Cardiovascular Physiology Flashcards
How long does it take a particle to move a distance x
t α x^2
What does Eisenstein’s equation mean for diffusion
What does this mean for the heart
It is extremely slow over long distances but very fast over short distances (especially if x<1)
It is hopelessly and catastrophically slow as the heart wall is ~1cm
How is an infarction characterised
The formation of a dense wedge shaped block of dead tissue on the heart following interrupted blood flow
What is ischaemia
Lack of oxygenated blood supply to tissue
How many litres of blood will the heart pump in an average human life time
~200,000,000
Why does breathing rock the heart
Its base is attached to the diaphragm
Are the two atrioventricular valves the same
No: Right Side is Tricuspid (R-S-T)
Left is mitral valve (bicuspid)
Where are the semi lunar valves?
What connective tendons do they have
Separate ventricles and arteries
(Both have 3 cups)
They don’t have any due to their shape
What are the 3 layers In blood vessels
Tunica initima (made of endothelium and elastic connective tissue)
tunica media, (dense population of smooth muscle arranged concentrically with fibres it elastin)
tunica adventitia (contains collagenous extracellular matrix )
Which tunica varies most in thickness between vessels
Media
What is the tunica media like in large arteries
Thick so they can expand and recoil to smooth pressure changes
These vessels can temporarily store energy
Nearly all body cells are within ___ of a capillary
10μm
How much of the blood is in the veins
2/3
Can veins constrict
Some can
Venoconstriction aids venous return to help maintain cardiac output
Where does oxygenated blood come from in the fetus
The placenta
How is the foetus well adapted to
Having limited oxygen
Foetal haemoglobin binds greater concentrations of oxygen and releases it at lower oxygen tensions
What is P50
Partial pressure of oxygen at which 50% of haemoglobin is saturated with oxygen
How does the foetal haemoglobin curve for P50 compare with maternal haemoglobin
Foetal is shifted higher and to the left
What are the 3 foetal shunts
Ductus venosus
Foramen ovale
Ductus arteriosus
What does the ductus venosus do
Shunts oxygenated blood from the placenta to the heart, bypassing the liver
How does oxygenated blood travel from the placenta
Through umbilical cord to the right atrium, bypassing the lungs
What does the foramen ovale do
Shunts blood from the right atrium to the left atrium
What does the ductus arteriosus do
Shunts blood from the pulmonary artery to the descending aorta
What does the cardiac cycle represent
All the events associated with blood flow through the heart during one complete heartbeat
What is the cardiac cycle
Blood is pumped through the 4 chambers. After systole there is a period of relaxation during which the ventricles refill. The atria then contract together to fill the ventricles. The ventricles then contract synchronously without any delay
What is contraction and relaxation
Contraction= systole Relaxation= diastole
Give the 5 stages of the cardiac cycle
Atrial systole Isovolumetric contraction Ventricular ejection Isovolumetric relaxation Late diastole
What is the proportion of blood that enters the ventricles
80% when atria are relaxed
20% when atria contract
What is the additional flow of blood from the atria into the ventricles during exercise
The atrial boost
Why does some blood go back into the venae cavae
There are no one way valves so a small amount is forced back when the atria contract
Where can the retrograde movement of blood to the vena cava during atrial systole be seen
In the jugular when someone has their head and chest elevated about 30%
What does it mean if an observable jugular pulse is higher on a sitting person
Right atrial pressure is higher than normal
Describe isovolumetric contraction
This is ventricular contraction without any change in ventricular volume
Ventricular systole begins as the spiral muscle bands contract and squeeze blood upwards
Blood pushing on AV valves forces them closed
With these valves and semilunar valves closed the blood has nowhere to go so pressure quickly builds
Describe ventricular ejection
As the ventricles contract, they generate enough pressure to open the semi-lunar valves and blood is ejected into the arteries.
High pressure blood forces out the low pressure blood, pushing it further into the vasculature
Ventricular blood enters the aorta faster than old blood can leave the aortic tree hence arterial pressure rises and large elastic arteries expand
Describe isovolumetric relaxation
After ejection, the ventricles relax and pressure falls rapidly
As pressure falls below aortic pressure, a small amount flows backwards and closes the aortic valve
The final 1/3 of ventricular blood flows away from the heart against a pressure gradient
What is the diacrotic notch
A brief rise in arterial pressure when blood flows backwards after ejection
What is late diastole
When both sets of chambers are relaxed and ventricles begin to fill with blood passively before atrial systole
What is the simplest direct assessment of heart function
Auscultation
What do lub and dub represent
Lub- closure of AV valves
Dub- closure of semilunar valves
What does a whooshing sound mean in auscultation
Valvular incompetence
What are the 3 main parts of a normal ECG and what do they reflect
P wave - atrial depolarisation
QRS complex - ventricular depolarisation
T wave - ventricular repolarisation
Why is atrial repolarisation not shown on an ECG
It is masked by the QRS
What is the RR interval used to measure
Heart rate on an ECG
What can channelopathies affecting myocardial Na and K channels result in
Long Q-T syndrome
What was the trouble with the drug Seldane
It caused long Q-T syndrome
It was a non sedating antihistamine that binds to K repolarisation channels
What is point A ot the pressure volume loop
Ventricle has completed contraction and contains minimum amount of blood. It is relaxed so pressure is at a minimum
Once pressure in the left atrium exceeds that of left ventricle, the mitral valve opens, increasing volume in left ventricle.
Relaxing ventricle expands so volume increases with no change in pressure
What is point B of cardiac pressure loops
Ventricle after atrial systole
It now contains maximum volume
What is end diastolic volume
When the ventricle is maximally full after relaxation
What happens after point B in loop
When ventricular contraction begins, mitral valve closes. As both valves are closed, pressure increases dramatically with no change in volume
What is point C on loop
Isovolumetric contraction
How is point D reached
Aortic valve opens so volume falls rapidly
What is end systolic volume
The blood left at the end of ventricular contraction
What does the width of the heart pressure volume loop represent
What about the area
Difference between EDV and ESV (ie the stroke volume)
Ventricular stroke work
How is point A returned to?
Isovolumetric relaxation
What is aortic stenosis
When left ventricular emptying is impaired due to high outflow resistance caused by reduction of valve orifice area when it opens
This increases the pressure gradient across aortic valve such that systolic pressure within ventricle is increased
It also increases the force opposing ventricular emptying, increasing end systolic volume
What does heart contractility depend on
How much the myocytes are stretched
Stretch α force of contraction
Describe the experiment about increased preload and the Starling Law
Peripheral resistance (afterload) and heart rate are constant, preload is increased. This increases cardiac output and must be solely due to increased stroke volume. Ventricular and Aortic pressure is increased as more blood is ejected. This causes ventricular walls to stretch, increasing the EDV and stimulating the Frank- Starling Mechanism
Describe the experiment involving increased afterlaod
Heart rate and filling pressures are maintained and peripheral resistance is increased
Heart finds it harder to force blood round the system so there is increases aortic and left ventricular pressure
As it is pumping against greater resistance, stroke volume falls. Also due to having a higher ESV
However EDV will also increase so walls will stretch and will stimulate the Frank Starling mechanism
Increasing the after load has a bi-phasic effect. What does this mean
There is an initial fall in cardiac output followed by a recovery of cardiac output
What is the Anrep effect
Sustained myocardial stretch activates stretch-dependent Na+/H+ exchangers, bringing Na+ into the sarcolemma and reducing the Na gradient brought about by the NCX.
NCX stops working properly and Ca builds up in the sarcolemma so is taken up by SERCA pumps
This increases Ca induced Ca release and therefore increases force of contraction
Where do both parasympathetic and sympathetic branches to the heart come from
The cardiovascular centre in the medulla oblongata
What do impulses from the cardiac accelerator nerves do
Releases noradrenaline which binds to β1 receptors on cardiac muscle fibres
At the SAN this increases frequency of contraction
At contractile fibres in the ventricles, noradrenaline increases contractility
What is the positive chrono-tropic effect
Increased frequency of contraction
What does it mean to have a positive inotropic effect
Increased contractility
How do parasympathetic nerves reach the heart
What do they release
What does it do
Vague nerves
Acetylcholine which acts on muscarinic receptors in the nodes
Reduces heart rate but no effect on contractility
What are the endocrine influences on the heart
Adrenaline (released from the medulla) acts on β1 receptors to increase frequency and contractility
What is the initial membrane potential of the SAN
…
-60 mV
It can depolarise spontaneously
What is the pacemaker potential
What is changed to affect heart rage
The SAN’s slowly increasing potential
The slope to get to threshold (~-40 mV)
What is Darcy’s Law
Q= ΔP/R
It is the hydraulic equivalent of Ohm’s law
What is perfusion pressure
ΔP or Pa-Pv
What is blood flow equivalent to
Perfusion pressure
—————————-
Vascular resistance
What is cardiac output equivalent to
Blood pressure
————————
Vascular resistance
What is arterial pressure determined by
Cardiac output and vascular resistance
What does cardiac output =
Stroke volume x heart rate
Why does blood lose energy as it flows
Friction from the walls
Describe laminar flow
The flow of a liquid through a tube can be thought of as parallel streams, with the stream closer to the wall being the slowest because there is the greatest friction and the subsequent layers slide past at increasing velocities.
In a Newtonian fluid this forms a parabola
How is the parabola of laminar flow different in blood from water
Is is blunter in blood
In addition to friction, what 3 factors affect resistance to laminar flow
Tube radius (r) Tube length (L) Viscosity (η)
Give Poiseuille’s Law
R ~ Lη/r^4
What does Poiseuille’s law mean? (3)
1- The resistance to fluid flow offered by a tube increases as the length of the tube increases
2- resistance increases as viscosity increases
3- resistance decreases as radius increases
Capillaries are v small so have a small radius. How do they decrease resistance despite this?
They are short (<1mm usually)
Why may capillaries not want to have low resistance
How is this achieved
Gives more time for diffusion
Connected in parallel so Have a huge cross sectional area
What is blood viscosity determined by
How is it calculated
The ratio of red blood cells to plasma
Haematocrit
Normally viscosity is constant. Why would it change
Increases in haematocrit occur with residence at high altitudes
Decreases can occur due to anaemia
What is the Fahræus-Lindqvist effect
A decrease in viscosity as the tube’s diameter decreases
Why does the Fahræus-Lindqvist effect occur
Erythrocytes move towards the centre of the vessel. This leaves a plasma cell-free layer adjacent to the wall.
As it has fewer red blood cells it’s effective viscosity is lower so reduces resistance to blood flow
How are resistance and radius related
R is inversely proportional to r^4
Where does the greatest reduction in pressure occur
As blood flows into the arterioles
What characterises the SNS
Consider ganglia and NTs
Short pre-ganglion is fibres
Pre-ganglionic NT is ACh
Post-ganglionic NT is noradrenaline
What is the peripheral vascular resistance controlled by
Sympathetic nervous system
Contains mostly vasoconstriction nerves
How does noradrenaline affect blood vessels
Causes vasoconstriction
What are arterioles and venules innervated by
Sympathetic vasoconstrictor nerves
What does constriction of
a) arterioles
b) venules
Mean?
a) increased arterial blood pressure due to increased total peripheral vascular resistance
b) increased venous return
What is the most efficient way to dial ye blood vessels
Inhibit sympathetic tones
How does adrenaline affect blood vessels
Why is it different
Vasoconstriction in peripheral circulation to maintain MAP
However it causes vasodilation in skeletal muscle
Allows us to redistribute oxygen and nutrients to where they are most needed
Can the vasodilator arterial response to ACh change
Why
It can become a vasoconstrictor response if the endothelial lining is rubbed away
ACh acts indirectly: ACh stimulates the endothelium to secrete nitric oxide (NO) which causes vasodilation
Is NO stored in the endothelial layer
No
How is NO formed in the endothelial layer
Arginine is cleaved by NO synthase which is regulated by the intracellular Ca-calmodulin complex.
This means that agents which promote extracellular Ca2+ entry increase the rate of NO synthesis
What is a blood pressure monitor called
Syphgmomanometer
How does a syphgmomanometer work
Cuff is inflated beyond arterial pressure so blood flow is cut off. Then pressure is released
When pressure falls below systolic arterial pressure, blood flows again. As blood flows through the compressed artery a thumping noise is heard. When it is first heard this is the systolic pressure, and when it disappears is the diastolic pressure.
What is the sound heard on a syphgmomanometer
The Korotkoff sound
What does MAP=?
D+ (1/3)(S-D)
What is arterial stiffness
A measure of the rigidity of blood vessels
Why may arterial stiffness increase
With age and disease, vessels deposit calcium and collagen
How can an increase in pulsatility be calculated
An increase in the systolic: diastolic pulse (SD ratio)
Or
An increase in Pulsatility Index (S-D/mean)
What does increases PI signify
Increases vascular resistance
What does the simplest reflex arc include
A sensor which sends information to the brainstem (integrator) via afferent pathways. The integrator sends commands to effector organs via efferent pathways
What are arterial mechanoreceptors usually referred to as
Where are they
Arterial baroreceptors
Carotid sinus and aortic sinus
What happens when the carotid baroreceptors are stimulated
Send afferent info to the medulla via carotid sinus nerves, which join onto the glossopharyngeal nerve
What happens when the aortic baroreceptors are stimulated
Send info to brainstem via the aortic nerve which joins into the vagus nerve
What kind of fibres does the vagus nerve contain
Both efferent and afferent
What do baroreflexes do
Restore arterial blood pressure to normal
Give consequences of
a) hypotension
b) hypertension
a) reduces perfusion of oxygenated blood to tissues
b) damages fragile circulations such as in the brain
What is the reason for the location of each baroreceptor
Carotid- maintains blood pressure for the cerebral circulation
Aortic- governs systematic arterial blood pressure homeostasis
Are the baroreceptors finically active?
What does this mean
What stimulates them
Yes
They send continuous bursts of APs to the brainstem via their respective afferent pathways
Stretch of the baroreceptor fibres. This increases the frequency of APs triggered
What happens when frequency of APs from baroreceptors increases
Stimulation of cardiac inhibitory centre which increases efferent parasympathetic discharge and inhibition of cardiac acceleratory centre
This decreases heart rate and force of contraction so decrease cardiac output
What else does increased AP frequency from baroreceptors cause other than in heart
Signals sent to vasomotor centre to reduce sympathetic discharge which leads to a fall in arteriolar and venomotor tone
How can the sensitivity of arterial baroreflex be assessed
Measuring heart rate responses to controlled changes such as injecting a vasoconstrictor drug (eg phenylephrine)
What is phenylephrine
A synthetic form of noradrenaline which causes peripheral vasoconstriction, thus increasing arterial blood pressure
What is sodium nitroprusside
A vasodilator which will cause a fall in blood pressure
When testing baroreceptor sensitivity what can be set up
What should it look like
How can sensitivity be calculated
A stimulus response curve, with heart rate on y and blood pressure in x
Sigmoidal
At the maximum slope, Sensitivity = ΔHR/ΔP
What is central re-setting
Occurs during defence reaction
A rise in ABP is not accompanied by a fall in heart rate as the baroreflex is reset centrally to operate at a higher pressure
What is peripheral resetting
When pressure is raised in a sustained manner, the curve shifts right so the set point changes
This allows greater resting pressure without a sustained increase in AP frequency from baroreceptors but may lead to hypertension
Give an example of peripheral resetting
At birth
Foetal ABP is ~40mmHg but a newborn’s is double that
Peripheral resetting shifts from foetal set point to post natal set point
What did Blanco and colleagues discover in 1988
Baroreceptor sensitivity decreases with age since the slope diminished from foetal to post natal life
Where are the arterial chemoreceptors
Aorta and carotid bodies
They have the same innervation as the baroreceptors
What is peripheral chemoreceptor tissue made of
Glomus cells which act as O2 sensors and are stimulated by a fall in PO2 in arterial blood
What do glomus cells contain
Lots of mitochondria and dark vesicles, which contain peptides needed for chemotransduction
What is hypoxaemia
Environmental hypoxia which results in A fall in arterial PO2 (PaO2)
Does hypoxaemia cause an increase or decrease in AP frequency
Increase
What are the axes of the chemoreflex function curve
How is sensitivity found
Where is the set point
discharge (y)
PaO2 (x)
Gradient of slope
The end of the curve where it becomes a straight line
What is peripheral chemoreceptor resetting
Give an example
Shift of chemoreceptor discharge curve towards a different PO2
Birth
What is the PO2 of adult blood and foetal blood
What does this mean for foetal chemoreceptors
Adult: 90-100 mmHg
Foetal: 25-40 mmHg
They have a lower set point and must reset at birth
What happens if the arterial chemoreceptors do not shift their set point at birth
They are silenced by the oxygen rich extra uterine environment which may lead to cot death (SIDS)
What are the cardiovascular responses to hypoxia
Increased heart rate and blood flow, especially to brain, heart and adrenal glands
Promoted vasodilation in peripheral circulation
Describe the experiments of Daly and Scott
They induced hypoxia in dogs that were either allowed to breathe spontaneously or mechanically.
In spontaneously breathing dogs, hypoxia elicited an increase in respiratory rate and decrease in femoral vascular resistance
Dogs with controlled ventilation, who were not allowed to hyperventilate, hypoxia produced reduced heart rate and increased femoral vascular resistance
What did Daly and Scott conclude
Hypoxia elicits Primary chemoreflex cardiovascular responses which became modified by hyperventilation to the secondary response
What is the primary chemoreflex cardiovascular response
A fall in heart rate and increases resistance
How does the body know to do first or second response to hypoxia
During hyperventilation, stretch receptors in the lung increase their afferent discharge to the brainstem. The is inhibits Vagal discharge to the heart and sympathetic outflow to peripheral circulation
What response is given when an adult mammal dives under water
Primary
Why does a foetus make breathing movements
To develop intercostal muscles and alveoli
Why may foetal hypoxia occur
What action does the foetus take to tackle hypoxia
Compression of umbilical cord
Ceases to make breathing movements as movement takes up energy
During foetal hypoxia, which response is taken
Primary (like a diving adult)
There is reduced heart rate and increased femoral resistance
Current =
g x ΔV
Conductance x voltage difference
When are cells more polarised than Ek
Almost never
Perhaps in skeletal muscle post fatigue which can hyperpolarise beyond Ek due to Na pump activatity
Why do inward rectifiers never conduct inwards
K+ currents are always outwards
The conductance of an inward rectifier increases as…
The electro-chemical gradient becomes less outwards
Simply, how do inward rectifiers work
Like a swing door that only opens inwards- small amounts of extracellular K can get in but if lots of intracellular K is present the door slams shut
When do inward rectifiers conduct well and poorly in the cardiac cycle
Conduct well at resting potential as this is close to Ek
But conduct a lot less well in plateau phase when Vm»_space; Ek
Why do inward rectifiers have low conductance in the plateau phase
Prevents too much K+ being lost
Why is the current of K+ small when Ek is close to Vm
Ik= gk(Vm-Ek) so Ik is small here
Why is Ik small at plateau phase
gk is small
Describe Guyton’s experiments
WhAt did he find
He replaced dog’s hearts with high output pumps
Reducing pumping capacity below normal reduced CO
Increasing pumping capacity did not increase CO
What concepts did Guyton’s experiments show
The heart is necessary to maintain CO but it does not normally limit CO
Flow=?
Pressure gradient
—————————
Resistance
What happens if Pv (venous pressure) becomes negative relative to atmospheric pressure
Tubing will collapse
Why does increasing heart rate or contractility in isolation not increase cardiac output
The heart can not increase increase arteriovenous pressure gradient beyond the point where Pv becomes negative as this would collapse veins and limit venous return and hence cardiac output
What is the main determinant of cardiac output
Mean systemic filling pressure
What must you do to increase arterial pressure?
Why can you not do this?
What, then, is the solution?
To increase Pa you must decrease Pv
Pv=0 usually so would become negative If decreased
Increase mean systemic pressure
How do you increase mean systemic pressure
Filling circulation or venoconstriction
What volume of blood is the stressed volume
~20%
Are veins compliant
What happens if they get too stretched
Yes very
They become stiff
As blood is pumped from the veins to the arteries, is the venous fall in pressure greater than the arterial increase in pressure
No as veins are much more compliant than arteries (almost 10-fold)
How to calculate compliance
ΔV/ΔP
What is maximum arteriovenous pressure gradient set by
What does this imply? (2)
Mean filling pressure
1) The heart cannot change the mean pressure
2) Mean pressure determines maximum cardiac output
Cardiac output=?
(ABP- RAP)
——————
TPR
How is ABP-RAP created and limited
Created by the heart and limited by MSFP
What is TPR
Total Peripheral Resistance: treats all vascular pathway resistance as one resistance but is primarily determined by arteriolar resistances
Why is RAP often excluded from CO equation
It is v small
How is CO measured by the body
It is not directly measured
It is instead regulated to maintain ABP
Why would an increase in MSFP increase RAP, if CO was constant?
Pressure would increase throughout the system so greatest % increase would be in the right atrium where P was initially lowest
In reality what happens if RAP increases
Stroke volume would increase (Frank-Starling) and so CO would increase. This would ensure RAP stays close to 0
Why does increased TPR not decrease CO
Increased TPR=increased afterload which results in ventricular stretch (Frank Starling) so SV and CO remain constant
What happens if heart rate increases in isolation
SV drops and CO barely changes as the heart cannot pull blood from the venous circulation
How can you double MSFP
Increase blood volume by 20% (this doubles the stressed volume)
What happens if you increases blood volume by 20%
Doubles MSFP
Doubles CO
What happens if 20% of blood is lost
What stops this happening
MSFP is reduced to zero
As 60% of blood is in the venules and small veins, venoconstriction means MSFP can be maintained until about 40% of circulating volume is lost. Venoconstriction can triple MSFP
Why does venoconstriction not really affect TPR
TPR is primarily determined by arterioles
Why does arteriolar constriction not affect MSFP
<1% of blood is there
Why is venous return reduced by increased RAP
When is VR=0
VR = (MSFP-RAP)/RvR
When MSFP=RAP
How does a decrease in RAP affect VR
VR increases
Are VR and CO equal
Why
Yes they must be
The heart cannot create or store blood
What is RvR
Can it change
Resistance to venous return
It can, especially in exercise, but isn’t specifically regulated
Why does it appear as if venous return drops as RAP increases
Difference between MSFP and RAP gets smaller
How would raising MSFP affect the RAP vs VR graph
What would happen if you reduced RvR
It would shift upwards
Increase the slope without changing MSFP (ie root of the function wouldn’t change)
Why does increasing RAP increase CO
Frank Starling
What to remember about CO and VR vs RAP curves
MSFP only shifts VR curve
TPR only shifts CO curve
What is shock
When cardiac output is inadequate to supply sufficient metabolic substrates for aerobic respiration
What is hypovolaemic shock
Severe loss of circulating volume
What is cardiogenic shock
What’s distributive shock
Shock caused by cardiac pathology
Shock due to a severe fall in vascular tone
How to find MSFP on VR vs RAP graph
Or
CO vs RAP graph
X intercept
Describe the process of systolic blood pressure to diastolic BP
The heart rapidly ejects blood into the aorta, causing pressure to rise to a peak (systolic BP) and creating a pressure gradient so blood flows away from the aorta and pressure drops to a trough (diastolic BP)
What are the usual values of systolic and diastolic blood pressure
120-80mmHg
How to calculate mean blood pressure from pressure wave
Diastolic pressure + 1/3 of pulse pressure
How to calculate pulse pressure
Systolic - diastolic BP
How does mean BP change with age and between genders
Increases with age
Higher in men
Why does pulse pressure increase in exercise
How does this affect mean pressure
Blood flows away faster in diastole when TPR drops
Mean pressure stays constant as systolic pressure increases as diastolic pressure decreases
ABP=?
CO x TPR
What are the 3 mechanisms for monitoring blood pressure
High pressure baroreceptors
Arterial chemoreceptors
Low pressure baroreceptors
Where are elastic lamellae found
Intermeshed with stretch sensitive nerve endings in regions with little collagen and smooth muscle in baroreceptors
Do the baroreceptors all deal with the same pressure changes
No
Carotid sinus is more sensitive than aortic
Between them they cover 50-200 mmHg
Describe Heymans’ Nobel Prize winning experiment
Carotid sinus of Dog B was connected to circulation of Dog A. A was given noradrenaline, increasing its BP and this triggered an immediate reflex fall in BP in B
What happens to ABP if arterial baroreceptors and chemoreceptors are denervated
Why
Why is this important
ABP becomes much more more variable but mean ABP remains constant
Variability is due physiological changes such as changes in posture
Constancy of mean suggests it is also controlled by other mechanisms
Demonstrates importance of high pressure baroreceptors and chemoreceptors in the short term control of ABP
When do arterial chemoreceptors affect ABP
ONLY When BP is very low or when PO2 is massively reduced
How do medullary chemoreceptors detect high arterial CO2
Reduction in brain pH
Where else to stretch detectors exist
What are these areas called
Low pressure areas
Eg junction of atria and corresponding veins
Cardiopulmonary baroreceptors
What do cardiopulmonary baroreceptors detect
What happens if they are denervated along with aortic/ carotid denervation
RAP
if RAP is raised, it suggests the circulation is over filled such that the heart can not maintain low venous pressure
Mean ABP rises as well as increases variability
What does low RAP suggest
CO is working maximally for the current MSFP
What happens when cardiopulmonary baroreceptors are triggered
As pressure increases, Firing rate increases Along vagus to nucleus tractus solitarius (NTS) in the medulla and then onto hypothalamus.
Fluid and Na are retained, raising circulating volume and MSFP
How can a drop in ABP before exercise be avoided
Inputs to the medulla from the cortex (where the decision to exercise is taken), from the cerebellum (as part of the coordinated motor programme) and from muscle and joint receptors
Describe sympathetic efferents controlling ABP
Bulbospinal pathways activate glutamatergic synapses between T1 and L3.
These pre-ganglionic neurons have nicotinic synapses with nerves of prevertebral and paravertebral ganglia.
Post ganglionic nerves run with large blood vessels to muscular arteries, arterioles and veins
Sympathetic activity generally causes vasoconstriction through noradrenaline on α1 adrenoreceptors
a) What does arteriolar vasoconstriction increase
b) What about venoconstriction
a) increases TPR
b) increased MSFP
What is the resting potential frequency of sympathetic vasoconstrictor nerves
Why is resting frequency not 0
1-4 Hz but can raise to 10Hz to reduce flow to almost 0
So sympathetic inhibition can reduce ABP
Also means that damage to a nerve will reduce BP there
What do chromaffin cells do
Release adrenaline which acts similarly to sympathetic innervation (by acting on α1 receptors)
Does adrenaline affect all organs equally
No Some tissues (notably coronary blood vessels and skeletal tissue) have more β2 than α1 so vasodilation occurs here
How do we know Vagal stimulation to the heart shows tonic activity in slowing heart rate
Inhibition of the vagus at rest using atropine produces accelerated heart rate
TPR can fall by upto 6 times during exercise. How is ABP maintained
CO must be increased, requiring venoconstriction to increase MSFP, as well as reduced Vagal and increased sympathetic heart stimulation
What is hypertension
Why is it a problem a
ABP>140/90mmHg
Leads to overwork of the heart and vessel damage
What is atherosclerosis
A build up if inflammatory lipid deposits beneath vessel endothelium
How does atherosclerosis cause problems
Narrowing of blood vessels, restricting flow
Endothelial damage (prompting thrombosis): local and distant blockage
Weakening of vessel walls, leading to aneurysm
What is the difference between the cardiac hyper trophy caused by exercise vs hypertension
Exercise causes eccentric hypertrophy where ventricular volume increases with muscle mass
Hypertension causes concentric hypertrophy where the heart expands inwards, reducing ventricular volume
Give the 3 main problems of concentric hypertrophy
Increased myocardial demand
Diastolic disfunction (cardiac filling and stroke volume is impaired)
Increased risk of arrhythmia
What is systolic dysfunction
When the heart is unable to fully empty
Why can flow only be regulated by resistance
Flow=pressure gradient/ resistance
As pressure gradient is constant, flow can be determined by regulating upstream arteriolar resistance
What are the 3 principles mechanisms for regulation of arteriolar resistance
Nerves
Hormones
Local tissue metabolism
Why is CO usually proportional to VO2 (volume of oxygen used per minute)?
How can this knowledge be used?
Cardiac output ~ VO2
VO2 can be used as a proxy for CO in Studies of atheletes
Flow is always a function of ____ and ____
Pressure gradient and resistance
Give the equation for flow through a capillary bed downstream from a single arteriole: Q=…
Pa-Pv
———————
R(pre) +R(cap) +R(post)
What can flow through a capillary bed downstream of a single artery be simplified to
Why
Q~ 1/Ra
Arteriolar resistance makes up 70% of total series resistance and is the only directly regulated resistance and the pressure gradient is constant
What is Ra
How does this differ from central, autonomic control of arteriolar resistance
Ra = local control of arteriolar resistance
Ra matches local blood flow to local metabolic demand whilst central control deals with TPR to maintain Constant mean ABP
What forms does local Vaso-control take
What forms does central control take
Local: metabolic, myogenic, or from vasoactive compounds released by capillary endothelium
Central: neurogenic or endocrine
How is arteriolar smooth muscle arranged
Circumferentially
What is tension in vascular smooth muscle a function of
Ca2+ concentration as well as modulation via phosphorylation of Myosin Light Chain Kinase
What are the 2 broad intracellular control systems that all control pathways for vascular smooth muscle converge on?
Regulation of myosin binding site of actin by caldesmon and regulation of myosin light chain kinase by phosphorylation
What is functional hyperaemia simply
A profound increase in blood flow after circulation has been cut off for some time
Which changes of the blood typically accompany increases metabolism
What do these factors promote
Reduced PO2 Increased PCO2 Decreased pH Increased adenosine Increased extracellular K+
Vasodilation of systemic arterioles
Do reduced PO2 and increased PCO2 affect all circulations equally
No
It promotes vasodilation of arterioles in skeletal muscle
But
Promotes vasoconstriction in pulmonary circulation where such changes reflect poor ventilation
Which changes accompany aerobic metabolism
What do these stimulate? What is this a direct effect of?
Decreases pH
Increased lactic acid concentration
Vasodilation
Intracellular pH on smooth muscle
Does phosphorylation of MLC promote or inhibit binding to actin
What happens if it is phosphorylated when bound to actin
Promotes
Latch bridge formation can occur
When can MLC be phosphorylated
When MLCK is activated by Ca-calmodulin (uses ATP)
What happens if pressure changes in cerebral vascular beds
What does this mean
Why may this lead to problems
Which other vascular beds act like this
Vascular diameter changes to reduce flow change
Increases pressure leads to increased resistance and flow increases much less than expected
It may cause poor lymphatic drainage
In the heart and kidneys
Where is the optimal place to detect local changes in metabolism
Capillary endothelium
What was nitroglycerin
What are the side effects
Angina drug
Causes severe headaches
Adrenaline acts on α1 receptors. What else does it act on, causing vasodilation, and what are these linked to?
β2 receptors which are linked to the G protein Gαs, which activates adenylate cyclase, raising cAMP levels and activating PKA
What does PKA do
Phosphorylates myosin light chain kinase, reducing its activity and so reducing phosphorylation of MLC
What are eicoanoids
Arachnidonic acid derivatives, mostly involved in clotting and inhibitory responses
How are eicosanoids synthesised
What is the clinical significance of this enzyme
By cyclo-oxygenase
It is inhibited by aspirin
2 forms of prostaglandins
Vasoconstrictory
Vasodilatory
What is thromboxane A2
What opposes it
An eicosanoid produced by platelets and a very potent vasoconstrictor
Prostacyclin (produced by the endothelium)
What is the rationale behind using aspirin to prevent MI
It irreversibly blocks COX-1, which is required to produce thromboxane A2 and prostacyclin.
However, endothelial cells have nuclei but platelets don’t. Therefore, endothelium can produce more prostacyclin (which opposes clotting) but thromboxane A2 is significantly diminished so the chance of thrombosis is decreases
As exchange between tissue and capillaries occurs, it exchange rate falls. How is this opposed?
Blood flows to deliver fresh plasma restoring the concentration gradient
How many capillaries perfuse at rest
20-24%
How do ions and water get through capillary walls
Water can pass through cells via aquaporins (AQP1) and between cells
Crystalloids ONLY diffuse between cells
How do colloids diffuse through capillary walls
What if this goes wrong
They don’t (capillaries are normally impermeable to colloids such as plasma proteins)
Protein permeability can increase inflammation
How are capillaries classified
According to their “leakiness”
Name the 3 types of capillary
Continuous
Fenestrated
Sinusoidal
Discuss continuous capillaries
Most common variety with interendothelial junctions about 10-15nm wide, allowing relatively easy passage of water and ions
Where are continuous capillaries different
Brain and testes where interendothelial junctions are very tight
Where are fenestrated capillaries found
How are they specialised
Epithelia such as small intestine
They have fenestrae (“windows”) through the cells to allow ion diffusion through as well as around
Discuss sinusoidal capillaries
Found in liver
Large gaps between cells as well as fenestrae to allow trans-endothelial passage of proteins
What is Fick’s Law
What is each term
Q=AP([X]c - [X]if)
Q= flow A= capillary surface area P= permeability [X]if= concentration of X in intestinal fluid [X]c= concentration of X in capillary
How to increase capillary surface area
Increase number of capillaries that are perfusing in a tissue
Can capillary permeability change
Yes
Endothelial cells can change shape such as increases leakiness in response to histamine as part of inflammatory response
What does capillary concentration of X depend on
Rate of delivery into capillary (capillary blood flow x arterial concentration)
Rate of extraction from capillary (Q)
How to calculate rate of delivery to capillary
capillary blood flow x arterial concentration
What does [X]if depend on
Rate at which X is used
Rate of extraction from capillary
Is water movement across capillary walls diffusive
No it is convective
The driving force is hydrostatic pressure difference (ΔP) and Δπ (effective osmotic pressure difference)
How does capillary hydrostatic pressure change along a capillary
It drops due to resistance and water movement
Can Pif be negative
Yes In non encapsulated organs
What exerts osmotic pressure
Only solute that cannot easily cross the capillary wall ie the colloid
What does “colloid” include
What is their total concentration
Albumin
Globulins
Fibrinogen
1.5 mM
What was Starling’s equation (for capillaries!)
What does each term mean
Jv = K((Pc-Pif)-σ(πc-πif))
Jv= volume flow
K= hydraulic permeability
σ= colloid reflection coefficient
The rest is just net filtration pressure (ΔP-Δπ)
What is σ
A factor between 0 and 1 to account for capillary leakiness
What does a σ of 1 mean
Total impermeability to protein so full osmotic pressure is exerted
What happens to pressure at the venous end of capillaries in feet when standing
Increases
How does capillary pressure relate to venous and arterial pressure
Why
Closely follows venous but not arterial
Pc must always be greater than venous pressure however high resistance arterioles between arteries and capillaries, high ABP is not associated with increases capillary blood flow or increased Pc
Does reduced ABP lead to reduced Pc
Why
Yes
Directly (resistance in arterioles) and sympathetic drive for arteriolar resistance/ vasoconstriction
What is autotransfusion
When tissue fluid helps buffer blood volume after a drop in Pc
Why does haematocrit drop after blood loss
Tissue fluid dilutes blood to maintain blood volume
Usually there is a net outward movement of water from capillaries. Why do we not all swell up
Lymphatic system drains the tissues
Where do fluids return from the lymphatic system to the venous
Via the thoracic duct at the subclavian veins
How do initial lymphatics prevent water escaping
They have many interendothelial junctions behaving as microvalves allowing fluid in but not out. These empty into larger lymphatics which have valves and some smooth muscle
What is lymphoedema
When lymph drainage is blocked
What is interstitial oedema
When rate of filtration of fluid out of capillaries exceeds its removal of lymphatics And fluid collects in the interstitium
Why is oedema bad
Increases distance of capillaries to tissues interfering with solute exchange
What happens in severe end stage. Heart failure
Failure to adequately perfuse organs resulting in organ failure
What is the heart’s job on the most basic level?
What does “heart failure” imply?
To pump blood from veins to arteries
Atrial pressure is too high and arterial pressure is too low
What should RAP be and why
Close to 0 otherwise it impedes venous return
Why is it possible to find hypertension and heart failure in the same patient if “heart failure” involves a ABP that is “too low”?
Heart failure occurs and ABP is lower than the set point and it cannot be raised
What happens when ABP is lower than the set point and cannot be raised
The body responds as it does to a haemorrhage
It increases sympathetic drive causing venoconstriction, vasoconstriction, and retention of fluids.
This raises TPR and MSFP.
What happens when TPR is raised in heart failure?
MSFP?
Increased TPR means increasing cardiac workload
CO is normally limited by MSFP but in heart failure CO is limited by the heart so increasing MSFP makes v little difference. Instead atrial pressure will rise
What do the symptoms of heart failure result from
1) inability to adequately raise CO
2) increases atrial pressure
What is the problem with increases atrial pressure
It implies raised venous pressure and therefore raised capillary pressure which leads to oedema
Difference between pulmonary and peripheral oedema
Pulmonary is left side heart failure
Peripheral is right side heart failure
How can heart failure be treated if the valves are fine
Drugs that inhibit responses to low BP such as ACE inhibitors, diuretics and beta adrenergic blockers
These lower MSFP and TPR thus reducing oedema and cardiac oxygen demand
What is functional hyperaemia
Increased blood flow to muscles to meet increased metabolic demand
What are the distinct phases of functional hyperaemia
Phase I~ very rapid increase in blood flow from 2-20 seconds after initiation of contractions
Phase II~ from about 20s about contractions during which there is a slow increase in blood flow to sustained high levels
How do we know that increased extracellular K+ is a factor of Phase one in hyperaemia
Muscle APs produce immediate increases in extracellular [K+]
What is the effect of interstitial [K+] increase in Phase I of hyperaemia
It hyperpolarises arteriolar smooth muscle, closing VG Ca2+ channels , thus relaxing the muscle
What is the expected result of raised extracellular [K+]
What actually happens in Phase I and why
Depolarisation
Hyperpolarisation occurs
Raised [K+] enhances Na/K ATPase activity
And enhances activation of inward rectifying K+ channels
(Therefore intracellular K+ and K+ permeability both increase)
How do we know that increased extracellular K+ is a factor of Phase one in hyperaemia
Muscle APs produce immediate increases in extracellular [K+]
What is the effect of interstitial [K+] increase in Phase I of hyperaemia
It hyperpolarises arteriolar smooth muscle, closing VG Ca2+ channels , thus relaxing the muscle
What is the expected result of raised extracellular [K+]
What actually happens in Phase I and why
Depolarisation
Hyperpolarisation occurs
Raised [K+] enhances Na/K ATPase activity
And enhances activation of inward rectifying K+ channels
(Therefore intracellular K+ and K+ permeability both increase)
How can vasodilation in phase I of hyperaemia be reduced and by how much?
Blockade of Na/K ATPase (by ouabain) or of inward rectifiers (using barium)
Upto 60%
What are the 2 fast causes of functional hyperaemia
Increased extracellular K+
Muscle pump
What is muscle pump
Contractions accelerate venous return
This enhances CO but may reduce local venous pressure which enhances pressure gradient through capillaries
In some animals but not in humans (🙄) what else plays a role in phase I?
What happens in the cat?
Neurogenic vasodilation
Sympathetic cholinergic nerves cause a direct increase in blood flow
How does adrenaline affect phase I
Causes vasodilation: it may not be fast enough to contribute to phase I but could be an anticipatory response
Is Phase II controlled by one main factor
How do we know
No
Multiple redundancies exist, meaning inhibition of one factor changes magnitude of hyperaemia slightly but other factors compensate for it
How does increased extracellular K+ affect phase II
It is important?
How likely is a direct effect of reduced PO2 on muscle arterioles during hyperaemia and why?
Although PO2 falls in capillaries during exercise, it does not fall in the vicinity of arterioles
What does increases offloading of O2 from haemoglobin during hyperaemia lead to? (2)
Release of ATP and NO from red blood cells
Low O2 enhances ectonucleotidease activity that produce vasodilatory adenosine from ATP
What does adenosine do in hyperaemia
Accumulates around active muscle fibres
It is a strong vasodilator, acting on A2A receptors, increasing cAMP levels in smooth muscle
How is pH linked to vasodilation
ATP is released partly via CFTR channels in response to reduced intracellular pH
What happens when cAMP levels rise in smooth muscle
PKA is activated which opens K(ATP) channels which hyperpolarises the cell, acting synergistically with increased K+
What is the effect of lactic acid on hyperaemia
No direct effect that is distinct from it effect on pH
What happens to TPR during exercise
What does this necessitate? How is this achieved?
Drops to ~20% of its resting value
An increase in CO to maintain ABP
Sympathetic venoconstriction, reduced cardiac Vagal stimulation and increased myocardial sympathetic stimulation
How is resistance to venous return reduced in exercise
The muscle pump
How much do MSFP, VR, and CO change in exercise
How does the muscle pump affect RvR
How do all the above factors affect ABP
MSFP: increases 3x
VR and CO: increase 6x
RvR is halved
ABP actually increases in exercise
How can you separate central command to exercise from actual occurrence
What does this indicate
Using curare to block the NMJ
Heart rate increases without actually exercising
What is the role of baroreceptors in exercise
Maintain stability of BP around a raised set point
How would you test to see if O2 uptake is the limiting factor in exercise
What is the result
Measure performance at normal and raised levels of PO2
Raising inhales PO2 does not significantly improve performance
How would you test to see if The ability for muscles to perform is the limiting factor in exercise
What is the result
Compare power output when pedalling an exercise bike with 1 leg vs with 2 legs
With 2 legs it is less than double with 1
This suggests during 2 legged muscles are not able to reach maximum output
What is the ultimate limitation on whole body power output in exercise
Circulation
The response to haemorrhage usually comprises of which 2 stimuli
Reduced blood volume
Pain
Uncompensated blood loss causes, sequentially…
Reduction in blood volume, MSFP, venous return/ CO, and blood pressure
How does the body respond to blood loss
Arterial and low pressure baroreceptors detect these changes, reducing inhibition of medullary vasomotor areas
Other than baroreceptors, how else may medullary vasomotor areas be stimulated?
Cortex and hypothalamus May stimulate the medulla as a response to pain/ fear
What is the response once medullary vasomotor centres are stimulated in haemorrhage
What is the overall effect
Sympathetic nerves increase arteriolar and venous tone and heart rate (Vagal Tone to heart falls)
Catecholamines, angiotensin II and ADH are released
Vasoconstriction
What are the micro vascular changes after haemorrhage
1) reverse stress relaxation (when smooth muscle contracts when stretch is reduced)
2) mobilisation of tissue fluid as reduced Pc shifts the balance of Starling forces towards reabsorbtion of fluid
What happens long term and then even longer term after haemorrhage
10 minutes: renal conservation of water and salt. Thirst and sodium appetite act to restore circulating volume
24-48 hours: plasma proteins are replaced by synthesis in the liver
5-7 days: increases RBC production replaces those lost
How is increased red blood cell production stimulated
By a release of erythropoietin from kidneys in response to reduced O2 delivery
What was the triggering event for public awareness for cardiovascular disease
Death of Franklin D Roosevelt whose blood pressure had soared to 300/190 in 1945
The Framingham Heart Study (1948) resulted from this
Who realised the cardiovascular system is a closed circulatory system
William Harvey
Name an adaptation of the heart that compensates for the high oxygen demand
Cardiac myocytes contain more myoglobin than skeletal muscle cells
