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Body-Systems-Notes-Bec-2

Body Systems: Structure and Function (University of Sydney)

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BIOS1170(Body(Systems:(Structure(and(Function(
Rebecca(Harrisson((
((((((

Semester!2!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!The!University!of!Sydney!!

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Fluid!Learning!Objectives!
1. Define and give examples of fluids
• A fluid is a substance that flows readily e.g. liquids and gases. It deforms
continuously when a force is applied (push pull motion).
• In biological systems fluids can be excreted or secreted from the body and act as
solvents and to carry nutrients and waste products or even a vector for deisease.
For example:
o Blood
o Plasma
o Bile
o Gastric Juices
o Saliva
o Urine

2. Define the terms and give the SI units and commonly used units:
3. Convert pressure readings from one unit to another

a. Mass: of an object is the amount of matter in it ! SI kg

b. Volume: of an object is the space it occupies ! SI
! m3 / mL / dL / cm3 / cc
! 1m3 = 1m x 1m x 1m
! 1cm3 = 1cm x 1cm x 1cm

c. Density: the mass of a unit volume of a substance e.g mass of one litre of milk. It
tells us how light or heavy substances are. SI d or r (rho) and measured in kilograms
per metre cubed (kg m-3)

d. Weight: a body’s relative mass or the quantity of matter contained by it, giving rise to
a downward force; the heaviness of an object. The force due to gravity
[ w = m x ag] where ag = 9.8 ms-2 SI is newtons (N)

e. Pressure: to obtain the pressure (P) of a system dived the force (F) by an area in
which it occupies (A). SI is Pascal (Pa) and commonly used units are atmosphere
(atm), mmHg, millibar (mb) or pounds per square inch (psi).

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4. Distinguish between the terms: relative pressure and absolute pressure

• Absolute pressure is the total pressure/ pressure above zero pressure of a vacuum
i.e. cannot be less than or equal to 0.
• Relative pressure is a measure of the difference between two pressure systems.
Can be +ve or –ve
• Blood pressure is a relative pressure ! 110mmHg blood pressure is greater than
atmospheric pressure.

5. State the relationship between pressure and depth in a fluid

• Increase in depth will increase pressure in a linear relationship.
• Every 10m depth in water provides extra 1 atm in pressure

ΔP = h d

6. State and apply Pascal’s principle

• Pascal’s principle is the pressure exerted any
where on a confined liquid is transmitted equally
without loss in all directions throughout the liquid
and at any position acts at right angles to the
surface of the liquid.
• Pin = Pout and therefore greater area = higher
pressure

Hydraulic Pressure is Pin = Pout ! Fin = Fout

A =A
in out
Atmospheric Pressure is due to
weight of air above us and it decreases with the
increase of altitude because of less air above and the
density has decreased. Making it more difficult to relate
exactly atmospheric pressure with altitude [P ≅( Po - do
x ag x h]. Where Po is atmospheric pressure at sea level
(zero height) and do is density of air.

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7. Define the terms buoyant force and buoyant pressure

• Buoyant force is the upward force on an object partly or fully immersed in fluid. The
force is equal to the weight of the fluid in which the object displaces.
• Buoyant pressure is the tendency of a body of water to push in an upwards force and
the air to push down, creating objects to float or sink.

8. Carry out calculations involving buoyant forces on submerged objects

9. State Archimede’s principle in hydrotherapy

• Archimede’s principle is the buoyant force on a body
immersed in a fluid is equal to the weight of the fluid
displaced
• Explains why a body feels light when under water
• Weight loss of submerged body = weight of fluid
displaced ! boats displaces more water thus more
weight loss thus float.

10. Describe the applications of Archimede’s principle in hydrotherapy

• Hydrotherapy refers to water exercises used for healing or rehab
• Patients find it easier due to the weight loss concept
• Useful for patients who have difficultly exercising a weak limb out of water
• For patients unable to support the weight of their body otherwise therefore they are
allowed to exercise under water.

11. Define the term: flow rate

• (Q/R) rate of flow: is the volume of fluid which passes a given point in a space per
second (R = V/T)
• Relationship is that the greater the area (allowing flow) = greater rate ! R = vA
• For example: flow rate (R) through a horizontal pipe is the product of velocity and
flow (v) and the area of cross-section (A) of the pipe:
Q = vA v = velocity and A = area of cross-section

12. State the continuity equation using words and symbols

• Continuity equation: v1A1 = v2A2
• Allows for constant flow rate
• V and A compensate for each other
• It is incompressible fluid traveling along a fixed
structure (pipe) the answer is absolute

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13. Describe the three types of fluid flow based on the extent of internal fraction
• Ideal flow: no friction

• Laminar/streamline flow: friction = loss in KE

(kinetic energy) ! there is a parabolic
distribution of velocity (greatest velcotiy at centre of
flow and lowest at walls)

• Turbulent flow: most loss in KE – very narrow

vessel & high velocity = turbulent lowering KE and
low pressure.

14. State Bernoulli’s equation

• A statement of conservation of energy applying to the flow of an ideal fluid.
• In the laminar flow of an ideal incompressible fluid, the sum of pressure, kinetic
energy per unit volume and potential energy per unit volume remains unchanged.

• As velocity decreases, pressure increases

15. Give examples of the application of Bernoulli’s principle, and carry out
calculations using Bernoulli’s equation
• Applications:
o Lift of an airplane
o Blowtorch
o Nebuliser
o Venturi meter

16. Define the terms:

a. Viscosity: a mesure of internal friction to flow in a fluid blood is viscous (proteins
and molecules)
o Fluids differ in viscosity values e.g. syrup is more viscous than water
and grease more viscous in engine oil.
o Viscosity produces parabolic distribution of velocities in laminar flow

b. Surface tension: (y) tension at the surface of a fluid opposing forces which attemot
to increase the area
o Molecules at the surface of a fluid experience a net inward force are in
a state of tension
o Water – polar molecule with –ve and +ve end

c. Surfactants: active agents

o Composed of molecules containing polar and non polar ends
o Accumulated at surface of water with polar heads down and non polar
heads up
o Reduces surface tension

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17. State Pouseuille’s Equations for laminar and turbulent viscous flows, and
apply these to blood flow
• Pouseuille’s law applies to flow of real fluids when there is KE loss due to viscosity

• Valid for streamline flow of fluid that is incompressible and has constant viscosity
• Is not strictly applicable to blood flow
• Turbulence blood flow contains particles whose
diameter = capillary diameter.
• Laminar flow:
• Turbulent flow: produces a reduction in pressure.
Application to blood flow is when radius of a vessel is
halved; blood flow will be 1/16th of original value.
Atherosclerosis will reduce the radius of an artery thus
pressure increase.

18. Define the term end pressure and state Laplace’s law relating lateral pressure
and wall tension
• End pressure according to Bernoulli’s principle; as velocity decreases, pressure
increase = very high hydrostatic pressure produced at the blocked end.
• Pascal’s principle is pressure is transmitted equally in all direction and acts as right
angles to the surface
• End pressure can cause bulging and rupture of blood vessel (aneurism)

• Laplace’s law:
o Relates the pressure across a closed membrane or liquid film to the
tension in the membrane or film
o The exact form of the equation depends on the shape of the closed
surface
a. Spherical membrane requires a greater pressure difference to
sustain a small sphere than a large one
P1 – P0 = 2y/r
b. Soap bubble
P1 – P0 = 4y/r

c. Cylindrical tube
P1 – P0 = y/r

19. Describe the role of surfactants in breathing

• We use surfactant to reduce surface tension in mucous lining of pulmonary alveoli
• Alveoli secrete a surfactant that reduces surface tension by a factor of 15
• There is a fixed amount of surfactant tension in each alveolus
• When deflated, surfactant/ tension low hence alveolus expands easily (exhale)
• As alveolus expands, surfactant increases and surface tension decreases
• First breath of life requires an extraordinary effort to overcome the surface tension of
the wall as the alveoli are completely collapsed

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Cardiovascular!System!Learning!Objectives!
1. The anatomy of the heart, blood vessels and lymphatics
a. The external and internal features of the heart
External features of the heart include:
• Apex ! knuckles: most inferior and lowest point of the heart, slightly anterior and
lateral. Mostly consists of left ventricle
• Base ! wrist: Superior, flat section of the heart. Mostly consists of left atrium, top of the
heart (without the blood vessels/arteries)

Internal features of the heart include:

Left Atrium and its Auricle
• Expendable extension of an atrium (floppy)
• Collects blood from the left and right pulmonary veins that enter the posterior of the Left
atrium. It then pumps the blood through to the left ventricle.
• Bicuspid valve: pair
o Permits blood flow from left ventricle to atrium
o Prevents back flow during contraction
o Chordae Tendinae ! strings where free edge cusp is anchored to, avoiding swinging
of doors, which would otherwise permit blood flow in 2 directions. Tension is created
to close cusps from swinging back in the atria
o Papillary muscles ! muscles at base of ventricles that attach to chordae tendinae
and walls of the ventricles – when muscle contracts it pulls on chordae tendinae
keeping it taut and valves shut
o Trabeculae carneae ! muscular ridges and columns on the interior wall of ventricles
o Musculi pectinati ! muscular ridges on the interior surface of the auricles and part of
the right atrial wall

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Right atrium and it Auricle

• Receives blood from the systematic circuit through the superior and inferior vena cava and
dumps it into the right ventricle. The cardiac veins of the heart return blood to the
coronarysinus, a large, thin walled vein that opens into the right atrium in between the vena
cava. (Top left when looking at a diagram)
• Auricle: ear shaped extensions
• SVC: opens into posterior/superior portion of right atrium ! delivers blood from head, neck,
chest, upper limbs to RA through SVC
• IVC: opens into posterior &t inferior of right atrium
• Delivers blood from lower limbs, rest of trunk, viscera to RA through IVC and pumps blood
into right ventricle
• NB Pre birth, child atria are joined through and oval opening. At birth this opening closes
leaving a small, shallow depression known as the fossa ovalis.

Left ventricle

• Blood received from left atrium once it has passed the bicuspid valve and pumps blood into
the systematic (body) circuit via the aorta.
• Blood is pumped through aortic semi-lunar valve aorta —> oxygenated blood —> body
• Thick walls that line the heart enabling it to develop sufficient pressure to push blood to rest
of body
• No moderator band

Right ventricle

• Receives deoxygenated blood from the right atrium through tricuspid valve
• Pumps it into the pulmonary circuit via the pulmonary trunk splits into the left and right
pulmonary arteries to become oxygenated at each lung.
• Pumps blood through pulmonary semi-lunar valve ! pulmonary arteries ! deoxygenated
blood ! lungs to be oxygenated
• Moderator band: delivers stimuli for contraction to the papillary muscle ! tenses chordate
tendineae ! right ventricle contracts

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b. The major components of the cardiac conducting system

• Function: network of cardiac muscle cells responsible which uses electrical impulses to
distribute stimuli contraction
• Sinuatrial node (SA): posterior wall of right atrium near SVC 11 ! contains pacemaker cells
establishing heart rate
• Atrioventricular node (AV): in the floor of right atrium near the opening of coronary sinus
o Pulse slows as nodes are smaller
o Takes longer to send impulses which is essential asatria must contract before
ventricle
• AV bundle: top of atrioventricular septum
o Allows electrical connection between atria & ventricles
o Enters AV node —> R&L bundles at a great velocity —> purkinje fibres —>
ventricular contraction
• Purkinje fibres: conduct actions rapidly

c. The coronary circulation

1. Deoxygenated blood enters Right atrium through Superior vena cava & Inferior vena cava
2. Enters tricuspid valve ! Right ventricle
3. right/left pulmonary arteries into right/left lungs for oxygen
4. Pulmonary veins ! oxygenated blood into left atrium
5. Bicuspid valve ! left ventricle
6. Ascending aorta ! aortic arch ! descending aorta
7. Body
8. Repeat

Coronary arteries: supply blood to heart muscle

1. Left coronary artery: divides into circumflex and inter ventricular artery
• Anterior interventricular branch: major branch of left coronary artery
o Extends inferiorly into anterior IV sulcus
o Supplies blood to most of the anterior part of heart
o Left marginal artery lateral wall of left ventricle
• Circumflex branch
o Branches from left coronary artery and extends to posterior side of the heart in
the coronary sulcus
o Supplies blood to much of the posterior wall of the heart
2. Right coronary artery: divides to right marginal and posterior inter ventricular branches
• Posterior interventricular branch
o Branch of the right coronary artery
o Lies in posterior interventricular sulcus
o Supplies blood to the posterior and inferior part of heart
• Marginal branch
o Larger branch of coronary artery
o Begins inferior to right atrium then spreads across it
o Supplies blood to lateral wall of right ventricle
• Sinuatrial nodal branch
o Near superior vena cava
o Branches off right coronary artery
3. Arterial anastomoses - numerous arterial anastomoses link branches of left and right
coronary arteries - this is to prevent blockages

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Nourishment of the Heart - Blood Supply

• The heart is one of the most energy-demanding organs of the body.

• Unlike skeletal muscle, with every beat of the heart every cardiac muscle cell contracts and
continue to contract throughout life
o Never rests, rest = death
o No recovery time
• Aerobic metabolism in cardiac muscle cells is highly efficient
o ~Up to 40% of the myocardial cell’s volume is made up of mitochondria (the
O2- dependent energy organelles)
o Compared to ~5% in the case of skeletal muscle.
• Although all the blood passes through the heart, O2 and other nutrients cannot be extracted
from the blood in the chambers because (i) the endothelial lining of the chambers is not
permeable & (ii) the cardiac muscle wall is too thick for diffusion of O2 to take place.
• The myocardium blood supply is from the coronary arteries
• The coronary arteries arise from the base of ascending aorta at the aortic sinuses
• Blood cannot flow into the coronary arteries when the ventricles are contracting (systole)
o Contracting cardiac muscle compresses coronary arteries
o The opened aortic valve covers the openings to the coronary arteries
• During ventricular relaxation (diastole) blood in the aorta is under high pressure and will flow
into the coronary arteries
• Note: this phasic perfusion of the heart can become a problem during exercise when HR is
high because diastolic time is reduced just when demand is greater.

d. The nerve supply of the heart and blood vessels

Nerve Supply

• Nerve supply is from autonomic nervous system

• They influence the pumping action of the heart through affecting heart rate and stroke
volume
• Sympathetic: speeds up pumping
o Nerve supply to SA &AV nodes, coronary vessels & atrial/ventricular myocardium
o Increase cardiac output by 50-100% & heart rate up to 250-300bpm (using force of
muscular contraction)
• Parasympathetic: slows down pumping
o Carried to heart through vagus nerves
o Supply SA, AV node, atrial myocardium
o Slow to 20-30bmp and has little effect on stroke volume

Blood Vessels - Cardiac veins

• Great cardiac vein travels along side anterior interventricular artery and then curves
posteriorly with the circumflex artery.
• Middle cardiac vein travels with the posterior interventricular artery
• Small cardiac vein drains blood from right side of heart.
• All these veins drain into the coronary sinus which opens into the right atrium
• Blood vessels consist of elastic tissue, smooth muscle and connective tissue, plus layer of
endothelium on internal surface
•
• The typical blood vessel is comprised of 3 layers
o Tunica intima: internal layer of a blood vessel, includes the endothelium &

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surrounding connective tissue. Artery: outer layer of tunica intima contains elastic
fibres (internal elastic membrane)
o Tunica Media: middle layer. Contains smooth muscle in a framework of connective
tissue. In small arteries usually thickest layer. Collagen fibres bond tunica media to
tunica intima and externa.
o Tunica Externa: (tunica adventitia) is the outer layer of a blood vessel. It is a
connective tissue sheath. Artery: collagen and elastic fibres. Vein: elastic fibres and
smooth muscle. Binds to adjacent tissue and anchors vessel in place

e. How the microstructure of different types of blood vessels relates to their

function
• Structure relates to function
• Arteries: (conduit vessels)
o lots of elastic tissue (esp. proximal)
o thick walls
o smooth muscle contract
o internal diameter (i.d.) - 0.5 - 25 mm
• Elastic arteries
o Tunica media; thick with very elastic fibres
o Tolerates large pressure changes
o Aorta, pulmonary trunks
• Muscular arteries:
o Tunica media; very smooth muscle cells
o Easily distribute blood flow
o Brachial artery
• Arterioles: (resistance vessels)
o Tunica media; 1-2 layers of smooth muscles
o Constricts + dilates
o Control blood flow within muscles, organs & bones
o Lots of smooth muscle
o Thick walls, - i.d. 30-500 µm
• Capillaries: (exchange vessels)
o Has to be endothelium
o Rests on a basement membrane
o Only blood vessel which permits metabolic exchange between blood and surround
tissue
o Perfect size: avoid clotting
o 1 layer of endothelial cells
o i.d. ~8 µm
• Continuous capillaries:
o Most common type – skeletal muscle, bones & skin
o Has complete endothelial lining
o Permits diffusion of nutrients between endothelial cells
o Prevents loss of blood cells
• Fenestrated capillaries:
o Contains 60-80nm pores that penetrate the endothelial cells
o Each pore is bridged by a twin diaphragm
o Thinness permits rapid exchange of water & solutes
o Found in kidney: filtration of liquid; endocrine glands: hormones readily distributed;
digestive system: nutrients absorbed by fen. cap.

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• Veins: (conduit & capacitance vessels)

o Elastic & smooth muscle
o Capable of contraction & dilatation
o Relatively thin walls, i.d. 0.5-30 mm
• Venules: little veins
• Tunica media; 1-2 layers smooth muscle cells + collagen fibres
• Tunica adventitia is thick
• Collect blood from capillary beds to heart
• Valves present formed by folding of tunica interna
• Reduced pressure
• Lumen of venule is generally wider than equivalent arteriole
• Leads back to veins
• mainly connective tissue
• i.d.~ 20 µm

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f. Lymphatic vessels
• Lymphatic capillaries: dead ends
o Originate as pockets, not tubes
o Larger diameters than blood capillarieis
o Thinner walls than blood capillaries
o Flattened or irregular outline

• Lymphatic vessels: where lymphatic capillaries join = larger lymphatic vessels

o Like small veins, pale green colour
o Inner layer layer consists of endothelium surrounded by an elastic membrane
o Outer layer is a thin layer of fibrous connective tissue
o One way valves similar to veins

• Lymph nodes: round oval (bean shaped) bodies distributed along various lymphatic cells
• Superficial or deep
• Filters the lymph that enters through lymph vessels, removing bacterial & other materials
• Connected in series so lymph leaving one lymph node is carried to another lymph node

g. The location and role of valves (in the heart, blood vessels, lymphatic vessels)
• Right atrioventricular (tricuspid): three cusps between right atrium & ventricle
o Prevents back-flow of blood from right ventricle to right atrium
• Left atrioventricular (bicuspid/mitrial): two cusps between left atrium and ventricle
o Prevents back-flow from left ventricle to left atrium
• Aortic (semilunar): between left ventricle & aorta
o Prevents back-flow from aorta to ventricles
o No chordate tendinae or papillary muscles as arterial walls do not contract
o Support each other during closing
• Pulmonary (semilunar): between right ventricle & pulmonary trunk
o Prevents back-flow from pulmonary trunk to right ventricle
o No chordate tendinae or papillary muscles as pulmonary walls do not contract
• Blood cannot flow into the coronary arteries when the ventricles are contracting (systole)
o Contracting cardiac muscle compresses coronary arteries
o The opened aortic valve covers the openings to the coronary arteries

• During ventricular relaxation (diastole) blood in the aorta is under high pressure and will flow
into the coronary arteries
• Note: this phasic perfusion of the heart can become a problem during exercise when HR is
high because diastolic time is reduced just when demand is greater.

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2. The features of the mammalian circulatory system: a dual circulation connected in

series.
• We have a dual circulatory system - all
mammals and birds
• In effect, the heart consists of two pumps that
operate together
• The pulmonary and systemic circulatory
systems are arranged in series allowing an
equal high content of O2 to travel through the
body.
• If it were in parallel, only half would travel to
pulmonary and other half would travel to
systemic ! Congenital Heart Disease (hole
in heart)
• Right: systemic circuit drains into right side
through vena cavas to lungs so that gas
exchange can take place
• Left: pulmonary circuit drains into left so the
LV can pump oxygenated blood through aorta
and to rest of body
• Pulmonary circulation: heart to lungs back to
heart
o RV ! lungs through pulmonary trunk (arteries) ! LA through pulmonary veins
o Where gas exchange takes place
o Pressure: lower than systemic as it travels a shorter distance
• Systemic circulation: delivers oxygenated blood & nutrients to all organs/tissues
o LV ! body through aorta ! oxygen is used up, becomes deoxygenated ! repeat
o Pressure: greater as it travels a longer distance

3. The origin and regulation of electrical events of the heart (with reference to
microstructure of the cardiac myocyte).
Electrical Properties of the Myocardium

• Excitable cells are those that can be stimulated ! nerves, muscles, glands
• This excitability is comes from special properties of the cell’s membrane
• All cells have a membrane potential, brought about by the balance of electrical charge from
ions on either side of the cell’s membrane (especially Na+, K+, Ca2+).
• Excitable cells have a membrane potential that can change in response to a stimulus !
depolarization (action potential)
• Channel: A protein located within the cell membrane that forms a “hole” in the membrane
through which ions can pass. They are normally selective to certain specific ions.
• Voltage-gated channel: A channel that is closed at rest (ions cannot pass through). At a
certain Vm the channel will change shape to an open conformation, whereby ions can pass
through.
• Membrane potential (Vm): The electrical charge (voltage difference) across a cell’s
membrane. Usually the inside of a cell is more –ve than the outside and so the resting
membrane potential (Vm) is –ve (typically -60 to -90 mV). Vm is said to be polarised.
• Vm is determined by the balance of negatively and positively charged ions such as Na +,
Ca2+, K+ and Cl- on either side of the cell’s membrane.
• Depolarisation: the process of the voltage difference across the cell membrane moving
towards 0. At rest Vm is negative in excitable cells. Upon activation of certain channels in
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the cell membrane, there is rapid influx of positive ions (usually Na+ or Ca2+) into the cell,
causing the Vm to move towards 0.
o This is known as an action potential
o In fact, the Vm “overshoots” 0 and becomes positive (approx +40 mV).
• Repolarisation: After an action potential, the cell is depolarised. Certain channels (typically
K+) open and the movement of ions across these channel bring the Vm back to its resting
polarised (-ve) state.

Ion Movement In A Pacemaker Cell

THE HEART RATE IS DETERMINED BY THE RATE OF ACTION POTENTIAL DISCHARGE

• The heart beat is generated by autorhythmic myocardial cells that display pacemaker
activity
• Pacemaker cells are located in four sites (SA node, AV node, AV bundle & Purkinje fibres)
• These cells have different rates at which they depolarise. The cells with the fastest rate are
those in the SA node.
• Normal rate of action potential (AP) discharge in different sites
o SA node: every 0.75-0.85 s (70-80 per minute
o AV node: every 1-1.5 s (40-60 per minute)
o AV bundle: every1.5-3s(20-40 per minute)
o Purkinje system: every 1.5-3 s (20-40 per minute)
• Cardiac muscle: is made up of two types of cells: contractile + nodal
• Contractile: contract
• Nodal cells: generate and propagate electrical signal
• The spread of cardiac excitation is coordinated to ensure efficient pumping
• SA node ! AV node ! AV bundle ! R & L bundle branches ! Purkinje fibres
• SA node relays electric action potentials through the heart generating spontaneous action
potentials as a greater frequency pacemaker.
• SA node: functions as a pacemaker.

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• AV node: rate of impulse propagation is slowed ! ventricle along AV bundle ! complete

trial contraction animation
o Atria beats ! blood in ventricle ! ventricle beats ! blood to body
o This order must follow otherwise uneven beat results which is an indication that blood
is not pumping to body, instead it is pumping into atria
o AV bundle: left and right branches ! Purkinje fibres ! complete depolarisation
• It is important to delay the propagation of the action potential at the AV node as:
o It allows the ventricles to completely fill before contracting as it takes a further 300ms
o The delay allows atrial contraction to complete before ventricular contraction begins
o Atria beats ! blood in ventricle ! ventricle beats ! blood to body

Sa Node

• It provides source of auto activity

• Nodal cells: small-diameter, cardiac muscle cells that merge with the cardiac muscle cells of
the right atrial wall. Thus, when action potential is generated in the SA node, heart contracts
spontaneously and rhythmically
• If the SA node is damaged, the next fastest tissue takes over the rhythm (i.e. the AV node)
• SA node is affected by autonomic nerves and circulating catecholamines
o The average resting heart rate in an adult is ~ 70 BPM. Childrens’ heart rates are
faster than adults (generally speaking smaller animals HR are faster than large
animals).
o The speed at which pacemaker cells in the SA node depolarize determines the rate
at which the heart contracts.
o HR is modulated by neural and hormonal input.
o Parasympathetic (vagal)
" rest and digest
" neurotransmitter is acetylcholine (ACh).
" increase in K+ conductance.
" activation of the cardiac vagal cells ! decrease in slope of pacemaker
potential ! decreased HR
" slower depolarisation
o Sympathetic
" Fight and flight
" The catecholamines noradrenaline (from sympathetic nerves) and adrenaline
(from adrenal gland)
" increase in Na+ conductance through the funny channel.
" activation of cardiac sympathetic nerves —> increase in slope of pacemaker
cell —> increased HR
" rapid depolarisation

Action Potential

• Action potential: upon activation of certain channels funny channel = rapid influx of ions
such as Na+ the cell becomes more +ve and mV becomes positive, reaching a threshold.
• Increase so that inside cell is more positive than outside. This is what generates the
contraction.

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ACTION POTENTIAL IN MYOCARDIAL CONTRACTILE CELL IS DIFFERENT TO

PACEMAKER CELL

The Ionic Mechanism Underlying Action Potential Of Myocardial Contractile Cell

1. Rapid depolarization:
• Cause: Na+ entry
• Duration: 3–5 msec
• Ends with: Closure of voltage-gated fast sodium channels & opening of K+ channels
2. Plateu
• Cause: Ca+ entry, ↓K+ loss
• Duration: ~175 msec
• Ends with: Closure of slow calcium
3. Repolarization
• Cause: K+ loss
• Duration: 75 msec
• Ends with: Closure of slow potassium channels channels & opening of slow K+ channels

• Refractory period: between the initiation of an action potential and restoration of the normal
resting potential. The cell will not respond to stimuli and hence a new action potential is not
created, therefore no contraction occurs
• Nodal cells form a specialized high conduction-speed pathway through heart
o Absolute: moment the Na+ opens at threshold until it closes
o Relative: when [Na+] regain normal resting conditions

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Comparison Of Skeletal Muscle To Cardiac Muscle

• In skeletal muscle, contraction occurs after the refractory period. This means that skeletal
muscle can generate another action potential before contraction is complete leading to a
summation of contraction force i.e. increased tension
• In cardiac muscle, refractory period continues until contraction is nearly complete
• The refractory period of myocardial cells (250 ms) is very much longer than skeletal muscle
cells (approx 10-25 ms)

• This is significant because, unlike skeletal muscle, the refractory period of the cardiac
muscle cell also lasts for the duration of the contraction
• Tetanic contractions of the cardiac muscle is not possible

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UNIQUE PROPERTIES OF CARDIAC MUSCLE ALLOW THE RAPID AND COORDINATED

SPREAD OF THE AP THROUGH MYOCARDIUM

• Contraction of cardiac muscle is triggered by a wave of action potentials (AP) sweeping

across the myocardial cell membranes
• The heart beats rhythmically because of regular, self-generating APs (autorhythmicity)
• AP spreads throughout myocardium rapidly and in a coordinated manner so ventricular
fibres contract virtually simultaneously (pumps effectively)
• The rapid propagation of the APs across the heart is due to 2 factors: - 1. low-resistance
junctions (intercalated discs) between muscle fibres (allow AP to pass) - 2. specialized
conducting muscle fibres that facilitate rapid & co-ordinated spread of excitation. This is
especially in the AV bundle, bundle branches and Purkinje fibres.

Conduction Of The Electrical Signals In The Heart

The Electrocardiogram (Ecg)

• Because the spread of depolarisation through the heart is coordinated and highly
reproducible, it is possible to easily identify the cardiac signal from all the other electrical
activity that is being generated by the body.
• This signal is conducted throughout our tissues because of the high concentration of
electrolytes (ions) in our extracellular fluid.
• Therefore, the electrical events that occur in the heart can be recorded by placing surface
electrodes on the body.
• This recording is called an electrocardiogram (ECG).
• It is non-invasive (does not hurt)
• The ECG can be used clinically to diagnose numerous cardiac conduction problems and
myocardial infarcts.
• The ECG is divided into waves and segments between the waves. The intervals are the
combination of the wave and the segment.

TYPICAL ECG

• Major Components
• P-wave: atrial depolarisarion
• QRS complex: ventricular depolarisation and atria repolarising simultaneously
• T wave: ventricular repolarisation
• PR segment: AV nodal delay
• ST segment: ventricular contraction (emptying)
• TP interval: ventricles relaxation (filling)

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The ECG

A Typical ECG: Major Components

• P-wave: (50-80 ms) - atrial depolarisarion

• QRS complex: (80-120 ms) - ventricular depolarisation and atria repolarising simultaneously
• T wave: - ventricular repolarisation
• PR interval (120-200 ms) - AV nodal delay
• ST segment (80-120 ms) - ventricular contraction (emptying)
• TP interval: (70-500 ms) - ventricles relaxation (filling) and varies with heart rate

What Determines The Shape Of The Ecg/ The Axis Of The Ecg

• An ECG displays the voltage between a pair of

electrodes
• currents travelling at a 90° angle to a lead will
create no deflection
• A depolarizing current that is travelling towards the
positive electrode will cause an upward ECG
deflection

• A depolarizing current travelling away from the

positive electrode will inscribe a downward
deflection

• A repolarizing current that is travelling away from

positive electrode will cause upward ECG deflection

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Diagnosing Cardiac Conditions

• PR interval
o Represents atrial depolarisation and contraction
o Incorporates period of AV nodal delay
o Max duration 200 ms
o If > 200 ms, suggests damage to internodal pathways, or commonly AV node.

• Second and third degree heart block

o 2nd degree heart block
" Missed QRS
" AV node problem
" Experience “missed beats”
o 3nd degree heart block
" normal P wave
" no link to QRS
" Ventricles generate own signal (such as from bundle branch)

• Atrial Fibrillation (AF)

o Atrial fibrillation is the most common rhythm disorder.
o The most common symptom is a fast and irregular heart rate, although it may be
asymptomatic.
o AF increases the risk of stroke
o The normal electrical impulses generated by the sinoatrial node are overwhelmed by
disorganized electrical impulses usually originating in the roots of the pulmonary
veins, leading to irregular conduction of impulses to the SA node.

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• Long QT syndrome and sudden cardiac death

o The QT interval is the time required for the ventricles to undergo a single cycle of
depolarization and repolarization
o Normal values are between 0.3-0.45 s
o A prolonged QT interval may be caused by many factors, including conduction
problems, coronary ischaemia, myocardial repolarisation, some medications,
hypocalcaemia.
o It extends the length of the refractory period causing an unstable period in the heart’s
electrical activity.
o May be due to re-opening of Ca2+ channels at end of plateau phase
o Long QT syndrome is a congenital heart defect that can cause sudden unexpected
death, even in healthy children and young adults.
o It is often asymptomatic until an event occurs.
o A premature heart beat (QRS) occurring during the lengthened QT interval can
trigger a ventricular tachycardia.

• ST elevation
o Normally the ST segment is at the iso-electric point.
o Under conditions of cardiac ischaemia or infarct (heart attack), this may be elevated
or depressed, depending on the site of the ischaemia.

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4. How the heart functions as a pump

Excitation- Contraction Pumping

• In a contractile cell, the action potential is caused by sodium, plateau phase is caused by
calcium
• Increases the amount of calcium internally
• Sarcoplasmic reticulum is a storage of calcium
• Calcium enters through membrane
• This causes release of calcium from sarcoplasmic reticulum.
• Calcium allows the actin and myosin to bind (removes proteins that prevent this)

Phases Of The Cardiac Cycle

Phase 1

• Ventricular diastole – late

• Atrial contraction forces a small amount of additional blood into relaxed ventricles.
• Atrial systole ends, atrial diastole begins
• Ventricular relaxation
• Passive flow of blood into left atrium (& left ventricle through mitral valve
• During this phase:
o Sa node depolarizes
o Wave of depolarization sweeps over atria (which then contracts)
• High value = systole (arteries at their max/contraction)
• Low value = diastole (relaxation/ arteries at their lowest)

Phase two

• Ventricular systole- isovolumetric phase:

• Ventricular contraction pushes AV valves closed but does not create enough pressure to
open semilunar valves (too much
pressure in the arteries)
• Therefore, all 4 valves are closed
• Ventricular pressure rises
• Atrioventricular valve closes
• When this pressure exceeds aortic
pressure: aortic valve opens

Phase three

• Ventricular systole- ventricular ejection:

• As ventricular pressure rises and
exceeds pressure in the arteries, the
semilunar valves open and blood is
ejected.
• Pressure in ventricles exceeds the
pressure in the arteries
• Blood ejected into the arterial system
• Ejection most rapid during early part
• Terminated by the end of ventricular contraction
• Ventricular pressure falls rapidly and aortic valve closes

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Phase four

• Ventricular diastole
• Isovolumetric relaxation.
• As ventricles relax, pressure in ventricles drops; blood flows back against cusps of
semilunar valves and forces them closed. Blood flows into the relaxed atria.
• All valves closed
• Ventricular pressure falls
• Aortic pressure falls much less rapidly than ventricular pressure
• Because aortic run-off is much less rapid, being dependent on peripheral resistance

Phase five

• Ventricular diastole- early

• All chambers are relaxed
• Ventricles fill passively.
• NOTE: ventricle is >80% full prior to atrial systole occurring (which is during late ventricular
diastole - Phase 1)

5. The factors that influence cardiac output and how it is regulated, including the
mathematical formulae used to describe these factors.

Factors Affecting Cardiac Output

• Change Heart Rate - Autonomic Nervous System - sympathetic activation increases HR -

parasympathetic activation decreases HR - Hormones (adrenaline, noradrenaline) - acting
on adrenergic receptors (β1)
• Change Stroke Volume - Change pre-load (end diastolic volume) - Change afterload (blood
pressure) - Change contractility
• Pre-load: defined as the tension in the ventricular wall at the end of diastole. For practical
purposes this is measured as the ventricular end-diastolic pressure.
• After-load: defined as the pressure that the ventricles must overcome to eject blood. This is
the aortic pressure at the time the aortic valve opens.

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Frank-Starling Law Of The Heart

• Frank-Starling Law: The greater the filling of the

ventricle (i.e. end-diastolic ventricular volume), the
greater will be the force of contraction (and hence
stroke-volume)
• Consequences of Frank-Starling Law
• A change in return of blood to right or left ventricle is
immediately followed by a change in output (e.g. on
changing posture when venous return suddenly decreases or increases).
• The cardiac output tends to be maintained in the face of changing aortic pressure (afterload)

Frank-Starling Law: Effects Of Change In Venous Return

1. Increase in venous return

2. Increased end-diastolic ventricular volume
3. Increased force of ventricular contraction
4. Increased stroke volume
5. Increased cardiac output

Frank-Starling Law: Effects Of Change In After-Load

1. Increase in after load

2. Reduced stroke volume
3. Increased end-systolic ventricular volume
4. Increased end-diastolic ventricular volume
5. Increased force of contraction
6. Stroke volume increases, back towards original value

Neural And Hormonal Control Of Cardiac Contractility

• Cardiac contractility is defined as the ability of the heart to contract, at any given end-
diastolic ventricular volume
• Activation of cardiac sympathetic nerves, or an increase in circulating adrenaline, increases
cardiac contractility (indicated by red arrow). - this effect is due to an increase in
intracellular [Ca2+] in myocardial fibres.
• Activation of cardiac vagal nerves leads to a decrease in myocardial intracellular [Ca2+],
resulting in a reduced cardiac contractility (indicated by
blue arrow).
• NOTE: The force of contraction of the heart therefore
depends upon both (i) the end- diastolic ventricular
volume and (ii) extrinsic factors that affect contractility.
• Cyclic AMP activates protein kinases, which then
phosphorylate:
• (1) Slow Ca2+ channels, promoting entry of more Ca2+
from the extracellular space;
• (2) SR protein that causes the SR to release more Ca2+,
• (3) Myosin, which increases the rate of myosin cross
bridge cycling.
• (4) In addition, phosphorylation of the SR calcium uptake
pump removes Ca2+ more rapidly from the cytoplasm,
thus promoting relaxation.

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• Inotropic : affects the contractility of the myocardium

• Thus, positive and negative inotropic effects refer
to increases or decreases, respectively, in cardiac
contractility e.g. sympathetic +ve, parasympathetic –
ve
• Chronotropic: affects the heart rate
• Thus, positive and negative chronotropic effect
refers to increases or decreases, respectively, in
heart rate e.g. sympathetic +ve, parasympathetic –
ve

Redistribution Of Cardiac Output During Exercise

• Reasons for blood flow changes:

• Heart and skeletal muscle: mainly local metabolic factors
causing vasodilation
• In the heart, blood flow occurs mainly during ventricular
diastole (coronary vessels are compressed during ventricular
systole)
• Skin: mainly decrease in sympathetic vasoconstrictor effects,
plus effects of bradykinin in sweat, both causing vasodilation,
as part of thermoregulatory reflexes
• Kidney and abdominal viscera: mainly increase in
sympathetic vasoconstrictor activity
• Brain: no change, because cerebral blood flow mainly
affected by local metabolic activity (i.e. neural activity), which
does not change as a result of exercise

Why Do We Measure Blood Pressure?

• Mean blood pressure represents the driving force for blood flow, so knowing BP allows us to
know something about blood flow.
• Abnormal BP can lead to medical problems
• High —> tissue damage; low —> syncope (fainting)
• Chronic hypertension is a major risk factor for myocardial infarction (heart attack) and
cerebrovascular events (stroke), renal disease.
• In clinical setting, BP can give an idea of cardiovascular stability. Hypotension:
• Internal bleeding (unconscious patient arrives at hospital or after surgery) - poor cardiac
function (heart failure)
• Acute hypertensive episode
• Recreational drug use (eg cocaine, ecstasy, amphetamine all raise BP).
• Hypertension: high BP
• Hypotension: low BP

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Measuring Blood Pressure

• 1718-1727: Stephen Hales first measured blood pressure.

• He placed a brass pipe into the carotid artery of a horse and connected it to a glass tube
• He measured the height that the blood moved up the tube
• 8’3” (251.5 cm) - 136cmH2O=100mmHgso - equivalent of 184 mmHg. - height of column of
blood rose & fell with each heart beat.
• Systolic Pressure (SBP) - max. BP - occurs during ventricular systole
• Diastolic Pressure (DBP) - min. BP - occurs at end of ventricular diastole
• Pulse Pressure (PP) - SBP-DBP - Mean Pressure (MBP) - DBP +1/3 PP
• Mean blood pressure (MBP) is the average blood pressure during a cardiac cycle.
• MBP is closer to diastolic than systolic pressure because the ventricle is in diastole longer
than systole (~60-65% of cardiac cycle at rest)
• Systolic and Diastolic Blood Pressure - Arterial Blood Pressure = 120 (systolic) / 80
(diastolic)

Why Is The Regulation Of Arterial Blood Pressure Important In Homeostasis?

• Homeostasis depends upon the blood flow to all regions in the body being sufficient for the
metabolic requirements of each region.
• Regional blood flow can vary according to local demand, via metabolic autoregulation.
• However this depends upon the perfusion pressure (i.e. arterial blood pressure) being
maintained within reasonable narrow limits (think about Poiseuille’s Law).
• The main mechanism regulating blood pressure in the short term (i.e. seconds or minutes)
is the baroreceptor reflex.

Short-term control of blood pressure

• Baroreceptors are spray-type nerve endings lying in

the walls of the aorta and carotid artery (carotid sinus)
that are stretched when the pressure increases.
• They are tonically active at normal levels of arterial
pressure, and are able to detect changes in mean
pressure over the range 50 mmHg (threshold) to ~160
mmHg (saturation level).

Baroreceptor Reflex Control Of Blood Pressure - The

Effect Of Posture

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6. The factors that influence blood flow and blood pressure and the mathematical
formulae used to describe them. Regulations of blood flow and blood pressure,
including local, humoral and neural influences

The Determinants Of Resistance And Blood Flow

• The fundamental purpose of the cardiovascular system is to generate a pressure to drive

blood flow through the vessels.
• Once a pressure is generated, the amount of flow is dependent upon the resistance - the
higher the resistance the lower the flow - the lower the resistance the higher the flow

POISEUILLE’S LAW

• Q= πr4 ∆P/ 8ηL

• η = viscosity of blood
• ∆P = QR
• Q=∆P/R
• R = 8ηL/πr4
• Poiseuille’s Law shows that resistance = kL/r4
• Radius of vessel 1 is twice that of vessel 2 Resistance of vessel 1 is 1/16th that of vessel 2
• Assuming pressure gradient (∆P) is the same, Flow through vessel 1 is ....... that of vessel 2

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A Small Amount Of Arterial Occlusion Can Have A Dramatic Effect On Flow

• Increasing of fat in the arteries

(arteriosclerosis)
• Therefore, the flow decreases as
the radius decreases due to fat
increase
• Therefore, you require more
pressure (higher blood pressure,
dangerous)

Resistance Of A Network Of Blood Vessels

• The arterial and venous systems offer relatively little resistance to flow
• The arteriolar system as a whole has a relatively high resistance (60-70% of the total
resistance of the entire circulation)
• The capillary system as a whole has a resistance, which is less than that of the arteriolar
system, even though capillaries have the narrowest internal diameter of all blood vessels.

Cardiac Output And Total Peripheral Resistance

• For a system of vessels, Ohm’s law also applies: Pressure gradient (∆P) = Q R
• In the case of the entire systemic circulation
• ∆P = mean arterial pressure (MAP) –
• Right atrial pressure (RAP)
• Q = total flow through the systemic circulation = cardiac output (CO)
• R = total resistance of the systemic circulation, referred to as the total peripheral resistance
(TPR)
• TPR = MAP-RAP
• Thus, for the entire systemic circulation, MAP - RAP = CO x TPR • But RAP ~ 0 mmHg,
therefore (to a good approximation):
MAP=COxTPR
• E.g. If map =105, rap = 5 mmhg, and co = 5 l/min, tpr = (105-5)/5 = 20 mmhg/l/ min
• Note: mean pulmonary arterial pressure is ~1/3 that of map, and therefore pulmonary
vascular resistance is also ~1/3 that of tpr. Why must that be so?
• Our body is able to increase/ decrease CO

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Blood Flow Velocity Is Slowest Through Capillaries

• Changes in total cross- sectional area, and blood velocity, at

different sites in the systemic circulation
• Flow rate = volume of blood/unit time
• Flow velocity = speed, or distance blood flows/unit time
• at each branching point, the total cross sectional surface
area is greater than the mother vessel (aorta)

Arterial And Venous Capacitance

• The elastic properties of a blood vessel can be measured by

determining the relationship between the static pressure and
volume of a segment of that vessel.
• This is called the capacitance (or sometimes compliance).
• Capacitance (C) = ∆V/∆P
• where ∆V is the change in volume, and ∆P the
corresponding change in pressure.

How much does the volume change with an increase in

pressure?
• Venous capacitance is about 20 times arterial
capacitance (walls of veins are more distensible).
• Therefore an increase or decrease in total blood
volume is taken up into, or lost from, the venous
system.

Factors Affecting Arteriolar Radius (And Therefore Vascular Resistance)

• Local factors: myogenic activity, metabolites, histamine, heat/cold

• Autonomic nerves: sympathetic vasoconstrictor nerves (nearly all
beds), parasympathetic vasodilator nerves (very few beds)
• Circulating hormones: adrenaline, noradrenaline, vasopressin,
angiotensin II
• Normal arteriolar tone
• Vasoconstriction ! increased contraction of circular smooth
muscle in the arteriolar wall, which leads to increased resistance
and decreased flow through the vessel
• Vasodilation ! decreased contraction of circular smooth muscle
in the arteriolar wall, which leads to decreased resistance and
increased flow through the vessel

Local Factors: Metabolites

• Increase in muscle metabolic activity (in specific region)

• Increase in consumption of O2 and production of CO2 and other metabolites
• Decrease in local O2 concn and increase in concn of CO2 and other metabolites in
extracellular fluid
• Vasodilation of arterioles in local region
• Increase in local blood flow
• Increase in rate of supply of O2 and removal of CO2
• O2 and CO2 levels in extracellular fluid return to normal

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Auto-Regulation Of Blood Flow To A Vascular Bed By Local Factors

↓BP ! ↓blood flow ! accumulation of metabolites ! vasodilation ! ↑blood flow

↑BP ! ↑blood flow ! wash out metabolites ! vasoconstriction ! ↓blood flow

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7. The microcirculation and exchange of substances

The Microcirculation

• Arterioles contain relatively high proportion of smooth muscle; thick walls, i.d. 30-500 µm;
resistance vessels. They are innervated by sympathetic nerves.
• Capillaries consist only of a single layer of endothelial cells. i.d. ~8 µm; exchange vessels.
They form a complex network.
• There are pre-capillary sphincters (band of smooth muscle) at their origin. These open in
response to increase in metabolite concentration. - e.g. during exercise, the number of
open capillaries in skeletal muscle may increase 20-fold.
• The density of capillaries varies in different tissues, according to the normal metabolic
activity of that tissue (e.g. high in skeletal muscle, brain, glands, much less in bone or
cartilage).
• Venules have an i.d. of ~20µm; mainly consist of connective tissue.
• The metarterioles contain some smooth muscle, and serve either as arterio - venous shunts
(esp. in skin), or else give rise to capillaries.

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Capillary Anatomy

The Microcirculation: Many Capillaries Are Not Open At Rest

• This shows the effects of opening or closing pre-capillary sphincters on the number of open
capillaries. If the number of open capillaries is increased, then the average time for
exchange within the capillaries is also increased

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Effects Of Changes In Metabolic Activity On Capillary Exchange

Movement Of Substances Across The Capillary Wall

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Movement Of Substances Across The Capillary Wall

Diffusion Transcytosis

Most important mechanism of exchange Endothelial cells encapsulate a substance on

one side of the membrane (endocytosis),
Substances move along a concentration transport the vesicle across the membrane and
gradient: - [high] → [low]; eg. glucose and O2 release the material on the other side
diffuse out of blood, CO2 & wastes diffuse into (exocytosis)
blood
Least important mechanism of exchange - i.e
Through cell (lipid soluble) - O2, CO2, steroid only a small number of substances moved in
hormones (eg cortisol) this way

Between cells (intercellular clefts or pores) - Examples include insulin, fatty acids.
glucose, electrolytes

With lipid-insoluble molecules of increasing size,

the rate of diffusion becomes progressively less,
until at a molecular weight of 60,000 the
diffusion is minimal.

Movement Of Plasma Across The Capillary Wall

• Plasma and dissolved solute moves across the capillary membrane via the process of bulk
flow ! the fluid (water and the various constituents, other than proteins) moves as a unit in
contrast to diffusion based on individual concentration gradients
• Fluid moves through water-filled pores.
• When pressure inside the capillary exceeds pressure outside, fluid is pushed out —>
filtration
• When pressure outside is greater than pressure inside, fluid moves into capillary —>
reabsorption
• Important in regulating the distribution of extracellular fluid between plasma and interstitial
fluid
• Filtration = movement of fluid out of capillary
• Reabsorption = movement of fluid into capillary

Colloid Osmotic Pressure

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Filtration & Reabsorption

• Fluid flow outwards = k {sum (outward forces) - sum (inward forces)}

• Therefore, fluid flow outwards = k {(Pc + πIF) - (PIF+ πp)}
• Fluid flow outwards = k {(Pc + πIF) - (PIF + πp)
• At arterial end, fluid flow outwards=k{(35+1)-(0+26)=10k
• This value is positive, therefore FILTRATION occurs
• At venous end, fluid flow outwards= k{(17 +1) - (0+26)=-8k
• This value is negative, therefore REABSORPTION occurs

8. The role of the lymphatic system and its relationship to the circulation
Lymph Fluid Empties Into The Venous Circulation

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The Lymphatic System Is An Accessory Route By Which Interstitial Fluid Can Be Returned
To The Circulation

• On average, slightly more fluid is filtered out of the capillaries than is reabsorbed (~3
litres/day).
• This, plus protein that leaks out of capillaries, is returned to the circulation via the lymphatic
system
• Transport of lymph occurs by means of compression of lymphatic vessels by skeletal
muscle contraction, aided by one-way valves in vessels
• The lymph percolates through lymph nodes which contain phagocytes that destroy bacteria
- part of body’s defence system
• Oedema (edema; lymphedema) is build up of fluid in interstitial space.
• This occurs as a result of
o Reduced concentration of plasma protein
o Increased capillary permeability, e.g. Via histamine in allergic reactions or tissue
injury
o Increased venous pressure, causing increased capillary hydrostatic pressure;
o Blockage of lymphatic vessels

9. The pathophysiological processes underlying the development of common

cardiovascular diseases
• Coronary artery disease refers to regions of partial or complete blockade of parts of
coronary circulation, normally due to a fatty deposits (atherosclerotic plaque), which in turn
can cause blood clots.
• The cause of atherosclerosis is not fully understood. 13
• Risk factors include, smoking, obesity, high blood pressure, lack of exercise, high
cholesterol levels.
• There are two sources of cholesterol
o Dietary: mostly from animal products: including meat, eggs, butter
o Manufactured: cholesterol is made by cells, especially liver cells
• LDLs and HDLs: Cholesterol is lipid and is not soluble in blood. Most Endothelium
cholesterol binds to plasma proteins (lipoproteins). The name refers to the density of the
protein: HDL = high density lipoprotein, LDL = low density lipoprotein, VLDL = very low
density lipoprotein.
o LDL is the “bad cholesterol”. LDL transports cholesterol into cells (including
endothelial cells of blood vessel).
o The presence of oxidised LDL in the blood vessel wall is a trigger for inflammation
which leads to the development of a plaque
• The enlarging plaque reduces blood flow and can affect oxygen delivery to the cardiac
muscle (myocardial ischaemia).
• Thromboembolism: However the most serious consequence is that the plaque causes
damage to the endothelium which in turn causes the production of a blood clot (thrombus).
• The thrombus can enlarge until it completely blocks the vessel or it may break off from its
attachment and be pushed
downstream (embolus) where it
can plug a smaller vessel.
• Such sudden occlusion of
a coronary vessel is the
major cause of a myocardial
infarction (heart attack).

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Treatments for heart attack

• Cardiac muscle cells do not regenerate and are replaced by non-contractile scar tissue
o Heart muscle loses strength
o May also cause arrhythmia or ventricular fibrillation
• However treatment can be very successful if caught in time.
o Clot busters: injection of thrombolytic agent. Binds to fibrin component of blood clot
and breaks down clot
o Streptokinase or tissue plasminogen activator (t-pa))
o Tenecteplase: recombinant dna mutation of t-pa that is more specific and longer
lasting
• Best practice is now considered coronary artery angioplasty/ stenting.
o Inflating a balloon to compress thrombus against inside c. Artery
o A tube placed in the coronary artery to keep artery open

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Respiratory!System!Learning!Objectives!
1. The organs, passages and musculoskeletal framework of the respiratory system
The respiratory system is the external movement of gas between the atmosphere and the lungs as
well as the internal utilisation of oxygen by the cells. It is needed to supply oxygen for aerobic
energy production and to regulate pH levels.

The respiratory system through two parts:

• Conducting system – involved in gas movement for ventilation
• Gas exchange system

Concentration gradients control the movement of gas through the system:

• oxygen concentration (partial pressure) is highest in the atmosphere (ie. the inspired air),
lowest in the cells
• carbon dioxide concentration is highest in the cells, lowest in the atmosphere

• Each step in the respiratory system represents a limitation to gas flow ! If resistance is
increased at any point in the respiratory system, movement of gas through the system will be
decreased.
• Respiratory care aims to decrease resistance to gas flow eg. by removing mucus
• Any increase in resistance will decrease O2 delivery to tissues ! decrease exercise capacity
= decreased function

Respiration is dependent on the gas laws:

• Gas will move down (along) a pressure gradient from higher to lower pressure (bulk flow) !
occurs quickly. Bulk flow enables diffusion to continue.
• Gas will move down a partial pressure (concentration) gradient from higher to lower
concentration (diffusion) ! concentration gradient. Diffusion and bulk flow occur together.
• The pressure exerted by a gas in a mixture of gases is equal to the total pressure multiplied by
the fraction of the total pressure it represents
• The atmosphere is always 79% n2 and 21% o2
At sea level the atmospheric pressure is 760 mmhg
Po2 = 21% x 760 = 160 mmhg
At 5000 m the atmospheric pressure is 500 mmhg
Po2 = 21% x 500 = 105 mmhg

• The pressure driving o2 to the lungs can be increased by increasing the inspired oxygen
concentration Eg. Breathing 40% o2 at room pressure Po2 = 40% x 760 = 304 mmhg
• Pressure and volume are inversely related P1v1 = p2v2

Structure Of The Conducting System

Upper airways
• Nose
• Paranasal sinuses
• Pharynx
Lower airways
• Larnynx ! protects the trachea and lungs
• Trachea and Bronchi ! ciliated cells move dust & mucous
• Bronchioles ! no cartilage or cilia, contain smooth muscle

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• Nose comprises of:

o Lateral walls – part of the skull
o Nasal passages – separated by septum
o Three conchae project from lateral walls – they slow air flow and create turbulence
Lining tissue is highly vascular - contains large expandable veins:
o Warms, moistens and cleans the inspired air
o Mouth breathing increases heat and water loss

• Sinuses ! Principal role is to lighten the skull

• LARYNX
Structure made of 3 unpaired cartilages:
o Epiglottis ! Seals larynx during swallowing ! protect the trachea and any foreign
material getting in
o Two cartilages hold the trachea open ! Thyroid cartilage and Cricoid cartilage
o Three paired cartilages ! Corniculate, Arytenoid and Cuneiform
o Larynx protects the trachea using two mechanisms – cartilages and vocal cords (also
known as vocal folds)
Vocal Cord Dysfunction
o Dysfunctional breathing in athletes can be due to VCD
o Can mimic exercise-induced asthma
o Common cause of upper airways obstruction during exercise !exercise-induced
dyspnoea.
" The vocal cords close during inspiration
" Can occur at any level of exertion
o Causes:
" Noisy breathing, dyspnoea, wheezing and sensation of obstruction at the neck
and upper
" Flow rates, minute ventilation and sao2 drop quickly, rapid rise in CO2

• TRACHEA AND PRIMARY BRONCHI

o Trachea made of 15-20 posteriorly incomplete cartilagenous rings that prevent
collapse and overexpansion.
o Stacked structure prevents occlusion of trachea during head movement ! rectangular
stacks
o Mucosa of trachea and bronchi comprises:
" Ciliated cells
" Goblet (mucous producing) cells
" Sero-mucous glands in sub mucosa

Trachea divides into

o Two primary bronchi – one supplying each lung
" Right is larger and descends more steeply
o Primary bronchi divide into secondary bronchi – one supplying each lung lobe
" Right lung has three lobes, left lung has two
" Secondary bronchi are made of cartilage plates
o Secondary bronchi divide to form tertiary bronchi
" Right lung has 10 tertiary bronchi, left lung 8 - 10
o Tertiary bronchi divide to form bronchioles
" Do not have cartilage in walls
" Have much smooth muscle

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• RESPIRATORY BRONCHIOLES, ALVEOLAR DUCTS AND ALVEOLI

o The only areas where gas exchange occurs
o Respiratory bronchioles and alveolar ducts have outpouchings – alveoli
o They terminate in the alveolar sacs.

o There are about 23 generations of airway division between the larynx and the alveoli
" Larger airways are held open by cartilage
" Respiratory bronchioles are held open by elastic tissue ! susceptible to
collapsealveoli are designed to maximise diffusion:
" Large surface area
" Very thin walls
" Large numbers of capillaries
o Alveoli abut one another and are surrounded by elastic tissue.

• MUCOCILIARY DRAINAGE
o Occur more slowly in smaller airways compared with larger.
o To be effective requires:
" Normal cilia
" Optimum thickness and viscosity of mucous.
o The mucous acts as a trap for bacteria: decreased clearance means bacteria remain in
airways !increased risk of infection

• PATHOPHYSIOLOGY
o Decreased clearance ! sputum retention ! collapse and consolidation of lung tissue

o Decreased clearance occurs in: Most common disease is cystic fibrosis

" The aged
" Sleep
" Disease
" Dry cold air

o Increased clearance occurs with:

" Intense exercise
" Postural drainage
" Percussion
" Nebulisation

2. Relate the function to the histology of the respiratory system

Anatomy Of The Lungs
• Contain bronchial tree and respiratory portion (gas exchange portion) of the respiratory system.
• Located in the thoracic cavity separated by mediastinum. ! suspended in the cavity and does
not actually attach anywhere. The mediastinum creates 2 distinct sides and anything that needs
to run through the chest walls is located inside the mediastinum.
• Pleura line ! pleura roles is to allow the lungs to run smoothly across the chest wall while we
exhale and inhale – pleurisy is the disease that creates friction and the 2 surfaces are no long
smooth = painful
o Outer surface of lungs (visceral – organs pleura - walls)
o Inner surface of thoracic wall (parietal pleura)
• Pleural membranes produce fluid that acts as a lubricant.

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• The base of each lung rests on the diaphragm. The apex projects to a point superior and
posterior to the clavicle.
• The costal surface is in contact with the ribs.
• These all enter and leave through the hilus:
o Bronchi
o Pulmonary vessels
o Lymphatic vessels
o Nerves

• Each lung is subdivided into lobes.

• Right lung is larger – has three lobes
o Superior - separated by horizontal fissure
o Middle - separated by oblique fissure
o Inferior
• Left lung has two lobes
o Superior - separated by oblique fissure
o Inferior
• The lobes are divided into bronchopulmonary segments.
• Each is supplied by
o A tertiary bronchus
o A pulmonary artery branch
o A pulmonary vein branch
• And surrounded by connective tissue
• Individual bronchopulmonary segments can be surgically removed.

3. The process of ventilation, including the gas laws and the relationship between
pressure, resistance and flow and the role of the inspiratory and expiratory
muscles, the various pressures inside the chest, the role of the pleura in
facilitating ventilation
Pulmonary Circulation
• Lungs are supplied by both pulmonary (right ventricle – involved in gas exchange) and systemic
circulation (left ventricle – supplying the blood that the lung needs to survive).
• Pulmonary circulation
o Is low pressure
o Originates in right ventricle (is not required to do as much work thus not as strong as
the left ventricle) and terminates in left atrium
o Carries deoxygenated blood into the lungs for gas exchange.
• Systemic circulation
o Supplies bronchi and bronchioles
o Bronchial artery is branch of thoracic aorta
o Bronchial veins draining into azygos veins.
• Lymphatic drainage ! oedema
• Lungs contain lymph nodes and vessels.
• Lymph from the lung drains to
o Pulmonary lymph nodes within the lung !
o Bronchopulmonary lymph nodes at hilus !
o Larger lymphatic vessels !
o Thoracic duct
• Lymph nodes are rarely visible on dissection specimens

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Gas Movement Within The Airways

• Gas movement from the atmosphere to the lungs occurs in two phases:
o Movement between the atmosphere and the upper airways: largely due to bulk flow
o Movement between the upper airways and the alveoli: largely due to diffusion,
although there is some bulk flow of gas into and out of alveoli
• Diffusion is a slow process so:
o Changes in alveolar gas composition occur slowly
o The alveolar gas is not replaced on each breath
• In order for the process of diffusion to continue, the concentration gradients must be maintained
by bulk flow
• Changes in lung volume are responsible for pressure gradients down which the gases move.
o Pressure changes in the alveoli !
o Pressure changes in the bronchioles !
o Pressure changes in the upper airways
o When upper airway pressure > atmospheric pressure ! expiration occurs
• Muscular effort is required to produce gas flow because
o The column of gas in the airways has inertia which must be overcome to initiate gas
movement.
o The lung and chest wall are elastic - this opposes inflation - as lung volume increases
the elastic forces become greater
o The airways represent a resistance to gas flow - the impedance - the flow rate
(determined by frequency) determines the impedance

Respiratory pump
Inspiratory muscles
• Contraction of diaphragm
o Lowers dome - predominates when supine ! changes due to posture, is vital when
lying down. Double dome shape into the thorax at end-expiration (relaxed) and
downwards dome at end-inspiration (contracted).
o When the diaphragm drops down it increases the thoracic volume and compresses the
abdominal contents.
o Lifts and flares ribs
o Parasternal and scalenes also active ! moves the walls upwards and outwards as a
secondary muscle to increase volume of the thorax
• On standing
o Diaphragm shortens, parasternals and scalene more activated ! work in partnership
to allow maximum gas exchange occurring in the lungs
o Less vital and the weight of the lungs pushing down only changes the volume is less.
o With exercise ! inspiratory muscles more activated with increasing ve ! minute
ventilation
• Respiratory disease ! additional recruitment of other rib cage muscles and neck inspiratory
muscles if there are
o High lung volumes and/or
o High resistance ! more muscular effort required to move the gas through the
passageway
• Expiratory muscles ! quiet at supine rest, activated on standing. Recruitment at:
o High ve
o High resistance
• Expiration is generally passive - relying on elastic recoil of the energy stored during inspiration.
• The muscular effort has an oxygen cost, which may become excessive when resistance or
impedance increase. The total work of breathing is the work required to overcome resistive
forces
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4. Factors that affect ventilation with reference resistance and compliance, work of
breathing
• FORCES ACTING ON THE LUNGS ! inflating the lungs
• Various forces functionally link the chest wall and the lungs.

1. ALVEOLAR PRESSURE: pressure tends to keep the lungs inflated

2. NEGATIVE INTRAPLEURAL PRESSURE: the pressure in the space between the two pleural
layers is subatmospheric: this tends to suck the lungs outwards
3. INTRAPLEURAL SURFACE TENSION: the pleural space is filled with fluid. Surface tension
makes the outer layer of the lungs loosely adhere to the inner wall of the chest
4. ELASTIC FORCES: elastic tissue in the lung opposes inflation and facilitates deflation

Pneumothorax (“air in the thorax”)

• An example of imbalance between inflating and deflating forces
• If gas enters the intrapleural space, the negative intrapleural pressure (a force keeping the
lungs inflated) is lost. The elastic forces (collapsing the lung) dominate, and the lung deflates
Four types:
1. Open
2. Closed
3. Spontaneous
4. Tension ! serious, can kill you in 10 minutes
TRANSPULMONARY PRESSURE
• The difference between the
o Alveolar pressure (pressure inside the lung) and
o Intrapleural pressure (pressure surrounding the lung)
• At end inspiration or expiration the alveolar pressure equals the atmospheric pressure
• On inspiration the intrapleural pressure falls ! the transpulmonary pressure increases ! the
lung inflates

LUNG COMPLIANCE
• The magnitude of the change in lung volume produced by a given change in transpulmonary
pressure
o High compliance ! easier to expand lungs
o Low compliance ! harder to expand lungs
• Surface tension at the air water interface in the alveoli is the major determinant of compliance -
it tends to “stick” the walls of the alveoli together
• Alveolar surface tension varies with lung volume
• At low volumes:
o Surface tension is greater
o Compliance is lower
o It is more difficult to inflate the lungs
• Surfactant decreases surface tension, increases compliance
• Deficiency of surfactant occurs with newborn respiratory distress syndrome
• ARDS ! Adult respiratory distress syndrome ! Decreased compliance occurs with exudate or
oedema in the interstitium: total work of breathing increases. Can occur by smoke inhalation,
electrocution and smoking. Oedema ! the lungs can be similar and fill with water which
becomes too much for the respiratory muscles and they fail; a ventilator is used to replace the
muscles and prolong the life of the patient until solution is found.

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5. Measurement of ventilation, measures of volume and capacitance, pulmonary

function tests, common disease of the airways
Pressure - Volume Relationships In The Lung
• The relationship between pressure and the change of volume is not constant.
• At low volumes, extra work is required to overcome the surface tension in the alveoli
• At high volumes, the elastic tissue is stretched - so more effort is needed to stretch it further
Pressure - Volume Relationships In The Chest
• The chest wall is compressible and distensible
• At the end of a normal expiration (FRC) the inward recoil of the lung balances the outward recoil
of the chest - the chest wall is at equilibrium

Flow Volume Curves

• Expiratory airflow is affected by:

o Expiratory force
o Airway diameter
o Lung and chest distensibility
o Airway collapse
• Peak expiratory flow occurs early in expiration-
o When the lung is under the greatest stretch, and elastic recoil is greatest.
o High flow rates are achieved early as gas leaves large airways.
o Flow decreases later when smaller airways make greater contribution
• During expiration, decreased effort results in decreased flow.
• However, above a threshold, the only effect is on the initial stages of the expiration ! we have
limited ability to regulate the expiratory flow rate.
• The closing volume is the lung volume at which small airways begin to close so flow decreases.
• During inspiration, greater effort results in greater flows – only dependent on muscular effort.
• However inspiration is most difficult at
o Low volumes (when surface tension is greatest)
o High volumes ( when elastic forces are greatest)

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Pressure Measurements

To measure the strength of the respiratory muscles we can measure the pressure generated at the
mouth by inhaling and exhaling against a closed valve.

Respiratory Volumes

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• The total amount of air that can be moved through the airways by a maximal inspiration which is
followed by a maximal expiration is the VITAL CAPACITY (VC)
• The amount of air moved through airways during normal breathing is the TIDAL VOLUME (VT)
• The extra air that can be added to the lungs after a tidal inspiration is the INSPIRATORY
RESERVE CAPACITY
• The extra air that can be removed from the lungs after a tidal expiration is the EXPIRATORY
RESERVE CAPACITY
• The amount of air left in the lungs after a maximal expiration is the RESIDUAL VOLUME
• The amount of air left in the lungs after a tidal expiration is the FUNCTIONAL RESIDUAL
CAPACITY (FRC)

Pulmonary Function Tests

• Pulmonary function testing is useful for
o Screening for obstructive and restrictive disease and observing its progression
o Evaluating pre surgery
o Evaluating suitability for ventilator weaning.
• FEV1: forced expiratory volume in one second – spirometry
o Most useful in the evaluation of obstructive diseases
o Less helpful in assessing restrictive diseases.
o PEFR: peak expiratory flow rate
• FEV1 TESTING
o Begins with a full inspiration
o The volume of gas expired during a forced maximum expiration is measured over one
second. This is FEV1 - a rate measurement.
• The total volume of gas expired during the forced maximal expiration is measured. This is the
FVC (forced vital capacity) - a volume measurement
• A normal result gives a ratio FEV1 / FVC > 80%
• Low FEV1 may be due to
o Airways obstruction
o Loss of expiratory muscle power
• FEV1 must be interpreted using, age, gender, height, race matched normals
• Due to variation, values in range 80% - 120% of predicted are considered normal
• Patient positioning and comfort must be standardised.
• Subjects should sit with the head held in a neutral position.
• Uncomfortable temperatures, uncomfortable clothing or seating lead to inaccuracy
• Forced Expiratory Flow at 25% of FVC (FEF25%).
• Flow rate at the 25% point of the total volume (FVC) exhaled
• Indicates condition of fairly large to medium size bronchi
• Forced Expiratory Flow at 75% of FVC (FEF75%).
• Indicates the status of small airways
• COPD shows up in the smallest airways first

Peak Expiratory Flow Rate

• A very useful measurement to check on asthma control
• In COPD, PEFR will be decreased
• PEFR has several advantages:
o Peak flow meters are cheap
o Tests can be done easily at home
o It provides good information on asthma control
o It has a physiotherapy effect

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6. The process by which gas is exchanged between the alveoli and the blood,
including the concept of partial pressures, the significance of dead speac,
ventilation and perfusion matching
Ventilation
• Minute ventilation (ve) is controlled to maintain gas pressures in the blood at the correct levels
ve = vt x respiratory frequency (rf)
• Is set to match the needs to:
o Deliver oxygen to the tissues
o Remove carbon dioxide
• Ve must match metabolic requirements
• When we exercise, need to eliminate co2 increases so ventilation increases ! hyperpnoea
• If ventilation is excessive and pco2 decreases this is hyperventilation
• The alveolar ventilation (va) is the amount of gas reaching the alveoli - it is the key determinant
of blood gas levels.
va = rf x (vt - vd)
• If vt falls, rf must rise ! rapid shallow breathing is inefficient
• Vd is the dead space ventilation - the gas which is located in the airways, but outside the regions
where gas exchange can occur. (no gas exchange)
• Gas in anatomical dead space cannot enter the blood ! important for expired air resuscitation

Anatomical Dead Space

• The volume of gas in the respiratory system outside the alveoli
• If the anatomical dead space increases, the work of breathing and the tidal volume will increase

Alveolar Dead Space

• The gas going to regions of the lung where perfusion is not matched: the wasted ventilation

Gas Exchange
• Occurs only in the respiratory bronchioles & alveoli
• Gas movement between the blood and the alveoli occurs as a result of passive diffusion only
• To facilitate diffusion alveoli have:
o Large surface area
o High capillary density
o Thin walls

Chronic Obstructive Pulmonary Disease (Copd)

• 10% of the world’s population have COPD
• The common abnormality is a limitation to expiratory airflow, due to narrowing of the airways
• Airway diameter is usually determined by the tone of the bronchial smooth muscle
• Parasympathetic (bronchoconstrictor) tone dominates sympathetic (bronchodilator) tone (norm)
• Airway calibre is decreased by:
• Bronchoconstriction
o Oedema
o Bronchial secretions
o Loss of elastic recoil
• Common causes are:
o Asthma
o Chronic bronchitis
o Emphysema

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Flow at 50% VC is significantly reduced

Asthma
• Constriction of bronchioles narrows airways
• Constriction usually results from:
• Exposure to allergens
• Cold dry air (exercise induced)
• In addition to narrowing of airways get
o Increased mucous production
o Formation of mucous plugs
o Airway oedema
• Gas movement through narrow airways causes wheezing
• Mucous causes cough
• Acute asthma can be fatal, associated with hypoxaemia and fatigue of respiratory muscles
• Death often associated with excessive reliance on bronchodilators – these drugs only treat
symptoms
• Corticosteroids may create long term benefit by reducing allergy
• Exercise-induced bronchoconstriction (EIB)
o Transient airway narrowing shortly after strenuous exercise
o Highly prevalent but not limited to athletes with asthma
• Caused by hyperpnoea:
o Shift from nasal to mouth breathing !increased need to heat and humidify air !
abnormal heat and water losses in lower airways
• Get increased
o Thermal
o Osmotic
o Mechanical
o Stresses on airways
• Severe EIB can occur when hot dry air is inspired.
• Treatment EIB is same as asthma: bronchodilator and antiinflammatory

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Chronic Bronchitis
• Narrowing of airways occurs as a result of hypertrophy & hyperplasia of mucus glands.
• Increased secretions narrow the airways further.
• Usually occurs in smokers - main sign is morning cough

Emphysema
• Develops as a progression of chronic bronchitis
• Caused by elastases resulting from smoking which destroy pulmonary tissue
• Main problem is loss of alveoli which decreases the surface area for diffusion - O2 can’t enter
blood
• To maintain diffusion need to increase concentration gradient ! treatment is supplemental
oxygen
• Loss of elastic tissue causes airway collapse during expiration (airflow obstruction)
o Increasing airway pressure will help keep airways open and allow gas flow to occur
o Pursed lip breathing can be used to achieve this - it increases resistance to expiration.
Consequently, expiratory pressure increases.
• Positive expiratory pressures can exceed the critical closing pressure of the airway.
• Emphysema is characterised by increased functional residual capacity ! the lungs are
relatively "full"
o The diaphragm is therefore flattened
o The diaphragm generates peak tension at ~ 130% of resting length
o In end stage cases, lung reduction surgery may facilitate elastic recoil

Copd Exacerbations
• Usually due to infection
• Also
o Other cardiac or respiratory disease
o Cold air
o Pollution
o Medication non-compliance
• Complications
o Causes systemic inflammation
o Skeletal muscle damage
• COPD Management
o Stop smoking
o Decrease environmental risks
o Influenza vaccination
o Β 2 agonist
o Inhaled corticosteroid
o Anticholinergics

Abnormal Diaphragmatic Function

• Often associated with COPD that results in fatigue.

• Normal contraction of the diaphragm creates a positive intra abdominal pressure.
• This makes the abdomen move outwards on inspiration - this is more noticeable in children
• If it is fatigued the diaphragm will move upwards on inspiration ! it is drawn upward by the
negative thoracic pressure created by the accessory muscles
• As a result, the abdomen moves inwards during inspiration

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Restrictive Lung Disease

• The abnormality is a limitation to expansion of the lung
• Common causes are:
o Diseases of the rib cage
o Diseases of the respiratory muscles
o Diseases of the pleura - pain or compression
o Diseases of lung tissue - stiff lungs
o Osteoporosis - limits chest volumes
• There is no limitation to airflow so FEV1 is normal (or increased) compared with FVC - the
absolute value is decreased
• The force which is limiting expansion of the chest may facilitate expiration
• FVC will be decreased and FEV1/FVC normal to increased

Comparing Obstructive and Restrictive diseases

Obstructive Restrictive
FVC Normal to decreased Greatly decreased
FEV1 Greatly decreased Normal to decreased
FEV25- Greatly decreased Normal to decreased
75

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7. Normal blood gases and how they can be affected in common disorders
Normal Blood Gas Values

• Systemic arteries & pulmonary veins

PO2 = 100 Torr (1 Torr = 1 mmHg)
PCO2 = 40 Torr

• Systemic veins & pulmonary arteries

PO2 = 40 Torr
PCO2 = 46 Torr

Abnormal Arterial Blood Gases

Hypoxaemia (low po2)
• Caused by
1. Diffusion Limitation ! occurs when there is disease in the alveoli or pulmonary vessels
2. Right To Left Shunts ! Some blood always flows directly from the right to the left side of the
heart, by-passing the lungs
3. Our arterial PO2 is always slightly low due to shunting
4. Alveolar Hypoventilation
5. Low Inspired FIO2
6. V/Q Mismatch

• For normal gas exchange to occur, ventilation and blood flow in the various regions of the lung
must be matched
• Some V/Q mismatch is normal
o gravity pulls more blood into the lower regions of the lung
o ventilation is higher in the upper regions due to larger alveolar size and higher
transpulmonary pressure

• The lung can be divided into three zones:

o Upper zone: higher V, lower Q
o Middle zone: V & Q are matched
o Lower zone: lower V, higher Q

• Effect of V/Q mismatch is to increase alveolar dead space

o WITH HIGH V/Q ! (eg pulmonary thromboembolism) PAO2 is high;
PACO2 is low
o WITH LOW V/Q ! (eg. pulmonary fibrosis) PACO2 is high;
PAO2is low
• When local hypoxia develops, vasoconstriction occurs: blood is shunted away from the hypoxic
area: this may cause right sided heart failure
• When blood flow to an area decreases, airway resistance increases: gas is shunted away from
the area due to low PCO2
• V/Q is also affected by body position
• Exercise induced arterial hypoxaemia (EIAH)
• Occurs in ~50% of highly trained male athletes, >50% of females and at a lower exercise
intensity
• Hb saturation falls below 90%

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• HYPOCAPNIA (LOW PCO2- got rid of too much carbon dioxide) ! Due to alveolar
hyperventilation
• HYPERCAPNIA (HIGH PCO2 – too much carbon dioxide in the blood, therefore not removing it
from your system fast enough; causing hypercapnia and poisons the body) ! Due to alveolar
hypoventilation

Respiratory Failure
• Characterised by ! Abnormal blood gas values – PaO2 < 60Torr &/or PaCO2 > Torr
• Orthopnoea ! difficulty in breathing associated with body position
• The system may fail in (anywhere in the respiratory system) such as:
o The airways
o The gas exchange surface
o The respiratory pump
o The respiratory muscles

7. The process by which gases are transported between the lungs and the tissues,
focusing on oxygen and carbon dioxide, the key role of haemoglobin dissociation
curve
Gas Transport From Lungs To Tissues
• Gas transport still relies on movement along concentration gradients.
• The blood is transporting the gases (the plasma is predominantly water) blood is mostly water
however the water does not have much of a carrying ability of oxygen! Therefore a carrying
solution is needed = haemoglobin!
• Oxygen has low water solubility
• The water solubility of carbon dioxide is much higher
• To transport oxygen, a carrier - haemoglobin (Hb)- is required
• Each Hb molecule can carry four oxygen molecules (it has four binding sites)
• Saturation is a measure of how many binding sites are occupied: if every Hb molecule is carrying
four oxygens, the saturation is 100% - although this level is never reached, the maximum is 95 -
98%
• ! Strength of the bonds and other molecular pulls has to do with the saturation as well as the
gases exchanging those it will never be 100%
• Saturation can be misleading as it may have 75% saturation but carry 18 Oxygen molecules
while 2 haemoglobin can have 100% saturation but only carry 8 oxygen molecules therefore must
use arterial
• Arterial oxygen content indicates how much oxygen the blood is carrying
• Content = saturation X [Hb]
• Pulse Oximeter is the equipment used to measure (the redness or blueness of the blood)
• If a person has normal [Hb] and normal saturation O2 transport is normal
• If a person has low [Hb] and normal saturation O2 transport is low ! saturation can be normal in
severe anaemia
• There is a relationship between oxygen pressure and saturation
o When the PO2 is high, saturation is high
o When the PO2 is low, saturation is low
• This relationship is represented by the Hb dissociation curve

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• When the PO2 is high (in the lungs) the dissociation curve is flat
o Small changes in PO2 in the lungs don’t affect saturation
• When the PO2 is low (in the tissues) the dissociation curve is steep
o At low PO2, small changes in PO2 cause large changes in saturation

Shifting The Hb Dissociation Curve

• If the curve is shifted to the right, the
saturation will be lower at a given PO2 ie.
The Hb will have given up more O2. Shifts
in the Hb dissociation curve don’t affect
haemoglobin saturation in the lungs

• What shifts the curve to the right?

• The need for more oxygen in the tissues
o Increased PCO2
o Increased [H+] and lower ph
o Increased temperature
o Increased 2,3 - DPG - produced
in rbcs during glycolysis,
hypoxemia

Transport Of Carbon Dioxide

• Most carbon dioxide is carried as bicarbonate ions in the blood
• Some CO2 is also carried
o dissolved in the plasma
o as carbamino compounds (reversibly bound to Hb)
• The bicarbonate is produced by the carbonic anhydrase reaction
H+ + HCO3- H2CO3 H2O + CO2

• In the tissues PCO2 is high

H+ + HCO3- # H2CO3 # H2O + CO2
In the lung PCO2 is low
H+ + HCO3- ! H2CO3 ! H2O + CO2

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+
8. Control of ventilation, including the role of arterial levels of O2, CO2 and H
Control Of Ventilation
• Ventilation must be controlled to regulate the blood gases ! homeostatic mechanism of control
therefore works as a negative or positive feedback loop.
• There are wide fluctuations in VO2 and VCO2, but PaO2 and PaCO2 don't change under normal
circumstances (must be stimulated)
• Therefore ventilation must be changing in response to metabolic changes.
• The respiratory rhythm is generated in the respiratory centre of the medulla oblongata ! place of
control for basic and involuntary systems.
• The activity of the respiratory centre is influenced by inputs from the Pons (part of the brain, just
above the medulla – receives more complex messages that have been sent to the medulla) and
the Vagus (nerve bringing information back from the lungs)
• Basic rhythmic activity of respiratory muscles that is modified by:
o Voluntary cortical control
o Involuntary control eg. Swallowing (don’t swallow and breath at same time),
coughing, sneezing

Chemical Control Of Ventilation

• If PCO2 increases, our pH will fall: ! must be controlled to allow normal functioning
• H+ + HCO3- H2CO3 H2O + CO2
• Arterial PCO2 (PaCO2) is only allowed to change by + 1 Torr before respiration is altered:
o If PaCO2 increases, ventilation increases
o If PaCO2 decreases, ventilation decreases
• PaO2 is allowed to fall much more severely before ventilation is stimulated
• PaO2 must fall from about 100 Torr to 50-60 Torr before ventilation is increased.
• The increase in ventilation caused by an increase in PaCO2 is called the hypercapnic drive
• The increase in ventilation caused by a decrease in PaO2 is called the hypoxic drive
• Normal respiration relies on the hypercapnic drive (most important as it is a strong force used to
breathe). If the hypercapnic drive is suppressed, the hypoxic drive (secondary force to
hypercapnic) may be insufficient to maintain breathing.
• Requires a system to measure blood gas values - uses chemoreceptors.

Peripheral Chemoreceptors
• Carotid bodies and Aortic bodies
• Most important in response to changes in PO2

Central Chemoreceptor Function

• Located on surface of medulla
• 85% of PCO2 response is mediated centrally.
• CO2 which enters the CSF enters carbonic anhydrase reaction:
-
• H+ + HCO3 H20 + CO2
• A decrease in pH of CSF stimulates ventilation
• PCO2 response may be lost due to hypercapnia, eg in COPD patients
-
• With prolonged hypercapnia, pH will slowly return to normal due to diffusion of HCO3 into CSF
• Mechanical Inputs from Airways and Lungs ! medulla gets information about lungs and
physically changes the size of the lungs to due with inspiration and expiration
o Inflation of the lung inhibits inspiration
o Deflation of the lung stimulates inspiration

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• Regulated by pulmonary stretch receptors located in smooth muscle of airways

• Effect is to limit inspiratory volumes. Also adjusts depth of breathing to what is most economical.
• Irritation of the Upper Airways ! Airways contain irritant receptors
• Chemical or mechanical stimulation causes coughing

9. The common diseases that affect the respiratory system and the
pathophysiological changes they produce
Respiratory System And Exercise
• The respiratory system has large reserve capacity
• No measurable changes with training in:
o Lung parenchyma,
o Airways or
o Chest wall
• Strength and endurance of respiratory muscles improves with training
• If airway resistance increases during exercise get increase in the work of breathing, which may
affect exercise performance.
• To maintain airway resistance near resting level:
o Upper airway dilator muscles activate before muscles of inspiration to open glottis;
o Bronchial smooth muscles relax (due to less parasympathetic tone);
o Expiratory muscles recruited to reduce end-expiratory lung volume.
• Many endurance athletes show significant expiratory flow limitation, which results in increased
end-expiratory lung volume (over liquidized lungs) that leads to
o reduced compliance and
o increased work of breathing
• Normal hyperventilatory response to exercise is limited ! dyspnoea, EIAH, poor performance.
• Positive expiratory pressures increased afterload on ventricles.
• More common in women because of smaller lung volumes and narrower airways
• Epithelial injury occurs during severe hyperpnoea.
• Loss of integrity of the physical barrier ! Potential for penetration by pathogens
Respiratory System And Obesity
• Obesity causes
o Reductions in expiratory reserve volume,
o Functional residual capacity,
o Compliance and
o Respiratory mechanics
• These lead to restrictive ventilatory defect.
• Low functional residual capacity ! expiratory flow limitation and airway closure during quiet
breathing.
• This increases the work of breathing ! dyspnoea.

Respiratory System And Ageing ! less functional

• Increased rigidity of the upper airways become stiffer !increased work of breathing thus requires
more energy for basic functioning level and less capacity to increase breathing at times of stress
• Increased rigidity of the chest wall
• Loss of elastic tissue ! senile emphysema
• Less functional ciliated cells
• Decrease in the effectiveness of the larynx as a seal
• Decreased sensitivity in the chemoreceptors
• Kyphosis ! restrictive lung disease

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Gases!Learning!Objectives!!
!
1. State and apply Boyle’s law, Charles’s law and Avogadro’s law for ideal gases
Empirical Laws of Gases: Boyles, Charles, Avogardo’s Laws

Boyle’s Law

• At a given temperature, the volume occupied

by a certain amount of a gas is inversely
proportional to its pressure
• PV=constant at a given Temperature and
Number of moles (n)

Charles’ Law

• At given pressure, for a certain amount of a gas,

volume increases linearly with the increase in
temperature.
• At a given pressure, the volume of a given
amount of gas is proportional to its temperature in
Kelvin:

WHY ABSOLUTE ZERO?

• If the extrapolation of V versus T graph is

correct ! volume of a gas would become zero
at - 273.15oC and negative below the
temperature
• Negative volume and for that matter zero
volume is not possible for material objects. !
Hence -273.15oC is considered to be the lowest
temperature that can ever be reached.

ABSOLUTE OR KELVIN SCALE DEFINED

T(K) = ToC + 273.15

25C = 25+273.15 = 298.15K

Avogadro’s Law

• At a given temperature and pressure, the volume of a gas is proportional to the number of
moles of the gas.
• Gas is proportional to the number of moles of the gas
• V n at constant T and P Constant at constant T and P
• Guy Lussac’s Law ! at a given volume, the pressure of a given amount
of gas is proportional to its temperature in kelvin

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2. Apply Boyle’s law to breathing

• We breathe about 12 times a minute
• Inhaling and exhaling about 0.50 L of air each time
• In breathing in, volume of chest cavity is increased by
o Lowering the diaphragm
o Raising the chest cavity
• In breathing out, volume of chest cavity decreased by
o Raising the diaphragm
o Lowering the rib case

3. State and apply the ideal gas law equation

Combined Gas Law Equation

• Simplification of ideal gas law equation

• R = molar gas constant = 8.314 J K-1 mol _1

4. Define the terms and distinguish between the two

(i) Ideal gas
• A gas that obeys the equation: PV = nRT under all conditions of temperature and pressure.
• Real gases only approximate ideal behaviour
• Some do better than others (e.g. oxygen better than carbon dioxide, helium better nitrogen)
• Better at high temperatures and low pressures

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(ii) Real gas

• Only approximate ideal behavior
• Some do better than others (oxygen better than carbon dioxide)
• Better at high °c and low ‘p’
• Distinguish: real gas does not necessarily obey the equation whilst real gas does

5. Explain why real gases deviate from ideal behaviour

• Due to the chemical nature and bonding of gases, some may change to solids or liquids at
certain temperatures and pressures
• Those with higher dispersion forces (larger molecules) and greater interactions (H bonding
etc.) Behave less ideally

6. Define the terms: (i) saturated vapour pressure and (ii) boiling point (in terms of
saturated vapour pressure)
Saturated Vapour Pressure

• The pressure exerted by molecules in the vapor phase in equilibrium with the molecules in the
liquid phase, is called the saturated vapor pressure.
• Different liquids have different SVP
• SVP increases with the increase in
temperature
• Vapors do not obey the idea equation
therefore air is saturated

Dry gas:

Wet Gas:

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Boiling point
• Boiling point of a substance is the temperature at which the vapour pressure of a liquid equals
the environment pressure surrounding the liquid
• If temperature B, vapour pressure B, more molecules are able to escape into the gas phase

7. Define the term: partial pressure

Mixtures Of Gases

• The air that we breathe in is mainly a mixture of oxygen and nitrogen

• Concept of partial pressure
o In a mixture of gases, the pressure due to each component gas is called its partial pressure.
o PO2 represents partial pressure of oxygen
o PN2 represents partial pressure of nitrogen

8. State and apply Dalton’s law of partial pressure

Dalton’s Law Of Partial Pressure

• The total pressure of a mixture of gases is equal to the sum of the partial pressures of the
component gases.

Calculating Partial Pressures ! Calculate the mole-fraction (xA) of the component gas

• Problem: A gas sample contains 4.0 moles of oxygen and 6.0 moles of nitrogen. Given that the
total pressure is 100 kPa. Calculate the following:

(a) Mole fraction of oxygen

(b) Partial pressure of oxygen Solution:

(a) X(O2) = (4/10) = 0.4 (b) P(O2) = 0.4 x 100 = 40 kPa

9. Carry out P-V-T calculations for both dry air and air saturated with water vapour
Calculations Of Air Saturated With Water Vapour

• Vapours do not obey the ideal gas law equation: PV = nRT

o Hence, air saturated with water vapour will not obey gas law equations
o So, to apply gas law equations, take away the contribution of water vapour from the total
pressure of the ‘wet’ air.
o P1V1/T1 = P2V2/T2 is true only for dry air
• Ptotal=Pdryair+PH2O
• Problem: A sample of air at 27oC saturated with water vapour has a total pressure of 762.0
mmHg. Given that SVP of water at 27oC is 26.7 mmHg, determine the partial pressure of dry air
in that air sample.
• Solution: P dry air=762.0-26.7=735.3mmHg

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Expressing Lung Volumes

• VATPS ! volume at ambient temperature and pressure of saturated air

• VBTPS ! Volume at the body temperature (310 K) and ambient pressure of saturated air
• VSTPD ! Volume at standard temperature and pressure of dry air (273 K and 101.3 kPa)

10. State Henry’s law, and describe its clinical applications

Henry’s Law ! As the pressure due to a gas is increased, its solubility in a liquid is also
increased so that

• Solubility = P gas x Solubility coefficient (SC)

• Different gases have different SC’s for the same solvent eg at body temperature, SC for the
same solvent
o O2 = 0.024
o CO2 = 0.57
o N2 = 0.012

Nitrogen Narcosis

• Giddiness and other symptoms associated with increase in concentration of dissolved nitrogen in
blood plasma and interstitial fluid
• This could happen if air is used for breathing in deep sea diving

Clinical Applications Of Henry’s Law

• Hyperbaric oxygenation - Causes more oxygen to dissolve in blood - Used as a treatment for
• Carbon monoxide poisoning
• Infection due to anaerobic bacteria such as gangrene
• Hyperbaric chambers may also be used for treating certain type of heart diseases, crash injuries,
smoke inhalation, drowning, burns, etc.

!
! !

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Renal/Urinary!System!Learning!Objectives!!
1. The general functions of the urinary system and how the urinary system contributes
to the homeostasis of the body
Three functions of the urinary system

1. Excretion - removal of organic wastes from body fluids

• The most toxic of wastes are the nitrogenous wastes

• Urea: by-product of protein breakdown
• Produced in liver - 2nh3+co2 ! co(nh2)2
• Uric acid: by product of nucleic acid breakdown
• Creatinine: from creatine phosphate in muscle
• Creatine phosphate is a source of high energy phosphate present in skeletal muscle and
brain
• Can donate phosphate to form atp in first 2-7 seconds following intense exercise,

2. Elimination - discharge of waste products

• Urinary tract — organs that eliminate urine

• Ureters (paired tubes
• Urinary bladder (muscular sac
• Urethra (exit tube)
• Micturition (urination) — process of eliminating urine
• Contraction of urinary bladder (smooth muscle)
• Forces urine through urethra, and out of body - reflex action (micturition reflex)

3. Homeostatic regulation

• Blood plasma volume (water balance) and solute concentration (salt balance)
• Blood pressure
• Blood plasma volume (water balance), (ii) solute concentration (salt balance) and (iii) blood
pressure
• Regulates blood volume and blood pressure by adjusting volume of water lost in urine
• Regulates plasma ion concentrations - sodium, potassium, and chloride ions (by controlling
quantities lost in urine) - calcium ion levels (through synthesis of calcitriol)
• Helps stabilise blood ph by controlling loss of hydrogen ions (h+) and bicarbonate ions
(hco3-) in urine
• Conserves valuable nutrients by preventing excretion while permitting excretion of organic
waste products

2. The anatomy of the organs involved in the production, storage and elimination of
urine
a. Location of the left and right kidney and major relationships of the ureter,
bladder and urethra in the male and female.
The kidney: position in body

• Typical adult kidney is about 10 cm long, 5.5 cm wide, and 3 cm thick

• Located on either side of vertebral column
• Left kidney lies superior to right kidney
• Superior surface capped by adrenal gland

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• Position is maintained by: - overlying peritoneum - contact with adjacent visceral organs -
supporting connective tissues
• Hilum: point of entry/exit for renal artery, vein and ureter
• The kidney is located in a retroperitoneal position
• Three layers of connective tissue protect and stabilise the kidney
• Fibrous capsule: a tough layer that surrounds the kidney
• Perinephric fat: surrounds the fibrous capsule
• renal fascia: tough fibrous outer layer that anchors kidney to the surrounding tissue

Comparison of male and female urethra

• The urethra extends from neck of urinary bladder to the exterior of the body
• The male urethra is 18–20 cm long and comprises
• Prostatic urethra passes through centre of prostate gland
• Membranous urethra includes short segment that penetrates the urogenital diaphragm
• Spongy urethra (penile urethra) extends from urogenital diaphragm to external urethral
orifice
• The female urethra is very short (3–5 cm) and extends from bladder to vestibule
• External urethral orifice is near anterior wall of vagina

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The circulation of the nephron

• The circulation of the nephron is unique and allows for the functions of the kidney to be
carried out
• It comprises:
o A high resistance arterioles (afferent arteriole)
o A high pressure capillary network (glomerular capillaries)
o A second high resistance arteriole (efferent arteriole)
o A low pressure capillary network (peritubuar capillaries)

b. Location and structure of the internal and external sphincters of the bladder and their role in
continence
The Ureters And Bladder

• The Ureters are a pair of muscular tubes that extend from kidneys to urinary bladder
o Begin at renal pelvis
o Run along the posterior abdominal wall
o Penetrate posterior wall of the urinary bladder
o Peristaltic contractions begin at renal pelvis and sweep along ureter every 30s
forcing urine toward urinary bladder
• Pass through bladder wall at oblique angle
• Ureteral openings are slit-like rather than rounded to prevent backflow of urine when
bladder contracts
• The Urinary Bladder is a hollow, muscular organ that functions as temporary reservoir for
urine storage
• Full bladder can contain 1 litre of urine
• Wall of the bladder is made up of smooth muscle (detrusor muscle)
• Inner lining of bladder, has folds called rugae that disappear as bladder fills
• Trigone is a triangular area bounded by the openings of ureters and the entrance to urethra
! acts as a funnel to channel urine from bladder into urethra
• 2 urethral sphincters
o Internal: smooth muscle
o External: skeletal muscle

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c. Blood supply of the kidney

• Each kidney receives blood via the renal artery
• Divides into segmental arteries
• Divide into interlobar arteries
• Divide into arcuate arteries
• Give rise to cortical radiate arteries (cra)
• Each cra gives rise to numerous afferent arterioles
which in turn feed into the glomerular capillary
• The glomerulus feeds into the efferent arteriole and
then to the peritubular capillaries
• The venous drainage is largely in the same pattern as
the arteries in reverse
• Cortical radiate vein ! arcuate vein ! interlobar vein
! renal vein

d. Anatomy and histology of the kidney

The kidney: macroscopic structure

• The kidney is made up of 2 layers and a renal sinus (internal cavity)

• Renal cortex is the outer layer
• Renal medulla is the inner layer - made up of 6-18 triangular structures called renal
pyramids - renal papilla: tip of pyramid projects into renal sinus
• Each pyramid is separated by some cortical tissue forming the renal columns (extend into
medulla)

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• Renal lobe: one renal pyramid, overlying cortex and adjacent columns
• Urine is produced in a renal lobe and drains into a minor calyx
• 4-5 minor calyx merge to form major calyx major calyx
• 2-3 major calyx form renal pelvis
• A large funnel-shaped chamber
• The renal pelvis fills most of the renal sinus - renal pelvis drains into the ureter which drains
the kidney —> bladder

3. Relate the function of the nephron to its structure.

The Nephron Is The Function Unit Of The Kidney

• Although the kidneys comprise less than 0.5% of total body weight, they receive ~20% of
the cardiac output.
• The afferent arteriole supplies the glomerular capillary which in turn feeds the efferent
arteriole
• The efferent arteriole gives rise to the peritubular capillaries, which surrounds the tubule
• In juxtamedullary nephrons, capillary loops called vasa recta dip down into the renal
medulla
• Where loop of Henle is located

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THE JUXTAGLOMERULAR APPARATUS

• In each nephron the final part of the ascending limb of the loop of Henle passes between
the afferent and efferent arteriole, to form a region known as the juxtaglomerular apparatus.
It comprises:
o Specialised Epithelial Cells In The Loop Of Henle That Are Sensitive To [Na+].
o Known As The Macula Densa (“Dense Spot”)
o Specialized Smooth Muscle Cells In The Afferent (And Efferent) Arteriole Called
Juxtaglomerular Cells That Produce And
Secrete The Enzyme Renin.
o Crucial In Production Of The Hormone
Angiotensin II

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4. Describe the process of urine formation and the factors controlling it. Details of
filtration, reabsorption and secretion
Steps Of Urine Formation

• Filtration:
o Water and solutes move out of the glomerular capillary into the capsular space via
o Hydrostatic and colloid osmotic pressure
o Larger molecules such as plasma proteins cannot leave the blood
o Filtration is dependent only on size of molecules (i.e. Not chemically specific).
• Reabsorption:
o Movement of water and solutes back into blood (from tubular fluid)
o Unlike filtration, reabsorption is a selective process involving either diffusion or carrier
proteins (pumps)
o Water reabsorption ocurs via osmosis (follows “salts”) - Secretion: - the transport of
additional solutes from the blood into the tubular fluid - a back-up for filtration - many
drugs are eliminated from body via secretion

Filtration
Occurs In
The

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Renal Corpuscle

• Renal corpuscle comprises glomerulus and Bowman’s capsule

• Bowman’s capsule consists of 2 layers of epithelia - parietal (outer) layer - visceral (inner)
layer
• Between these 2 layers is the capsular space, where the filtrate collects
• The visceral layer consists of specialized epithelial cells called podocytes (podos = foot)

The Vascular Supply To The Nephron

• Surrounding the glomerular endothelium are podocytes. These help to limit filtration

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Filtration Membrane

• Podocytes have long “finger”-like (or “foot”-like) processes that wrap around the glomerular
capillaries leaving narrow filtration slits between them.
• Note: glomerular capillaries are “fenestrated” (Latin fenestra: “window”) - endothelium
contains large pores that allow larger solute to cross and increasethe rate of movement
across the endothelium
• However, podocytes overlay the endothelium, forming a barrier to limit the passage of larger
substances from the blood - e.g. substances as large as proteins still cannot pass easily
through the filtration slit
• Between the glomerular endothelium and the podocytes is the basal lamina - part of the
extracellular matrix secreted by epithelial cells, comprising collagen, laminin and other
structural proteins (acellular)

Glomerular Filtration Is Capillary Filtration

• During filtration water and small solutes are forced via pressure across the capillary
endothelium into the interstitium - sum (outward forces) – sum (inward forces)
• Outward forces are capillary hydrostatic pressure & interstitial fluid colloid osmotic pressure
• Inward forces are interstitial fluid hydrostatic pressure and plasma colloid osmotic pressure
- In the kidney filtration does not move fluid into the interstitial fluid, but into Bowman’s capsule.
- Note: The fenestrations in the glomerular capillary allow larger molecules to pass across the
endothelium. However, this is limited by the podocytes and formation of the filtration slits. -
therefore large solutes such as plasma proteins still mostly cannot move across the filtration
membrane.

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Filtration In The Nephron

Glomerular Filtration Rate

• Approximately 20% of blood plasma passing through kidney is filtered by the glomerulus.
• How much does this equal?
Renal blood flow is about 21% of total cardiac output
o CO = 5500 ml/min
o RBF = 21% X 5500 ml = 1155 ml blood/min
renal plasma flow
• Renal plasma flow
o 55% whole blood is plasma
o 55% X 1155 ml/min = 635.25 ml plasma/min
• Therefore 20% X 635.25 = 127.05 ml plasma per min
removed by glomerular filtration
o Approx 183 litres/day
• Normal Urine outputs 1-2 L/day
o Min urine output ~ 500 ml/day to excrete
solutes
• The rest of the fluid (~182 L/day or 99%) is reabsorbed
into the blood stream by the renal tubules.

COMPARISON OF BLOOD PLASMA AND URINE

• The filtrate has the same composition as blood plasma

• Because glomerular filtration is only selective on size
and not chemical properties, the filtrate is in effect
blood plasma, apart from protein.
• It must be processed to conserve nutrients and water while eliminating the wastes.
• Normal urine is a clear, sterile liquid.

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• Composition varies with metabolic and hormonal events.

• Yellow colour comes from the pigment urobilin, a biproduct of bilirubin (breakdown of red
blood cells)
• Normal urine volume = ~1000-2000 ml/day

Processing Of Tubular Fluid ! The urinary excretion of a substance depends on its filtration,
reabsorption, and secretion

Tubular Reabsorption

• Virtually all plasma constituents except plasma proteins are filtered at the glomerular capillary
- so the filtrate is (largely) protein-free blood plasma
• Therefore, in addition to all the waste products, the filtrate also contains water, valuable
nutrients and electrolytes.
• These essential materials can be returned to the blood by the process of reabsorption.
• In general, the nephron tubule has a high reabsorptive capacity for substances needed by
the body and much lower reabsorptive capacity for waste products or products of no value -
e.g. ≥ 99% of water, glucose, Na+ are reabsorbed - 0% of phenol is reabsorbed. However
some wastes are reabsorbed (e.g. urea)
• Unlike filtration, reabsorption is a highly selective process that involves transepithelial
transport.

Summary Of Reabsorption In The Nephron Table (And Collecting Ducts)

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Transepithelial Transport

• Throughout its length, the nephron tubule wall is made up of a single layer of epithelial cells
that lie in close proximity to the peritubular capillaries.
• The two sides of the tubule epithelial cells have different properties and are described as two
separate membranes:
• the luminal or apical membrane faces the lumen
• the basolateral membrane faces the interstitial fluid
• Interstitial fluid lies between the nephron tubule and the peritubular capillary.
• To be reabsorbed, solute must cross 5 distinct barriers, as shown below. This entire process
is known as trans-epithelial transport.

HOW ARE SUBSTANCES TRANSPORTED ACROSS THE TUBULAR EPITHELIUM?

• Diffusion - passive: via a concentration gradient

o Simple: diffuse straight through the membrane eg O2,
steroids
o Facilitated: = channel mediated diffusion (eg Na+ or K+
channel)
• Active transport (carrier-mediated transport)
o Requires energy
o Primary active transport (utilizes ATP directly) ! e.g.
Na+/K+ atpase
• Secondary active transport
o Utilizes energy indirectly from “other” concentration
gradients;
o Typically [Na+] generated via Na+/K+ atpase
o Cotransport, counter transport (or anti-transport, antiport)
• Osmosis
o Diffusion of water, follows concentration gradients

Tubular Reabsorption Relies On Active Transport

• Reabsorption of water and solute from the tubular fluid across the epithelium depends on
active transport because the tubular fluid has same concentration as the extracellular fluid
• There is minimal
concentration gradient
(and passive diffusion
requires a concentration
gradient)

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The Importance Of Na+ Transport For Reabsorption

• Approx. 80% of the energy expenditure by the kidney is devoted to Na+ transport, indicating
the importance of the process.
• Na+ is reabsorbed throughout most of the tubule, although to varying degrees
o ~99.5% of filtered Na+ is usually reabsorbed:
o 67% in proximal tubule,
o 25% in loop of Henle,
o 8% in distal tubule and collecting duct.
• Na+ reabsorption plays different important roles in each of these segments
o In the proximal convoluted tubule it plays an important role in the reabsorption of
glucose, amino acids, water, Cl- and urea.
o In the loop of Henle, Na+ reabsorption plays a crucial role in the kidney’s ability to
concentrate urine and conserve water
o In the distal convoluted tubule, Na+ reabsorption is variable and under hormone
control
• In the proximal tubule the Na+-K+ ATPase in the basolateral membrane is essential for Na+
reabsorption and reabsorption of other solute. It is the primary driving force for reabsorption.

Na+ Reabsorption Is Via Primary Active Transport

• Intracellular [Na+] is low because of the Na+-K+ ATPase pump in the basolateral membrane
that actively eliminates Na+
• Therefore Na+ can diffuse from tubular fluid into the epithelial cell due to the concentration
gradient.
• This means that the reabsorption of Na+ from the tubular fluid is a form of active transport.
• The epithelial cell also uses this Na+ gradient to drive the movement of other solutes.

Na+ Reabsorption
Drives The
Transport Of
Other Solute

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Reabsorption In Loop Of Henle

• The two limbs of the loh have very different

permeability characteristics
• The descending limb of loh is permeable to water
but impermeable to ions ! reabsorbs water
• The ascending limb loh is permeable to ions but
impermeable to water ! Reabsorbs solute (Na+,
K+, Cl-)
! Na+-K+-2Cl- transporter (active transport)
• Usually more solute than water is reabsorbed —>
tubular fluid is more dilute (hypo-osmotic) when it
reaches the distal convoluted tubule

Distal Convoluted Tubule And Collecting Duct Provide “Fine Tuning” Of Reabsorption
Under Hormone Control

• Reabsorption of H2O
o Regulated by vasopressin (ADH), primarily in
collecting duct
o Increase number of water pores (aquaporins) in
membrane
• Reabsorption of Na+
o Two paths for Na+ reabsorption, one is constitutive
(Na+-Cl- symport), the other regulated by
aldosterone (Na+-K+ antiport).
• Reabsorption of Ca2+
• Constitutive: 65% Ca2+ reabsorbed in PCT, 20% in
loop of Henle
• Regulated by parathyroid hormone (PTH). A decrease
in plasma [Ca2+] à! Secretion of PTH
• Insertion of Ca2+ channel in apical membrane

Water Regulation

• To maintain our water volume the amount of

water we consume must equal the amount of
water we excrete
• consume ~ 2.2 liters water/day
• aerobic metabolism produces ~ 300ml/day -
glucose+O2→CO2+H2O
• increased water loss can occur - hot
environment - exercise - diarrhoea ! disrupt
homeostasis
• Body compensates by altering thirst
• (↑or↓ intake) and altering urine output - urine
output can vary from 430 ml to 20 litres/day

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Final Urine Volume Is Determined By Water Reabsorption In Collecting Duct

• Water reabsorbed throughout the nephron tubule due to osmotic forces largely related to
reabsorption of Na+ ! supported by low hydrostatic pressure in peritubular capillaries (~13
mmHg)
• Of the water 180 L/day filtered at the glomerulus:
o 117 L (65%) is reabsorbed in the proximal tubule
o 27 L (15%) is reabsorbed by the loop of Henle
o remaining 36 L (20%) is variable and subject to regulation, under control by vasopressin
• Water movement is largely via water channels called aquaporins. Different types of
aquaporins are present in different parts of the tubule. The water channel in the proximal
tubule is aquaporin-1. It is always open.
• In contrast, in the distal tubule and collecting duct it is aquaporin-2, and the number of
channels is controlled by the hormone vasopressin.

Final Urine Volume Depends On Water Reabsorption In Collecting Duct

• Vasopressin is produced in the hypothalamus and secreted into blood from the pituitary gland
! stimulus for secretion is low blood pressure or low blood volume.
• Vasopressin receptors on basolateral membrane are activated
o second messenger system producing cAMP
o → aquaporins inserted into apical membrane

• Water is reabsorbed via osmosis

• Urine volume is reduced and urine
solute concentration is increased (up
to 1200 mOsmol)

[URINE] CAN BE INCREASED 4X [PLASMA] BECAUSE OF

JUXTAMEDULLARY LOOP OF HENLE

• Water can be reabsorbed from collecting duct by osmosis up to

concentration of 1200 mOsmol because salt concentration of interstitial
fluid surrounding the collecting duct has this high concentration.
• Achieved by counter current multiplication in the loop of Henle & urea
recycling

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5. The micturiton reflex and the role of the autonomic nervous system
Regulation Of GFR Micturition Reflex

Glomerular Filtration Rate Needs To Be Maintained Relatively Constant For Homeostasis

• The glomerular filtration rate is the amount of filtrate formed per minute by the two kidneys -
typically ~125 ml/min - aka 125 ml is entering the nephrons every min
• Maintaining GFR is crucial for correct renal function
• If GFR is low —> less blood plasma is entering the nephron and travelling through the tubule
• fluid flows more slowly → more time for reabsorption → more waste solute is reabsorbed
• → accumulation of waste in blood
• If GFR is high —> more blood plasma is entering the nephron and travelling through the
tubule
• Fluid flows more quickly → less time for reabsorption → less reabsorption of water and solute
• → dehydration and electrolyte depletion
• GFR is controlled by filtration pressure which is ~10 mmHg. What happens if arterial pressure
changes? - small change in blood pressure can completely ruin renal function though
• How? - glomerular filtration pressure is maintained in face of changing systemic arterial
pressure, thus maintaining GFR

AUTOREGULATION OF GLOMERULAR FILTRATION IS VIA INTRINSIC CONTROL

MECHANISMS

• Changes in GFR caused by changes in MAP are prevented by intrinsic regulatory

mechanisms
• Within physiological limits, glomerular pressure is maintained constant to keep GFR constant.
• This is accomplished by adjusting the radius of the afferent & efferent arterioles to adjust flow
rates
• opposing actions of the afferent and efferent arterioles

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• Example:
o high MAP —> i) constriction of afferent and dilatation of efferent arteriole - → ↓blood
flow to glomerulus - —> (ii) dilatation of efferent arteriole
o ↑ blood flow from glomerulus
o net effect to maintain glomerular hydrostatic pressure and maintain constant GFR

Two Control Mechanisms Control Gfr

• Myogenic Mechanism. This is an intrinsic property of vascular smooth muscle. It contracts

when stretch and relaxes when not stretched.
o Rising MAP stretches vascular smooth muscle in afferent arteriole, causing it to
constrict —> increasing resistance to flow
• Tubuloglomerular feedback.
o Salt sensitive cells in the macula densa
o When GRF is high, there is less time for reabsorption and [NaCl] remains high.
o Cells in macula densa respond by releasing “vasoconstrictor” chemicals (eg. ATP) that
cause the afferent arterole to constrict.
• This reduces GFR and reduces flow rate through the nephron tubule

Extrinsic Control Of Gfr

• The intrinsic control mechanisms work to maintain GFR in the face of changes in MAP.
• However, the GFR can also be changed on purpose by extrinsic control mechanisms that
over-ride the autoregulatory effects.
• Extrinsic control of GFR is mediated by the sympathetic nervous system (the
parasympathetic nervous system does not exert any effect on the kidneys).
• If plasma volume is decreased – for example by haemorrhage – there will be a fall in MAP
that is detected by the arterial baroreceptors and the reflex response is to increase MAP
towards normal (↑HR & ↑TPR)
• However, although this helps to maintain MAP, blood volume is still reduced. In the long
term, plasma volume must be restored.
• Compensation for reduced blood volume ! reduce urine output so more fluid is conserved

Extrinsic Control Of Gfr (Cont)

• Urine volume can be reduced in part by reducing GFR.

• Sympathetic fibres innervate afferent arterioles
• increased sympathetic activity → constriction of afferent arteriole, a decrease in blood flow to
the glomerulus (decrease glomerular pressure) and a decrease in GFR.
• Renal sympathetic nerves are activated during exercise —> decrease renal blood flow (up to
75% decrease).

Hormonal Control Of Renal Function

• Two hormones contribute to regulation of GFR: angiotensin II decreases GFR and atrial
natriuretic peptide (ANP) increases GFR.
• Angiotensin II has many effects, including being a potent vasoconstrictor - constricts afferent
and efferent arterioles and reduces renal blood flow, thereby decreasing GFR
• Angiotensinogen —> angiotensin l —> angiotensin II (—> aldosterone) 29
• Specialised smooth muscle cells in the wall of the afferent arteriole called
• Juxtaglomerular cells (or granular cells) secrete renin - Stimulus: ↓nacl, ↓ECF volume and
↓BP. Also ↑sympathetic activity.

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Hormonal Control Of Renal Function

• High blood volume and natriuretic peptides

• Natriuretic peptides provide an opposite action to angiotensin (& aldosterone/ vasopressin)
by increasing GFR and promoting Na+ and water excretion.
• Two main peptides; atrial natriuretic peptide (ANP) and brain natriuretic peptide (BNP).
o ANP synthesized in atria, BNP synthesized in ventricular myocardial cells and certain
brain neurons.
• Both natriuretic peptides are released by the heart when myocardial cells stretch (i.e. such as
with increased blood volume).
o natriuresis: inducing excretion of large amounts of sodium in the urine
• Effects:
o dilatation of afferent arteriole and constriction of efferent arteriole (↑glomerular pressure→
↑GFR)
o enhance Na+ and water excretion by reducing reabsorption from collecting duct
o inhibit renin, aldosterone and vasopressin secretion
o decrease sympathetic activity via central action
• ↑urine production & ↓blood volume

Urination: Micturition Reflex

• Once filtrate leaves the collecting duct it can no longer be modified.

• The filtrate is now urine. It flows into the renal pelvis and down the ureter to the bladder.
• Urine is stored in the bladder until micturition (the process of urinating)
• Micturition is a reflex
o the stimulus is bladder stretch
o the response is contraction of bladder and relaxation of urethral sphincters
• Micturition is a simple spinal reflex that is subject to inhibitory control by higher centres (both
unconscious and conscious control)
• When the bladder is in a relaxed state both sphincters are contracted! contraction of
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external sphincter controlled by tonic activity of motor neuron

• A full bladder excites stretch receptors (1) to elicit micturition
o stimulate parasympathetic neuron (2) that projects to detrusor muscle in bladder wall
—> bladder contracts (3)
o internal sphincter passively pulled open
o inhibit somatic motor neuron (2) to relax external sphincter
• Role of sympathetic nervous system to aid continence?

6. The role of the urinary system in regulation of blood pressure

7. Outline the endocrine functions of the kidney

• Secretes active Vitamin D
• Produces the hormone erythropoietin, which is the main factor for red blood cell formation by
the bone marrow
• Renin-angiotensin system:
o Final portion of the ascending limb of the LoH passes between the afferent and
efferent arterioles
o Region of the LoH and arterioles contain specialised cells known as the
juxtaglomerular complex
o Juxtaglomerular complex secretes the enzyme renin in response to
" Decrease in glomerular BP
" Decrease in osmotic concentration in ascending limb LoH
" Sympathetic stimulation
• Renin activates angiotensin which has a number of actions that increase BP and blood
volume (in turn helps to increase/maintain GFR)
o Vasoconstriction (increase TPR Increase BP)
o Increases vasopressin release (increase water reabsorption & increase blood volume)
o Increases aldosterone release (increase Na reabsorption & increase blood volume)
o Increases thirst (increases blood volume)

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8. Outline some common pathologies of the urinary system and management

Urinary Incontinence

• Urinary incontinence is inability to control urination voluntarily.

• Trauma to either internal or external sphincter can lead to incontinence
• With age, sphincters tension reduces and the bladder is less effective at retaining urine
• Types of incontinence
• Urinary retention: can’t go to toilet.
• Causes: post surgery anaesthesia, following epidural or spinal anaesthesia; or outflow
obstruction (e.g. Prostate disease) —> overflow leakage
• Treatment —> urinary catheter. If due to anaesthesia, will recover with time
• Urethral stricture: commonly seen in young men following accidents (e.g. Bike accidents)
• Damage to urethra—> scarring, stenosis (constriction)
• Can be permanent. Treatment is balloon dilation of urethra
• Stress incontinence: sphincter control
• Causes: obstetric injury, pelvic floor weakness
• Increased pressure—> urination; e.g. When someone coughs or laughs

Neurogenic Incontinence

(1) Automatic bladder

• Cause: loss of motor and sensory nerve tracts

• Complete transection of the spinal cord above the sacral segments
• Voluntary control & awareness is lost
• Bladder reacts to spinal reflex only - simple micturition reflex takes over - involuntary
urination

(2) Uninhibited neurogenic bladder

• Also called infant bladder

• Causes: interruption of inhibitory corticospinal (descending) pathways that impede sphincter
opening and bladder contraction
• Seen in stroke, brain injury, multiple sclerosis, parkinson’s disease
• Frequent, uncontrollable micturition
• Patient aware of need to void

(3) Atonic bladder

• Causes: damage to sensory &/or motor bladder nerves

• Peripheral nerve injury
• Diabetes, damage during pelvic
• Surgery, bladder infection
• Loss of awareness or desire to urinate
• Bladder does not empty
• Bladder becomes stretched by excess urine build up, damage to the bladder wall
• Overflow leakage

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Renal Failure Is A Large Fall In Gfr

• Urine elimination and the resulting clearance of wastes from the plasma is essential for
maintaining homeostasis.
• When the functioning of the kidneys is so disrupted that they cannot perform their regulatory
and excretory function sufficiently to maintain homeostasis, renal failure has occurred.
• Renal failure is a decrease or cessation of glomerular filtration
• The most serious consequences of renal failure are retention of H+ (metabolic acidosis) and
• Retention of K+ (leads to cardiac failure)
• Recall – there are ~ 1 million nephrons per kidney —> kidneys have a large reserve capacity
(i.e. Damage must be severe to affect glomerular filtration). Kidney disease usually has to be
developing for years before complete failure occurs
• Grades of renal failure:
o Renal insufficiency: decline function, GFR ~25% normal. Plasma urea levels raised
o Renal failure with greater loss of function. Can be fatal in days.
o End stage renal disease: GRF 10-15% normal
• Multiple causes
o Infectious organisms: either blood born, or via urinary tract
o Toxic agents, such as lead, arsenic, insecticides, overdose or long term exposure to
aspirin or ibuprofen (nsaids)
o Insufficient renal blood supply: can occur with heart failure, haemorrhage, shock,
atherosclerosis
o Obstruction of urine flow, such as kidney stone, leading to back pressure and reducing
glomerular filtration

Nephrotic Syndrome

• Nonspecific disorder in which the renal corpuscle is damaged

• Many causes: eg diabetes, immune disorders, hepatitis, cancer
• Glomerular filtration is damaged
o a large amount of protein is lost in the urine (proteinuria)
o 3.5g protein/day as opposed to <25 mg/day
• Filtration slits in podocytes that permit protein filtration
• Large protein loss leads to lowering of blood colloid osmotic pressure and oedema
o Movement of plasma out of blood vessels into interstitial space
• New blood proteins will be produced by the liver in response to the loss
• However this may ultimately lead to liver failure
• Treatment: restrict fluid intake, treat infections or underlying causes, monitor and control
blood sugar, reduce sodium and increase protein intake ! poor prognosis in older patients.

Renal Hypophosphataemia

• “Vitamin resistant rickets”

• Inherited as an X-linked dominant trait in children
• Characterized by hypophosphataemia (low phosphate) and normocalcaemia (normal
calcium) in blood
• Failure of phosphate reabsorption in nephrons
• Osteoid production occurs but conversion of osteoid to bone is inadequate unmineralized
bone portion of bone that forms prior to maturation of bone
• Phase where mineral covers the collagen matrix does not take place properly.
• Bone is made up of collagen matrix without a mineral covering, so the bones become soft.
• Result: skeletal deformities
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Renal Tubular Acidosis

• Accumulation of acid in the body due to failure of kidney to secrete appropriate amount of
acid in urine.
• May be caused either
o Failure to reabsorb sufficient bicarbonate ions (HCO3-) from the filtrate in the proximal
tubule (proximal RTA)
o Insufficient secretion of acid (H+) into the distal tubule (distal RTA)
• Chronic acidity of the blood leads to growth retardation, bone demineralisation, and
progressive renal failure.
• Nephrocalcinosis or kidney stones due to alkaline tubular fluid
• Acidosis is also associated with low blood K+ (hypokalaemia)
• Treatment is by giving oral bicarbonate

Renal Dialysis

• Renal dialysis is a medical procedure that can

supplement or replace normal kidney function.
• Two forms: haemodialysis and peritoneal dialysis
• Blood is pumped through a fenestrated tube that is
bathed in dialysis fluid which has similar properties to
plasma (eg osmolarity, [glucose]) ! no diffusion of
glucose or salt will occur
• However, there is a concentration gradient
• For the diffusion of wastes, eg urea and creatinine !
these waste substances will be removed while blood
retains its salts and nutrients
• Takes 3-5 hours/day for 3 days/week

Dialysis Is Not A Perfect Replacement For The Kidney

• The kidneys also function as a part of the endocrine system producing the hormones
erythropoietin and vitamin D.
o vitamin D3 is produced from cholesterol in the skin of vertebrates after exposure to
ultraviolet light (UVB).
o vitamin D3 is carried in the bloodstream to the liver, where it is converted into the
prohormone calcidiol.
o Calcidiol is then converted into calcitriol, the biologically active form of vitamin D, in the
proximal tubule
• Dialysis is an imperfect treatment to replace kidney function because it does not correct the
endocrine functions of the kidney.

Kidney Transplant

• Surgical implantation of a new kidney from a living donor (~60%) or cadaver (40%)
• The recipient’s non-functioning kidneys are normally not removed, as outcome has been
shown to be better
• The success rate depends on the recipient’s immune response against the donated kidney

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Acid!and!Base!Learning!Objectives!!
1. Regulation of pH in the intracellular and extracellular fluid.

2. The pH of the blood and how it is affected by carbon dioxide and bicarbonate
ion concentration.

3. How the body responds to changes in carbon dioxide and bicarbonate levels

4. The role of the respiratory system in the regulation of hydrogen ion

concentration

5. The role of the kidneys in the regulation of hydrogen ion concentration

6. The terms:

a) Acidosis

b) Acidaemia

c) Respiratory acidosis

d) Metabolic acidosis

e) Alkalosis

f) Alkalaemia

g) Respiratory alkalosis

h) Metabolic alkalosis
!

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