Clinical Science and Molecular Medicine (1975) 48, 2 3 9 ~ 2 4 2 s .
Plasma noradrenaline concentration and blood pressure in essential
hypertension, phaeochromocytoma and depression
W . J. LOUIS, A . E. D O Y L E
AND
S. N . A N A V E K A R
University of Melbourne, Department of Medicine, Austin Hospital, Victoria, Australia
Summary
1. Mean plasma noradrenaline concentration was
elevated in forty-four patients with established
essential hypertension. Eighteen of these hypertensive patients had resting plasma noradrenaline
concentrations in the normal range.
2. Patients with endogenous depression had higher
mean plasma noradrenaline concentrations but
significantly lower blood pressure than patients
with essential hypertension.
3. Patients with phaeochromocytoma had plasma
noradrenaline concentrations twenty-eight times
greater than those found in essential hypertension,
but blood pressures were less than 20% higher.
4. It is concluded that excess of sympathetic drive
only partly explains the level of the blood pressure in
essential hypertension.
Key words :blood pressure, depression, hypertension,
phaeochromocytoma, sympathetic activity.
Introduction
The autonomic nervous system plays a key role in
the regulation of blood pressure through its ability to
alter cardiac output, vascular resistance and the
release of hormones from the adrenal medulla and
the juxtaglomerular apparatus (Assaykeen &
Ganong, 1971).
Previous studies with a sensitive double-isotope
derivative assay for plasma noradrenaline indicated
that there was a close relationship between the levels
of the blood pressure and plasma noradrenaline in
patients with essential hypertension. Moreover, after
Correspondence: Professor W. J. Louis, Clinical Pharmacology and Therapeutics Unit, Austin Hospital, Heidelberg
3084, Victoria, Australia.
239s
ganglionic blockade there was a highly significant
correlation between change in resting blood pressure
and change in plasma noradrenaline, suggesting that
the level of the blood pressure is at least in part due
to excess of sympathetic activity (Louis, Doyle &
Anavekar, 1973 ; Louis, Doyle, Anavekar, Johnston,
Geffen & Rush, 1974).
We report here measurement of blood pressure
and plasma noradrenaline in normotensive subjects
and in patients with essential hypertension, labile
hypertension, phaeochromocytoma and endogenous
depression. These results suggest that the excess of
sympathetic activity seen in essential hypertension
only partly explains the level of the blood pressure
in this disease.
Methods
Fourteen normotensive volunteers, forty-four
patients with essential hypertension, nine patients
with labile hypertension, and five patients with
endogenous depression were studied. All were free
of overt renal disease and none had ever had
hypotensive drugs. All patients were admitted to
hospital, confined to bed and, in addition to an
unrestricted diet, were given 100 mmol of NaCl
daily. On the third day in hospital, a cannula was
inserted into a vein in the left forearm. One hour
later, blood was drawn for estimation of plasma
catecholamines. Blood pressure was measured at
intervals by the auscultatory method. Fifteen patients
with phaeochromocytoma were also studied. Some
of these patients had been receiving treatment before
the study. However, at the time of study patients
were in hospital on no treatment.
The venous blood samples (10 ml) were taken into
cold centrifuge tubes containing 40 mg of dry sodium
W. J. Louis, A . E. Doyle and S. N . Anavekar
240s
citrate and 10 mg of ascorbic acid. The plasma was
separated by centrifugation and assayed for noradrenaline and adrenaline (Engelman & Portnoy,
1970; Louis & Doyle, 1971).
Results
These are summarized in Table 1. Mean plasma
noradrenaline concentration in patients with essential
hypertension (0.40 k 0.21 ng/ml) was significantly
elevated when compared with normotensive subjects
and patients with labile hypertension studied at a
time when they were normotensive. Although the
mean value was elevated, eighteen of the forty-four
patients with hypertension had resting plasma
noradrenaline concentrations in the normal range
(0.13-0.33 nglml). These patients with plasma
noradrenaline in the normal range had a mean blood
pressure of 1494 f 12.4 (SD) mmHg systolic and
95.1 t 11.8 diastolic, which was significantly
(P<0.005 for both systolic and diastolic blood
pressure) higher than that found in normotensive
subjects (Table I), but significantly lower than in
patients with essential hypertension and elevated
plasma noradrenaline concentrations, in whom
mean systolic blood pressure was 166.2 k 13.4 mmHg
(P<0.005) and mean diastolic blood pressure
108.8 k 16.3 mmHg (P<0.0025).
Patients with depression also had elevated plasma
noradrenaline concentrations, which were significantly higher than those in essential hypertension. By
contrast systolic and diastolic blood pressure were
significantly less in depression than in essential
hypertension (Table 1).
Patients with phaeochromocytoma had extremely
high plasma noradrenaline concentrations and
elevated systolic and diastolic blood pressure.
Plasma noradrenaline concentrations were twentyeight times higher than in essential hypertension.
This was associated with a mean diastolic blood
pressure 13 mmHg higher than that in patients with
essential hypertension.
Discussion
These studies confirm previous reports of elevated
mean plasma noradrenaline concentrations in
patients with essential hypertension (Engelman,
Portnoy & Sjoerdsma, 1970; De Quattro & Chan,
1972; Louis et a / . , 1974). In previous work it has
been demonstrated that the elevated noradrenaline
reflects an excess of sympathetic drive (Louis rt a / . ,
1973, 1974). The results presented here suggest that
this excess of sympathetic drive is not the sole
explanation for the blood pressure elevation in
essential hypertension. Eighteen of forty-four
patients with essential hypertension had plasma
noradrenaline concentrations in the normal range
and a n elevated mean blood pressure. In a small
group of patients with endogenous depression mean
plasma noradrenaline values were significantly
higher than in essential hypertension without the
same degree of blood pressure elevation. These
results suggest the excess of sympathetic drive
TABLE
1. Plasnia noradrenaline and blood presslire leuels in the uarioits patient groups
Mean valueskso are shown. P is the significance of difference from the norrnotensive value.
Blood pressure (rnrnHg)
Plasma noradrenaline
(ndml)
Systolic
Diastolic
Norrnotensive
( n = 14)
0.20k 0.22
128k8.1
77k7.1
Essential hypertension
( n = 28)
Labile hypertension
( n = 9)
Depression
(n = 5)
Phaeochromocytoma
( n = 15)
0.40 f0.2 I
(P< 0.01)
0~22+0~15
158.1f 12.2
(P<O.OI)
104.9f 10.1
0.74k 0.09
(P<O.OI)
1 1 . 1 11.8
(P< 0.01)
*
104.5+ 45.9
(P<O.O5)
137f7.2
(P< 0.05)
1 8 3 f 43.4
(P< 0.01)
(P< 0.01)
80+ 7.6
86+ 6.3
( P < 0.05)
1 1 6 + 28.9
(P< 0.01)
Sympathetic activity in hypertension
demonstrated in established essential hypertension
is acting in the presence of other factors, perhaps a
hyperactive vascular system. This would be consistent with the idea that the level of the blood
pressure in essential hypertension reflects both
autonomic and non-autonomic components (Doyle
& Smirk, 1955).
The results with phaeochromocytoma are not
easy t o interpret. Noradrenaline in these patients was
extremely high (twenty-eight times greater than in
essential hypertension), whereas mean diastolic
blood pressures were 11 mmHg higher than in
essential hypertension (Table 1). However, it is not
possible to make a meaningful comparison as in
phaeochromocytoma catecholamines are secreted
directly into the venous system, whereas in essential
hypertension the plasma noradrenaline reflects
only spillover from adrenergic neuron release and a
large increase in sympathetic drive may be reflected
in only a small increase in plasma noradrenaline.
The adrenergic neuron is in very close relationship
with the a-receptor, and the local concentration of
transmitter noradrenaline a t the neuro-effector
junction is high. It is quite possible that the noradrenaline concentrations in the biophase of the
a-receptors of vascular smooth muscle are similar in
phaeochromocytoma and essential hypertension.
Acknowledgments
We are indebted t o Ms L. Graf and Ms L. Adams
for their technical assistance. These studies were
supported by the National Heart Foundation of
Australia and the National Health and Medical
Research Council of Australia.
References
ASSAVKEEN,T.A. & GANONC,W.F. (1971) Sympathetic
nervous system and renin secretion. In: Fronriers in
Neuroendocrinology, p. 67. Ed. Martini, L. & Ganong,
W.F. Oxford University Press, New York.
DE QUATTRO,
V. & CHAN,S. (1972) Raised plasma catecholamines in some patients with primary hypertension.
Lancet, i, 806-809.
DOYLE,
A.E. & SMIRK,
F.H. (1955) Neurogenic component
in hypertension. Circulation, 12, 543-552.
ENGELMAN,
K . & PORTNOV,
B. (1970) Sensitive double
isotope derivative assay for norepinephrine and epinephrine. Circulation Research, 26, 53-57.
ENCELMAN,
K., PORTNOY,
B. & SJOERDSMA,
A. (1970)
Plasma catecholamine concentrations in patients with
hypertension. Circulation Research, 18, 141-146.
LOUIS,W.J. & DOYLE,
A.E. (1971) The use of a doubleisotope derivative plasma assay for noradrenaline and
adrenaline in the diagnosis and localisation of phaeo-
241s
chromocytoma. Australian and New Zealand Journal
of
Medicine, 3, 212-2 17.
LOUIS,
W.J., DOYLE, A.E. & ANAVEKAR,
S. (1973) Plasma
norepinephrine levels in essential hypertension. New
England Journal of Medicine, 288, 599-601.
LOUIS,
W.J., DOYLE,
A.E., ANAVEKAR,
S.N., JOHNSTON,
C.I.,
GEFFEN,
L.B. & RUSH,R. (1974) Plasma catecholamine,
dopamine-beta-hydroxylase,and renin levels in essential
hypertension. Circularion Research, 34-35 (Suppl. I),
1-57-1-63.
Discussion after Dr Louis’s paper
TARAZI:The relationship that you have shown between
plasma noradrenaline and diastolic blood pressure is
fascinating indeed : do you have any data in hypertensive
patients with renal arterial disease? The reason for this
question is that, like you and others, we have found that
the degree of blood pressure reduction following ganglionic blockade, both in patients with essential hypertension and in normotensive subjects, correlated very well
with initial blood pressure level and with total peripheral
resistance. In contrast, in patients with renal arterial
disease, the reduction in pressure by trimethaphan could
not be predicated from either their control arterial pressure levels or from total peripheral resistance-suggesting
the interference of some factor not evident in the other
groups (Tarazi, R.C. & Dustan, H.P., 1973: Clinical
Science, 44, 197-212). I was wondering therefore whether
you had any plasma catecholamine measurements in these
patients?
LOUIS:We are studying this problem of renal hypertension at the moment and we really have no data that would
be worthwhile putting forward, except to say that renal
hypertension is a very difficult thing to define because the
patients vary so much in their degree of renal function, in
the degree of hydration and so on.
FOLKOW:
At the end of your presentation, you mentioned
serotonin and its potentiated vasoconstrictor action.
However, you used a vascular preparation from the
gastrointestinal tract and the mesentery. In these tissues,
particularly in the true resistance vessels in the intestinal
wall, serotonin appears to be physiologically involved in
the local neurogenic control, but in a very complex way.
It has a dilator action on the gastrointestinal mucosal
resistance vessels, at least in cats, where such local
nervous mechanisms seem to contribute to the regional
functional hyperaemia. If this is the case also in rats, it is
difficult to assess the implications of the vasoconstrictor
effects that exogenous serotonin evidently induces in
isolated preparations.
LOUIS:Dr Folkow, the situation is much more difficult
than we think. However, in answer to your question, we
have similar data in other peripheral blood vessels and in
the aorta.
GROSS:Serotonin has also different effects in various
species.
WALLIN:
In your measurements of plasma noradrenaline
you showed a considerable overlap between normotensives and hypertensives. We have some data showing
that sympathetic output may vary with age, and therefore
242s
W. J. Louis, A . E. Doyle and S. N . Anavekar
the overlap may be reduced if you take age into consideration.
LOUIS:We have not split our patients into age groups.
We really have not enough patients to analyse this
properly.
SIMPSON:
I have not studied this particular aspect of the
inhibition of serotonin synthesis leading to a blood pressure drop in the Smirk strain of hypertensive rats. However, we have always found in these rats that the vascular
response to serotonin is disproportionately higher than
the response to noradrenaline.
L o u r s : This is very interesting. I think Dr Chalmers has
data on these aspects.
UNIDENTIFIED
SPEAKER: Have you measured the nor-
adrenaline and the serotonin level after p-chlorophenylalanine (PCPA), because it is very well known that
PCPA depletes noradrenaline?
LOUIS:There is a reduction of noradrenaline in the brain
following PCPA, and I am not saying by any means that
PCPA is acting purely by blocking serotonergic fibres.
The main reduction is, however, in serotonin, whereas
there might be perhaps a 5-10% change in noradrenaline.
If you block serotonin, you get changes in blood pressure
and then, when you stop to look at it, you can find that
there is serotonin in sites where it could well modify
resistance vessels. Whether serotonin does turn out to be
an important regulator of peripheral resistance has yet to
be sorted out, but 1 think that it is interesting that it is in
such a high concentration in these sites.