cardiovascular physiology run

8/2/2019 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 pressureright 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.

cardiovascular physiology run

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