Arterioles and the Control of Capillary Blood Flow Flashcards
What do cardiac output matches with?
Blood flow through tissues must be regulated to ensure adequate local delivery of O2 and metabolic substrates,
and removal of metabolic products such as CO2 and lactic acid. Indeed, blood flow is so well matched to
metabolic demand that over the whole body, cardiac output is usually proportional to VO2 (the volume of O2
used per minute). Indeed, VO2 is often measured as a proxy for CO in studies of athletes, for example.
Capillary blood flow and arteriolar resistance
In general, local control of arteriolar resistance (Ra)
matches local blood flow to local metabolic
demand, whilst central, autonomic control of
arteriolar resistance controls TPR to maintain a constant mean ABP. This means that it is entirely
possible for local demand to produce vasodilatory
signals that are in opposition to generalised
vasoconstrictory signals. Local control can be
metabolic, myogenic, or from vasoactive
compounds released in a paracrine fashion by the
capillary endothelium. Central control is neurogenic
or endocrine (hormonal).
Arterial blood pressure (ABP) is maintained at a
relatively constant level by central mechanisms, as
we’ll see in Lecture 4. As flow = pressure gradient /
resistance, this constant pressure gradient allows
blood flow through individual tissues – even
individual capillary beds – to be regulated simply by
regulating the upstream (arteriolar) resistance.
There are three principal mechanisms for the
regulation of arteriolar resistance: nerves;
hormones and other vasoactive substances; and
local tissue metabolism. Arteriolar resistance
reflects a balance of these often opposing
influences, as, for example, local demand for
vasodilatation competes with systemic
vasoconstrictory signals regulating ABP. This lecture
first looks at why capillary flow and pressure is
regulated, and then at how this regulation is
achieved in general. Flow is always a function of the
pressure gradient and the resistance. The flow
through a capillary bed downstream from a single
arteriole is therefore given by:
𝑄̇ = 𝑃𝑎 −𝑃𝑣/𝑅𝑝𝑟𝑒 + 𝑅𝑐𝑎𝑝 + 𝑅𝑝𝑜𝑠
Where the pressure gradient is the difference
between Pa (the arterial pressure) and Pv (the
venous pressure), and the resistance is the sum of
the series resistances of the pre-capillary, capillary
and post-capillary resistances. However, because
the arteriolar resistance makes up about 70% of this
total series resistance and is the only directly
regulated resistance, and because the pressure
gradient is usually kept fairly constant, we can
simplify the relationship to:
𝑄̇ ∝1/𝑅𝑎
In general, local control of arteriolar resistance (Ra)
matches local blood flow to local metabolic
demand, whilst central, autonomic control of
arteriolar resistance controls TPR to maintain a constant mean ABP. This means that it is entirely
possible for local demand to produce vasodilatory
signals that are in opposition to generalised
vasoconstrictory signals. Local control can be
metabolic, myogenic, or from vasoactive
compounds released in a paracrine fashion by the
capillary endothelium. Central control is neurogenic
or endocrine (hormonal).
Arteriolar smooth muscle is arranged
circumferentially ( Figure 3). Thus, its contraction
increases the tension in the vessel wall and hence
causes vasoconstriction. Relaxation of the smooth
muscle reduces vessel wall tension, allowing the
blood pressure to open the vessel, causing
vasodilatation. The tension in vascular smooth
muscle is primarily a function of the intracellular
Ca2+ concentration, but can also be modulated by
phosphorylation of myosin light chain kinase.
Control of arteriolar smooth muscle
The control pathways all converge on two
broad intracellular control systems that are better
understood: regulation of the myosin-binding site
of actin by caldesmon (Figure 4), and regulation of
myosin light chain by phosphorylation (Figure 5).
Regulation of the myosin-binding site of the actin
filaments.
At higher Ca2+ concentration, the calmodulin will bind with the actin filament to allow binding of actin and myosin. Entering low Ca2+ concentration, caldesmon will bind to the actin which results in muscle relaxation.
Regulation of the myosin light chain (MLC).
At higher Ca2+ concentration, calmodulin binds to myosin which initiates the phosphorylation of MLC by the myosin light chain kinase. This promotes its binding to actin. If dephosphorylated when bound to actin, latch bridge formation can occur.
Metabolic control of arteriolar resistance-funcitonal hyperaemia
It is very simple to demonstrate local regulation of
blood flow. Blood flow can be measured in the arm,
and then a cuff is inflated around the upper arm to
above arterial pressure for around ten minutes.
When the cuff is remove, a profound increase in blood flow through the arm will be recorded. This is
termed reactive or functional hyperaemia.
The best-studied vasculature is probably that of
skeletal muscle, where rapid and enormous
changes in metabolic rate occur under physiological
conditions and are reproducible in experiments. Its
control will be considered in more detail in the final
lecture on the circulation in exercise. Nevertheless,
in all tissues, changes that typically accompany
increased metabolism, or normal metabolism in the
face of reduced local blood flow, include reduced
PO2, increased PCO2, decreased pH, increased
adenosine and increased extracellular K+.
These factors promote vasodilatation of systemic
arterioles (though note that reduced PO2 and
increased PCO2 have the opposite effect in the
pulmonary circulation, where such changes reflects
poor ventilation and not poor perfusion.)
In addition, changes that accompany anaerobic
metabolism, including decreased pH and increased
lactic acid concentration, also stimulate
vasodilatation. This appears to be a direct effect of
intracellular pH on smooth muscle.
Myogenic control of arteriolar resistance
If blood vessels behaved as rigid tubes, flow
through them would be proportional to the
pressure gradient. However, if pressure changes
then some vascular beds – particularly those of the
brain, heart and kidney – respond by changing their
diameter to reduce the change in flow. Thus,
increased pressure leads to increased resistance,
and flow increases much less than would be
expected. This also serves to maintain a constant
capillary pressure in these organs; this may reflect
the poor lymphatic drainage of heart and brain, and
the necessity of regulating filtration pressures in
the kidneys.
Note that myogenic autoregulation will tend to
have a similar effect to metabolic autoregulation.
Thus, increased arterial pressure would tend to
directly cause vasoconstriction by the myogenic
mechanism, and indirectly cause vasoconstriction as increased perfusion washed out local
metabolites.
The role of the endothelium
The capillary endothelium is in the optimal physical
location to detect local changes in metabolism. Its
importance in regulating vascular responses was
first noted when it was realised that acetylcholine
could dilate arteries only when the endothelium
was intact (whereas noradrenaline constricted
them even when the endothelium had been
removed.); see Figure 6.
Acetylchline-sympathetic-dilate
Furchgott, Ignaro and Murad won the Nobel Prize
in 1998 for the discovery that the signal from the
endothelium to the vascular smooth muscle was
NO (nitric oxide.) Thus, acetylcholine (and a
vasodilator peptide, bradykinin) stimulate NO
production by the action of nitric oxide synthase on
L-arginine in the endothelium. NO is lipophilic and
diffuses quickly, stimulating a soluble guanylyl
cyclase in the vascular smooth muscle. A cGMPdependent protein kinase then phosphorylates
MLCK, inhibiting it.
Vasodilator drugs based on nitrates have been used
for over 130 years, ever since it was realised that
nitroglycerin relieved angina (and caused severe
headaches.) More recently, sildenafil (perhaps
better known as Viagra) was discovered to reduce
cGMP breakdown, thus enhancing this pathway, (by
inhibiting cGMP-specific phosphodiesterase type
5).
More generally, endothelium releases a range of
vasodilator and vasoconstrictor substance, as well
as pro-coagulants, anti-coagulants, fibrinolytics,
antibacterials, growth factors etc. Under
physiological conditions, the net effects of this are
anticoagulant and vasodilatory. Thus, endothelial
damage or dysfunction is associated with raised
vascular resistance, hypertension, atherosclerosis
and an increased risk of clots. Such endothelial
dysfunction may result from diabetes,
hypertension, smoking, atherosclerosis,
hyperlipidaemias etc., and so may represent an
important common pathway for the circulatory
pathology associated with these risk factors
Systemic control of arteriolar resistance
As we will see in the Lecture, the brain can regulate
TPR via sympathetic noradrenergic innervation of
arterioles. This acts via the α1 receptor: this is linked
to the G-protein Gαq, which activates
phospholipase C, raises IP3, and thereby triggers
Ca2+ release from the SR.
Circulating adrenaline, produced from the adrenal
glands in response to preganglionic cholinergic
sympathetic fibres, can also act on α1 receptors,
though is a less potent agonist than noradrenaline.
Its main effect in moderate concentrations is to
cause vasodilatation of coronary and skeletal
muscle arterioles, acting through β2 receptors.
These are linked to the G-protein GαS, which
activates adenylate cyclase, raising cAMP levels and
thereby activating protein kinase A (PKA). PKA
phosphorylates myosin light chain kinase (MLCK),
reducing its activity and hence reducing the
phosphorylation of myosin light chain (MLC).
Some tissues are relatively unaffected by
sympathetic activity, in particular the brain. Skeletal
and cardiac muscle are vasodilated by increased
circulating adrenaline in exercise. Thus,
sympathetic activity in exercise causes patterns of
vasoconstriction and vasodilatation that tend to
divert blood from kidneys, gut and skin in favour of skeletal muscle, and the heart. Greater levels of
sympathetic nerve activity, for example following
haemorrhage, then produce generalised reductions
in blood flow to almost all tissues to preserve blood
supply to the brain. In extremis this can result in
renal failure and even gut necrosis, whilst brain
perfusion might remain adequate. These effects are
summarised in Table 1.
Finally, and beyond the scope of this lecture, blood
flow can be controlled in specific organs for a
variety of reasons. A particularly well-studied
example is control of skeletal muscle flow during
the initiation of exercise. This will be discussed in
the final lecture. In addition, examples including
thermoregulatory increases in skin blood flow,
increased gastrointestinal blood flow during
digestion, and in particular the control of renal
arterioles, will all be discussed in your other lecture
series.
Other vasoactive substances – eicosanoids
Eicosanoids are arachidonic acid derivatives with
actions on blood vessels (amongst others). They are
involved in clotting and inflammatory responses.
Most are synthesised by the enzyme cyclooxygenase, and are therefore of some clinical
significance because this is the enzyme that is
inhibited by aspirin (COX-1) and certain other nonsteroidal anti-inflammatory drugs.
The eicosanoids include a number of substances
called prostaglandins, which can be
vasoconstrictory (PG-F) or vasodilatory (PGs I, D and
E). They are involved in the inflammatory response,
and in some of the changes that take place during
parturition.
Another eicosanoid, thromboxane A2 is produced
by platelets and is a very potent vasoconstrictor,
and also causes platelet aggregation. It is an
important part of the clotting response. Its actions
are opposed by another eicosanoid, prostacyclin
(PG I2) produced by the endothelium. Endothelial
damage tends to alter the balance between these
two substances in favour of thromboxane A2, and
hence can lead to reduced blood flow and clotting.
This is the rationale behind using aspirin to prevent
myocardial infarction: aspirin irreversibly blocks
COX-1, required to produce both these substances,
but because endothelial cells have nuclei but
platelets don’t, endothelium can synthesise more
COX-1, and hence produce prostacyclin, whereas
the production of thromboxane A2 is significantly
diminished.
Summary: ways to control arteriolar resistance
Mechanism:
caldesmon+calmodulin
MLCK
Ways:
Central, autonomic control using neurotransmitter and hormone. (Noradrenaline, adrenaline, acetylcholine)
-mainly vasoconstriction to maintain the peripheral resistance thus the ABP.
Local control using myogenic and metabolic control -mainly for vasodilation which follows the metabolic demand
Arterioles are the site of control for blood pressure with highest resistance comparing to arteries and veins. The resistance can be controlled through vasoconstriction or dilation. The mechanism converges into two pathways, one is to control the binding site of actin to myosin through the binding of calmodulin and caldesmon. At high calcium concentration, calmodulin is bound to actin allowing actin-myosin binding and at low calcium concentration, caldesmon binds to actin to inhibit that.
Another way is through myosin light chain, which is controlled by myosin light chain kinase, with the calmodulin at sufficient calcium concentration, the MLCK phosphorylates the myosin which allows actin-myosin binding. The binding of myosin-actin results in smooth muscle contraction thus vasoconstriction to increase the resistance.
The control can be initiated through central, autonomic control through neuronal, endocrine pathways and local control through metabolic, myogenic and local vasoactive compounds released in paracrine fashion with local responses. In general, local resistance follows the metabolic demand while the central control maintains the peripheral resistance thus the ABP. So, it is entirely possible for local demand to produce vasodilatory signals that are in opposition to generalized vasoconstrictory signals.
Metabolic control results in vasodilation in response to usual changes accompanied increased metabolism like increased extracellular potassium, lactic acid, adenosine and PCO2 and decreased PO2 and pH. The changes lead to the vasodialation in the systemic arterioles This can be demonstrated by functional hyperaemia.
Myogenic control of arterioles is used to regulate the flow. If the vessels act as rigid tubes, the increase in the pressure would increase the flow proportionally. The vessels instead would change the diameter to reduce the change in the flow. Thus, increase in pressure would increase the resistance, so the increase in flow is much less than would be expected.
The myogenic autoregulation will tend to have a similar effect to metabolic regulation. With the increase of arterial pressure would tend to directly cause vasoconstriction by the myogenic mechanism, and indirectly cause vasoconstriction as increased perfusion washed out local metabolites.
The central control which relies on the neuronal pathway uses autonomic nervous system, the parasympathetic nervous system uses neuron transmitter acetylcholine and its vasodilatation response on the vessels requires intact endothelium for vasodilation. While noradrenaline can act without it by the sympathetic nervous system. This explains the damage of endothelium is associated with raised vascular resistance, hypertension, and atherosclerosis. The mechanism of acetylcholine is by activating the synthesis of NO by the action of nitric oxide synthases. The final route is to inhibite MLCK whiinhibitch results in smooth muscle relaxation.
The sympathetic noradrenaline innervation of arterioles. This acts via the 1 receptor: this is linked to the G-protein Gq, which activates phospholipase C, raises IP3 and thereby triggers Ca2+ release from the SR.
The circulating adrenaline stimulated from the hypothalamus to the preganglionic acetylcholinergic sympathetic fibres, can also acts on the 1 receptor, though is a less potent agonist than noradrenaline. Its main effect in moderate concentration is to act on the 2 receptor causing vasodilation of coronary and skeletal muscle arterioles. These are linked to the G-protein Gs, which activates adenylate cyclase, raising cAMP levels and thereby activating protein kinase A. PKA phosphorylates myosin light chain kinase, reducing its activity and hence reducing the phosphorylation of myosin light chain.
Some like the brain are unaffected by the autonomic nervous system, which maintains the blood flow. While increased level of circulating adrenaline will results in vasodilation of the heart and skeletal muscle, this results in a re-distribution of the blood.
Eicosanoid are arachidonic acid derivatives with actions on blood vessels. They are involved in clotting and inflammatory response. Most are synthesized by the enzyme cyclo-oxygenase which is inhibited by aspirin. The eicosanoid include a number of substances called prostaglandins, which can be vasoconstrictory or vasodilatory.
Two important eicosanoids prostacyclin and thromboxane A2, the prostacyclin is produced by the endothelium while thromboxane is by platelets. Application of aspirin inhibit both through action on COX-1, but the balance changes due to the endothelium with nuclei producing more prostacyclin while thromboxane is diminished.
