Cardiovascular Physiology Run
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Transcript of Cardiovascular Physiology Run
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Cardiovascular Physiology Run
There are two main heart valves:
Atrioventricular: These prevent backflow of blood from the ventricles into the
atria. The bicuspid one between the left atria and ventricle, and the tricuspidone between the right atria and ventricle.
Semilunar: Prevent the backflow of blood from the arteries into the atria.
Blood flows from the atria to the ventricles, throughout the arteries, to the
arterioles, into the capillary bed, out into the venules and then into the veins.
Blood flows in a closed double circuit, from the pulmonary to the systemic
circulation. Organ distribution is achieved by parallel blood vessels.
The pressure in the systemic circulation (95mmHg) is higher than that in thepulmonary circulation (15mmHg). This is because the capillaries in the lungs are
thinner, and the systemic circulation has to be pumped across a greater distance.
Tube mechanicsBlood flow
Blood flow is determined by two parameters: pressure and resistance. Blood
flows along a pressure gradient. There must be a pressure difference for flow.
Flow is proportional to the pressure difference. However, it is only directly
proportional if the blood flow is laminar.
Laminar flow: Flow is smooth with no swirling. The fluid closest to the walls ismotionless due to forces between them (the no slip condition). The laminae of
fluid flows faster as it approaches the centre, with Vmax at the centre. It is
silent.
Hence, the cells are displaced towards the centre, so there is a marginal plasma
layer next to the wall. The red cells tend to accumulate near the centre, known
as axial streaming. Also, when small blood vessels branch off, they receive
blood from the layers nearer the wall which means that it is plasma-rich with
low viscosity.
Turbulent flow: Blood flows in swirls and eddies and is noisy. Some energy is
dissipated as heat, so greater pumping action increases the workload of the
heart.
Turbulent flow can be used diagnostically in measurement ofarterial blood
pressure (Korotkoff sounds) and diagnosis ofheart valve problems.
Heart valve problems: In stenosis (narrowing), there is turbulent flow. In a
leaky valve, there is turbulentbackflow. You hear a murmur.
However, ejection of the left ventricle can produce turbulent flow becausevelocity is very high. This is innocent systolic murmur. In severe anaemia,
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reduced viscosity and increased cardiac outputresult in turbulent flow.
Turbulent flow occurs normally in the ventricles to mix the blood properly.
Resistance is a measure of how difficult it is for blood to flow between two
points of different pressure. It is determined by 3 factors:
1) Length of the tubedirectly proportional2) Viscosity of the fluiddirectly proportional3) Radius of the tubeinversely proportional
The main change that can occur is to the radius of the arterioles entering the
organ/tissue. Smooth muscle controls thisit is oriented circularly, and
contraction causes narrowing.
Increasing haematocrit can increase viscosity, but that is only if you are on EPO
or something that increases number of RBCs.
However, the summing of resistance depends on series or parallel arrangement
of the tubes. In series, the total resistance is the sum of all resistances.In
parallel, the 1/Rtotal= 1/R1 + 1/R2 + 1/R3 In the capillary beds, the
resistance is low so that exchanges of nutrients and waste materials can occur.
The greatest drop in blood pressure across the arterioles is also due to
numerous parallel circuits.
Hence the basic flow equation: Flow = delta Pressure/resistance
Excitation-contraction coupling of the heart
At the posterior wall of the right atrium, the sinoatrial node initiates heart
beat. Therefore, it is the pacemaker of the heart and produces a sinus rhythm.
The depolarisation spreads towards the atrioventricular (AV) node via the
three internodal tracts of the larger arterial myocytes, and is fast at about
1m/s.
At the AV node, transitional myocytes are smaller with fewer gap junctions.
The conduction velocity is slowed down to about0.05 m/s from the AVN to the
bundle of His.The spread of electrical activity through the node takes about 0.1seconds, allowing the atria to finish contracting and send blood into the
ventricles prior to ventricular contraction.
The depolarisation spreads down the Bundle of His, with right and left
branches. They travel down the interventricular septum and finally into the
Purkinje fibres of the ventricles. These fibres conduct very quickly, so that both
ventricles can contract at the same time.
Note: changes in muscle contractility are ionotropic. Changes in heart rate are
known as chronotropic effects.
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Cardiac action potentials
Normal cardiomyocyte membrane potential is about-80mV. There is a high
concentration ofK+ intracellularly and a higher concentration ofNa+ and
Ca2+ extracellularly.
The pacemaker potential comes from the SAN. The threshold for discharge is
about-40mV. It resting potential is therefore unstable. The steeper the slope of
the potential, the higher the heart rate.
This is due to the sodium and calcium channels which allow slow, inward
background currents to slowly depolarise the cells. The background potassiumcurrentis slowly reduced as well, leading to depolarisation. No voltage-
dependent sodium channels are present, so depolarisation is entirely up to
calcium influx (slow Ca2+ channels).
Hyperpolarisation (K+ leaks out) causes an influx of Na+ to regenerate the
pacemaker potential.
The ventricular action potential has a stable membrane potential, and a
plateau phase.
Initial depolarization is due to fast voltage gated sodium channels.Subsequent depolarization and plateau is due to slow voltage-gated Ca2+
channels. The plateau phase of the action potential is sustained by
dihydropine calcium channels, which open at a slower rate than the sodium
channels. Some of the calcium which enters these receptors binds to the
ryanodine receptors of the SR, which releases even more calcium, for
sustained muscle contraction.
Repolarisation is brought about by the opening ofpotassium channels. The
sodium channels are inactivated and remain inactivated. This contributes to a
refractory period, which is long to avoid tetanic contractions in the heart. These
only close quickly towards the end to complete repolarisation.
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Calcium-ATPase pumps on the SR and plasma membrane return about 80% of
the calcium into the SR. Na+/Ca2+ cotransporters on the plasma membrane
exchange excess calcium for sodium, which is then removed by the Na+/K+
ATPase pump.
ECG principles
This is a record of the hearts electrical activity, recorded from outside the body.Small currents flow in the medium surrounding the heart and can be measured.
These currents are due to different parts of the heart with their different
negative and positive charges. The body is a good conductor.
Clinical uses:
1) The anatomical orientation of the heartand the relative sizes of itschambers.
2) Disturbances in cardiac rhythm and conduction3) The extent and location ofischaemic damage to the myocardium4) The effects ofdrugs or abnormal concentrations ofvarious plasma
electrolytes on the heart.
Standard bipolar limb leads in a negative to positive direction:
1) Lead I (0 degrees): Right arm to left arm2) Lead II (60 degrees): Right arm to left leg3) Lead III (120 degrees): Left arm to left leg
When a wave ofdepolarization moves towards the recording (+ve) electrode,
the ECG shows an upward deflection. A negative deflection is caused by:
1. Depolarisation moving away from the recording electrode2. Repolarisation moving toward the recording electrode
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The PR interval is the time taken for the wave of depolarization to pass from the
SAN, through the atria, the AVN, Bundle of His, Purkinje system to the ventricle.
During the ST segment, the entire ventricular myocardium is depolarized.
Abnormal cardiac rhythms
1) Shift of the pacemaker from the SAN to other regions. If the SAN fails,the nextautorhythmic tissue, the AVN, acts as the pacemaker.
2)Abnormal impulse formation from the SAN3) Blocking or delay of impulse conduction through the heart. If the AVN
fails, the SAN and Purkinje fibres work independently, leading to
independent contraction of atria and ventricles (ventricles areslower)
4) Spontaneous generation of impulses through the heart (eg ventricularfibrillation). If the Purkinje fibre is sending signals at a faster rate than the
SAN, the whole heart will be driven more rapidly. (Ectopic focus)
Complete AV conduction block: The P wave is dissociated from the QRS
complexes. Conditions that can cause this are:
1) Ischaemia2) Compression of the AV node by scar tissue
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3) Inflammation of the AV node (fever)4) Extreme stimulation of the heart by the vagus nerve
Autonomic innervation of the heart
Parasympathetic nerves do not innervate heart muscle and therefore have noeffect on the force of contraction. They only affect heart rate and AV
conduction. Sympathetic nerves increase both and force of contraction too.
The sympathetic innervation stems from the cardioacceleratory centre in the
medulla. There is also a cardioinhibitory centre, which is parasympathethic.
The sympathetic input is via sympathetic cardiac nerves from the
sympathetic chain ganglion, and acts on beta-adrenoceptors. The
parasympathetic input is from the vagus nerve, which acts on muscarinic
receptors.
The SAN is supplied by the right vagus nerve, which reduces the firing rate of
the pacemaker cells. The AVN is supplied by the left vagus nerve, which slows
the conduction through the node.
Sympathetic input innervates both the nodal tissue and heart muscle.
Preganglionic fibres synapse in the stellate and cervical ganglia, before
travelling in the cardiac nerves to the heart. NA causes the pacemaker potential
slope to become steeper, and an increase in the inward sodium and calcium
currents. The action potential of myocytes is shortened due to an increased K+
current, and relaxation is faster due to more rapid sequestration of Ca2+. The
conduction through the AVN is faster, and there is an increase in the Ca2+current during the plateau phase, which increases the intracellular Ca2+ and
force of contraction. All this is mediated by increased levels of cAMP. It has both
direct effects on ion channels and indirect effects on regulatory enzymes.
Sympathetic nerves increase pacemaker activity, and thus heart rate. The
parasympathetic nerves have the opposite effect. The heart is normally under
vagal tone, about 70 beats per minute.
Parasympathetic nerves cause a reduction in the slope of the pacemaker
potential. There is the decrease in intracellular cAMP and reduced
phosphorylation of the ion channels that contribute to depolarisation. There is
slighthyperpolarisation due to the opening of G-protein sensitive K+ channels.
Abnormal sinus rhythms include tachycardia, over 100bpm (stress, anxiety,
fever) and bradycardia less than 30bpm(in athletes)
The heart as a muscular pump with cardiac output
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Cardiac muscle is called myocardium. The inner surface of the heart is lined by
endocardium, which consists of endothelial cells. The outer surface is
epicardium, composed of connective tissue and fat.
Cardiac muscle is striated, with a sarcomere layout. Contraction involves
shortening of the sarcomeres and cross-bridge cycling, which requires ATP.Calcium entry is via the T tubules and sarcoplasmic reticulum. Calcium binds
to a component of the troponin complex, which alters the position of the
adjacenttropomyosin, exposing a specific myosin-binding site on the actin
filament.
Intercalated discs contain large numbers ofgap junctions, which are formed
by connexins. Vertical sections contain short ones, while horizontal sections
contain long ones. They also contain desmosomes which hold the cells together.
Cardiac output
CARDIAC OUTPUT = STROKE VOLUME x HEART RATE
Cardiac outputis the volume of blood pumped at each minute. (Litres/minute)
Stroke volume is the volume of blood pumped at each heartbeat.
(Litres/contraction)
Heart rate is the number of contractions per minute.
Typical values of cardiac output is about 5 litres per minute. However, thisincreases to about 20-25 litres per minute, or 30-40 litres per minute in highly
trained athletes.
Cardiac output is reduced in heart disease. This principle is exploited in an
exercise stress test.
Two mechanisms by which the strength of cardiac contraction/stroke volume is
altered:
1) Changes in muscle cell length (end diastolic volume)The stroke volume is the strength of ventricular contraction.
Stroke volume = end diastolic volume (volume after atrial filling) endsystolic volume (volume after ventricular systole)
2) Changes in calcium release (contractility)The Frank-Starling relation states that the energy released during
contraction depends on the initial fibre length.
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The greater EDV causes increased pressure in the ventricle, which stretches the
heart muscle fibres. Increased length towards optimal length allows increasedforce of contraction, until the muscle is overstretched.
Control of stroke volume by EDV is an intrinsic property of the heart. An
increase in venous return automatically causes an increase in stroke volume.
This relation is important in the matching of outputs between the left and right
ventricles. For example, if there is an increase in the stroke volume of the left
side, this increases the filling pressure of the right side, which increases the right
EDV and hence increases the right stroke volume.
Contractility is a change in contractile energy not due to changes in muscle
length (EDV). It is affected by the amount of Ca2+ released from the SR during
contraction. This depends on:
1) The amount of Ca2+ stored in the SR.2) The amount of Ca2+ entering the cell through the voltage-dependent
Ca2+ channels. Remember the Ca-induced-Ca release.
Some extra info: NA acts on beta-receptors, which activates adenylate cyclase
and increases cAMP levels. A protein kinase is activated, and changes the
conformation of Ca2+ channels on the membrane as well as the SR. Theactivation of the SNS and NA also increases venous pressure, to increase EDV.
Sympathetic activation increases contractility, and moves the Starling curve
upwards. This causes increased Ca2+ entry and release from the SR.
The cardiac cycle
Systole is the period of ventricular contraction and blood ejection.
Diastole is the period between contraction (ventricular relaxation and blood
filling).
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Phases:
1a) Passive filling of ventricles
The pressure in the left atrium is greater than the pressure in the left ventricle.
TheAV valve is open and blood flows from the atrium into the ventricle. Thepressure in the aorta is greater than the pressure in the ventricle, so the aortic
valve is shut. There is no excitation of the heartduring this time, so nothing
shows up on the ECG.
1b) Atrial contraction
Blood is pumped into the ventricles, coinciding with the P wave of the ECG. The
pressure in the ventricle rises slightly, but the contribution of the atria is
relatively minor (good news for those with atrial fibrillation but reasonable
cardiac output
however, this can lead to emboli formation). The aortic valve is
still shut.
Phase 1 is ventricular filling.
2) Isovolumetric ventricular contraction
The excitation spreads to the ventricle, and it begins to contract. This
corresponds to the QRS complex of the ECG. The pressure in the ventricle rises.
TheAV valve snaps shutwhen the ventricular pressure is greater than the atrial
pressure. This makes the LUB sound (first heart sound). It is best heard near theapex of the heart and is caused by movement of blood in the ventricles and the
vibration of the ventricular walls.
However, the aortic valve is still closed. The ventricle is a sealed system, hence
the term isovolumetric. The ventricular pressure rises sharply.
3) Ventricular ejection
The aortic valve opens when the ventricular pressure is greater than the aortic
pressure. Blood is ejected from the ventricle into the aorta. TheAV valve
remains shutto prevent backflow of blood into the atrium. The atria start to fill
with blood at this point.
When the blood has left the ventricle, the ventricular pressure starts to fall and
the ventricle begins to relax. This corresponds to the T wave of the ECG towards
the end of the ejection phase.
4) Isovolumetric ventricular relaxation
When the ventricular pressure is less than the aortic pressure the aortic valve
snaps shut. This makes the DUB sound (second heart sound). This sound is best
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heard towards the base of the heart. As the pulmonary and systemic circulations
operate at different pressures, this is often heard as two separate sounds.
TheAV valve is still closed, and the ventricle is again a sealed system.
The ventricular pressure falls below the atrial pressure and the AV valve opensagain. The cycle is repeated.
Note: there is a small dip and rise in aortic pressure shortly after ventricular
ejection. This is the dicrotic notch and is due to the slight increase in aortic
pressure due to rebound from closed valves.
Arteries, arterioles and the distribution of blood flow
Blood vessels have three layers:
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1. The tunica interna, an endothelial layer. They release substances thateither constrict or dilate the blood vessel. Note: capillaries are only made
up of endothelial cells + basement membrane.
2. The tunica media, or smooth muscle layer, which is circularly arranged.There are sheets ofelastic tissue as well. The smooth muscle changes thediameter of the blood vessel, and the elastic layers allows stretch and
recoil to store potential energy of systole to use during diastole.
3. The tunica externa which is a connective tissue layer with lots ofcollagen. It has a protective function and anchors the blood vessel to
surrounding structures.
Arteries
These are conduit vessels. Large arteries are thick walled with lots of elastic
tissue in them (elastic arteries). They act as pressure reservoirs. Arterial
pressure varies during the cardiac cycle, known as the pulse.
Important: The pressure in the artery depends on:
1) The volume of fluid in it: stroke volume2) The distensibility of its walls (compliance)
Even though blood flow out of the heart occurs during ventricular systole, blood
still flows to peripheral tissues during diastole. During systole, about 2/3rds of
the blood stretches the walls of these arteries, and 1/3 actually flows. Thisincreases the pressure. During diastole, the walls recoil, pushing the blood into
arterioles and capillaries.
Diastolic pressure does not change much with age, but systolic pressure does, as
artery walls stiffen. This is Isolated systolic hypertension.
The peak pressure is the systolic pressure, and the lowest one is the diastolic
pressure. Pulse pressure is the difference between the two. Mean arterial
pressure is roughly the diastolic pressure + 1/3 pulse pressure. It is the
average of the arterial pressures measured millisecond by millisecond over a
period of time.
Mean arterial blood pressure is about 93mmHg.
Auscultatory method of determining blood pressures
A stethoscope is placed over the brachial artery. The pressure cuff is inflated
until the pressure is well above the arterial systolic pressure, to occlude the
artery so that there are no sounds. The pressure is gradually reduced until
Korotkoff sounds are heard, which are made by the blood jetting through the
artery and by vessel wall vibrations. They are tapping and intermittent. Theythen become louder.
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The diastolic pressure is when the sounds become muffled and continuous;
when these disappear the cuff pressure is well below diastolic pressure.
Larger arteries are elastic, smaller arteries are muscular. Due to their large
diameter, arteries have lower resistance to flow, and loss of pressure is minimal
across arteries. Muscular arteries have an external elastic lamina between
their tunica externa and media, and an internal elastic lamina between their
tunica media and interna.
Arterioles
These are termed resistance vessels, because the drop in BP is greatest across
them. They control the proportional distribution of blood flow via changes in
diameter, usually due to changing circumstances such as exercise (when cardiac
output increases). The greatest increase in blood flow occurs at the skin, muscle
and heart.
Contraction of circularly oriented smooth muscle constricts the arterioles, and
relaxation dilates them. They are normally under some level of continuous
contraction to allow for both contraction and dilation. During contraction, wall
thickness increases due to overlap of muscle fibres. The pressure gradient of
blood doesnt normally change.
When tissue metabolic activity increases (active hyperemia), the blood flow
increases. This is achieved by arteriolar dilation. This is usually caused by local
chemical factors such as increased CO2, decreased O2, increased metabolites
such as adenosine (ATP usage), increased H+. Hormones such as histamine and
prostaglandins can affect control as well, and endothelial cells can release nitric
oxide to cause dilation.
Local physical influences
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1) Myogenic response to stretch (pressure autoregulation). When theblood pressure increases the stretch of the arteriole, there is constriction.
When the stretch is decreased, there is dilation. This allows organs to
have constant blood flow even as mean arterial pressure changes.
(Remember F = delta P/R) It lies between 60 and 140 mmHg, though it
can change. This is particularly well developed in the brain.
2) Temperatureheat causes dilation, and cold causes constriction. Coldreduces oedema due to reduced blood flow.
Reactive hyperemia is the period of increased blood flow following a period of
occlusion. Lack of flow causes an increase in the concentration of vasodilation
factors. These dilate the arteries so that the resistance is low and the oxygen
deficit has been paid. The magnitude and duration of the response increases with
the duration of occlusion.
Reflex control of arterioles
Most arterioles have a rich sympathetic supply, which releases NA. They act on
alpha-receptors on smooth muscle to cause constriction. Smooth muscle has
resting sympathetic tone. There is no significant PNS to the arterioles, except in
erection, and also to cerebral and coronary vessels.
Hormones: NA causes constriction on alpha-receptors, butdilation on beta-
receptors. Constrictors include angiotensin II and vasopressin, while bradykinin
and atrial naturietic (Na excretion) peptide dilate arterioles.
The endothelium
The endothelium is a single layer of squamous epithelial cells. It functions like
Teflon, a non-stick surface, and lines all blood vessels, the heart and lymphatics.
It is the largest endocrine organ in the body at 10^13 cells.
Endothelial cells differ in phenotype according to the region and organ they
inhibit. Arterioles have longer cells arranged in the direction of blood flow. There
are many tight junctions. Veins have shorter, wider cells.
They have a wide range on functions, including:
Hemostasis and thrombosis Altering vascular permeability Vasodilation and constriction Regulation of blood cell-vessel wall interaction Vascular remodellingprevents overgrowth of smooth muscle Matrix synthesiscollagen and elastin Inflammation
Impairment of endothelial function (endothelial dysfunction) leads to
vasoconstriction, expression ofproinflammatory molecules and thrombosis.
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A host of chemical modulators mediate this. There is reduction in circulating
endothelial progenitor cells, as well as detachment and apoptosis of endothelial
cells.
This condition is a risk factor for CVD, and is the first detectable change in the
genesis ofatherosclerosis.
Factors released by endothelium:
Vasodilators eg NO and prostacyclin, endothelium-derivedhyperpolarising factor
Vasoconstrictors eg endothelin, thromboxane, angiotensin II Growth promoters and inhibitors Haemostatis and thrombolytic factors
NO is a diffusible factor, and is lipid-soluble. It is synthesised from L-arginine by
NO synthase. NO also prevents platelet aggregation and adhesion, as well asleukocyte adhesion, due to inhibiting adhesion molecule expression. It inhibits
smooth muscle proliferation. It acts via a guanylate cyclase pathway.
Shear stress is caused by the viscous drag of blood against the vessel walls. This
contorts the endothelial cells in the direction of flow, increasing NO release.
When NO release occurs at the capillary beds (microcirculation), and this in turn
increases the flow and shear stress on upstream small arteries, causing them to
relax as well.
Shear stress is normally caused by laminar flow. Turbulent flow leads to
reduced vasodilation, pro-inflammatory and procoagulation properties.
Ach acts on endothelial cell receptors to stimulate NO release. Endothelial cells
have plenty of muscarinic receptors, but no PNS innervation.
Prostacyclin (PGI2) is diffusible, and is a metabolite ofarachidonic acid by
COX1 enzymes. Itinhibits platelet aggregation. It acts via an adenylate cyclase
pathway.
Endothelium-derived hyperpolarising factor (EDHF) causes vasodilation as
well as smooth muscle hyperpolarisation. It is unclear whether EDHF is adiffusible factor such as arachidonic acid metabolites, K+ ions, H2O2, or a
contact-mediated mechanism where spread of hyperpolarisation is via
myoepithelial gap junctions.
NO and PGI2 are more prominent in arteries, while EDHF action is more
prominent in resistance vessels.
Clinical applications
In the clinic, endothelial function is assessed using a cuff around the brachial
artery, and inflating it for 5 minutes to cause ischaemia and dilation of the
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vessels. Release of the cuff causes shear stress and increase in blood flow, as well
as NO release.
Coronary angiography acetylcholine infusion: In healthy coronary arteries,
this causes vasodilation. But in unhealthy ones, it causes vasoconstriction
instead. (Ach stimulates the tunica media, not endothelial cells.) There is also anincrease in vasodilation response to external nitrates due to lack of endogenous
NO. Glyceryl trinitrate is an endothelium-independent vasoldilator used to test
smooth muscle function (also used for angina).
Diabetes: BH4 is an important cofactor for endothelial NOS. Oxidative stress
(sources are NADPH oxidases, xanthine) leads to increased production of free
radical species, which uncouples the eNOS from this. The affected eNOS produces
free oxygen radicals, which reacts with NO to form nitrate peroxidases. Impaired
EDHF may also be the reason for neural degeneration in diabetes.
Pregnancy: Alcohol may decrease endothelium-dependent relaxation. There is
reduced EDHF and NO, and an increase in PGI2 to compensate.
Microcirculation and the lymphatic system
Capillaries are made up of a single layer of endothelial cells. They are 5-8
microns in diameter, and RBCs of 7 microns go through in a single file. They are
highly permeable to water and small solutes, but not to large proteins.
There are pores between adjacent endothelial cells to allow for this.
Blood flow through capillaries is slow, because of branching which gives italarge cross-sectional area for exchange of substances.
Pathways of movement
1) Diffusion of lipid-soluble substances through plasma membranes2) Diffusion of lipid-insoluble substances through endothelial pores3) Bulk flow of water and dissolved substances4) Endo and exocytosis, plus selective pumps
Types of capillaries
1) Continuous: they have tight junctions between endothelial cells, and onlysmall molecules can pass passively. They have specific transcellular
transport processes. Can be found in the BBB.
2) Fenestrated: have about 60-80 nm pores, butcontinuous basal celllamina. Serum proteins can pass passively. Found in endocrine glands,
intestines, pancreas and kidney glomeruli.
3) Sinusoidal: have 30-40 micron gaps, allow RBC and WBC to passpassively. No continuous basal cell lamina. Found in bone marrow, lymphnodes and adrenal gland.
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Metarterioles (terminal arterioles) allow shunting of blood from arteriole to
venule. Precapillary sphincters are found at the end of the metarteriole and
control the flow into and out of individual capillaries. Hence, most capillaries are
not open at rest. Blood flow can bypass capillary beds by means of
arteriovenous anastomoses or AV shunts.
1) Some capillaries are fenestrated, such as those in the kidney, to allowsmall molecules to pass through with ease. The endothelial cells in the
brain have tight junctions which contribute to the BBB.
2) There is hydrostatic pressure across capillaries (Pcone of theStarling forces). Pressure is higher at the arterial end, at about 32mmHg,
and lower at the venous end, at about 17mmHg. This pressure tends to
force fluid out of the capillaries into the interstitial spaces.
3) The interstitial fluid pressure (Pif, another Starling force) tends to forceblood back inward across the capillary membrane. Pif is usually negative,
due to suction of fluid from the extracellular space by the lymphatic
system. Thus fluid tends to be forced out into the tissues.
4) Colloid osmotic pressure of capillary blood (Pi p) and interstitialfluid (Pi if) are due to large proteins which suck the fluid into their
compartments.The blood plasma has a higher oncotic pressure, and
tends to draw fluid back in. Only this pressure is an inward force; the rest
are outwards.
NET FILTRATION PRESSURE= NET HYDROSTATIC PRESSURE NET
ONCOTIC PRESSURE
As the net filtration pressure is higher at the arteriolar end, about 2-4 litres of
fluid accumulates in the extracellular space. Capillary beds lose about 25-50% of
their plasma proteins this way.
Lymphatics
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The lymphatic system consists oflymph, which is interstitial fluid that drains
into lymphatic capillaries. These capillaries are blind-ended and have minute
valves of endothelial cell flaps, as well as larger valves consisting of entire
cells. They have anchoring ligaments that bind them to the extracellular
matrix. Large gaps in the basal lamina enable bacteria and lymphocytes to
enter.
Walls of larger vessels have smooth muscle cells and internal one-way valves. A
lymphangion is the segment between two valves. Lymph pumping is driven by
three mechanisms:
1) Rhythmic contraction of lymph vessels in response to stretch2) Skeletal muscle contraction3) Respiratory movements (inspiration produces suction)
Lymph vessels from the right side of the head and neck, right arm and right
thorax enter the right lymph ductat the junction of the rightsubclavian and
internal jugular vein. Lymph from everywhere else enters the thoracic ductat
the junction of the left counterparts of these veins.
Cellular population consists of NK, T and B cells, macrophages, dendritic cells
and reticular cells (synthesises type III collagen). Lymph tissue consists of
lymphocytes in connective tissues of mucous membranes and other organs.
Primary lymph organs are the red bone marrow and thymuswherelymphocytes become immunocompetent. Secondary lymph organs are lymph
nodes, spleen and tonsils, where immunocompetent lymphocytes live.
Clinical stuff-oedema
Oedema occurs when the outflow of fluid from capillaries exceeds the capacity
of the lymphatic system to carry it away. Any imbalance in one of the four
Starling forces can cause this. Pc and Pi if normally force fluid outwards, and P if
and Pi p normally force fluid inwards.
1) Pc: changes in systemic arterial pressure and constriction/dilation of
arterioles. Dilation of arterioles increases pressure at the arterial end of the
capillary bed. Changes in venous pressure also affect this: an increase causes
increased filtration due to a backup of pressure in the capillaries.
Pulmonary oedema: if your left heart fails, blood accumulates in the alveoli of
the lungs due to increased pulmonary venous pressure.
Peripheral oedema: if your right heart fails, blood pools in the ankles and feet
due to increased pressure in the systemic veins.
2) Plasma protein concentration: liver cirrhosis reduces plasma protein
production, and kidney disease can result in increased excretion of plasmaproteins. This can lead to ascites.
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3) Lymphatic obstruction by parasites such as Brugia Malayi can cause
elephantiasis. This is a form oflymphedema, which affects patients after a
mastectomy sometimes.
Veins and venous return
Veins are capacitance vessels, storing about65% of the bodys blood. Thepressure gradient between the venules and right atrium is small, hence
resistance is low.
As a volume reservoir, they are thin walled and very distensible.
Venous pressure is the pressure difference between the veins and right atrium.
Right atrial pressure = central venous pressure; peripheral vein pressure =
peripheral venous pressure. This is affected by 2 parameters:
1) Volume of blood2) Distensibility
Smooth muscle in the walls of veins receive SNS input, and contraction stiffens
the vein walls, increasing venous pressure (increased venomotor tone). So this
increases the volume of blood returning to the heart, increases the EDV, and by
Starlings Law, stroke volume and cardiac output.
Skeletal muscle pump: Skeletal muscle squeezes on the veins to push the blood
back to the heart, especially useful during exercise. To do this, one-way valvesare needed, and this counteracts hydrostatic pressure.
Respiratory pump: during inspiration, thoracic pressure drops and abdominal
pressure increases. The diaphragm descends. The veins in the abdomen are
squeezed, and blood is pushed into the thorax. Valves are important too.
Cardiac suction: The AV valve is pulled down during contraction of the
ventricle. This expands the atrial space, and sucks blood from the veins into the
atria. When the ventricles relax, the pressure is lower than that of the atria,
sucking blood too.
Varicose veins are abnormally and permanently enlarged and twisted surface
veins. When a person stands too much, their veins are stretched, increasing the
cross-sectional area. Unfortunately the valves remain the same size and dontclose completely. Backflow of blood occurs, and blood pools in the superficial
veins. This usually happens to perforating veins connecting the deep and
superficial veins, and also veins in the groin.
VENOUS RETURN IS REALLY IMPORTANT: if the return is too low, there is not
enough blood for adequate stroke volume. Cardiac output falls and not enough
blood is delivered to organs and tissues of the body. Therefore, cardiac outputmust match venous return.
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Vascular function curves.
This describes the relationship between right atrial pressure and venous
return. Note: negative pressure denotes below atmospheric pressure.
Psf (mean systemic filling pressure) is the equilibrium pressure in the
systemic circulation after stopping blood circulation. It is quite similar to themean circulatory filling pressure, due to the negligible effect of pulmonary
circulation.
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Sympathetic stimulation causes constriction of blood vessels and even the
chambers of the heart, hence increasing pressure even at smaller volumes. A
steep curve indicates that small changes in sympathetic activity can have large
effects on Psf.
Decrease in blood volume (haemorrhage) or increased venous compliancedecreases venous return.
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Increase in blood volume (transfusion) or decreased venous compliance
increases venous return.
Note: the Vascular Function Curve describes the behaviour ofthe vascular
system alone. The Frank-Starling Curve describes the behaviour ofthe heartalone. If you plot them together, the intersection pointis the equilibrium point,
describing the actual operating state of the CVS.
The Vascular Function Curve can be shifted by things such as:
1) Changes in venomotor tone (stiffening).2) Changes in blood volume.3) Changes in the level of constriction/dilation of upstream arterioles. A
constriction shifts both curves downward, as TPR has increased, and less
blood flows into the veins. A dilation shifts both curves upward. In bothcases the right atrial pressure remains the same.
Postural hypotension
This is due to decreased right atrial pressure. Blood pools in the legs and trunk,
leading to a reduction in filling pressure of the right atrium. This results in a fall
in cardiac output and arterial pressure.
Increased blood pressure at the legs increases filtration and as a result, oedema
in the legs.
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Modelling the Circulatory System
Systemic Vascular Resistance = Mean arterial pressure- right atrial pressure/CO
The further downstream a resistance is, the more important the contribution.
This is where venous resistance causes BP to plummet. Supine hypotension inpregnant women is a manifestation of thislying down compresses the IVC.
Turn onto left to decompress it.
Venous resistance can also manifest as a stiffening of venous walls during
hypovolemic shock.
Cardiac output = venous return = Mean systemic pressure resting atrial
pressure/resistance to venous return
Preload is the left ventricular end diastolic volume. It goes up in heart failure,
due to an accumulation of blood.
Afterload is the arterial resistance against which the ventricle must contract.
Aortic pressureleft ventricle; pulmonary artery pressureright ventricle.
Resistance to venous return is the resistance encountered by the average
element of circulation in returning to the heart.
RVR = Mean systemic pressure right atrial pressure/ cardiac output
Stressing volume is the volume that stretches the walls of the vessels. There is aVo which maintains the tubular structure of the walls.
Mean circulatory pressure = Stressing volume / compliance. Long-term
regulation of mean circulatory pressure is undertaken by the kidney.
Compliance is the rate of change of volume with pressure.
Short-term regulation of mean arterial pressure
Mean arterial blood pressure is determined by 2 factors:1) Cardiac output, affected by heart rate and stroke volume. Strokevolume is affected by venous return (EDV) and contractility.
2) Total peripheral resistancethe sum of the resistance of all the bloodvessels. Mainly determined by arterioles, which are controlled by local
and reflex mechanisms.
3) Total blood volumedecreaseMAP falls, increaseMAP rises.Increased blood volume affects the volume of blood in the veins, and
therefore, stroke volume and cardiac output.
MAP = CO x TPR (derived from the F= delta P/R equation)
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The mean arterial blood pressure must be maintained at a suitable level to
provide adequate perfusion of organs and tissues. Sudden falls can be restored
by increasing CO, TPR or both.
Baroreceptor reflex (short-term control)
Pressure detectors are the arterial baroreceptors. These are mechanosensitive
sensory nerve endings found in the aortic arch and carotid sinus. If pressure
rises, the rate of firing increases, and if pressure falls, the rate decreases.
Note: other receptors are stretch (volume receptors) in the atria and large
veins. They regulate blood volume and body water. (Long-term control)
Chemoreceptors in the aorta and carotid sinus detect changes in blood O2, CO2
and pH. They influence both respiratory and cardiovascular function.
These are bipolar neurons, with cell bodies located in the petrous and nodose
ganglions. (ganglions of glossopharyngeal and vagus nerve) They both
terminate in the nucleus tractus solitarius.
The control centre is the medullary cardiovascular centre comprising the
cardiac and vasomotor centres. These control sympathetic and
parasympathetic nervous output to the heart, arterioles and veins.
Orthostatic hypotension
Standing upright means that gravity causes the blood to pool in the veins of the
lower leg. This increases filtration, leading to swelling of ankles and feet. Also,there is decreased venous return. The fall in pressure leads to the discharge of
sympathetic nerves, to cause the heart to contract more strongly and
constricting the arterioles as well as increasing venomotor tone.
Orthostatic hypotension happens frequently in the elderly due to a dampened
baroreceptor reflex. Hypovolemia in the case of reduced blood volume or severe
dehydration leads to this as well. Accentuated peripheral dilation due to very
warm environment or drugs leads to a decrease in TPR.
Long-term regulation
Baroreceptors are not the mechanism, because if the MAP remains consistently
high or low for prolonged periods the receptors adapt or reset.
Long-term control relies on the kidneys, via regulation ofblood volume by
retention and excretion of Na+ and water.
ADH (vasopressin)
This is produced by the hypothalamus. It constricts arterioles to increase TPR,
but more importantly, it causes the kidneys to conserve body water by
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decreasing urine production. This leads to increased blood volume, so increased
CO. Blood pressure goes up.
Aldosterone
This is a mineralocorticoid, produced by the adrenal cortex. It increasessodium retention by the kidneys, and therefore, water retention too. Has the
same effect as ADH.
Renin-angiotensin system
Angiotensin is produced by cleavage ofangiotensinogen from the liver, by
renin from the kidneys, to angiotensin I. Angiotensin converting enzyme in
the vascular endothelium of the lung converts angiotensin I to angiotensin II.
Angiotensin II has multiple actions, including stimulation ofaldosterone and
ADH secretion. It also constricts arterioles to increase TPR. It has direct effects
on the kidney: it constricts the renal arterioles, and slows blood flow in the
peritubular capillaries, so that water is reabsorbed faster from the kidney
tubules. It also acts on tubular cells to increase the reabsorption of sodium and
water.
Atrial natriuretic peptide
Produced by the atria of the heart, this promotes sodium and water excretion,
reducing blood volume. It also dilates arterioles, decreasing TPR. It decreases
blood pressure.
Very long-term regulation of MAP: pressure natriuresis mechanism
The two primary determinants for long-term arterial pressure control are:
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1) The pressure shift of the renal output curve. This can be due to kidneyabnormalities.
2) The level of water and salt intake.Cardiovascular response to challenge
During exercise, blood flow to the muscles is increased, to deliver O2 and
nutrients as well as remove CO2 and waste. Two main changes:
1) Increasing cardiac output by increasing both heart rate and strokevolume. CO increases almost in proportion to the exercise intensity.
Heart rate is increased first by withdrawal of PNS stimulation, and then
increasing SNS stimulation as well as circulating NA. A small effect is seen
from the increase in body temperature.
Stroke volume increases due to an increase in venous returnathletes
will have increased EDV due to enlarged ventricular cavities. Also,
increased SNS stimulation and levels of NA will increase contractility.
Venous return increases by 3 factors:
1) Stiffening of the vein walls due to SNS activity.2) Muscle pump action3) Respiratory pump action
2) Redistributing blood flow so that more goes to the muscles, including thediaphragm and respiratory muscles of the chest. With exercise, cardiac
output increases, and the distribution of blood to various organs
changes substantially.
There is increased blood flow to muscle tissue and local vasodilation.
Also, there is increased blood flow to the heart. There is increased
skin vasodilation in heat loss as the core temperature rises (however
this decreases in intense exercise). There is greater perfusion oflung
tissue and hence a fall in resistance. Blood flow to the brain is constant.
During exercise, the blood flow through the lungs increases by exactly the same
amount as does the total cardiac output.
CO = SV x HR.
1) Training increases CO.2) Lowers resting HR as well as making itrecover more quickly (maximum
is still the same)
3) SV increases at rest and at exercise. This is due to hypertrophy. The EDVincreases due to increased blood volume, and the slower heart rate gives
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more time for ventricular filling. Contractility increases so that more
blood is ejected per systole. SVmax is also increased.
Arterial pressure: Systolic increases, diastolic remains the same. Mean
increases, but not much. MAP = CO x TPR. As CO increases, TPR decreases due to
dilatation of the arterioles.
Higher centres in the brain communicate with the medullary cardiovascular
centre as they recognise exercise as a normal physiological response.
Baroreceptors are reset upward.
Response to haemorrhage
Short-term effects: Decrease in mean arterial pressure due to reduced blood
volume. The fall in cardiac output is caused by the fall in the right atrial
pressure, due to reduced venous return.
Long-term control: Water is absorbed from the interstitial spaces back into the
capillaries. This reabsorption is due to reduced arterial pressure and
arteriolar constriction. Thirst centres in the brain stimulate increased water
intake.
There are two phases:
Phase 1: Vasoconstriction, which maintains blood pressure by increasing total
peripheral resistance. During haemorrhage, the baroreceptor reflex maintains
arterial pressure.
Phase 2: Vasodilation, and the blood pressure plummets. This is hypovolaemic
shock.
Circulatory shocktypes
Any condition where the blood pressure falls and blood circulation becomes
inadequate.
Hypovolaemic: haemorrhage, severe dehydration, burns where plasma is lost.
Vascular: Blood volume remains normal but circulation is poor due to extreme
dilation of blood vessels. Molecular regulators include reduction in ADH levels,
hyperpolarisation to prevent entry of Ca2+.
Septic: This is usually caused by a systemic bacterial infection. Bacterial toxins
can be powerful vasodilators.
Anaphylactic: allergic reaction (type I hypersensitivity), bodywide dilation of
blood vessels caused by histamine release. Treated with NA.
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Neurogenic: ANS failure, leading to loss of normal sympathetic tone and
vasodilation. This causes blood to pool in the veins, reducing venous return and
cardiac output. Can be caused by anaesthetics, which depress the vasoconstrictor
activity of the brainstem.
Cardiogenic: Can occur in severe heart failure, or if there is a buildup of fluid inthe pericardium. There is a decrease in heart contractility.