Clinical Science (1979) 57,839-88s
Volume and cardiac output increases in primary
hypertension: contrasting situations in two hypertensive rat
strains with different genetic predisposition
B. F O L K O W
Department of Physiology, University of Goteborg. Sweden
In any organism acute volume loading of sufficient
extent increases mean arterial pressure due to the
induced elevation in stroke volume, and hence in
cardiac output. However, normally these volumeinduced haemodynamic effects are more or less offset by reflex sympathetic inhibition and vagal
bradycardia via ‘volume’ and ‘bare'-receptors. A
particularly obvious and reliable indicator of this
reflex counter-regulation is the reduced heart rate,
seen both in animals and man. First, when such
reflex mechanisms are interfered with, the volumeinduced elevations in cardiac output and mean
pressure may become marked and cause autoregulatory rises in total peripheral resistance
(TPR), which may occur within minutes (e.g.
Folkow, 1952; Folkow & Gberg, 1961; Guyton,
1977).
An entirely different kind of acute mean
pressure elevation, also commonly linked to initial
increases in cardiac output but without any
‘primary’ volume expansion, occurs normally
during mental arousal. Then a centrally differentiated neuro-hormonal pattern (the ‘defence reaction’) suppresses vagal tone and increases sympathetic activity to heart, capacitance vessels and
most systemic resistance vessels except those in
skeletal muscle, myocardium and brain (Folkow &
Neil, 1971). The centrally induced skeletal muscle
vasodilatation i s initially often so powerful as to
cause a net TPR reduction. It is, however, not
seldom offset by a local ‘autoregulatory escape’
(Djojosugito, Folkow, Lisander & Sparks, 1968),
causing a return towards or even beyond initial
values for TPR. The elevation in cardiac output is
here characterized by a neurogenic increase in
heart rate, and often also in stroke volume as a
variably balanced consequence of increased
inotropism and capacitance vessel constriction,
Abbreviation: TPR, total peripheral resistance.
which latter improves diastolic filling (e.g. Folkow,
Lisander, Tuttle & Wang, 1968). The balance
between these neuro-hormonal cardiac output and
TPR adjustments varies, however, both between
individuals and between situations. It can in
animals (Folkow et af., 1968) as well as in man
(Brod, 1960) range from pronounced cardiac
output increases, over-ruling even considerable
TPR reductions, over to dominant TPR elevations,
depending on the current balance between muscle
vasodilatation and vasoconstriction elsewhere.
Therefore, the cardiac output increase is here a
common though far from obligatory haemodynamic consequence of a central neuro-hormonal
pattern, as influenced by both reflex and local
modulations in variable proportions.
Both these two variants of acute elevations in
mean pressure thus exhibit initial cardiac output
increases but are otherwise entirely different. In the
‘volume variant’, neurogenic mechanisms counteract the volumedependent increases of cardiac output and mean pressure, most easily detected by the
reflex heart rate reduction. In contrast, the ‘neurogenic variant’ is initiated by central excitatory influences and is per se independent of the volume
situation, but here a heart rate increase is virtually
obligatory. On the whole, heart rate is an easily
followed and very sensitive indicator of alterations
in cardiovascular neurogenic control (Folkow,
Lafving & Mellander, 1956), recently shown also in
spontaneously hypertensive rats (ThorCn & Ricksten, 1979).
These two types of acute cardiac output and
mean pressure elevations may serve as models for
the far more gradual events characterizing some
important variants of early primary hypertension,
as explored in genetically hypertensive rat strains.
The Milan rat strain of spontaneous hypertension
(MHSrats; Bianchi, Baer, Fox, Duzzi, Pagetti &
83s
84s
B. Folkow
Giovanetti, 1975) appears to be a typical ‘volume
variant’, whereas the Okamoto-Aoki spontaneously hypertensive (SH) rat (Okamoto, 1972)
seems dominated by central neuro-hormonal influences, at least when early phases of these two
types of rat primary hypertension are considered
(Folkow & Hallback, 1977).
According to Bianchi et al. (1975) a ‘primary’
deviation in MHS rat kidney design and function
results in a modest salt and water retention, which
in early phases increases blood volume up to- 10%
(Rippe, Lundin & Folkow, 1978). In early adult life
MHS rats display modest mean pressure and TPR
elevations associated with increases in stroke
volume and pulse pressure but with clear signs of
reflex heart rate reduction (Hallback, Jones,
Bianchi & Folkow, 1977). In this phase cardiac
output is therefore largely normal, compared with
matched controls, but vagal activity to the heart is
accentuated with sympathetic activity modestly
depressed. Reflex cardiovascular control evidently
serves to counteract the haemodynamic consequences of the ‘primary’ volume increase in MHS
rats, as described above for acute volume loading.
On the other hand, when MHS rats are exposed to
alerting or stressful stimuli they respond largely as
do their normotensive controls, without any accentuated defence reactions.
The situation in SH rats is entirely different, at
least in the early phases of life. This ‘neurogenic
variant’ of primary hypertension exhibits a central
hyper-reactivity to environmental stimuli with
modestly enhanced sympathetic activity and
reduced vagal tone in most ‘resting’ awake
situations, a neuro-hormonal pattern that is further
accentuated by alerting stimuli. Blood volume is,
however, if anything slightly reduced also in very
young SH rats, with signs of mild haemoconcentration and increased capillary transfer (Rippe
et al., 1978). Haemodynamically, young SH rats
are characterized by a modest elevation in mean
pressure compared with Wistar-Kyoto (WK)
normotensive rats in the resting awake state, partly
due to a mild TPR increase and partly to a cardiac
output elevation that is mainly a consequence of a
heart rate increase. During arousal this mild neurogenic cardiac output elevation is considerably
accentuated in SH rats but with little TPR shift, as
is common also during ordinary defence reactions
in normotensive animals. When cardiac neurogenic control is blocked the difference between SH
and WK rats in mean pressure remains, but is now
entirely due to a TPR elevation in SH rats
(Hallback & Lundin, 1978).
With increasing age and elevation in mean
pressure in SH rats, cardiac output slowly falls,
even towards subnormal values (e.g. Albrecht,
Hallback, Stage, Weiss & Folkow, 1975;
Noresson, Folkow 8c Hallback-Nordlander, 1979),
and the increased TPR is now the dominating
feature, with blood volume remaining low or
normal. To a major extent this gradual TPR rise
reflects the early initiated ‘structural autoregulation’ encompassing all systemic precapillary
resistance vessels, including those in the kidneys
(Folkow, 1978). Here it causes a structurally based
elevation of the pre- to post-glomerular resistance
ratio, which is a most efficient way of resetting the
renal ‘long-term barostat function’.
These animal models illustrate strikingly how
primary hypertension can, indeed, be initiated by
entirely different routes: in MHS rats via a
‘primary’ volume increase of renal origin where the
neurogenic control, if anything, tends reflexly to
damp the development. In contrast, in SH rats a
‘primary’ accentuation of central neuro-hormonal
influence seems to be of dominant importance for
the early elevation in mean pressure, and here
blood volume remains slightly subnormal throughout. In pace with the gradual elevation in mean
pressure, structural cardiovascular adaptation occurs, and this ‘common denominator’ for all
variants of hypertension increasingly dominates the
haemodynamic pattern, resetting cardiac output,
resistance as well as short-term and long-term
barostat functions to a higher equilibrium, as outlined by Folkow (1978).
Finally, the question arises which of these two
animal models best reflects the most common
variant of early human primary hypertension. To
judge from haemodynamic analyses in borderline
hypertension, the ‘neurogenic variant’ seems to be
more common in man than the first-mentioned one.
A modest heart rate increase, based on reduced
vagal tone and accentuated sympathetic activity, is
thus a very common finding in man, and plasma
volume is usually in the lower normal range (Julius
& Esler, 1976; Frohlich, 1977). Purely volumedependent variants should, among other thiigs,
exhibit slight reflex reductions in heart rate and also
low renin concentrations, which is hardly a
common finding in early human cases. Thus, when
clearcut volume-dependent human hypertension is
experimentally induced, as by mineral corticoid
addition (Distler, Philipp 8c Luth, 1979), considerable reductions of heart rate and plasma noradrenaline are seen, reflecting the expected reflex
damping of neurogenic excitatory influences. On
Round Table I : Cardiac output and volume in hypertension
the whole, low renin hypertension in man constitutes only about 25% (Dunn& Tannen, 1977),
and a considerable fraction of these evidently represents fairly advanced cases where the renin
reduction may well be secondary.
However, because of the randomly mixed
‘genetic coding’ in man, primary hypertension is
here likely to exhibit a spectrum of variants concerning predisposin’g hereditary elements, with
chances for correspondingly variable haemodynamic patterns in early phases.
References
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& FOLKOW,
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Scandinavica, 94,378-385.
BIANCHI,G., BAER,P.G., FOX, U., DUZZI, L., PAGEIT, D. &
GIOVANETTI,A.M. (1975) Changes in renin, water balance
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BROD, J. (1960) Haemodynamic response to stress and its
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A., FOLKOW,B., LISANDER,B. & SPARKS,H.
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GUYTON,A.C. (1977) Personal views on mechanisms of hypertension. In: Hypertension, pp. 566-575. Ed. Genest, J., Koiw,
E. & Kuchel, 0. McGraw-Hill, New York.
HALLBACK,
M., JONES,J.V., BIANCHI,G. & FOLKOW,
B. (1977)
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HALLBACK,M. & LuNDIN, S. (1979) Background of hypokinetic circulation in young SHR. In: Nervous System and
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JULIUS,S. & ESLER, M.D. (Ed.) (1976) The Nervous Sysfem in
Arterial Hypertension. C.C. Thomas, Springfield, Illinois.
OKAMOTO,K. (ED.) (1972) Spontaneous Hypertension. Its
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B. & HALLBACK-NORDLANDER,
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(1979) Cardiovascular ‘reactivity’ to graded splanchnic nerve
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RIPPE, B., LUNDM, S. & FOLKOW,B. (1978) Plasma
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DISCUSSION
Gross: Thank you very much indeed, Dr Folkow,
for these very interesting new data you just
showed. The point you raised at the end was the
role of the autonomic nervous system, and that it
should be more considered.
Brod: Most of the data of which we have heard are
based on experimental hypertension in animals,
and one may question their relevance for the
human disease. We have completed almost 200
haemodynamic studies over the past 8 to 10 years,
in patients with various types of hypertension. In
essential hypertension, we have shown, some 20
years ago, that the elevation of blood pressure
probably starts with a high cardiac output, and that
only over years does total peripheral vascular
resistance begin to rise. This does not mean that the
peripheral vascular resistance is not influencing the
blood pressure from the beginning. The regional
haemodynamics change quite early, as we have
shown in the same study. There is a vasoconstriction in the kidneys, in the skin, in the
splanchnic area, and also the veins are in a constricted state. What are not constricted are the
vessels in the muscles. The haemodynamic pattern
is identical with that of an acute emotional state in
a normotensive subject and with that of a defence
reaction in animals. The situation is different in
chronic renal disease at an early stage, i.e. in
patients with a glomerular filtration rate of 80-90
ml/min who start to become hypertensive. They
86s
Round Table I : Cardiac output and volume in hypertension
have a high cardiac output and a completely
normal total peripheral resistance. It may, of
course, be argued that also here the peripheral
vascular resistance participates, because one
always says that there is a reciprocal relationship
between the cardiac output and the peripheral
vascular bed. However, we have also seen several
patients with chronic renal disease who developed
hypertension later, but at the moment we examined
them they were normotensive and their cardiac
output was high and total peripheral vascular
resistance was in a low-normal range. This high
cardiac output in chronic renal disease is not redistributed as in essential hypertension. Also in
renovascular hypertension, Frohlich, in 1966,
produced data on 17 young patients with fibromuscular dysplasia, a high cardiac output and a
total peripheral resistance which was normal or
low. We, at the same time, had data on ten patients
with hypertension and renal arterial stenosis, but
on the basis of essential hypertension. Their cardiac
output was normal and their peripheral vascular
resistance was high. Only years later it became
clear that we had examined different stages of this
disease. If one examines early, one finds, as we
know from our present experience, very high
cardiac outputs. So I should say that in the natural
history of the human disease hypertension develops
over the stage of a high cardiac output and normal
or even low total peripheral vascular resistance. I
should like to address one question to the members
of the panel. Do any of the physiologists know
what happens if one raises the cardiac output not
by nervous means or an emotional stress, but for
instance by pacing? What happens to the total
peripheral vascular resistance? I am asking this,
because the conclusions regarding the reciprocal
relationship of the cardiac output and the peripheral vascular bed are based on experience from
situations where the vascular bed in the skeletal
muscles dilates independently of changes of cardiac
output.
Leuer: It is raised in paroxysmal tachycardia, I
think.
Korner: It is not easy to raise the cardiac output by
pacing, is all I can say, and we have tried it several
times in our dog models, and we have not had a
great deal of success; it mostly falls above a critical
heart rate.
Guyton: A few years ago we had some experiments in which we paced the heart, and in the
normal situation the cardiac output did not rise, but
if ever we had an excess of volume in the animal, so
that the right arterial pressure was above zero, then
pacing always increased the cardiac output. The
difference was that if you have a zero pressure and
try to pace the heart and the heart pumps harder,
the veins just close up, so you cannot get in. But if
you have an adequate pressure in the veins, then
you can pace the heart and get an increased
cardiac output.
Frohlich: I was just going to say that fever will
increase cardiac output, at which time the pressure
may stay normal and vascular resistance fall.
Gross: Pressure may even come down in fever.
Morgan: My question is to Dr Korner and Dr
Davis. I was impressed how well their data correlated with the mechanism that Dr Guyton
proposed today, except in one experiment. That is
when they added extra sodium to the animal. Those
experiments went on for only 3 weeks. Now in
laboratory animals that seems to be a long period,
but the evidence in human studies is that it may
take 5 , 10, 15 or 20 years for hypertension to
develop. My question is: have you studied those
animals 1 year later? A question in general to the
whole panel is, if high cardiac output does convert
into high peripheral resistance, what is the mechanism? No one in the panel has mentioned the
possibility, suggested by the studies on the red cells,
that arterial cell composition changes.
Korner: We certainly have not studied these
models for as long as this. The only comment that I
can make relates to a point of terminology, but
perhaps one should talk about it here. Why I have
always Liked Dr Folkow’s term ‘structural factors’
is that there is an implication in the context of
hypertension of pathological changes. We have seen
this morning from the data that Dr Jennings
reported from our laboratory how reversible this is,
when you bring the blood pressure down. The term
‘long-term autoregulation’ implies to me at any rate
functional mechanisms, for which there is no real
evidence. I think we ought to regard these
structural changes as secondary consequences of
the high blood pressure, and they, of course, have
implications on vessel responses to sympathetic
stimulation, but they can be reversed by lowering
the blood pressure. We still have a lot to do about
finding out and identifying individual causes of
hypertension, and as you said in your talk earlier,
Mr Chairman, there are probably many of them.
Round Table 1: Cardiac output and volume in hypertension
Hornych: In collaboration with Dr Safar and other
colleagues, we studied haemodynamics and
measured prostaglandins in the arterial and venous
blood of small groups of borderline hypertensive
patients and essential hypertensive patients. In the
former, we found highly increased levels of PGE,,
which is a vasodilator and has a positive inotropic
effect. In borderline hypertensive patients and
essential hypertensive patients we found a positive
correlation with the levels of PGE, in arterial and
also in venous blood, with elevated cardiac output.
In essential hypertensive patients, the levels of
PGE, were much lower, and the ratio in comparison with PGF,, was decreased; this means that
there was more PGF,, and less PGE,. Therefore it
may be that in the transitional borderline hypertensive state, as was stated by Dr Brod, cardiac
output is high and total peripheral resistance
normal or decreased in comparison with essential
hypertensives, who have a normal or decreased
cardiac output and an increased total peripheral
resistance, which may depend on the level of
circulating prostaglandins.
Gross: Any further comments?
Guyton: The only comment 1 have would be that
the term ‘autoregulation’ has to do with the
regulation of blood flow; it does not specify
whether the flow changes come about as a result of
vasoconstrictor phenomena or changes in vascular
wall thickness. I would call both of these ‘functional‘ changes, and I think that Dr Folkow would
probably agree with that.
Lever: There seems to be some confusion between
two questions: firstly, whether there is an increase
in cardiac output and, secondly, if there is an
increase in cardiac output, whether it is a sine qua
non in the development of hypertension. I wonder if
anybody could help me in distinguishing this,
because I do not think that the two issues necessarily come out clearly and separately?
Korner: I can supply the answer to this. In my
view, there is definitely no doubt that it is not
essential for the cardiac output to be elevated in the
development of hypertension, either in animal
experiments or in Qe human studies. In Dr Julius’
very substantial experience of borderline hypertensives, at least half the patients or even more had
normal cardiac outputs, and you really cannot
study them much earlier than he has. Earlier on, Dr
4
87s
Guyton cast aspersion on our particular kidney
preparation; I should just like to throw one back at
him. Let me preface my remark by saying that I
have the greatest admiration for his systemsanalysis approach, and I have learnt a tremendous
amount from it. The problem really is that the data
in many of the ‘blocks’ of his model are still very
inadequate, and I am sure he will be the first to
agree that there are many unknowns in the model.
We often skate over the inadequacies rather glibly.
The problem really is that the model of the type
used is an extremely efficient control system in its
own right, and it is often hard to know whether its
behaviour mirrors real life. I think we are still in the
position where we have experimentally to find the
right kind of data and more of them.
Folkow: I wish to comment on the remark from the
floor about the membrane events. As was pointed
out when this was discussed, this may be a factor
which affects not only cardiac and vascular muscle
cells, but possibly also central autonomic neurons
and hence tonic sympathetic activity, and in that
case we are back to the neurogenic element, but
through another avenue.
Guyton: Dr Korner and I have been good friends
for a long time. Last of all I want him to go home
and study all those blocks.
Gross: Now, at the end, I think we are not so far
from one another as it seemed in the beginning. I
am quite happy that Dr Guyton has said that the
infinite feedback-gain system makes a final adjustment, and I was quite happy about the drawing he
prepared during the discussion, where he had the
green volume effect against the red pressor effect. I
think it is a good step forward that you accept that
these two exist.
Guyton: We published that in 1969.
Gross: But not with respect to sustained hypertension. I should only like to say that we should not
make statements to the effect that one or the other
system or hypothesis is correct, but admit that
there are various pathogenic mechanisms, and that
the interplay between the different factors may
vary from one type of high blood pressure to the
other. I think one additional important point has
only been touched briefly, which may add some
new black boxes to the systems analysis, and this is
the membrane factor and the internal shifts of
sodium, potassium and fluid. We shall have to do
88s
Round Table I : Cardiac output and volume in hypertension
quite a bit more work about it, before we shall
eventually understand the regulation of blood
pressure and the different ways it may fail when
hypertension develops.
I should like to thank the members of this Round
Table, all those who have participated in the discussion, and the audience, who so patiently stayed
here to listen to our controversies and agreements.