Exercise, haemorrhage and hypoxia: the cardiovascular responses to specific stresses Flashcards
This lecture considers the physiological responses to some relatively common stresses. This will revise some of the control systems covered in the earlier lectures and consider how they produce an integrated, coordinated response. It will also allow some insight into the limiting factors in exercise.
The cardiovascular response to exercise
Exercise can be one of the greatest physiological
stresses to homeostasis, particularly in competitive
sports when activity levels are maximised, and in
cardiovascular disorders where the potential
responses are limited. The increased metabolic
demand of muscles during exercise requires
increased blood flow (functional hyperaemia) that
is primarily regulated by local mechanisms.
In individual muscles, blood flow can increase from
resting levels of 2-3 ml-1 min-1 100g-1 of muscle to
35 ml-1 min-1 100g-1
, a ~17-fold increase, suggesting
a 17-fold decrease in local resistance at constant
ABP. However, skeletal muscle makes up ~40% of
body mass, so dynamic exercise involving multiple
muscles will profoundly influence TPR. In intense
exercise, TPR may drop to ~20% of its resting value;
without cardiovascular homeostatic mechanisms,
this would produce a catastrophic drop in ABP to
20% of its resting value!
Systemic mechanisms are responsible for
maintaining ABP and cardiovascular homeostasis
despite this drop in TPR. The systemic responses
can result in a ~5-fold increase in cardiac output
(~3-fold increase in heart rate and ~50% increase in
stroke volume). They may also partially oppose the
locally-mediated vasodilatation in muscle, such that
the increase in blood flow through muscles
exercised in isolation can exceed the flow through
the same muscle during whole-body exercises.
Functional hyperaemia
Blood flow to active muscles increases very rapidly
during exercise. The response has two distinct
phases: Phase I, in which blood flow increases very
rapidly from ~2 to 15-20 s after the initiation of
contractions; and Phase II, from about 20 s after
initiation of contractions, during which there is a
slow increase in blood flow to sustained high levels
(Figure 22).
As mentioned in Lecture 7, activity in muscle, like in
any tissue, results in a wide range of local changes
that influence arteriolar diameter, including
reduced PO2, increased PCO2, decreased pH,
increased extracellular K+
, lactic acid production, as
well as increased extracellular ADP, AMP and
adenosine. Are any of these of particular
importance?
The fast phase of exercise hyperaemia
It is relatively straightforward to identify the most
important factors in the initial, rapid Phase I
increase in blood flow. This is because most local
changes occur too slowly to explain this rapid phase
of the increase in blood flow. The first exception is
K
+
: muscle action potentials produce immediate
and fast increases in extracellular [K+
] to as much as
10 mM, depending on activity levels, within 5-10 s
(Figure 23).
The rise in interstitial [K+] has a very unexpected
effect: it hyperpolarises arteriolar smooth muscle,
which closes voltage-gated Ca2+ channels and
thereby relaxes the muscle (see Figure 5). This is
odd: one would expect raised extracellular [K+] to
cause depolarisation. The mechanism of theobserved hyperpolarisation seems to be a
combination of two effects: raised extracellular [K+
]
both enhances Na+
/K+
-ATPase activity, and also
enhances the activation of inwardly-rectifying K+
channels (KIR). The increased intracellular K+ and
increased K+ permeability together result in
hyperpolarization. Pharmacologic blockade of
either of these routes for K+ entry (using ouabain or
barium respectively) attenuates vasodilatation by
approximately 60%.
The second fast cause of functional hyperaemia is
the “muscle pump” whereby muscle contractions
accelerate venous return. As discussed below, this
enhances CO, but may also reduce local venous
pressures, thereby enhancing the pressure gradient
through muscle capillaries.
In some animals, but probably not in humans,
neurogenic vasodilatation also plays a role. In the
cat, for example, sympathetic cholinergic nerves
directly cause a rapid increase in blood flow to
muscle at the start of exercise. Circulating
adrenaline can also cause vasodilatation of muscle:
this is not fast enough to contribute to phase I, but
may be released as part of an anticipatory response.
The maintained phase of exercise hyperaemia
It has been difficult to precisely identify the
mechanisms of Phase II hyperaemia. Multiple
redundancies mean that when the release or action
of one substance is inhibited, the magnitude of
hyperaemia can change little because other factors
then make a larger contribution. Furthermore,
changes in some key concentrations profoundly
influence others: for example, reduced PO2 clearly
alters skeletal muscle metabolism and the resultant
metabolic products, making it difficult to separate
direct responses to PO2 from responses to its
downstream influences. Nevertheless, it is possible
to identify some components of the response.
Raised extracellular K+
continues to have an important role. Activation of β2 receptors on vascular smooth muscle in skeletal muscles by circulating adrenaline has a vasodilatory effect.
A direct effect of reduced PO2 on muscle arterioles
is unlikely, because although PO2 falls in muscle capillaries during exercise, it has not been shown to
fall in the vicinity of the arterioles. However,
increased offloading of O2 from haemoglobin
results in the release of ATP and NO from red blood
cells. Low O2 also enhances the activity of the
ectonucleotideases that produce vasodilatory
adenosine from ATP. Adenosine also accumulates
around active muscle fibres: the source may be ATP
released by active muscle and acted on by
extracellular ectonucleotideases. This release of
ATP is at least partly via CFTR channels in response
to reduced intracellular pH, thereby linking pH
changes to the vasodilatation.
Adenosine is a strong vasodilator, acting on A2A
receptors to increase cAMP levels in smooth
muscle. This activates protein kinase A (PKA), which
in turn opens KATP channels. This hyperpolarises the
cell by the same mechanism as K+ accumulation,
and may therefore act synergistically with
increased K+
.
Lactic acid has not been shown to have a direct
effect that is distinct from its effect on pH.
A summary of functional hyperaemia
Functional hyperaemia in exercise is complex and
incompletely understood. Nevertheless, its effects
are clear: exercising muscle receives a blood supply
that is closely matched to its metabolic demands. Furthermore, this increase in blood flow results
largely or wholly from local vasodilatory influences.
It is then left to systemic control processes to
prevent the resultant reduction in TPR from having
dire consequences.
Systemic circulatory control in exercise: dealing
with the consequences of functional hyperaemia.
Exercise produces a drop in TPR, to as little as 20%
of its resting value in intense exercise. This
necessitates an increase in CO in order to maintain
ABP. As we saw in previous lectures, this is achieved
by sympathetic venoconstriction (to increase
MSFP), reduced cardiac vagal stimulation (to
increase HR) and increase cardiac sympathetic
stimulation (to increase HR and myocardial
contractility).
In addition, the “muscle pump” action of
contracting muscles on nearby veins pushes blood
towards the heart due to the presence of venous
valves. This can be considered to reduce the
resistance to venous return, thereby increasing VR
at any given MSFP. Thus, MSFP may increase 3-fold
in exercise, yet VR and CO might increase 6-fold,
suggesting that activity of the “muscle pump”
approximately halves RvR. The net result of these
influences actually causes mean ABP to rise slightly
in exercise (see Figure 26, below).
What produces the increased sympathetic activity
and reduced cardiac vagal activity? As shown in
Figure 19, the cardiovascular centre in the medulla
is well positioned to coordinate a response to
circulatory changes in exercise: it receives inputs
from higher brain centres involved in “deciding” to
exercise, from muscle and joint sensors that
respond to movements, and from arterial baro- and
chemoreceptors. Which are most important?
It is possible to separate the central command to
exercise from the actual occurrence of exercise
using curare to block the neuromuscular junction
(Figure 24). This clearly demonstrates that the
increase in heart rate during exercise can occur
without any actual exercise occurring. Such centrally-mediated cardiovascular responses
correlate with the perceived effort of exercise.
…In addition, the “muscle pump” action of
contracting muscles on nearby veins pushes blood
towards the heart due to the presence of venous
valves. This can be considered to reduce the
resistance to venous return, thereby increasing VR
at any given MSFP. Thus, MSFP may increase 3-fold
in exercise, yet VR and CO might increase 6-fold,
suggesting that activity of the “muscle pump”
approximately halves RvR. The net result of these
influences actually causes mean ABP to rise slightly
in exercise (see Figure 26, below)….
What, then, is the role of the baroreceptors in
exercise? Their influence appears, by an unknown
but centrally-commanded mechanism, to reset,
possibly in part due to joint and position sensors
competing with the baroreceptor inputs to the
nucleus tractus solitarius. The effective result is that
the baroreceptors then maintain the stability of blood pressure around a slightly raised set point
Figure 26.
Limiting factors in exercise
The highest cardiac outputs are seen in exercise.
Thus, it is reasonable to ask if cardiac output might
limit maximum performance, or whether maximum
performance is limited by some other factor, such
as the ability of muscles to perform work, or the
rate of O2 uptake in the lungs. The answer depends
on a person’s level of fitness, but is relatively easy
to ascertain.
With normal lungs, O2 uptake is not limiting, as can
be shown by measuring performance at normal and
raised levels of PO2: raising inhaled PO2 does not
significantly improve performance.
In reasonably fit people, it can be shown that the
ability of muscles to perform work is not limiting by
comparing power output when pedalling an
exercise bike with one leg versus pedalling it with
two. Power output with two legs is less than double
power output when using just one leg. This suggests
that during two-legged cycling, muscles are not able
to produce their maximum power output. Note,
however, that less fit people may not have
sufficient muscle aerobic capacity to sustain high
enough power outputs to produce this effect, and
may instead be limited by their unfit muscles.
Together, this suggests that the circulation provides
the ultimate limitation on whole-body power
output during exercise. Note that this limitation
exists despite mean blood pressure being sustained
even in the most intensive exercise. To put it
another way, it is not possible to exercise so hard
that ABP drops, suggesting that there is central
regulation of activity levels according to circulatory
requirements. To put it another way, one
component of the feeling of fatigue must relate,
albeit indirectly, to circulatory capacity.
Exercise in disease states
The ability of relative circulatory inadequacy to
regulate activity levels and produce the feeling of
fatigue has important consequences in disease
states involving reduced maximum cardiac output.
This particularly includes heart failure, for which
fatigue may be a prominent feature.
Haemorrhage
The response to haemorrhage usually comprises a
response to two stimuli: reduced blood volume,
and pain / emotional state.
Uncompensated loss of blood causes, sequentially,
a reduction in blood volume, MSFP, venous return
/ cardiac output, and hence blood pressure. Arterial
baroreceptors (carotid sinus and aortic arch) and
low-pressure baroreceptors (terminal great veins
and atria) detect these changes, reducing inhibition
of the medullary vasomotor areas. Higher brain
centres (cortex and hypothalamus) may also
stimulate these areas as a response to pain or fear.
This produces rapid (within seconds) responses.
Sympathetic nerves increase arteriolar and venous
tone and the heart rate, and vagal tone to the heart
decreases. In addition, catecholamines, angiotensin
II and ADH are released. These all have
vasoconstrictory effects, especially in high
concentrations, but also have important effects on
fluid balance that will be covered in the renal
physiology lectures.
Within minutes, two changes in the
microvasculature also contribute. The first is
reverse stress relaxation, whereby smooth muscle contracts when stretch is reduced. The second is
mobilisation of tissue fluid as reduced capillary
pressures shift the balance of Starling filtrationreabsorption forces towards reabsorption of fluid.
This can contribute perhaps 500 ml – 1 l to the
circulating volume.
In the longer term (onset in tens of minutes), renal
conservation of water and salt, thirst and sodium
appetite act to restore the circulating volume.
Finally (24-48 hours) plasma proteins are replaced
by synthesis in the liver, and (to 5-7 days) increased
red blood cell production restores lost
erythrocytes. This is stimulated by the release of
erythropoietin from the kidneys in response to
reduced oxygen delivery.
Hypoxia
There are essentially two cardiovascular responses
to hypoxia, and they are almost complete
opposites. Fortunately, this makes sense when one
appreciates that these contrasting responses
reflect two very different types external stress that
can produce hypoxia:
1) Lack of O2 due to an inability to breathe,
such as in breath-hold diving;
2) Lack of O2 due to reduced concentration in
the inhaled air, such as in an ascent to
altitude.
(Note that chronic lung diseases may combine
aspects of both stresses). In the first form, the
body’s priority must be to conserve O2 for the brain.
In contrast, if blood is still being oxygenated, albeit
at a reduced rate, then the ideal response would
include increased cardiac output to compensate for
the reduced PO2 in arterial blood (because O2
delivery is flow x concentration, so increased flow
can make up for decreased concentration).
Astonishingly, the body does indeed manage to
produce the appropriate response in each case.
First, we will look at the direct effect of reduced PO2.
We have seen already that this produces metabolic
vasodilatation in the tissues. With a limited amount
of O2 available, as in diving, this is not an ideal
response, as it would allow tissues other than the
brain to use the available O2 faster. Fortunately, the
reflex response to reduced PO2 (detected by the
carotid and aortic bodies and in central
chemoreceptors and integrated in the medulla) is a
slowed heart rate and systemic vasoconstriction,
mediated by a cardiac vagal reflex and the
sympathetic nervous system, respectively. This is
called the diving reflex or the primary
chemoreceptor response. It reduces cardiac work
to a minimum and the sympathetic drive
overwhelms the metabolic vasodilatation to divert
the available blood to those tissues with little
sympathetic vasoconstrictor innervation, the brain
and the heart.
In diving animals, such as the seal, this response is
particularly well developed, but even in humans
this diving reflex can be observed, especially in coldwater immersion, where the heart rate can drop to
as low as 20-30 beats per minute.
As noted above, this is not an optimal response
under conditions where oxygen concentration is
low, rather than there being a reduction total
oxygen amount, as in breath-hold diving. Yet,
reduced PO2 must activate the same pathways
whatever its aetiology. So, how can the body
generate a different response at altitude from that
during diving? The answer is the so-called
secondary chemoreceptor response. This occurs
when reduced PO2 produces an increased rate and
depth of breathing, as it normally does if breathing
is not restricted. Then, pulmonary stretch receptors
send afferent impulses via the vagus nerve to the
medulla, and stimulate the vasomotor centre. This
results in venoconstriction (to increase MSFP and
cardiac output), inhibits the cardio-inhibitory
centre (increasing heart rate), and causes a pattern
of vasodilatation and vasoconstriction that favours
vital tissues. The net result is a rise in cardiac
output to allow tissue oxygen needs to be met
despite reduced blood oxygen concentrations.
Animal models of obstructive sleep apnoea suggest
that chronic hypoxia may lead to chronic
hypertension by this mechanism.
