Transcript lezione 1 (vnd.ms-powerpoint, it, 538 KB, 10/8/08)

Regulation of circulation during
exercise: Neural and mechanical
controls.
Antonio Cevese
The aim of the heart and circulatory system
during exercise is to deliver the required
amount of oxygen to the working muscles,
by enhancing cardiac output in a manner
strictly (and linearly) related to whole body
oxygen consumption, which in turn
generally reflects the increased muscle
metabolism
The main mechanism increasing the output
of blood from the heart is a rapid fall
fall inin
skeletalskeletal
musclemuscle
arteriolar
resistance;
this
arteriolar
resistance
is, however, not enough, because the heart
must be adequately refilled to produce and
maintain increased output,
while total
total peripheral
peripheral shall
resistance
shall be readjusted in
resistance
be readjusted
order to prevent falls in arterial blood
pressure
All this is accomplished by concurrent
overflowofofblood
bloodfrom
from
the
central
veins to
overflow
the
central
veins
the right atrium, which is made possible in
first instance by mechanical factors, such
as the pumping action of rhythmic muscle
contractions and the increased intrathoracic
negative pressure during deep inspirations.
Obviously, besides neural commands to the
exercising muscles, the integrated response
to exercise includes a vast array of neural
andneural
endocrine
reactions
that
help
and endocrine
reactions
enhancing the overall working capacity of
any individual.
Not all control systems are essential. For
instance, the heart may loose its efferent
autonomic nervous control, and still be able
to serve its role and enhance cardiac
output during exercise
Worldwide, the number of individuals
surviving a cardiac transplant and carrying
out pretty normal life styles has risen
impressively in the last two decades: the
allograft heart is denervated and, in most
cases,
it
does
not
reinnervate.
Nevertheless, those individuals can raise
their cardiac output enough as to sustain
skeletal muscle work to some extent.
Even after heavy aerobic training, their
maximal performance does not rise to the
levels of élite athletes; however, it has
often been demonstrated that the limiting
factor is not the heart ability to increase
cardiac output, but it resides on the
muscles, because of the long lasting illness
that led to heart transplantation
This example is indeed quite remarkable,
because it illustrates how auxiliary
control
auxiliary control
function. In the case
systems help preserve a lost function
of the heart, the Starling’s mechanism allows the
stroke volume to increase as required and the
sinus node, freed from autonomic nervous
control, can still increase the heart rate, although
slowly, in response to circulating catecholamines,
in order to sustain the required cardiac output
The first event leading to cardiovascular
adaptation at the onset of exercise is a fall of
local arteriolar resistance in the active muscles.
Several studies demonstrated that muscle
contraction per se, besides metabolic events,
contributes to raise muscle blood flow: since
contraction squeezes the blood out of capillaries,
the arteriovenous pressure gradient temporarily
increases, thus easing the flow of blood from
arterioles to capillaries
It is important to realise that muscle
muscle metabolism
metabolism
rises
asa a
step
function, in parallel with the
rises as
step
function
sudden increase of developed force, while
cardiovascular adjustments require a real time to
rise to new steady state levels
The listing of putative vasodilating molecules is
long and still uncertain, and does not deserve
detailed citation. It is worth noting, however, that
nitric oxide
oxide has been added to the list. It is
evident, indeed, that the principal physiological
stimulus for enhancement of e-NOS activity, i.e.
shear stress, is strongly related to the increase in
blood flow and velocity.
Of particular importance an early observation
that combination of factors
factors always
always elicits
elicitsgreater
greater
vasodilating effects than each factor taken alone
Whenever skeletal muscles start contracting,
local factors decrease vascular resistance,
releasing part of the hindrance to outflow of
blood from the heart. This may have two main
consequences: in the face of a reduced afterload,
the heart can increase
increase its
its output
output of
of blood
blood; on the
other hand, the reduction of peripheral vascular
resistance lowers
lowersby
byitself
itselfarterial
arterialblood
bloodpressure
pressure
that is the force pushing blood through arterioles
to the capillaries of all body tissues. If the
increased output were exactly balanced with
decreased resistance, arterial pressure would not
change;
this,
however,
can
hardly
be
accomplished without a selective control system,
which operates to avoid excessive changes in
pressure.
The increase in cardiac output observed with a
maximal exercise amounts to four to six folds,
leading to over thirty litres per minute (in some
cases even a larger cardiac output has been
reported, but it is very
very difficult
difficult to measure it
accurately during heavy exercise, in humans), in
well-trained
endurance
athletes.
This
is
accomplished by enhancing stroke
volume and
stroke volume
raising heart
heart rate
rate. The heart, however, must be
continuously refilled with an equal amount of
blood returning to the atria though central
systemic and pulmonary veins.
To understand the potential for increasing venous
return, it must be recalled that the bulk of
circulating blood may be separated in two, albeit
indistinguishable, components:
the unstressed
unstressed volume
volume and the volume in excess.
excess
The first part is that volume which fills up all the
cavities in the circulatory system, including the
heart, without distending the elastic walls of the
vessels
The second part is the volume of blood forced
within the tubes, which must distend to
accommodate it and in so doing generate
pressure. The distending pressure has been
named “mean
circulatory pressure
pressure”. If the heart
mean circulatory
were suddenly stopped and the blood quickly
pumped from arteries to veins, the pressure
would rapidly decrease in the arteries and more
slowly increase in the veins; when arterial and
venous pressures are equal, so that any pressure
gradient is abolished, the mean circulatory
pressure is measured
In baseline conditions, the value generally
reported for mean circulatory pressure is 7
mmHg. It is clear, therefore, that any factor
changing mean circulatory pressure affects
venous return, and therefore, cardiac output,
provided the heart is accomplishing its pump
function properly
Mean circulatory pressure, in turn, depends on
the total volume of blood, on the unstressed
volume, and on the compliance of the vessels.
The blood volume is kept rather constant by
several neurohumoral mechanisms, involving,
among
others,
the
kidney
and
the
haematopoietic tissues. The control of blood
volume operates slowly, day after day. It must
however be mentioned that total blood volume
may be more or less quickly reduced by
haemorrhage.
The ratio between total and unstressed
volume, as well as vessel compliance, albeit
determined by structural events, such as
those accompanying body growth, can
change rapidly and are under neurohumoral
control.
Total blood volume is unequally distributed
between the arterial and the venous
vascular compartments, and more so the
excess volume, which is almost entirely
contained in the veins.
Our body in resting conditions holds a large pool
of blood distributed in its veins that can quickly
be mobilized on demand.
When respiratory mechanics
mechanics is forced, blood is
actively sucked towards the right atrium, and
pumped out of the abdominal veins by
contraction of abdominal muscles, which forces
expiration. The largest part of venous blood,
however, up to 80%, is located within venules
venules
and
small veins
veins, including those of skeletal
and small
muscles, which are particularly affected by the
squeezing action of the contracting fibres.
All vessels receive a tonic vasoconstrictor
sympathetic outflow, which can be modulated, in
first instance, by cardiovascular reflexes, and, at
a slower pace, by circulating vasoactive
molecules, including catecholamines.
The most known effect of an increase in
sympathetic vasoconstrictor outflow is a rise in
total peripheral vascular resistance, generally
leading to an increase (or prevention of a
reduction) of arterial blood pressure.
Also the veins exhibit an increase of vascular
smooth muscle tone, which exerts a large effect
on venous capacitance and compliance.
The consequence of the increased venous tone
consists in reducing unstressed volume (a larger
proportion of total blood volume becomes volume
in excess) and decreasing compliance. Therefore,
venous
easier both
both by
by an
an increase
increase
venous return
return is
is made
made easier
in
in the
the volume
volume of
of blood
blood that
that actually
actually circulates
circulates and
by
in venous
pressure.
andanbyincrease
an increase
in venous
pressure
The contribution of veins of different vascular
districts to the sympathetically driven enhancement of venous return is not equally distributed:
it is maximal in the splanchnic area, and minimal
in skeletal muscles.
The concept of a “peripheral
peripheral heart
heart” has been
conceived, by assigning the central heart the task
of pushing blood through arteries and arterioles,
and the peripheral heart the task of continuously
(and adequately) priming the central pump with
the larger amount of blood that is needed to fulfil
metabolic demands during skeletal muscle
contraction.
The surge of venous return that must feed the
right atrium with enough blood to keep up with
an increased cardiac output is generally quite
adequate.
Only persons with severe incompetence of
venous valves, disruption of autonomic control,
or serious loss of circulating blood volume (of
whatever origin) may experience acute
insufficiency of this function, leading to brisk
fall of arterial pressure with blurring sight,
vertigo and eventually fainting.
THE STARLING’S LAW OF THE HEART
Within limits, the heart can increase its output
in relation to diastolic filling, as stated by the
Starling’s law of the heart. Its role in the
normal cardiac performance during exercise,
however, has been challenged when it was seen
that the diastolic dimensions of the heart are
not usually increased during exercise, and may
even be reduced in mild exercise.
The role of the intrinsic mechanism remains
crucial in keeping the
thebalance
balance
between
between
the the
rightand
andthe
theleft
leftsides
sidesofofthe
thecardiac
cardiacpump
pump.
right
If exercise is performed in reclining position, no
increase in stroke volume occurs, since the
volume ejected is already similar to that
reached after starting exercise in standing
position.
The mechanism leading to the rapid increase in
stroke volume while standing is associated to
the need to compensate for the effects of
gravity on venous return and does not add any
further volume to cardiovascular dynamics
during exercise.
THE AUTONOMIC NERVOUS SYSTEM
The autonomic nervous system is evidently
implicated in cardiovascular adjustments to
exercise. The typical response includes a
widespread increase in the sympathetic output
to the heart and the vessels and a decrease in
the parasympathetic tone to the heart. These
adjustments are called into play in first
instance by the central
command that
central command
coordinates skeletal muscle contractions and
involves also the autonomic nervous system,
both directly and indirectly, by resetting the
reflex control systems.
The reflex control of the circulation is assigned
to two main sets of receptors: those located in
thelow-pressure
low-pressurecompartments
compartments (central veins,
atria and pulmonary veins), and those located
in the high-pressure
high-pressurecompartments
compartments (essentially, aortic arch and carotid bifurcation).
The low-pressure receptors are more properly
conceived as volume receptors, as a result of
the unequal distribution of blood volume
already discussed. Their main role consists in
enhancing hart rate when venous return
increases (the well-known Bainbridge reflex),
but also when the heart is unable to get rid of
the amount of blood it receives, such as in
heart failure. These receptors are mainly
involved in the neurohumoral control of total
blood volume.
Il volume di sangue è controllato dai fattori che
regolano l’emopoiesi e dal rene, che controlla
l’equilibrio fra assunzione e perdita di acqua e
soluti.
L’equilibrio
ionico
è
sotto
il
controllo
dell’aldosterone
(ormone
della
corteccia
surrenale) la cui produzione, a sua volta, è
stimolata
dall’angiotensina
(asse
reninaangiotensina-aldosterone):
presiede
alla
determinazione del riassorbimento facoltativo
di soluti (e acqua)
L’assorbimento di acqua è regolato a livello dei
dotti collettori dall’ormone antidiuretico (ADH –
vasopressina).
L’ADH è prodotto nei nuclei sopraottico e
paraventricolare dell’ipotalamo e accumulato
nella neuroipofisi, che lo immette in circolo,
secondo i seguenti stimoli:
L’osmolarità del plasma è avvertita dalle cellule
dell’ipotalamo, dette anche “osmocettori”:
quando questa aumenta, normalmente per
eccessiva perdita di acqua, aumenta la
liberazione di ADH e il riassorbimento renale
L’attività
dei
nuclei
sopraottico
e
paraventricolare è regolata anche in via riflessa
da fibre afferenti dai meccanocettori atriali
(recettori di volume). Quando l’atrio si distende
perché aumenta il ritorno venoso, la produzione
di ADH è inibita e aumenta l’escrezione di urina
diluita.
Il ritorno venoso può aumentare per mancanza
dell’accelerazione di gravità (voli spaziali,
decubito supino) o per eccessivo accumulo di
acqua.
Gli atri si distendono anche
contrattilità ventricolare è ridotta
quando
la
THE CONTROLLED VARIABLE
The variable classically designed as the
controlled variable in the cardiovascular system
is mean arterial pressure. Many different
control systems join in the task of keeping
mean arterial pressure essentially stable
throughout most daily circumstances, with
slow, medium and fast acting mechanisms. The
fast mechanisms are those related to the
autonomic nervous control.
The question, partially still open, is whether the
keep operating
operating during exercise,
baroreceptors keep
and, if they do, whether, and to what extent,
their functioning changes.
On first look, one can conclude that the
baroreflex fails its aim. Indeed, during dynamic
exercise, arterial pressure does change, with
the diastolic value tending to fall or keep
constant, while the systolic value invariably
rises, even to pretty high levels
(180-200
mmHg). Consequently, mean arterial pressure
is increased. Meanwhile, heart rate rises, even
up to the highest possible levels for each
individual.
Fast shifts in pressure, such as those occurring
during rapid changes in position, are still
efficiently
buffered,
indicating
that
the
baroreflex does control mean pressure levels,
albeit around a higher controlled level. It is
now
rather
clear,
therefore,
that
the
baroreceptor
baroreceptor set
set point is reset to higher levels,
probably as a consequence of the central
command; the operative range is shifted to the
right, while the gain is not changed.
Research on the baroreflex in humans is rather
difficult, because to characterize a negative
feedback loop-based control system it is
theoretically necessary to open the loop.
Classical experiments in animals (especially
dogs) took advantage of surgical isolation of
the carotid bifurcations, in order to be able to
change the pressure level in the sinus regions
independently of arterial blood pressure.
Obviously, this cannot be done in humans.
The baroreflex was studied under close loop
conditions, seeking for the relation between
arterial pressure and heart rate changes.
Spontaneous oscillations in these variables can
be studied, either by repetitively calculating
linear regression between the two variables for
few consecutive heart beats all changing in the
same direction, in a long strip of recorded beat,
or by taking advantage of cross-spectral
analysis.
On the other hand, fast changes in arterial
pressure can be induced by alternate
injections of a vasoconstrictor (phenylephrine)
and a vasodilator (sodium nitroprussiate),
while measuring heart rate, and again the
slope of the relation between the two
variables is obtained.
The baroreflex is also studied in open loop
conditions, by applying positive and negative
pressures into a cuff wrapped around the
neck, strictly held by a rigid collar.
Aerobic training does not seem to be beneficial
with respect to the baroreceptor function, since it
has been frequently reported that the baroreflex
baroreflex
training. More research
gain tends to reduce after training
is needed to clarify this topic.
The efferent branch of the baroreflex involves
both sections of the autonomic nervous system.
Since the first step in cardiovascular adaptation
to exercise is the fall in peripheral vascular
resistance, produced by a large array of local
factors, a sudden fall in arterial pressure might
occur, which unloads the baroreceptors and elicits
the reflex response.
The vagal outflow to the heart is reduced or
suppressed, producing a very rapid increase in
heart rate. More slowly, the sympathetic is
stimulated, which further enhances heart rate
and increases vascular smooth muscle tone.
The arteriolar tone is increased, leading to
widespread vasoconstriction, which does not
spare the skeletal muscle vessels. In exercising
muscles, the local vasodilatory effects largely
overwhelm the neurally induced vasoconstriction.
This observation led to the introduction of the
term “functional sympatholysis”, indicating loss of
any effect of vasoconstrictor sympathetic
efferents on contracting skeletal muscles.
This concept was challenged by further research,
demonstrating that sympathetic stimulation, as
that induced by baroreceptor unloading, does
reduce muscle vascular conductance during
exercise. In all other tissues, including non
working muscles, resistance is increased and
blood flow is more or less cut down. Thus, during
exercise, a profound redistribution of cardiac
output takes place.
Changes in the autonomic outflow induce global
global
alterations of the heart function
function.
The inotropic effect
effect is especially important,
because the heart pump function must increase
adequately, to transfer the large volume of blood
that returns from central veins during exercise
and to support the required cardiac output.
The positive inotropic effect is associated to a
well established lusitropic
lusitropic effect
effect, which helps the
heart to relax more quickly and effectively.
Also the systole
systole duration
duration is shortened. The
combination of these factors improves the
capacity of the heart both to accept the
increased venous return and to transfer
oxygenated blood to the arteries.
REDISTRIBUTION OF CARDIAC OUTPUT
While blood flow must increase in the working
muscles, and also in the coronary arteries that
obey the enhanced metabolic demand of the
heart, it is severely lowered in the splanchnic
area. Other relevant circulatory territories follow
their own rules.
skin is vasoconstricted
The skin
vasoconstricted, but subcutaneous
circulation may be enhanced by thermoregulation, so that exercise in a hot (and humid)
environment may lead to an overt conflict
between contrasting needs, taking away an
increasing fraction of cardiac output from working
muscles that are not able to reduce their flow
Thermoregulation may be hampered and a heat
shock is possible.
In contrast, cerebral circulation keeps its typical
autoregulation.
The kidneys tend to autoregulate their blood
flow: renal vasoconstriction does contribute to
the general increase in vascular resistance in
non-muscle tissues, but it is unrelated to
workload.
The most debated issue about the increased
vasoconstrictor sympathetic tone is whether
skeletal muscle arterioles are involved in the
vasoconstriction.
Although resting blood flow is low in non-working
muscles, further vasoconstriction is possible,
which helps keeping arterial pressure at
enhanced values. On the other hand, blood flow
cannot be cut down in muscles where metabolic
needs are larger, due to ongoing rhythmic
contractions. It has been demonstrated, however,
that
even
contracting
receive
contractingmuscles
muscles receive
vasoconstrictor
signals
from
sympathetic
vasoconstrictor signals
endings,
which limit the large vasodilatation
induced by local factors.
THE METABOREFLEX
If venous outflow from a working muscle group
(e.g.
an
arm)
is
blocked,
the
typical
cardiovascular responses outlast the contraction
period and signs of widespread sympathetic
stimulation persist until the hindrance to venous
flow is removed. This has been interpreted as
evidence of a so-called “metaboreflex”.
metaboreflex
Afferent fibres have been recognized as small
diameter group III and IV, the former being
probably connected to mechanoreceptors, and
the latter to chemoreceptors, although a large
polymorphism was demonstrated.
Mechanical stimuli are stretch and pressure
(within the tissue). For the chemical signal, a
large number of potential ions or molecules
generally released by the contracting muscle,
especially in ischemic conditions, has been
postulated. However, the most obvious, such as
hydrogen ions or lactic acid, have been ruled out,
while an important role has often been assigned
to K+.
Stimulation of muscle afferents inhibits the vagal
control on the heart, thus enhancing exercise
tachycardia, and activates sympathetic efferent
fibres. The effect is an increase in total peripheral
resistance and blood pressure. It has been
postulated that this reflex counteracts the local
vasodilating influences that widen vascular
conductance in the working skeletal muscle.
The mechano-metabo reflex is altered
altered in
in heart
failure patients
patients and is probably responsible for
excessive
sympathetic
stimulation,
with
hypertension and reduced exercise tolerance in
these subjects.