Flow = pressure difference / resistance
Thus, the two main factors in determining flow are pressure within a vessel, and the resistance of a vessel.
The velocity of flow is inversely proportional to the total cross-sectional area of a tube(s). The nature of the circulatory system means that cross-sectional area of all capillaries is much greater than that of large vessels, thus in the capillaries, the flow is much slower than in the larger vessels.
Poiselle’s law shows us that resistance is proportional to the length of a tube, and viscosity of the fluid, and inversely proportional to the radius if the tube.
Thus, the arterioles have the greatest resistance because they have a similar total cross sectional area to the larger vessels, but have a much smaller radius.
- Also note that the arterioles have a great deal of smooth muscle, which has a very large impact on total resistance , and ultimately on blood pressure.
Capillaries on the other hand, are very short (thus have low resistance) and have a huge combined cross-sectional area.
- Note that Poiselle’s law only applies when there is laminar flow (smooth flow). Where there is constriction, this can increase the velocity, and mess up the whole equation.
Blood pressure = cardiac output x systemic vascular resistance
Cardiac output = stroke volume
x heart rate
Thus blood pressure depends upon the systemic vascular resistance, and the cardiac output. Thus when we are manipulating blood pressure we can:
- Alter the amount of vasoconstriction / dilation
- Alter the heart rate
- Alter the stroke volume (strength of contraction of the heart)
The Frank-Starling phenomenon
When things affect the contractility of the heart, they can shift the Frank-Starling curve. Things that increase the CO (and contractility of the heart), shift the curve upwards, things that decrease the CO, shift the curve downwards.
The example shows how sympathetic stimulation shifts the curve upwards.
The normal control of blood pressure
This is mainly used in skin (hopefully other body tissues will have a fairly constant temperature!). when it is warm, vasodilation will occur, when it is cold, vasoconstriction will occur.
- This is caused by noradrenergic stimulation of α2-receptors
Below 12’C the situation is different. Neurotransmitter release is impaired. This means that noradrenaline can’t have its full effect, and instead prostaglandins are released, causing vasodilation. This is called paroxysmal cold vasodilation.
In most other tissues (i.e. not skin) vasodilation occurs in response to cold – this helps to keep these tissues at a constant temperature. Α1 receptors predominant in these areas over α2, and it is probably just that noradrenaline has less effect on α1 than α2, thus less vasoconstriction occurs as a result of noradrenaline release.
Various local metabolites can be released as a result of metabolic processes and these can cause vasoconstriction, e.g.:
- Acidosis (CO2 and lactic acid)
- PO2 from hypoxia
- ATP breakdown products (e.g. in exercise)
- K+ from active muscle (and active brain neurons)
These are just basically local hormones. Examples include:
- Histamine (vasodilation)
- Bradykinin (vasodilation) – this is an inflammatory mediator
- Serotonin (vasoconstriction)
- Prostaglandins (can cause both vasodilation and vasoconstriction)
- Thromboxane A2 (vasoconstriction) – also a platelet activator; involved in haemostasis
- Leukotrienes (vasoconstriction)
- Platelet activating factor (PAF) – (vasodilation)
Endothelium dependent mechanisms
Various things can cause the endothelium to release endothelium derived relaxing factor (EDRF). EDRF is actually several different factors, but the most important of these is NO (nitric oxide). This is a vasodilator
NO will then diffuse into smooth muscle cells, setting off a second messenger system (cGMP controlled), and cause smooth muscle relaxation, and ultimately vasodilation.
EDRF release is stimulated by:
- Bradykinin, ADP (e.g. in exercise), thrombin, substance-P, ACh, histamine.
The body must keep perfusion of tissues at a constant rate. This can be achieved through a process of autoregulation. According to:
- Flow = [pressure difference] / resistance
Then when pressure increases, so must resistance, to keep flow constant. This means that when pressure increases, there is vasoconstriction.
Here you can see that the flow rate can be kept fairly constant just by varying the diameter of the vessels, between the limits of 50 and 150mmHg. The red blobs indicate artery diameter.
It takes 30-60s for this effect to occur after the initial change in pressure.
Autoregulation is independent of nervous control, and only works over the above range. However, the limits in which it works can be altered by nervous stimulation by e.g. increased sympathetic drive.
Mechanisms of autoregulation
- Vasodilator washout – a faster flow will ‘wash away’ many of the cytokines responsible for vasodilating, thus natural vasoconstriction occurs with an increased flow.
- Myogenic response – increased pressure in a vessel will cause constriction of that vessel through stimulation of baroreceptors.
- In the heart – an increase in coronary artery pressure causes a rise in heart tissue P O2, which causes vasoconstriction.this can reduce blood flow the heart, thus reducing the strength of contractions, thus lowering BP by reducing cardiac output.
Flow can also be affected by blood gasses.
blood gasses not only can directly affect the contractility (and thus flow) of blood vessels, they also give an indication of metabolic activity, and thus an indication of how various metabolites can be affecting flow. A high PCO2 will cause an increase in flow (as the body tries to drive away the waste products of metabolism
). Conversely, a high O2 will cause a decrease in flow.
To keep flow between normal limits, you must have a PCO2 of between roughly 4-8mmHg
This is responsible for the increase in blood-flow that occurs when exercising. A low PO2 of an artery (because all the O2 is being taken up by the tissue for metabolism) will cause the artery to vasodilate.
I think; the PO2 effect is mainly seen in coronary arteries.
this is the increase in bloodflow to a tissue that occurs after the flow to the tissue has been interrupted. This enables a lot of blood to get to an ischaemic area quickly.
Vasodilator metabolites (released by ischaemic tissues) as well as prostaglandins are the main substances involved.
There is also a myogenic response (fall
in blood pressure causing dilatation).
In some tissues (e.g. the heart) there is a relative oversupply of blood after the precipitating event in relation to the amount of lack of bloodflow that initially occurred.
Ischaemic perfusion injury
When bloodflow to a tissue is impaired for a prolonged period of time then the mechanisms of reactive hyperaemia are impaired. In these instances, then reperfusion of the ischaemic tissue will lead to:
- Superoxide (O2-) and hydroxide (OH’) radical formation. These damage the tissue and the vessel wall causing further vasoconstriction
- K+ release and acidosis cause further damage
- The reperfused tissues have damaged plasmalemmal barriers to Ca2+ – thus the cells become flooded with calcium, causing calcium overload damage.
It is thought that e.g. after stroke and MI
, that ischaemic perfusion injury causes excess damage to the heart and brain.
Sympathetic stimulation basically causes increased contractility and rate of the heart (increased CO) vasconstriction! – but there is a special case
Sympathetic vasoconstricting nerve fibres innervate vascular smooth muscle. There is a basal level of activity of these nerves which causes normal vascularature tone.
- The neurotransmitter involved is noradrenalinewhich acts on α1- receptors, causing contraction
When there is an increase in sympathetic drive:
- Vasoconstriction decreases local blood-flow
- Vasoconstriction decreases local blood volume
- Vasoconstriction helps increase the pre-load of the heart – helping the heart to increase its CO
- Arteriolar constriction decreases capillary pressure, leading to a resorption of products from the interstitium back into the blood.
So, sympathetic stimulation will cause an increase in peripheral vascular resistance, and an increase is cardiac output. This is the basic response to shock.
Sympathetic nerves are distributed mainly to the ventricles of the heart, and not to other areas of the heart. They vastly outnumber the parasympathetic stimulation to the heart, and they release noradrenaline – which in this case acts on β1-adrenoceptors, increasing permeability of the cells to sodium, thus increasing the rate at which the cells can reach their threshold, and increasing the heart rate. They also increase the cell’s permeability to calcium, thus increasing contractile strength.
The special case
Noradrenaline and adrenaline can also act on β2- receptors – causing vasodilation. However, these receptors are only found in selected muscle beds (such as in skeletal muscle), and the effect of vasodilation is much less than the effect of vasoconstriction + increased cardiac output.
This is always a vasodilating action.
However, these nerves are not widely distributed, and the role they play in controlling BP and vascular resistance is very small. These nerves can be found in:
- The head
- Salivary glands
- Genitalia – the erectile tissue of the penis is filled by the parasympathetic dilation of blood vessels.
- GI mucosa
Their postganglionic fibres release ACh which acts on muscarinic receptors and relaxes vascular smooth muscle.
Parasympathetic nerves travel via the vagus nerve to innervate the heart. Here, they release ACh which reduces the heart rate. Without this constant stimulation, the rate of the heart would be
Nitergic vasodilating nerves
NO, as we have already seen, in a vasodilator. But not only does it act locally, it is also a neurotransmitter. Neurons that release NO are known as nitergic neurons.
Viagra (sildenafil) manipulates the normal functioning of these. It selectively inhibits phosphdiesterase in the smooth muscle of the genital vessels. This phosphdiesterase normally breaks down the cGMP that NO uses to set off its second messenger system.
More than 3x as much adrenaline is secreted as noradrenaline. Essentially, these products are both released by sympathetic activity, and will cause an increase in BP (although the actual picture is more complicated).
These are g-coupled receptors that are the target of the catecholamines. In this instance, this means mainly adrenaline and noradrenaline although, catechol and dopamine are also both examples.
There are two main types of receptor: α and β.
Activation of these causes:-
- Vasoconstriction of arteries (particularly coronary arteries)
- Vasoconstriction of veins
- Decreased motility of the smooth muscle in the GIt
There are 2 subtypes: 1 & 2. They basically all cause the same effects when stimulated, however, they have different affinity for catecholamines:
- Α1 have greater affinity for epinephrine
- A2 have greater affinity for norepinephrine
Essentially these cause heart muscle contraction and smooth muscle relaxation (vasodilation).
There are 3 different subtypes; 1, 2 & 3. However, unlike α receptors, activation of the different subtypes causes different effects.
Beta 1 receptors
Activation of these causes:-
- Heart muscle contraction – thus an increase in cardiac output – this occurs by raising the heart rate and also increased the stroke volume
- Release of renin for the JG cells
- Lipolysis in adipose tissue
Activation of these causes:-
- Smooth muscle relaxation – e.g. in the bronchi; hence the use of salbutamol, and vasodilation
- Glycogenolysis and gluconeogenolysis
- Increased release of renin
- Relaxation of detrusor muscle
- Inhibition of histamine release
- Contraction of GI sphincters
- Anabolism of skeletal muscle
- Lipolysis in adipose tissue
- Tremors! – otherwise beta3 blockers might be used as weight loss agents!
Adrenalin is the main activator if beta1 and beta2 receptors. For beta3, noradrenaline is the main activator.
- Both adrenaline and noradrenaline will increase heart rate and contractility through the activation of beta1 receptors
- Both adrenaline and noradrenaline will cause vasoconstriction via alpha receptors. This effect is greater than any vasodilation caused by beta2 activity, thus the overall effect is a rise in BP.
- Adrenaline causes vasoconstriction in the skin (alpha1 receptors) and vasodilation in skeletal muscle, myocardium and the liver (beta2 receptors). Thus the different actions of adrenaline are caused by the locations of the receptors it is acting on!
- Noradrenaline only causes vasoconstriction – because it has high affinity for alpha receptors, but low for beta.
- Adrenal gland stimulation results in mainly adrenaline release. This causes a large increase in cardiac output, as well as vasoconstricting and vasodilating effects. The overall outcome is a rise in BP; as the effects on cardiac output are greater than the effects on vasodilation.
This is a hormone produced by the hypothalamus
in response to increased blood osmolarity
(i.e. increased concentration of solutes in the blood), and to a lesser extent, in response to reduction in blood volume and pressure.
It causes increased retention of water by the kidneys.
See notes on renal control!
This is a long-term control of BP – as opposed to the baroreceptor reflex; which is short term
Basically, renin is secreted by the JG apparatus when blood pressure falls. It converts angiotensinogen to angiotensin-I, which is then converted to angiotensin-II by the ACE enzymes in the lungs. Angiotensin-II causes:
- Increased secretion of ADH
- Increases salt and water retention
- Increases cardiac contractility
- Causes vasoconstriction
ANP (released by atria) and BNP (released by the ventricles) – these are both released in response to stretching (i.e. an increase in BP) and these increase salt and water excretion by the kidneys.
Baroreceptors and central control
These are located in the carotid sinus and in the aortic arch. They respond to stretching of the vessel wall. They play a large role in short term blood pressure control. They constantly fire a signal at normal muscle tone. The rate of firing of the signal increases as the wall becomes stretched, and decreases as it contracts. The impulse generated by these baroreceptors are carried to the medulla by the:
- Glossopharyngeal nerves (carotid sinuses)
- Vagus nerves (aortic arch)
These signals stimulate the medulla to cause a:
- Increase in parasympathetic activity
- Decrease in sympathetic activity
- i.e. a decrease in BP
This causes a decreased heart rate, and vasodilation (decreased peripheral resistance).
When the baroreceptors are not very active, the medulla causes:
- A decrease in parasympathetic activity
- An increase in sympathetic activity
- An increase in renin secretion
- Catecholamine secretion
- i.e. – an increase in BP
The effectiveness of baroreceptors is reduced with:
You can also ‘reset’ the normal point for BP with
- Exercise – there is a central overriding effect; otherwise you would become tachycardic in exercise!
- Chronic hypertension
These are found in the:
- Great veins
- Pulmonary artery
The stimulation of these causes:
There are several types of receptor:
- Venoatrial stretch receptors – these are nerve endings found where the great veins join the atria. They are connected to sympathetic myelinated fibres. When these receptors are stimulated they cause tachycardia by increasing the sympathetic drive to the heart. They also cause an increase in salt and water excretion.
- The tachycardia produced is not really important because is is over-ruled by the slower unmyelinated mechoreceptor fibres. It is the increased salt and water excretion that are important.
- Unmyelinated mechanoreceptor fibres – these are found in the atria and left ventricle. When these areas are stretched, they fire inhibitory signals to sympathetic fibres – inhibiting the sympathetic fibres. This causes a bradycardia and peripheral vasodilation.
- Chemosenstivie fibres – these respond to bradykinin and other factors that might be released in ischaemic damage. It is thought that the pain of angina and MI is caused by the stimulation of these fibres. Stimulated causes bradycardia, increased respiration (trying to counteract the ischaemia that activated them) and peripheral vasodilatation.
Like the baroreceptors, these are found in the carotid and aortic bodies. They are stimulated by:
Their nerve fibres travel with the baroreceptors fibres in the glossopharyngeal (carotid) and vagus (aortic) nerves. At normal gas levels, these chemo receptors are mainly in charge of breathing. However, if the levels become abnormal, they can send signals that:
- Cause bradycardia
- Cause vasoconstriction
This occurs via increased sympathetic stimulation. However, they also affect the respiratory system, increasing tidal volume, which stimulates lung stretch receptors, causing an increase in heart rate. Thus the overall effect is:
and this occurs when there is essentially hypoxia/acidosis and hypercapnia.
These are not fully understood. It used to be though that these were all co-ordinated by the medulla, but it now appears to be a complex relationship between the medulla, hypothalamus, cerebellum (co-ordinates the response to exercise) and cortex(emotional responses). many of the reflex can function without all these areas, but they have a reduced capacity if one of the areas is missing. The medulla is probably the most important centre, although the hypothalamus has a lot to do with:
- temperature regulation
- vasopressin release
- fight / flight response
- baroreflexes (although it is not essential for these)
Special regulation in various bodily tissues
The heart has very high oxygen demands. It has a very high capillary surface area, and this coupled with the presence of myoglobin allows for extraction of over 60% of the oxygen from the blood.
- Blood flow in this region is mainly controlled by tissue PO2. A low PO2 will produce metabolic hyperaemia – which results in vasodilation
- Often in exercise there is also accompanying secretion of adrenaline which acts on the β2 receptors in the heart tissue to cause vasodilation.
Similar to heart muscle, in that myoglobin can help the tissue extract large amounts of oxygen, and that metabolic vasodilation is important. However it seems the metabolic vasodilation is more a result of cytokines and metabolic waste products and is less directly linked to the PO2.
Exercising muscle also release K+ (as well as H+) and this, combined with activation of stretch receptors causes local vasodilation, and sends signal down nerves to the CNS, which then causes vasoconstriction in other tissues.
The entire purpose of the cerebral circulation is to maintain adequate blood supply to the brain to prevent loss of consciousness. Whenever the flow becomes reduced large amounts of K+ are released, causing a metabolic hyperaemia – results in vasodilation.
- The anastomoses of the circle of Willis is good at maintaining blood supply in the young if one of the coronary arteries is blocked. However it is not very effective in the elderly.
The brain also has a massive influence over perfusion in general via the autonomic nervous system.
Perfusion of the brain will be maintained at the expense of perfusion of other tissues. This can only be maintained whilst blood pressure stays above 500mmHg.
- Cerebral vessels are very sensitive to PCO2. Hypercapnia will cause vasodilation. Hypocapnia will cause vasoconstriction.
Cerebral vessels do not have baroreceptors reflexes. Thus, when you hyperventilate, it may be possible to lower your PCO2 to such an extent that your cerebral vessels constrict, and you become unconscious – Chinese knockout! – the pressing on the chest in Chinese knockout probably also presses on the baroreceptors in the aortic arch, telling them pressure is high, and this may result in a lower heart rate thus helping the effect.
There is no local autoregulation of pulmonary blood flow. However, the vessels still respond to systemic factors, e.g. the secretion of adrenalin.
- The pressure at the apex of the lung is about 3mmHg – this pressure is so low that flow only occurs during systole, as during diastole, the pressure is not sufficient to open the vessels.
- At the base of the lung, it is about 21mmHg
The only real local factor is PO2 regulation. where PO2 is low, there will be constriction of vessels, and where it is high there will be dilation. This means that poorly perfused areas become poorly ventilated. This help to even out the V/Q mismatch. This is caused by hypoxia – there is hypoxic vasoconstriction. Note that this is the opposite to what happens in the heart; where a low PO2 will cause metabolic hyperaemia, and thus vasodilation – however, I presume the ‘low PO2’ in the heart is still much higher than the ‘low PO2’ of the lungs, and thus the hypoxic mechanism does not occur in the heart.
Renal blood flow
This is very closely regulated so that GFR can continue at (hopefully) a constant rate. Autoregulation only generally fails in severe hypotension.
This is controlled by:
- Local hormones (e.g. gastrin, CCK, VIP)
o These, in turn are linked to digestion products (e.g. glucose and fat)
- Increased vagal activity (again controlled by digestion products)
Basically, the presence of food causes an increase in mesenteric and splanchnic blood flow, and a tachycardia. There is also vasoconstriction of vessels in skeletal muscle.
There is normally no significant change in BP.
Posture and blood pressure
The process of moving from supine to standing is known as orthostaisis.
the effect of gravity causes a general drop in BP as blood pools in the legs. This is normally corrected immediately by the barorecetpor reflex
(within about 1sec). If there is a particularly warm environment (and thus the vessels of the skin are vasodilated), the then orthostatic hypotension
can be greater, even in healthy individuals.
When you stand up baroreceptors and cardiopulmonary receptors decrease their firing rate. This allows for increased sympathetic activity, which increases the HR and heart contractility. Peripheral vasoconstriction also increases. There is also some venoconstriction, that plays a limited role in reducing blood pooling.
Determining the cause
Postural hypotension can have many causes. The valsalva manoeuvre is a test of baroreceptors competence.
You ask the patient to do a forced expiration against a closed glottis. This type of event often occurs naturally; e.g. whilst lifting, coughing, defecating. A normal response to the manoeuvre is shown below:
- There is compression of the thoracic aorta as the pressure in the thorax rises
- The high intrathoracic pressure begins to also impede venous return
- Compression of the aorta suddenly stops as the manoeuvre is discontinued
- The baroreceptors initiate their response to the fall in pressure, initiating a reflex tachycardia that restores pressure to normal.
If the pressure continues to fall steeply in phase 2, and there is no reflex bradycardia after the manoeuvre, then something is affecting the baroreceptors reflex.
There is also a modified version, basically where you just hold you nose and blow out. This also clears the eustachian tubes.
Cardiovascular response to training
These occur in endurance and long-distance athletes
- More capillaries in skeletal muscle
- More mitochondria closer to capillaries
- Increased myoglobin concentration in muscle
- Thicker ventricular wall
- Increased stroke volume
The bradycardia is balanced out by the increased stroke volume such that the cardiac output remains the same.
During exercise, a trained athlete’s heart rate will be about the same as that of an untrained person. But because of their massive stroke volume, they can deliver much greater amounts of oxygen to tissues.
Syncope – vasovagal attack
This is basically fainting. It is a sudden and temporary loss of consciousness that occurs as a result of insufficient cerebral perfusion. Blood flow has to drop to half the normal value for this to occur. The causes can be pathological:
- Severe hypovolaemia
Or they can be physiological:
When the cause is psychological there is often a precipitating period of:
- Cutaneous vasoconstriction
Some of these mechanisms are trying to counteract the effect of a drop in BP.
During the actual vasovagal attack there is:
- Increase is vagal activity – this causes a bradycardia, as a result of parasympathetic activity, and the release of ACh
- Peripheral vasodilation due to decreased sympathetic drive
- This causes a reduction in blood flow, reducing cerebral blood flow
- Loss of consciousness happens within seconds
It is interesting to note that before the faint, the main features appear to be those of the ‘fight/flight response’ and thus, sympathetically mediated, but during the actual attack itself, the causes are parasympathetic (and due to a lack of sympathetic activity).
It is not known why exactly we faint. It may just be a primitive ‘playing dead’ response.
In hypovolaemic fainting, it is thought to be triggered by receptors in the nearly empty left ventricle. The faint then causes the person to lie supine, and this may then allow better perfusion.
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