An introduction to the circulation; capillary exchange Flashcards
The systemic circulation
As depicted in Figure 1, blood pressure is highest in
the left ventricle, aorta and large arteries, drops
steeply as it passes through the arterioles, and
continues to drop more gradually though
capillaries, venules and veins on its return to the
heart. Pressure is pulsatile, especially in the
arteries, but flow is continuous as there is always a
forward pressure gradient. This pulsatility reflects
the following cardiac cycle:
1) Left ventricular contraction increases the
pressure within the ventricle.
2) When this exceeds aortic pressure, the
aortic valve opens and blood flows into the
aorta, transiently exceeding the flow from
the aorta to the rest of the body.
3) The pressure in the aorta and downstream
elastic blood vessels therefore rises,
stretching these vessels, and peaking at a
value termed the systolic pressure.
4) As the ventricle begins to relax, blood is
prevented from flowing back into the
heart by the closure of the aortic valve, but
as blood flow to tissues continues, the
pressure in the arteries drops to a
minimum termed the diastolic pressure.
Pressure is important in the circulation. Flow (Q) in
any system – whether considering the circulation as
a whole, or an individual blood vessel – is always
determined by the pressure gradient (P) across
the resistance (R) of the system as follows:
Q= change of P/R
The magnitude of the pressure drops across each
type of blood vessels is proportional to the relative
resistance of each component of the circulation.
Poisseuille’s law shows that resistance to laminar
flow is proportional to viscosity () and length (L),
and inversely proportional to the fourth power of
the radius (r):
R= 8uL/(pi*r^4)
The term in this equation explains why large
vessels, such as the aorta (~30 mm diameter) have
relatively low resistance. Arteries can therefore be
thought of as distribution vessels, carrying blood to
all parts of the body with little loss of pressure. This
is why we can speak of Arterial Blood Pressure
(ABP): the pressure is essentially the same in all
large arteries.
Arterioles are much smaller, with diameters in the
range ~10 to 300 m. Their total resistance is much
higher than that of arteries or capillaries, allowing them to be the primary site for control of blood
flow in the circulation.
Capillaries, the site of exchange between the
circulation and tissues, are smaller still (5-10 m),
so why do capillary beds as a whole have lower
resistance than the arterioles? The answer is that
the number of capillaries in parallel is much greater
– perhaps 20x greater – than the number of
arterioles in parallel. Resistances in parallel sum
according to the following equation:
1/R= 1/R1+1/R2+…1/Rn
In addition, Poisseuille’s law actually breaks down
for capillaries, because capillary diameter is so
similar to the dimensions of a red blood cell (~7 m
diameter). This allows organised bolus flow, which
significantly reduces the resistance to flow of blood
through capillaries. This is termed the FahreusLindquist effect.
Capillary flow and pressure
The whole purpose of the circulation is to deliver
blood to the tissues, and the capillaries are the
exchange area between the circulation and the
tissues. Exchange of substances between cells and
capillaries is primarily by diffusion, and diffusion
time is proportional to distance squared (Einstein’s
Law), so no cell can be far from a capillary. Water
movements across the capillary membrane are also
a function of hydrostatic pressures, and have
important influence on the volume of the
circulation and the interstitial compartments. As
exchange occurs between capillaries and their
surrounding tissue, the composition of blood
plasma and interstitial fluid becomes more similar,
and thus exchange slows. Increased flow of blood
into the capillaries accelerates exchange by
delivering fresh plasma from the arterial circulation
and thus opposing the dissipation of diffusion
gradients.
Two types of circulation
The mammalian circulation is a closed system transporting blood around two circuits in series. The systemic
circulation carries blood from the left ventricle via arteries and arterioles to the exchange vessels – capillaries –
within all tissues and organs of the body apart from the lungs, returning via venules and veins to the right atrium
of the heart. The pulmonary circulation carries the same volume of blood from the right ventricle through the
lungs via a similar sequence of blood vessels, returning oxygenated blood to the left atrium of the heart, then
the left ventricle, thereby completing the “double circuit”. These lectures will focus primarily on the systemic
circulation.
This pulsatility reflects
the following cardiac cycle:
1) Left ventricular contraction increases the
pressure within the ventricle.
2) When this exceeds aortic pressure, the
aortic valve opens and blood flows into the
aorta, transiently exceeding the flow from
the aorta to the rest of the body.
3) The pressure in the aorta and downstream
elastic blood vessels therefore rises,
stretching these vessels, and peaking at a
value termed the systolic pressure.
4) As the ventricle begins to relax, blood is
prevented from flowing back into the
heart by the closure of the aortic valve, but
as blood flow to tissues continues, the
pressure in the arteries drops to a
minimum termed the diastolic pressure.
Poisseuille’s law
that resistance to laminar
flow is proportional to viscosity () and length (L),
and inversely proportional to the fourth power of
the radius (r):
The 1/r4
term in this equation explains why large
vessels, such as the aorta (~30 mm diameter) have
relatively low resistance. Arteries can therefore be
thought of as distribution vessels, carrying blood to
all parts of the body with little loss of pressure. This
is why we can speak of Arterial Blood Pressure
(ABP): the pressure is essentially the same in all
large arteries.
Distribution vessels, site of control, exchange
Arteries can therefore be
thought of as distribution vessels, carrying blood to
all parts of the body with little loss of pressure. This
is why we can speak of Arterial Blood Pressure
(ABP): the pressure is essentially the same in all
large arteries.
Arterioles are much smaller, with diameters in the
range ~10 to 300 um. Their total resistance is much
higher than that of arteries or capillaries, allowing them to be the primary site for control of blood
flow in the circulation.
Capillaries, the site of exchange between the
circulation and tissues, are smaller still (5-10 m),
so why do capillary beds as a whole have lower
resistance than the arterioles? The answer is that
the number of capillaries in parallel is much greater
– perhaps 20x greater – than the number of
arterioles in parallel. Resistances in parallel sum
according to the following equation:
Sum of 1/R= 1/R
In addition, Poisseuille’s law actually breaks down
for capillaries, because capillary diameter is so
similar to the dimensions of a red blood cell (~7 m
diameter). This allows organised bolus flow, which
significantly reduces the resistance to flow of blood
through capillaries. This is termed the FahreusLindquist effect.
Capillaries
Capillaries are extremely numerous: for example,
skeletal muscle contains about 500,000 capillaries
per gram, and it has been calculated that the total
surface area of capillaries is about 5000m2!
However, only about 20-25% of capillaries are
perfused at rest; the rest are empty and collapsed,
but can open as the tissue becomes more active.
Capillaries consist of a single layer of endothelial
cells, connected together by interendothelial
junctions, and surrounded by a basement
membrane.
The endothelial cells themselves are
permeable to gases (O2 and CO2). Most capillaries
are also permeable to water and crystalloids (ions):
water can pass between cells and also through cells
via water channel proteins called aquaporins
(AQP1), whereas crystalloids (Na+
, K+ etc.) can generally only diffuse between cells. Finally, most capillaries are normally relatively impermeable to colloids, such as plasma proteins, though protein permeability can increase in inflammation.
However, the structure of capillaries varies in
different organs, giving profound regional
differences in capillary permeabilities to different
substances. This should not be a surprise given the
different requirements of different organs. For
example, capillaries in the lung primarily need to
exchange O2 and CO2, whereas in the liver, they
must also allow passage of newly synthesised
plasma proteins, while in the renal glomeruli, bulk
flow of water is required.
Capillaries fall into three groups according to their
“leakiness”:
1) Continuous capillaries. This is the most
common type, and generally has
interendothelial junctions about 10-15 nm
wide that allow relatively free passage of
water and ions, except in the brain and the
testes where there are narrow tight
junctions between cells.
2) Fenestrated capillaries. These are often
found in epithelia such as the small
intestine and glands. Fenestrae
(“windows”) through the cells allow ion
diffusion through as well as between cells.
3) Sinusoidal (discontinuous) capillaries.
These are found e.g. in the liver. Large gaps
between cells as well as fenestrae allow
transendothelial passage of proteins.
Three groups of capillaries
1) Continuous capillaries. This is the most
common type, and generally has
interendothelial junctions about 10-15 nm
wide that allow relatively free passage of
water and ions, except in the brain and the
testes where there are narrow tight
junctions between cells.
2) Fenestrated capillaries. These are often
found in epithelia such as the small
intestine and glands. Fenestrae
(“windows”) through the cells allow ion
diffusion through as well as between cells.
3) Sinusoidal (discontinuous) capillaries.
These are found e.g. in the liver. Large gaps
between cells as well as fenestrae allow
transendothelial passage of proteins.
Capillary exchange of solutes (diffusion)-Ficks Law
According to Fick’s law, the mass flow Q̇(in mol s-1) of a solute, X, between the capillary (c) and the
interstitial fluid (if) across the capillary membrane
depends on its permeability (P), the surface area
(A) and the concentration gradient ([X]c – [X]if):
Q̇X = Ac PX ([X]c – [X]if)
This equation is useful in considering how the
delivery of a solute to a tissue might be changed in
response to a change in that tissue’s requirements.
Examining the terms of the equation in turn:
AC (capillary surface area). As most capillaries are
not perfused at rest, increasing the number of
capillaries that are perfused in a tissue will increase
the area for exchange, and will reduce the mean
diffusion distance. This can be accomplished by
vasodilatation of the upstream arteriole.
PX (the permeability of substance X). Endothelial
cells can change shape in response to signalling
molecules such as cytokines, widening
interendothelial clefts. An example is the increased
leakiness of capillaries in response to histamine as
part of the inflammatory response.
[X]c (the capillary concentration of X). This primarily
depends on two factors: the rate of delivery of X
into the capillary (capillary blood flow x arterial
concentration) and the rate of extraction of X from
the capillary (i.e. Q̇X itself).
[X]if (the interstitial fluid concentration of X). This
also depends on two factors: the rate at which X is
“used up” in the local tissue, and the rate at which
it is extracted from the capillary.
Thus, if the O2 usage of a tissue increases this will
tend to reduce [O2]if and, by increasing the
concentration gradient, increase Q̇O2 (i.e. increase
the uptake of O2 from the capillary). However, this
would tend to reduce [O2]c: fortunately, [O2]c can be
maintained by increasing blood flow (i.e. increasing
the delivery of arterial blood, high in O2, to
compensate for the increased removal of O2 from
the capillary).
Capillary exchange of water (convection) Starling’s equation
𝑱𝐕 = 𝑲((𝑷𝐜 − 𝑷𝐢𝐟) −𝝈(𝝅𝐜 − 𝝅𝐢𝐟))
Water movements across the capillary wall are
important because they influence both the
circulating volume and the local interstitial fluid
volume. Yet, water behaves rather differently from
the generic solutes considered above. As first
outline by Starling in 1896, water movements
across the capillary wall are convective rather than
purely diffusive, as is the case for solutes. The
driving force for water movements across the
capillary wall are the hydrostatic pressure
difference (delta P) and the effective osmotic pressure
difference (delta Pi):
delta P is the difference between the hydrostatic
pressures in the capillary (Pc) and in the interstitial
fluid (Pif). Pc drops along the length of the capillary
as a result of resistance and some outward
movement of water, and is somewhat pulsatile. Pif
can be negative in non-encapsulated organs with
respect to atmospheric pressure – perhaps -1 to -2
mmHg. The interstitial “fluid” is a complex gel of
proteoglycans and water within a network of
collagen fibres. Due in particular to water removal
by the lymphatics, the matrix is slightly under-filled
such that its elastic recoil provides an expanding
force, much as sucking water out of a sponge leaves
it ready to suck water back in. In encapsulated
organs, such as muscle, the brain and the kidney, Pif
tends to be slightly positive.
change of pi is the effective osmotic pressure, also called the colloid osmotic pressure or the oncotic pressure difference. Only solute that cannot easily cross the capillary wall can exert an osmotic force, so the osmolarity of Na+, K+ etc. is not relevant to .
Instead, it is determined by the osmolarity of the
solute that cannot cross the capillary, i.e. the
plasma proteins (the colloid). The most important
of these is albumin, but globulins and fibrinogen
also contribute. Their total concentration is very
small, approximately 1.5 mM; nevertheless,
because the colloid content of the interstitium is
very low, the resultant osmotic gradient is of
comparable magnitude to the hydrostatic pressure
gradient according to the van’t Hoff equation:
piV = nRT
Where pi is the osmotic pressure (usually expressed
in mmHg), V is the volume of solution (l), n = is the
number of particles in solution (mol), R is the gas
constant (8.314 J mol-1 K -1, or 62.32 mmHg l mol-1 K -1) and T is the absolute temperature (K). This gives
a colloid osmotic pressure of:
Pic = 0.0014 mol l-1x 62.32 mmHg l mol-1 K-1x 310 K
= 27 mmHg
The net flux of water across a membrane can be
calculated using Starling’s equation, similar to the
Fick equation. It shows that volume flow (JV, in ml
cm-2 s-1) is equal to the hydraulic permeability (K, in
ml min-1 mmHg-1 cm-2) multiplied by the net
filtration pressure (delta P - delta pi):
𝑱𝐕 = 𝑲((𝑷𝐜 − 𝑷𝐢𝐟) −𝝈(𝝅𝐜 − 𝝅𝐢𝐟))
Note that the terms of delta Pi are multiplied by 𝝈, the
colloid reflection coefficient. This is a
dimensionless correction factor between 0 and 1,
to account for any leakiness of the capillary to
proteins. At 1, this implies total impermeability to
protein such that the full colloid osmotic pressure is
expressed, and if less than one it implies that the
membrane is slightly leaky to proteins and so they
cannot exert their full osmotic effect.
The net filtration pressure (delta P - delta Pi) changes
significantly along the length of a capillary, primarily
due to the fall in delta P, as shown in Figure 2. This
usually results in water movement out of the early
parts of a capillary and into the late parts. The slight
remaining pulsatility of the blood pressure also
causes a temporal variation in filtration rate.
The significance of Starling filtration-reabsorption
capillary pressure (Pc) closely follows venous
pressure, but is not closely related to arterial blood
pressure (ABP).
The balance between hydrostatic and colloid
osmotic pressures varies throughout the body and
at different times. For example, pressure at the
venous end of the capillary is raised in the feet
when standing. These forces are also influenced by
arterial blood pressure, venous pressure, resistance
in the upstream arteriole, colloid pressure and the
leakiness of capillaries to proteins. Dr Sage will
consider some of these factors in more detail in the
renal physiology lectures.
In terms of understanding the circulatory influence
on Starling forces, it is important to realise that
capillary pressure (Pc) closely follows venous
pressure, but is not closely related to arterial blood
pressure (ABP).
This is because Pc must always be
higher than venous pressure for flow to occur in the
correct direction. Thus, Pc will inevitably rise with
venous pressures in, for example, heart failure
(where you can think of blood as “backing up”behind a failing heart). In contrast, because of the
high-resistance arterioles between arteries and
capillaries, and because of metabolic
autoregulation of arteriolar diameter, high ABP is
not usually associated with increased capillary
blood flow, nor increased Pc.
However, reduced ABP may indeed result in
reduced Pc – in part as a direct result, and in part
because of increased sympathetic drive and
arteriolar vasoconstriction to “non-vital” tissues.
This is actually very helpful after blood loss as it
allows tissue fluid to buffer blood volume in a
process called autotransfusion. This is why the
haematocrit (i.e. the concentration of red blood
cells) falls after blood loss: tissue fluid dilutes the
blood. This fall in haematocrit is a more sensitive
marker of blood loss than is a fall in blood pressure.
We will look at haemorrhage in more detail in the
final lecture of this series.
The lymphatic system
It is important to note that in most capillaries at
most times, there is a small net outward movement
of water from the capillaries. This clearly doesn’t
result in continual swelling of our tissues, so where
does it go? The answer is: into the lymphatic
system.
Lymphatics begin as small thin-walled channels of
endothelium in the interstitium that join to form
progressively larger vessels until they ultimately
allow fluid to return, via the thoracic duct, into the
vascular system at the subclavian veins. The initial
lymphatics have multiple interendothelial junctions
between cells that behave like micro-valves,
allowing fluid in, but preventing its egress. These
empty into larger collecting lymphatics that, like
small veins, have valves and some smooth muscle
in the walls.
Each day, a net 2-4 litres of fluid leaves the
capillaries by Starling filtration, and is returned to
the circulation by the lymphatics. The lymphatics
also return some 100-200 g of protein each day. The
Where does fluid go from the capillaries?
It is important to note that in most capillaries at
most times, there is a small net outward movement
of water from the capillaries. This clearly doesn’t
result in continual swelling of our tissues, so where
does it go? The answer is: into the lymphatic
system.
Lymphatics begin as small thin-walled channels of
endothelium in the interstitium that join to form
progressively larger vessels until they ultimately
allow fluid to return, via the thoracic duct, into the
vascular system at the subclavian veins. The initial
lymphatics have multiple interendothelial junctions
between cells that behave like micro-valves,
allowing fluid in, but preventing its egress. These
empty into larger collecting lymphatics that, like
small veins, have valves and some smooth muscle
in the walls.
Each day, a net 2-4 litres of fluid leaves the
capillaries by Starling filtration, and is returned to
the circulation by the lymphatics. The lymphatics
also return some 100-200 g of protein each day. The importance of this mechanism is seen in
lymphoedema, which results when the lymphatic
drainage to a limb, for example, is blocked (this can
occur due to infections such as filiariasis or due to a
tumour, for example.) It is important to note that
the lymphatic system also has an important role in
the immune system that is beyond the scope of
these lectures.
Oedema
If the rate of filtration of fluid out of capillaries
exceeds its removal by the lymphatics, fluid will
collect in the interstitium, expanding the
extracellular space. This is called interstitial
oedema. It can be localised or more generalised
(though even in generalised oedema the effects of
gravity on venous pressure tend to make the
swelling greatest in the lower parts of the body: socalled “dependent oedema”).
Oedema increases the distance between cells and
capillaries and therefore interferes with solute
exchange. In the systemic circulation, this can
starve cells of nutrients. In the pulmonary
circulation, fluid can collect in the alveoli,
interfering with gas exchange and decreasing lung
compliance.
Localised oedema can result from lymphatic
blockage or from increased capillary leakiness to
proteins in inflammation, ischaemia-reperfusion
injury, and in the brain following head injury.
Generalised oedema is only noticeable when the
interstitial fluid volume has increased by about
30%, or 3 l. This is equal to the plasma volume, so
must develop relatively slowly and requires salt and
water retention by the kidneys. It can be caused by
loss of colloid proteins in malnutrition, or from the
kidneys in the nephrotic syndrome. However, the
most common cause in the developed world is
congestive cardiac failure (see lecture 3).
