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Materiál k přednášce:
Hemodynamika v GIT
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Autoregulation of Organ Blood Flow
• intrinsic ability of an organ to maintain a
constant blood flow despite changes in perfusion
pressure
• if perfusion pressure is decreased to an organ
(e.g., by partially occluding the arterial supply to
the organ), blood flow initially falls, then returns
toward normal levels over the next few minutes.
• This autoregulatory response occurs in the
absence of neural and hormonal influences and
therefore is intrinsic to the organ.
• When blood flow falls, arterial resistance (R)
falls as the resistance vessels (small arteries
and arterioles) dilate. Many studies suggest
that that metabolic, myogenic and endothelial
mechanisms are responsible for this
vasodilation. As resistance decreases, blood
flow increases despite the presence of
reduced perfusion pressure.
• When perfusion pressure (arterial minus
venous pressure, PA-PV) initially decreases,
blood flow (F) falls because of the following
relationship between pressure, flow and
resistance:
The figure to the right shows the effects of suddenly reducing perfusion pressure from 100 to 70
mmHg. In a passive vascular bed, that is, one that does not show autoregulation, this will result
in a rapid and sustained fall in blood flow. In fact, the flow will fall more than the 30% fall in
perfusion pressure because of passive constriction as the intravascular pressure falls, which is
represented by a slight increase in resistance in the passive vascular bed. If a vascular bed is
capable of undergoing autoregulatory behavior, then after the initial fall in perfusion pressure
and flow, the flow will gradually increase (red line) over the next few minutes as the vasculature
dilates (resistance decreases - red line). After a few minutes, the flow will achieve a new steadystate level. If a vascular bed has a high degree of autoregulation (e.g., brain and coronary
circulations), then the new steady-state flow may be very close to normal despite the reduced
perfusion pressure.
If an organ is subjected to an experimental study in which perfusion
pressure is both increased and decreased over a wide range of
pressures, and the steady-state autoregulatory flow response
measured, then the relationship between steady-state flow and
perfusion pressure can be plotted as shown in the figure to the right
• When the vasculature is not maximally dilated, many organs will display
autoregulation as the perfusion pressure is reduced. When this occurs,
there will be a range of perfusion pressures (i.e., autoregulatory range)
where flow may not decrease appreciably as perfusion pressure is reduced.
• The "Constricted" curve represents the pressure-flow relationship when the
vasculature is maximally constricted and when autoregulation is not
present.
• This figure also shows that there is a pressure below which an organ is
incapable of autoregulating its flow because it is maximally dilated. This
perfusion pressure, depending upon the organ, may be between 50-70
mmHg. Below this perfusion pressure, blood flow decreases passively in
response to further reductions in perfusion pressure.
• This has clinical implications in coronary, cerebral, and peripheral arterial
disease, where proximal narrowing (stenosis) of vessels may reduce distal
pressures below the autoregulatory range; hence, the distal vessels will be
maximally dilated and further reductions in pressure will lead to reductions
in flow. There is an upper limit to the autoregulatory range; however, this
upper limit is seldom reached physiologically
Under what conditions does autoregulation occur and
why is it important?
• Different organs display varying degrees of
autoregulatory behavior.
• The renal, cerebral, and coronary circulations
show excellent autoregulation, whereas
• skeletal muscle and splanchnic circulations
show moderate autoregulation.
• The cutaneous circulation shows little or no
autoregulatory capacity.
There are situations in which arterial pressure does
not change, yet autoregulation is very important.
•
Whenever a distributing artery to an organ becomes
narrowed (e.g., atherosclerotic narrowing of lumen,
vasospasm, or partial occlusion with a thrombus) this can
result in an autoregulatory response.
• Narrowing (stenosis) of distributing arteries increases their
resistance and hence the pressure drop along their length.
• This results in a reduced pressure at the level of smaller
arteries and arterioles, which are the primary vessels for
regulating blood flow within an organ. These resistance
vessels dilate in response to reduced pressure and blood
flow.
• This autoregulation is particularly important in organs such as
the brain and heart in which partial occlusion of large
arteries can lead to significant reductions in oxygen delivery,
thereby leading to tissue hypoxia and organ dysfunction.
•
A change in systemic arterial pressure, as occurs for
example with hypotension caused by hypovolemia or
circulatory shock, can lead to autoregulatory responses in
certain organs.
• In hypotension, despite baroreceptor reflexes that constrict
much of the systemic vasculature, blood flow to the brain
and myocardium does not decline appreciably (unless the
arterial pressure falls below the autoregulatory range)
because of the strong capacity of these organs to
autoregulate.
• Autoregulation, therefore, ensures that these critical organs
have an adequate blood flow and oxygen delivery.
Myogenic Mechanisms Regulating Blood Flow
• Myogenic mechanisms are intrinsic to the smooth muscle
blood vessels, particularly in small arteries and arterioles. If
the pressure within a vessel is suddenly increased, the
vessel responds by constricting. Diminishing pressure within
the vessel causes relaxation and vasodilation. This response
is observed in vivo and in isolated, pressurized blood vessels.
• The myogenic mechanism may play a role in autoregulation
of blood flow and in reactive hyperemia. Myogenic behavior
has not been clearly identified in all vascular beds, but it has
been noted in the splanchnic and renal circulations, and
may be present to a small degree in skeletal muscle.
• Electrophysiological studies have shown that vascular
smooth muscle cells depolarize when stretched, leading to
contraction. Stretching also increases the rate of smooth
muscle pacemaker cells that spontaneously undergo
depolarization and repolarization.
Endothelial Mechanisms Regulating Blood Flow
• The vascular endothelium have an important role in
the regulation of smooth muscle function and in
modulating leukocyte and platelet adhesion to the
endothelium.
• As shown in the figure, various blood borne substances
that come in contact with vascular endothelial cells
(EC) cause the production and release of endothelial
factors that elicit contraction (+) or relaxation (-) of
vascular smooth muscle (VSM). These endothelial
factors modulate the effects of norepinephrine (NE)
released by sympathetic nerves (SN), and the effects of
tissue metabolites and humoral factors
Active Hyperemia
•
• The three most important endothelial-derived substances are:
nitric oxide (NO), endothelin (ET-1), and prostacyclin (PGI2). NO
and PGI2 act as vasodilators, whereas ET-1 serves as a
vasoconstrictor.
• Damage to the vascular endothelium due to atherosclerotic
processes or following ischemia and reperfusion alters the
formation and release of endothelial factors.
• When endothelial damage occurs, the endothelium produces less
nitric oxide and prostacyclin, which causes the adrenergic
vasoconstrictor tone to be unopposed. This can lead to increased
vascular tone and vasospasm.
• Furthermore, decreased production of both of these endothelial
factors can lead to increased platelet adhesion and aggregation,
and therefore enhanced thrombogenesis.
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•
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• The magnitude of active hyperemia responses differ
among organs because of the relative changes in
metabolic activity from rest and their vasodilatory
capacity. Active hyperemia can result in up to a 50-fold
increase in muscle blood flow with maximal exercise,
whereas cerebral blood flow may only increase 2-fold
with increased neuronal activity.
• Active hyperemia can also be influenced by competing
vasoconstrictor mechanisms. For example,
sympathetic activation during exercise can reduce the
maximal skeletal muscle active hyperemia compared
to what would occur in the absence of sympathetic
activation.
• Active hyperemia may be due to a combination of
tissue hypoxia and the generation of vasodilator
metabolites such as potassium ion, carbon dioxide,
nitric oxide, and adenosine.
Active hyperemia is the increase in organ blood
flow (hyperemia) that is associated with increased
metabolic activity of an organ or tissue.
An example of active hyperemia is the increase in
blood flow that accompanies muscle contraction,
which is also called exercise or functional
hyperemia in skeletal muscle.
Blood flow increases because the increased
oxygen consumption of during muscle contraction
stimulates the production of vasoactive
substances that dilate the resistance vessels in
the skeletal muscle.
Other examples include the increase in
gastrointestinal blood flow during digestion of
food, the increase in coronary blood flow when
heart rate is increased, and the increase in
cerebral blood flow associated with increased
neuronal activity in the brain.
The figure shows that there is a resting flow
associated with the basal oxygen consumption of
Reactive Hyperemia
• Reactive hyperemia is the transient increase in
organ blood flow that occurs following a brief
period of ischemia (e.g., arterial occlusion).
• Reactive hyperemia occurs following the removal
of a tourniquet, unclamping an artery during
surgery, or restoring flow to a coronary artery
after recanalization (reopening a closed artery
using an angioplasty balloon or clot dissolving
drug).
• In general, the ability of an organ to display
reactive hyperemia is similar to its ability to
display autoregulation.
Metabolic Mechanisms of Vasodilation
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the left panel shows the effects of a 2 min arterial occlusion on blood flow.
When the occlusion is released, blood flow rapidly increases (i.e., hyperemia occurs) that
lasts for several minutes.
The hyperemia occurs because during the period of occlusion, tissue hypoxia and a build
up of vasodilator metabolites (e.g., adenosine) dilate arterioles and decrease vascular
resistance. Then when perfusion pressure is restored (i.e., occlusion released), flow
becomes elevated because of the reduced vascular resistance.
During the hyperemia, the tissue becomes reoxygenated and vasodilator metabolites are
washed out of the tissue. This causes the resistance vessels to regain their normal vascular
tone, thereby returning flow to control.
The longer the period of occlusion, the greater the metabolic stimulus for vasodilation
leading to increases in peak reactive hyperemia and duration of hyperemia. Depending
upon the organ, maximal vasodilation as indicated by peak flow, may occur following less
than one minute (e.g., coronary circulation) of complete arterial occlusion, or may require
several minutes of occlusion (gastrointestinal circulation).
Myogenic mechanisms may also contribute to reactive hyperemia in some tissues. By this
mechanism, arterial occlusion results in a decrease in pressure downstream in arterioles,
which can lead to myogenic-mediated vasodilation.
Hypoxia:
• Decreased tissue pO2 resulting from reduced oxygen
supply or increased oxygen demand causes
vasodilation.
• Hypoxia-induced vasodilation may be direct
(inadequate O2 to sustain smooth muscle contraction)
or indirect via the production of vasodilator
metabolites.
• Note, however, that hypoxia induces vasoconstriction
in the pulmonary circulation (i.e., hypoxic
vasoconstriction), which likely involves the formation
of reactive oxygen species, endothelin-1 or products
of arachidonic acid metabolism.
Tissue Metabolites and Ions:
• Potassium ion is released by contracting cardiac and skeletal
muscle.
• Small increases in extracellular K+ produces hyperpolarization of
vascular smooth muscle and relaxation through stimulation of the
electrogenic Na+/K+-ATPase pump and increasing membrane
conductance to K+ (K+ activated K+ channels).
• Extracellular K+ increases when there is an increase in action
potential frequency, because with each action potential K+, leaves
the cell.
• Normally, the Na+/K+-ATPase pump is able to restore the ionic
gradients; however, the pump does not keep up with rapid
depolarizations (i.e., there is a time lag) during muscle contractions
and this causes K+ to accumulate in the extracellular space.
• Potassium ion appears to play a significant role in causing active
hyperemia in contracting skeletal muscle.
• Blood flow is closely coupled to tissue metabolic activity in most
organs of the body.
• For example, an increase in tissue metabolism, as occurs during
muscle contraction or during changes in neuronal activity in the
brain, leads to an increase in blood flow (active hyperemia).
• There is considerable evidence that actively metabolizing cells
surrounding arterioles release vasoactive substances that cause
vasodilation. This is termed the metabolic theory of blood flow
regulation.
• Increases or decreases in metabolism lead to increases or
decreases in the release of these vasodilator substances. These
metabolic mechanisms ensure that the tissue is adequately
supplied by oxygen and that products of metabolism (e.g., CO2, H+,
lactate) are removed.
• Another mechanism that may couple blood flow and metabolism
involves changes in the partial pressure of oxygen.
Tissue Metabolites and Ions:
• Adenosine is formed from cellular AMP acted
upon by 5'-nucleotidase.
• The AMP is derived from hydrolysis of
intracellular ATP and ADP.
• Adenosine formation increases during hypoxia
and increased oxygen consumption, especially if
the latter is accompanied by inadequate oxygen
delivery.
• Adenosine formation is a particularly important
mechanism for regulating coronary blood flow.
Tissue Metabolites and Ions:
• Carbon dioxide formation increases during states of increased
oxidative metabolism. It readily diffuses from parenchymal cells in
which it is produced to the vascular smooth muscle of blood vessels
where it causes vasodilation. CO2 plays a significant role in
regulating cerebral blood flow.
• Hydrogen ion increases when CO2 increases or during states of
increased anaerobic metabolism, which can produce metabolic
acidosis. Like CO2, increased H+ (decreased pH) causes vasodilation,
particularly in the cerebral circulation.
• Lactic acid, a product of anaerobic metabolism, is a vasodilator,
although in large part because of its pH effect.
• Inorganic phosphate is released by the hydrolysis of adenine
nucleotides. It may have some vasodilatory activity in contracting
skeletal muscle.
Splanchnic Ischemia
• rich collateral supply in this teritory – occlusions result in
comparatively little disturbances in blood supply
• portal venous system is of large capacity and can pool a
considerable proportion of blood volume
• muscle vascular plexus in intestinal wall has more
collateral circulation than mucosal plexus – in certain
types of ischemia mucosa has selectively undergone
complete necrosis
Physiology of Intestinal Circulation
• precapillary resistance vessels: site of local and
remote control system
• precapillary sphincters: control of the number of
perfused capillaries
• exchange vessels: place between intravascular and
extravascular compartments
• postcapillary resistance vessels: main determinant of
mean hydrostatic capillary pressure – fluid exchange
Physiology of Intestinal Circulation
• autoregulation:
- constant flow with pressures between 80-160
mmHg to keep hydrostatic pressure
- precapillary arterioles in villous circulation
• postprandial hyperemia
• intestinal counter-current exchanger for oxygen is
much more involved during hypotension
Splanchnic Ischemia
• occlusive (embolisation, massive venous trombosis):
- rare
- transmural infarction
- loss of circulating volume; peritonitis
• non-occlusive and relative:
- common in critically ill patients
- cardiac failure, hypovolemic shock, sepsis
Mechanisms of Splanchnic Ischemia
• GIT:
- barrier against very noxious intraluminal environment
- nutrients provide optimal conditions for the grow of
microorganisms and helmints
• mucosal circulation:
- essential to sustaine balance between agressive
intraluminal toxins and barrier components
- compensatory adjustments in capillary surfice area and
oxygen extraction
Ischemic Injury to Intestinal Mucosa
hypoxia:
• critical level of blood flow - ↓ intracellular energy stores
• amplification with counter-current exchange of O2 at the
villous base
• intracellular accumulation of hypoxantine
• Curlingův stresový vřed je akutní
gastroduodenální vřed, komplikace závažných
popálenin. Nejčastěji se nachází v pyloru. Vzniká
působením žaludečních šťáv na ischemickou
sliznici
• Patogeneze
• hypovolemie
• ↓ srdeč
srdeční výdej
• ↑ vazokonstrikce
• splanchnická
splanchnická hypoperfuze
Ischemic Injury to Intestinal Mucosa
postischemic reperfusion:
• free oxygen radicals
• activation of resident neutrophils – another source of
reactive oxygen metabolites
• promotion of conversion of xantine dehydrogenase to
xantine oxidase via proteolysis
• proteases (pancreas, granulocytes)
contra
protease inhibitors (α1- protease inhibitor)
Systemic Mediators of Splanchnic Origin
• ischemic bowel releases toxic agents which, in turn, affect
the cardiovascular system and lead to development of shock
and multiple organ failure
• bacterial translocation (bacterial leave the intestinal
lumen): role of macrophages, ischemic changes of intestinal
architecture
• endotoxins: Tr and Leu aggregation, abnormal tissue
perfusion, ↑ capillary permeability
• eicosanoids: splanchnic region is important source and a
target, as well
Splanchnic Organ Injury Syndromes
• stress ulceration: acute non-occlusive ischemic erosions
• ischemic hepatitis: centrilobular hepatocellular necrosis
• ischemic pancreatitis: due to circulatory disorders
without other predisposing factors
• acute intestinal ischemia: severe abdominal pain and
intense peristaltic activity
• focal ischemia of the small intestine: edema, cell
infiltration into the mucosa followed by fibrous stricture
• ischemic colitis: damage of mucosal and muscular
layers replaced by scar and stricture
• chronic intestinal ischemia (intestinal angina): pain
occuring in relation to meals; inability to produce
postprandial hyperemia
Gut as the Motor of Multiple System Organ Failure
• uncontrol infection: alterations in gut – adynamic ileus,
„third space“, hypermetabolism, loss of barrier function
- upper gut is colonised by pharyngeal microflora
- aspiration pneumonia = invasion of gastric flora
- bowel serves as a reservoir of pathogens, but also
as a modulator of immune responses
• source of endogenous vasodilators in hemorrhage,
cardiac failure, sepsis
- damage of mucosal barrier → bacterial translocation
→ toxins into the circulation