL
MSA
CONTROL
MSA
b IOH
0
A IOH
I
1
0
I
I
I
1
2
3
4
5
TIME AFTER INFUSION (mid
Fi g 2 The decline in levo-norepinephrine levels in plasma following constant-rate infasion to steady-state in control subjects and
patients with orthostatic hypotension. (MSA = multiple-system
atrophy; IOH = idiopathic orthostatic hypotension.)
plasma decreased more slowly than either of the NE
isomers (p < 0.01). The initial rates of disappearance
yielded half-lives (71/2) for 3H-1-NE, 14C-d-NE, and
3H-IS0 of 2.44, 2.37, and 3.47 minutes, respectively.
IOH patients cleared 3H-l-NE from plasma more
s1owl.y (p < 0.005) than did control subjects (Fig 2).
The initial rate of 3H-1-NE decline in MSA patients
was similar to that observed in controls. The 71/2 of
4.47 minutes in the I O H group was almost double the
value found in the control subjects. As might be anticipated, the results obtained with 14C-d-NE were virtually the same as those with the 1 isomer of NE (Fig 3).
However, a higher steady-state level of 14C-d-NE was
attained in IOH patients than in control subjects or
patients with MSA. Differences in the initial rates of
decline in 3H-IS0 among the three groups of subjects
were not significant. In the IOH patients, the initial
plasma disappearance rates were similar for all of the
infused catecholamines; in particular, the 71/2 for 3HI S 0 was 3.92 minutes, which was not significantly different from the 71/2 for the d-NE and 1-NE isomers in
this group (4.34 and 4.22 minutes, respectively).
Plasma clearance of NE was significantly lower (p <
1c
I
1
I
I
I
3
4
TIME AFTER INFUSION (rnin)
2
I
5
Fig 3. The decline in dextro-norepinephrineleoels in plasma ,611lowing constant-rate infasion to steady-state in control subjects
and patients with orthostatic hypotension. (Abbreviationsas in
Figare 2.)
0.02; Fig 4 ) in the I O H patients (3.35 2 0.25 Umin)
than in control subjects (4.79 & 0.47 Umin). The apparent volumes of distribution were similar for the
three groups of subjects, but the IOH patients had a
significantly lower apparent NE release rate (p <
0.005; see Fig 4). Although there was no correlation
between the preinfusion baseline plasma NE level and
NE clearance, the apparent NE secretion rate was
significantly correlated with the plasma NE levels
among all the subjects (r = 0.924; p < 0.001; Fig 5).
In control subjects, 1-NE clearance was proportional to
I S 0 clearance. MSA patients had similar clearance
rates for both catecholamines and these were similarly
correlated with each other. Since, as indicated earlier,
the NE clearance but not the I S 0 clearance was
significantly lower than normal in IOH patients, the
relationship between 1-NE clearance and I S 0 clearance differed for the IOH group. The ratios of 1-NE
clearance to I S 0 clearance in control subjects and patients with MSA were 1.30 0.10 and 1.19 ? 0.03,
respectively, both of which were significantly higher (p
< 0.02) than the ratio of 1.05 5 0.04 observed in the
IOH group.
*
Polinsky et al: Neuronal Norepinephrine Uptake
51
T
T
-._c
2.5
-E
2.0.-
.
B
E
w
T
I-
2
w
v)
T
I
1.5.
5
-1
w
[r
Lu
z
lNt
0.5 .
L
0Control (N=12)
MSA (N=6)
IOH I N = l l )
Control
*
**
p< 0.005
lKo.02
Fig 4. Plasma norepinephrine (NE) /eeeLs, NE clearance, and
NE release rate in control subjects and patients with either midtiple-system atrophy (MSA) or idiopathic ovtho.rtutir bypotemion
(IOH).
4.0
0
1.0 .
0
0 MSA
A IOH
7 3.0
z
.
m
-E
W
t
a
8
E
m
2.0
v,
W
z
1.o
0
I
I
I
I
1 0 0 m 3 0 0 4 0 0 5 0 0 6 0 0
PLASMA NE (pg/rnll
Fig 5 . The relationship ofplasma norepinephrine (NE) to the
NE secretion rate in control subjects and patients with orthostatic hypotension.
Discussion
As previously reported, the clearance of NE in patients with I O H is lower than in MSA patients 191.
This reduction might be expected because of the
biochemical and pharmacological differences of the
sympathetic nervous system dysfunction in these disorders. The low plasma NE levels in patients with I O H
52
Annals of Neurology
Vol 18 No 1 July 1985
I
are consistent with peripheral sympathetic neuronal
dysfunction and with the loss of catecholamine histofluorescence in perivascular nerve endings which has
been observed in muscle biopsies [13]. In contrast, the
normal basal N E levels and clearance in patients with
MSA are consistent with the view that peripheral
noradrenergic sympathetic neurons are intact in this
disease.
Clearance of I-NE is the result of neuronal and extraneuronal mechanisms, whereas I S 0 is removed
from plasma only by extraneuronal processes. In humans, the initial disappearance rates of radiolabeled
I S 0 and NE from plasma are similar after pretreatment with desipramine [ 101; this suggests that there
are no significant differences between the extraneuronal removal rates of I S 0 and NE. Thus, the
difference between clearance of NE and I S 0 provides
an index of the proportion of NE clearance resulting
from neuronal uptake. Since neuronal uptake is an
important mechanism for the removal of NE, but not
ISO, from the circulation, the reduced NE (but not
ISO) clearance in I O H is probably due to deficient
neuronal uptake. The initial rate of decline in
radiolabeled N E (but not 3H-ISO) was slower in IOH
than in control subjects or MSA patients. This phase
of removal presumably reflects neuronal uptake since
it is prolonged by desipramine but unaffected by cortisol [S]. The striking deficit in neuronal uptake in
I O H is further evident in the similarity between the
disappearance rates of NE and ISO. Pretreatment of
normal subjects with desipramine, a specific blocker of
neuronal uptake, reduces the clearance of exogenously
administered NE but does not alter the plasma N E
level 1:7, lo}. Thus, the prolonged pressor effect of
exogenously administered NE observed in some IOH
patients might result from reduced NE clearance 121.
In the single reported study of NE kinetics in patients with chronic autonomic failure, Esler and associates [9} found reduced NE clearance only in patients without evidence of central nervous system
dysfunction. These patients had normal plasma NE
levels. The IOH patients in the present study appear
to have had more extensive involvement of the sympathetic nervous system with fewer functioning noradrenergic neurons. This was manifested by very low
plasma NE levels as well as reduced NE clearance.
Possibly the IOH patients reported by Esler's group
were at an earlier stage of the disease and neuronal
uptake was selectively diminished relative to the synthesis and release of NE. The similarity in disappearance rates of 1-NE and d-NE isomers suggests that
neurcsnal uptake in humans, as in rats, is not
stereospecific, although intraneuronal (vesicular) storage andor metabolism appear to favor the 1 isomer 16,
111.
The proportion of NE clearance resulting from
neurclnal uptake can be derived from the ratio of clearance of NE and ISO. This ratio (1.05 _t 0.04) was
significantly lower in the IOH patients than that observed in the control subjects and MSA patients (1.26
0.06). These results indicate that in subjects with
normal NE clearance, neuronal uptake accounts for
approximately 20.6% of the total clearance of exogenously administered NE. The total NE clearance in the
IOH patients resulting from neuronal uptake was only
4.8%, only about one-fourth of that of subjects without a deficit in neuronal NE uptake. These values
probably represent overestimates because antecubital
venous blood samples would yield lower steady-state
levels of labeled NE due to extraction of NE by the
arm.
The results of this study demonstrate that the sympathetic nervous system deficit in IOH includes defective neuronal NE uptake. Although in the IOH patients both resting plasma NE levels and NE clearance
were diminished, there was a poor correlation between
these parameters. The apparent NE secretion rate,
however, was significantly correlated with the preinfusion plasma NE levels. Thus it appears that the low
plasma NE levels in IOH patients are primarily the
result of diminished release of NE. Only one IOH
patient had a normal plasma NE level; this patient also
had the lowest N E clearance in the IOH group. Also
of interest are the two MSA patients with elevated
supine plasma NE levels and normal NE clearances;
*
these patients may have inappropriately elevated sympathetic nervous system activity when supine.
References
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287~237-242, 1972
2. Bannister R, Sever P, Gross M: Cardiovascular reflexes and
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3. Bradbury S, Eggleston C: Postural hypotension: a report of
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(Suppl I) 46:147-148, 1980
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Polinsky e t al: Neuronal Norepinephrine Uptake
53
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