Original Articles
Norepinephrine Kinetics in Essential Hypertension
Defective Neuronal Uptake of Norepinephrine in Some Patients
MURRAY ESLER,
F.R.A.C.P.,
P H . D . , GRAHAM JACKMAN, P H . D . , ALEX BOBIK, P H . D . ,
PAUL LEONARD, DIANNE KELLEHER, B . S C , HELEN SKEWS,
GARRY JENNINGS,
F.R.A.C.P.,
AND PAUL KORNER,
B.SC,
M.D., M . S c , F.R.A.C.P.
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SUMMARY To assess sympathetic nervous system function in essential hypertension, we measured tbe
rates of release to and removal from plasma of the sympathetic neurorransmltter, norepinephrine. In normal
subjects, disappearance of tritiated /-norepinephrlne from plasma, after infusion to steady state, was biexponential, with t,V4 = 2.0 ± 0.4 minutes (mean ± standard deviation) and t,Vi = 33 ± 15 minutes. Tbe rapid
component of removal seemed to represent neuronal uptake of norepinephrine: the t, W was lengthened by the
selective inhibitor of neuronal norepinephrine uptake, desipramine; it was not changed by the extraneuronal
uptake blocker, cortlsol; and it was prolonged in patients with peripheral sympathetic nerve dysfunction
(idiopathic autonoroic insufficiency). In eight of 37 hypertensive patients, tbe t,V4 was > 2.8 minutes (range,
3.3-6.0 min), longer than in any normal subject; this appears to be presumptive evidence of the existence of
defective neuronal norepinephrine uptake. In these patients tbe rate of spillover of norepinephrine to plasma, of
transmitter escaping uptake after release, was 0.73 ± 0.39 Mg/m'/min (43 ± 23 ninoles/m'/min), higher
than in normal subjects, 036 ± 0.14 ng/m'/mia (2.1 ± 0.8 nmoles/m'/min) (p < 0.01). A defect in neuronal
uptake of norepinephrine, by exposing adrenergic receptors to high local norepinephrine concentration, may be
important in the parhogenesis of blood pressure elevation in some patients with essential hypertension.
(Hypertension 3: 149-156, 1981)
KEY WORDS • norepinephrine • arterial hypertension • sympathetic nervous system •
tricyclic antidepressant • cortisol • idiopathic autonomic insufficiency
T
HE finding of increased levels of the sympathetic neurotransmitter, norepinephrine, in
the plasma of some patients with essential
hypertension,1** although disputed,8- * suggests that
sympathetic nervous overactivity is involved in the
pathogenesis of the blood pressure (BP) elevation. But
the plasma concentration of norepinephrine provides a
very indirect measure of sympathetic nerve discharge
rate. Only a small proportion of the norepinephrine
released escapes to plasma; most is subject to local
reuptake by the sympathetic nerves.'1 * Furthermore,
the plasma concentration of norepinephrine is determined not only by the rate of spillover to plasma after
release, but also by the subsequent rate of removal of
norepinephrine from the circulation.'
We have developed methods for studying the
kinetics of norepinephrine in humans.9 The rates of
spillover of norepinephrine to plasma and clearance of
norepinephrine from plasma are determined using
radiotracer techniques. With these methods, the rate
of norepinephrine spillover to plasma in patients with
peripheral autonomic insufficiency has been found to
be significantly decreased,'110 indicating that the norepinephrine spillover rate provides at least qualitative
information about net sympathetic nerve activity.
In the evaluation of possibly increased norepinephrine spillover in patients with essential hypertension,
it seemed important to differentiate between a true increase in norepinephrine release (with increased sympathetic nerve firing rates) and increased spillover
from defective local inactivation of transmitter
(neuronal reuptake). To this end, a method based on
the analysis of tritiated norepinephrine postinfusion
decay curves has been developed for assessing
neuronal uptake of norepinephrine in humans.
We have applied these measures of norepinephrine
kinetics to the study of sympathetic nervous system
From the Baker Medical Research Institute, Commercial Road,
Prahran, Victoria, 3181, Australia
Supported by a grant from the National Health and Medical
Research Council of Australia.
Address for reprints- Dr Murray Esler, Baker Medical Research
Institute, Commercial Road, Prahran, Victoria, 3181, Australia.
Received April 4, 1980, revision accepted August 7, 1980.
149
150
HYPERTENSION
function in essential hypertension. The results
presented here suggest that in a proportion of patients
with essential hypertension, neuronal uptake of norepinephrine is defective, leading to greater spillover of
norepinephrine to plasma, and higher plasma norepinephrine concentrations.
Materials and Methods
i
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Experimental Subjects
Thirty-seven white patients (29 men, 8 women) with
essential hypertension (mean age 38 years, range
18-55) and 17 healthy volunteers (12 men, 5 women,
mean age 34 years, range 18-54) were studied. The
study protocol was approved by the Alfred Hospital
medical research ethics committee, and was fully
explained to all subjects, who gave their informed
consent. No women with childbearing potential participated in the study. Patients were recruited consecutively from the hypertension outpatient clinic of
the Alfred Hospital and from the Risk Evaluation
Clinic of the Baker Medical Research Institute. Normal volunteers were recruited by advertisement from
the general community. The average clinic BP of
patients (minimum of three visits) was above 155 mm
Hg systolic, or 90 mm Hg diastolic, or both. Five had
isolated systolic hypertension. None had a serum
creatinine concentration greater than 2.0 mg/dl (18
^moles/dl), Grade 3 or 4 hypertensive retinopathy, or
were in heart failure. Most patients had never received
treatment for hypertension, and none had been treated
in the preceding 6 weeks. Secondary hypertension was
excluded by clinical testing.
Investigation of Norepinephrine Kinetics
We studied the kinetics of norepinephrine using
methods we have previously described,9 measuring the
apparent rate of release of norepinephrine (rate of entry of norepinephrine to plasma), clearance of
norepinephrine from plasma, the time course of disappearance of norepinephrine from plasma, and
plasma norepinephrine concentration. When tritiated
norepinephrine (NE) is infused intravenously at a constant rate to reach plateau concentration (steady state
conditions), the rate of release of endogenous
norepinephrine into plasma and norepinephrine
clearance from plasma may be determined9' u using
the following equations:
apparent NE release rate =
NE- 3 H infusion rate
specific activity of plasma NE
(1)
NE clearance =
NE-3H infusion rate
steady state plasma NE-3H concentration
The calculated rate of norepinephrine release is "apparent" rather than "real" as it gives, rather than the
rate of release of norepinephrine from sympathetic
nerve varicosities, the rate at which released norepinephrine spills over into plasma.
VOL 3, No 2, MARCH-APRIL
1981
Norepinephrine Apparent Release Rate and Clearance
In 25 hypertensive patients and all normal subjects,
we determined the apparent release rate of norepinephrine and clearance of norepinephrine from
plasma. In principle, this involved the intravenous infusion of tritiated norepinephrine to reach plateau
concentration, and measurement of plasma tritiatednorepinephrine concentration and norepinephrine
specific activity at steady state, from which
norepinephrine release rate and clearance values are
derived.9' " Studies were performed with subjects resting supine in a single-bed ward. Tests were conducted
always in the morning, after subjects had eaten a light
breakfast. Tea, coffee, alcohol, and tobacco were forbidden during the preceding 12 hours. No patients
were hospitalized, all attending as outpatients on the
morning of the test. One hour prior to the commencement of the infusion, intravenous needles were inserted in antecubital veins for subsequent infusion of
norepinephrine and withdrawal of blood samples. In a
preliminary study9 on 10 patients and 10 normal subjects, tritiated norepinephrine was infused into an
antecubital vein of one arm at a constant rate of 0.35
,nCi/m 2 /min for 90 minutes, and 10 ml of blood was
sampled sequentially from the other arm for assay of
tritiated norepinephrine. The concentration of
tritiated norepinephrine had reached, plateau in
plasma in normal subjects and was at, or close to,
plateau in hypertensive patients by 60 minutes (not
quite to plateau in two patients) (fig. 1) in agreement
with previous reports.12-13 For the present study,
which did not include the 20 subjects participating in
the preliminary testing, the halftime of the slowest
component of norepinephrine removal, which influences the time to reach plateau concentration,11' u
was known, and the 90-minute infusion was immediately preceded by a bolus injection of 15 jtCi/m 2
of radiolabelled norepinephrine in all subjects, to
hasten the approach to plateau concentration,11' u and
to ensure that steady-state conditions were in fact
reached in every case. At 70, 80, and 90 minutes, 10 ml
of blood was withdrawn for determination of mean
plasma norepinephrine specific activity at steady state,
and a further 10 ml at 80 minutes for assay of plasma
norepinephrine concentration.
Time Course of Disappearance of Tritiated
Norepinephrine from Plasma
At the end of the infusion of tritiated norepinephrine, venous blood was sampled sequentially over
40 minutes, to follow the time course of disappearance
of norepinephrine from plasma. This was done in all
subjects, including 12 hypertensive patients in whom
norepinephrine release rate and clearance measurements were not performed. The components of the
norepinephrine disappearance curve were resolved by
graphical analysis.11
Mechanism of Norepinephrine Removal from Plasma
Because removal of norepinephrine from plasma
was found to be slowed in some patients with essential
NOREPINEPHRINE KINETICS IN HYPERTENSION/Er/er et al.
151
ministration of the selective extraneuronal uptake inhibitor, cortisol,7 500 mg (1.38 mmoles). This dose of
cortisol is adequate to achieve extraneuronal uptake
blockade in vivo. 7 ' I7
In addition, norepinephrine disappearance was
studied in six patients with idiopathic peripheral
autonomic insufficiency, who had peripheral sympathetic neuronal dysfunction18 including defective
neuronal uptake of norepinephririe.9'1B They were
tested to provide a further experimental group in
whom neuronal uptake of norepinephrine was subnormal. These patients had incapacitating orthostatic
hypotension, and no evidence of central nervous
system disease on clinical neurological examination.
For comparison, we tested four patients with an intact
peripheral sympathetic nervous system, but autonomic insufficiency and orthostatic hypotension from
central nervous system disease.18
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<
t
rr
100
Biochemical Methods
0
10
20
30
40
600
400
200
inn
* = 2-6 ±1-4
*
i
10
20
30
TIME (min)
• NORMAL
40
SUBJECTS
A ESSENTIAL HYPERTENSION
FIGURE 1. Time course of accumulation of tritiated
norepinephrine in plasma of normal subjects and hypertensive patients during constant rate infusion (0.35
tiCi/m2/min) in the preliminary experiment, and of disappearance of norepinephrine from plasma on terminating
the infusion.
hypertension, the mechanism of removal of norepinephrine from the circulation was investigated. The
principal means of removal of norepinephrine from
plasma is thought to involve a specific uptake
mechanism, the "norepinephrine pump," 7 ' "•16 in sympathetic nerve varicosities (neuronal uptake) and some
other tissues (extraneuronal uptake),7 so we tested the
effect of interference with neuronal and extraneuronal uptake of norepinephrine. The time course of
disappearance of norepinephrine from plasma was
studied in seven normal subjects, both before and 3
hours after selective inhibition of neuronal uptake by
the tricyclic antidepressant, desipramine, administered orally in a dose of 125 mg (470 jtmoles). 7 ' 16
The tests were performed 1 week apart, in randomized
order. Five additional normal subjects were similarly
studied, before and immediately after intravenous ad-
Methods were needed to measure tritiated norepinephrine in plasma, endogenous plasma norepinephrine concentration, and, independently, specific
activity of norepinephrine in plasma. The specific
activity assay9 utilized an initial adsorption of
norepinephrine on to alumina, with direct measurement of tritiated norepinephrine in an aliquot of acid
eluate by liquid scintillation counting, and radioenzymatic assay of unlabelled norepinephrine in the
remainder.20 The possibility that the eluate contained
tritiated dihydroxy metabolites which, if present,
would be extracted on alumina, was rigorously excluded.9 Plasma samples at 70, 80, and 90 minutes of
infusion were assayed, mean plasma norepinephrine
specific activity at steady state calculated, and apparent release rate of norepinephrine derived from this
value.9' "
Plasma norepinephrine concentration at steady
state was measured independently of the method used
for specific activity determination, using a different
assay,21 for establishing agreement or otherwise
between plasma norepinephrine values and norepinephrine release rate measurements. Plasma tritiated
norepinephrine was assayed, also independently of
specific activity measurements, to follow the time
course of accumulation of norepinephrine in plasma
during the infusion, to calculate norepinephrine
clearance at steady state,9' u and to study the disappearance of norepinephrine from plasma at the end
of the infusion.
Preparation and Storage of
Tritiated Norepinephrine
Levo norepinephrine 7,8-3H (N), of specific activity
24-28 Ci/mmole (New England Nuclear Corporation) was pharmaceutically prepared for human administration,9 and stored under nitrogen in glass vials
at - 2 0 ° C until needed (maximum storage, 2 months).
Thin layer chromatography was used to estimate
radiochemical purity prior to each experiment, with
98% purity being taken as the minimum acceptable.
152
HYPERTENSION
VOL 3,
No
2,
MARCH-APRIL
1981
Statistical Methods
Much of the data from hypertensive patients did not
follow a Gaussian distribution, necessitating the use of
nonparametric statistical methods. When applicable,
the Mann-Whitney U test22 and Spearman's rank correlation test,23 both distribution-free methods of
statistical analysis, were used. Normally distributed
data was analyzed using independent and paired sample / tests and linear regression analysis.23
Results
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Plasma norepinephrine specific activity was constant from 70 through 90 minutes of infusion, indicating that steady-state conditions prevailed, Norepinephrine specific activity in normal subjects at 70 and
80 minutes was 97% ± 4% (mean ± standard error)
and 101% ± 6% respectively of the 90-minute value.
In hypertensive patients, the corresponding figures
were 96% ± 4% and 99% ± 5%. The time course of
disappearance of tritiated norepinephrine from
plasma, after termination of the infusion, is shown in
normal subjects and hypertensive patients in fig. 1.
The disappearance curve for norepinephrine was biexponential, and could be resolved11 into a rapid removal
phase with a halftime (V/2) of 2.0 ± 0.4 minutes
(mean ± standard deviation) in normal subjects, and
a slow component with a halftime (V/2) of 33 ± 15
minutes.
The major mechanism by which norepinephrine is
removed from the circulation is thought to be uptake
by the norepinephrine pump.7' "•16 The fast component
of removal observed here almost certainly represented
neuronal uptake of norepinephrine by sympathetic
nerves, since the halftime of the first (but not the second) exponential was prolonged in normal subjects by
the selective inhibitor of neuronal uptake,
desipramine7 (p < 0.01, paired t test), while cortisol,
which selectively inhibits extraneuronal uptake of
norepinephrine,7 did not significantly affect the rapid
removal phase (fig. 2). Furthermore, the V/4, but not
the tj!/2, was prolonged in patients with idiopathic
peripheral autonomic insufficiency (p < 0.01,fig.2),
who have a generalized defect in peripheral sympathetic nerve function, including a defect in
norepinephrine uptake. 9 ' 19 The V/2 was normal, however, in patients whose autonomic insufficiency resulting from central nervous system disease (fig. 2)
was accompanied by normal peripheral sympathetic
function.18
The distribution of V/2 values in hypertensive
patients was nonGaussian (fig. 2), and differed
significantly from that of normal subjects (p = 0.05,
Mann Whitney U test). The V/2 was prolonged in
eight of 37 hypertensive patients, giving presumptive
evidence of slowed neuronal uptake of norepinephrine.
In these patients, the V/2 was 3.3 to 6.0 minutes, well
above the range of values found in normal subjects
(1.5 to 2.8 min). With duplicate measurement of
norepinephrine disappearance rates in five normal
NO DRUG DESIPRAMINE
NORMAL
SUBJECTS
ESSENTIAL
HYPERTENSION
NO
PERIPHERAL CENTRAL
AUTONOMIC
INSUFFICIENCY
FIGURE 2. Halftime of the rapid phase of removal of
tritiated norepinephrine from plasma. The ixYi was
lengthened by the selective inhibitor of neuronal
norepinephrine uptake, desipramine (p < 0.01). was not
significantly changed by the extraneuronal uptake blocker,
cortisol. and was prolonged in patients with peripheral sympathetic nerve dysfunction (p < 0.01), indicating that the
rapid component of norepinephrine removal from plasma
represented, to a substantial degree, uptake of norepinephrine by sympathetic nerves. The I1/2 was prolonged in patients with essential hypertension (p - 0.05, Mann Whitney
U test).
subjects and 14 hypertensive patients after intervals of
3 weeks to 2 years (mean, 7 months), V/2
measurements were highly reproducible (r = 0.87). In
the patients with prolonged V/2, halftime values were
consistently reproduced on replicate testing.
The apparent release rate, clearance, and plasma
concentration of norepinephrine in normal subjects
and hypertensive patients are shown in figure 3. The
plasma concentration of norepinephrine in hypertensive patients was 266 ± 120 pg/ml (1.57 ±0.71
pmoles/ml), 25% higher than in normal subjects
153
NOREPINEPHRINE KINETICS IN HYPERTENSION/fc/e/- et al.
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10
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NOREPINEPHRINE
RELEASE
15
RATE (,ug/min/mJ)
*E
•
*
^
NORMAL SUBJECTS
ESSENTIAL
HYPERTENSION
FIGURE 4. Relationship of plasma norepinephrine concentration to norepinephrine release rate in hypertensive
patients (rB =0.79. p < 0.091) and normal
subjects
(r = 0.58, p < 0.01).
3
Uj"
NORMAL
SUE3JECTS
ESSENTIAL
HYPERTENSION
FIGURE 3. Norepinephrine
apparent
release
rate,
clearance from plasma, and plasma concentration in normal
subjects and patients with essential hypertension.
whose concentration
was 212 ± 78 pg/ml
(1.25 ± 0 . 4 6 pmoles/ml, 0.05 <p< 0.1; Mann
Whitney U test). Total clearance of norepinephrine
from plasma, which is dependent on extraneuronal uptake and metabolism of norepinephrine in addition to
neuronal uptake, was similar in hypertensive patients
(1.34 ± 0 . 2 6 1/min/m2) to that in normal subjects
(1.32 ± 0 . 2 7 1/min/m2). Norepinephrine clearance
was approximately 10% lower in hypertensive patients
with a prolonged t,1/: value (1.19 ± 0.29 1/min/m2);
this difference was not statistically significant. The apparent rate of release of norepinephrine (rate of
spillover to plasma after release from sympathetic
nerves) was 0.44 ± 0.27 /xg/min/m 2 (2.6 ± 1.6
nmoles/min/m 2 ) in hypertensive patients and
0.36 ± 0 . 1 4 jug/min/m 2 (2.1 ± 0 . 8 nmoles/min/m 2 )
in normal subjects (difference not significant).
The distribution of norepinephrine release rate and
plasma concentration values in patients were similar,
with skewness toward higher values (fig. 3). Plasma
norepinephrine concentration and norepinephrine apparent release rate correlated significantly overall in
both hypertensive patients, r8 (Spearman's rank correlation) = 0.79, p < 0.01, and normal subjects,
r = 0.58, p < 0.02 (fig. 4).
The interrelationship between the slowed neuronal
uptake of norepinephrine noted in some hypertensive
patients, norepinephrine apparent release rate, and
plasma norepinephrine concentration is shown in
figure 5. Spillover of norepinephrine to plasma correlated inversely with neuronal uptake, gauged from
the halftime of norepinephrine rapid removal, in
hypertensive patients (rB = 0.63, p < 0.01,fig.5) and
also in normal subjects; r = 0.63, p < 0.01. In
patients with presumptive evidence of slowed neuronal
uptake, norepinephrine escaping uptake and spilling
over into plasma was increased, 0.73 ± 0.39
/ug/min/m 2 (4.3 ± 2.3 nmoles/min/m 2 ) compared
with 0.36 ± 0.14 /ig/min/m 2 (2.1 ± 0.8 nmoles/
min/m 2 ) in normal subjects (p < 0.01, Mann Whitney U test) and 0.37 ± 0.17 Mg/min/m 2 (2.2 ± 1.0
nmoles/min/m 2 ) in the other hypertensive patients (p
< 0.01). Plasma norepinephrine concentration, 364 ±
178 pg/ml (2.15 ± 1.05 pmoles/ml), was also higher
than in normal subjects, 212 ± 78 pg/ml (1.25 ± 0.46
pmoles/ml, p < 0.05; Mann Whitney U test,fig.5).
Discussion
Plasma concentration of the sympathetic nervous
system transmitter, norepinephrine, has been used as a
biochemical index of sympathetic activity in essential
hypertension. But since only a small fraction of
norepinephrine released by sympathetic nerves enters
the circulation, how well plasma norepinephrine concentration reflects sympathetic nerve firing rates is
open to question.8 Several workers have attempted to
154
FIGURE 5. Schema of peripheral kinetics
of norepinephrine in patients with essential
hypertension Spillover of norepinephrine (o
plasma (norepinephrine apparent release
rate) correlated inversely with neuronal uptake, gauged from the halftirne of norepinephrine rapid removal (Spearman rank
correlation = 0.63, p < 0.01). Patients with
presumptive evidence of defective neuronal
uptake had significantly higher norepinephrine apparent release rate and plasma norepinephrine concentration than normal
subjects.
HYPERTENSION
VOL 3, No
2, MARCH-APRIL
1981
>LOCAL
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NORMAL NORMAL IPTAKE
SUSJCCTS UPTA
avoid the problems of interpretation encountered
when measurements of plasma norepinephrine concentration ara relied upon to estimate sympathetic
nervous tone in essential hypertension, by instead
studying the kinetics of radiolabelled norepinephrine
andwts metabolites in plasma and urine."""
Cjur technique differs in several ways from those
published previously. The principal difference is that
we studied norepinephrine kinetics in the central compartment, thus enabling measurement of the rates of
norepinephrine release to and removal from plas-,
ma."1 u This wias made possible by our development of
an assay that allowed the concentration of both radiolabelled and endogenous norepinephrine in plasma to
be followed simultaneously during an infusion of
tritiated norepinephrine. The levo form of radiolabelled norepinephrine was infused, unlike in earlier
studies in which d,l-norepinephrine was used," 1 "
enabling steady-state conditions to be reached in the
central (plasma) compartment. Attainment of steady
state is a prerequisite for adoption of this modelindependent form of kinetic analysis. With d,lnorepinephrine, the time to steady state is much
prolonged,"1 M presumably because norepinephrine
uptake is in part stereospecific.7 Use of high specific
activity radiolabelled norepinephrine ensured that the
infusion was strictly a tracer one, insufficient unlabelled norepinephrine being administered to alter
BP, sympathetic activity, or norepinephrine clearance.
The infusion rate of 0.35 MCi/ma/min was equivalent
to 0.002 /xg/min (0.012 nmoles/min), raising plasma
norepinephrine concentration at the end of the infusion by no more than 3 pg/ml (0.018 pmoles/ml), far
below the threshold for cardiovascular and metabolic
effects."
The principal abnormality of norepinephrine
kinetics noted in hypertensive patients, present in approximately 20% (8 of 37), was prolongation of the
halftime of the rapid component of norepinephrine
disappearance from plasma. This halftime is not a
simple index of a single removal mechanism,11 and because disposition of norepinephrine in man is complex, defying precise compartmental analysis," the
rate constant of neuronal uptake of norepinephrine
cannot be calculated. But as the i^h was lengthened by
desipramine, a selective neuronal uptake blocker,7 not
changed by cortisol, a selective inhibitor of extraneuronal uptake,7 and prolonged in patients with
peripheral sympathetic nerve dysfunction, it appears
highly likely that neuronal uptake of norepinephrine is
its major determinant.
An alternative explanation of the prolonged halftime, namely, the presence of increased central pool
size11 in the patients affected, we tentatively excluded
by compartmental analysis adopting the model that
best fits the available data, a two-pool open system," 1 M which showed the volume of the central pool
to be unremarkable in hypertensive patients with prolonged halftime. Gitlow et al." have suggested that
neuronal uptake of norepinephrine is defective in some
NOREPINEPHRINE KINETICS IN HYPERTENSION/Er/er el al.
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patients with essential hypertension. Since uptake by
sympathetic nerve varicosities is believed to be the
pripcipal method of terminating the effect of norepinephrine after its release,7' " particularly at sites within the cardiovascular system where the sympathetic
synaptic' cleft is narrow,' a peripheral mechanism for
sympathetic nervous overactivity, based on defective
inactivation of the neurotransmitter, appears to be
present in a subset of patients with essential hypertension.
A defect of neuronal uptake of norepinephrine of
this type would be expected to lead, with even normal
rates of sympathetic nerve firing, to higher concentration of the transmitter at receptor sites, greater
stimulation of the cardiovascular system, and increased spillover of norepinephrine into plasma. This
certainly is the case jn animals in which nerve firing
rates are kept constant and neuronal uptake of
norepinephrine by sympathetic nerves is blocked
acutely with drugs.™
In the present study, although the apparent release
rate and plasma concentration of norepinephrine were
not significantly elevated in hypertensive patients
overall, patients with defective neuronal uptake of
norepinephrine did have a higher rate of norepinephrine spillover to plasma and higher plasma
concentration. Our results further suggest that the rate
at which norepinephrine leaks to plasma, after release
from sympathetic nerves, is determined, under resting
conditions, by the efficiency of the local mechanism
for norepinephrine inactivation at the synaptic cleft.
Although the higher plasma concentrations of
norepinephrine1*4 reported in essential hypertension
have most commonly been explained' in terms of increased'rates of sympathetic nerve firing, "originating
from central nervous system dysfunction,80 the defect
in' neuronal uptake of norepinephrine we describe
could be responsible.
It should be emphasized that desipramine did not
elevate the BP of normal subjects in this study.
Desipramine, in' fact, lowers the rate of spillover of
norepinephrine to plasma,' which, in the presence of
uptake inhibition, must be due to a substantial
diminution in release of norepinephrine by the sympathetic nerves. The mechanism of this effect is not
clear; an anticholinergic action of the drug within the
central nervous system" is one possibility.
Steady-state clearance of norepinephrine from
plasma was normal in hypertensive patients overall.
Norepinephrine clearance was 10% lower in patients
with a prolonged ti'/i value than in normal subjects,
but this difference was not statistically significant.
Clearance is lowered 20%-25% by desipramine in normal subjects, and similarly reduced in patients with
peripheral autonomic insufficiency." Total clearance
of norepinephrine from plasma was influenced to a
considerable degree by the slow component of removal, perhaps reflecting extraneuronal uptake and
metabolism, which was normal in hypertensive patients. Experimental studies in animals indicate that, if
norepinephrine is diverted from neuronal to extraneuronal uptake by a block of neuronal uptake,
155
metabolism is enhanced and removal of norepinephrine from the body overall is retarded less than
might be expected.7 Our results differ from a recent
report, based on a different method," that clearance of
norepinephrine from plasma is slowed in patients with
essential hypertension.
The finding of a defect in neuronal uptake of
norepinephrine, present in some patients, could be
reproduced consistently with repeat testing over 2
years in patients affected. The abnormality appears
not to be a secondary consequence of severe or longstanding hypertension: four of eight patients affected
were young men with mild high-renin hypertension.1
In all eight patients, a clearcut family history of
hypertension was obtained. Whether the patients with
defective neuronal uptake belong to a distinct subpopulation, distinct from the majority of hypertensive
patients, is uncertain. With the relatively small
number of patients studied, it is not clear whether the
t,1/: values in hypertensive patients followed a skewed
or a bimodal distribution. The pathophysiological
significance of the norepinephrine uptake defect
remains to be elucidated. But such an abnormality, by
potentiating at the adrenergic receptor level any increase in sympathetic nerve traffic that occurs with
mental stress," head-up tilting,""** and exercise,*7
could be the cause of the greater BP and plasma
norepinephrine responses to these stimuli that have
been repeatedly reported in a proportion, but certainly
not all, of patients with essential hypertension.*4"'7
It is our viewpoint that essential hypertension is a
syndrome with multiple primary causes, differing
from case to case, and that these discrete initiating
causes of the BP elevation may be identifiable in individual patients.' We propose' that a defect in
neuronal uptake of norepinephrine is one such initiating cause, present in a minority, perhaps 20%, of all
patients with essential hypertension.
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M Esler, G Jackman, A Bobik, P Leonard, D Kelleher, H Skews, G Jennings and P Korner
Hypertension. 1981;3:149-156
doi: 10.1161/01.HYP.3.2.149
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