MODULE: CARDIOVASCULAR SYSTEM

(Physiology II)

COLOUR GUIDE:

- Points of note.
- Definitions.
- Questions.
- Equations.
- (Other lecture-specific colours maybe applicable)

LECTURE 1.

Cardiac Muscle Division:

- Atrial muscles
- Ventricular muscles
- Muscles that dont contract but produce electricity/are conductive in nature (they don't
have myofibrils or don't have strongly developed myofibrils (myofibrils being actin and
myosin)). (Note: purkinje fibres are part of the conductive muscles)
- Cardiac muscle fibres have an elaborate shape, and they are connected to each
other via intercalated discs, which contain gap junctions. Gap junctions are protein
channels that connect muscle fibres’ channels to each other. Gap junctions allow the
flow of small ions through them, allowing the propagation of action potentials.
- The gap junctions are critical for the function of the cardiac muscle fibres so they may
remain in synchrony.
- Muscle fibres connected to each other through gap junctions are called “syncytial”
fibres. There’re atrio and ventrilo syncytial fibres. There are no gap junctions between
those two kinds. The electrical connection between them is done through the
atrioventricular bundle instead (also known as the bundle of His).
Cardiac Rhythm:

- Cardiac rhythm includes normal, simple “plateau” shapes on the graph.

- Heart muscles generate action potentials more or less rhythmically
- Action potentials can happen in any part of the heart’s muscles (atrial, ventricular, OR
conductive; they’re initiated by the conductive part.)
- They begin in these parts of the heart referred to as “sinus node/sinoatrial node”/ it’s
the pacemaker of our body.
- There are differences in action potentials based on where they’re found, though.
- (NOTE: the presence of a steady depolarization is called a plateau. These are
characteristics of cardiac muscle. This is not the case in skeletal muscle. The heart’s
action potentials are slower in comparison to skeletal muscles’.
- neurons: ~ 1 millisec | Cardiac muscle: ~300 millisec

- First phase: depolarisation. Na+ dependent channels open up. They’re very fast and
open up very quickly. They’re responsible for the initial upstroke of the action
potential, which reaches ~ 20+ millivolts from -80 millivolts.
- Following phase: a small hump, which leads to a slight repolarization. During this
phase, the inactivation gates are closed in Na+ channels, causing the hump.
- Following this, ca+ channels open up (voltage gated). They’re L type ca+ channels
that display relatively slow deactivation and they’re responsible for the formation of
the plateau.

Resting membrane potential: In the atria, is -85, and in the ventricles, is -80.

NOTE: Most excitable tissues (like the myocardium) have a refractory period/phase, which is
a period of muscle fibre activity wherein muscle fibres cannot or have difficulty generating
another action potential during or after another action potential.

Relative refractory period- period wherein the muscle has difficulty hosting another action
potential. RRPs last about 50-60 millisecs. If contraction is generated during RRPs, they’re
called premature contraction. Later premature contraction if it occurs during the end of an
RRP.

What causes the RP? The inactivation of voltage gated na+and ca+ channels.

NOTE: The action potentials propagate in one direction. They go from the sinus node, to the
atrium, to the ventricles-- in other words, from the top of the heart to the bottom.
Contractions, Coupling & Relaxation in Cardiac Muscle:

- Cardiac muscles have invaginations in the sarcolemma (muscular plasma

membrane) called the T tubules. AP travels into T tubules, where voltage gated
channels are opened. This includes calcium gated channels which allow the entrance
of calcium ions into the sarcoplasm.
- Additionally, calcium exits through the sarcoplasmic reticulum after the action
potential, which results in an overall large increase of calcium in the sarcoplasm.
- This calcium interacts with the myofibrils there, where the coupling and sliding of
actin and myosin occur.
- Difference between contraction in skeletal muscle and cardiac muscle? In cardiac
muscle, the largest amount of calcium is received from the outside of the ca+ gated
channels that enter when the action potential is first triggered. This is as
opposed to skeletal muscle, where the source is from the calcium stores within the
sarcoplasmic reticulum. Ca+ in ECF is important for cardiac contraction, but not
skeletal contraction.
- NOTE: the sarcoplasmic reticulum is relatively poorly developed in the cardiac
muscle compared to the skeletal muscle. Therefore, its role is more minor in cardiac
function.
- A single action potential can induce long lasting contractions of the muscle fibres,
unlike in the skeletal contraction of muscles. This is critical to the heart’s contraction.
- Special calcium transporters pump calcium out once it’s not needed. As a result, the
calcium concentration in the cell decreases, causing muscle relaxation.

Cardiac Cycle for Left Ventricular Function:

- The heart is characterised by its cyclical activity

- A cardiac cycle consists of two periods: systolic (muscle contraction period) and
diastolic (muscle relaxation period).
- Electrocardiogram: records the presence of ions in the ECF, calculating the
electrical activity of the heart.
- Phonocardiogram: records the sound of the valves of the heart opening and
closing.

Sinus, A-V nodes, and Purkinje system:

- Conductive pathway consists of: the sinus node, the AV node, the internodal
pathways, and the atrioventricular bundle, which separates into left and right
bundles.
- The conductive pathway’s capability to conduct action potentials is really high.
 - The sinus node is responsible for self-excitation and the generation of the cardiac
rhythm. In pathological conditions, the pacemaker function might shift to the AV node
or the Purkinje system instead. This would make the rhythm slower.

How does this self excitation take place?

- Action potential occurs (noteworthy: the sinus node has an unstable resting potential
unlike ventricular muscle, also it sits around -55 to -60 mv)
- The slow depolarization is called the pacemaker potential.
- The action potentials are of short duration (around 150 ms) in the sinus nodes, as
opposed to the 300 ms in ventricular muscle.
- The plateau formation here is less pronounced.
- The action potential here is relatively slow since the sodium channels do not
participate during the upstroke since the resting membrane potential is so
depolarised.
- The upstroke is caused by the activation of L type voltage gated channels; the
plateau is caused by the inactivation of the L type vol gated channels, and the
repolarization is cause by inactivation of the L type channels and the activation of
potassium channels.

Question for self: Name the differences between the action potentials between
ventricular muscle fibre and sinus nodal fibre.

Valves of the Heart:

Atrioventricular valves include:

- Mitral valve (has two cusps, can be found between the left atrium and ventricle).
- Tricuspid valve (has three cusps, can be found between right atrium and ventricle).

NOTE: the valves are connected by chordae tendineae to muscles called papillary muscles.
Also, the presence of valve structures help prevent the backflow of blood (regurgitation).

Other valves:

- Pulmonary valve: pumps blood from the right ventricle to the lungs. Has three cusps.
- Aortic valve: pumps blood from left ventricle to the aorta. Has three cusps.

END OF LECTURE.
 LECTURE 2.

TOPIC: Blood Circulation

- The blood circulation/system of the blood vessels is responsible for delivering

blood, delivering nutrients, oxygen and removing metabolic byproducts and
CO2 from different tissues.

Types of circulation:

1) Systemic Circulation- starts from the left ventricle. Provides blood to all the tissue of
the body, thereby delivering nutrients and oxygen to the rest of the body.
2) Pulmonary Circulation- It begins at the right ventricle and provides blood to the lungs,
allowing for the exchange of O2 and CO2 to take place.

Basic principles of blood flow:

- Blood flow to tissue is controlled by tissue need

- Cardiac output- the sum of local tissue blood flow, which is closely controlled. In
humans, this is about 5 litres per minute. It defines the output of the left ventricle per
minute into the aorta. It’s essential to maintain this minimum amount of cardiac
output- it can increase considerably during exercise and periods of physical strain,
but it’s important to maintain it to at least 5 litres per minute. If it decreases to less
than that, it could be dangerous and even fatal. Cardiac output is regulated by the
sympathetic and the parasympathetic nervous system (the baroreceptor system). It is
also regulated by hormones (humoral regulation)-- the kidney plays a considerable
role in this.
- Arterial blood pressure (ABP) is maintained at a normal steady level. It is important to
maintain it at the level that is, because if ABP drops, the cardiac output is
compromised, which might lead to circulatory shock.

Structure of the Circulation:

The circulation consists of-

1) Arteries- they bring blood from the heart to the rest of the circulation. They usually
have thick walls and are meant to withstand strong blood pressure.
2) Arterioles- Blood moves from the arteries to the arterioles, which are arteries that
are relatively smaller in diameter. They have very well developed smooth muscle
layers and thereby can constrict and dilate well and control local blood flow to
specific tissues or organs. Regular arteries also have the smooth muscle layers,
though they’re not as developed as arterioles.
3) Capillaries- Developed from arterioles, and they are the place where
microcirculation takes place. The exchange of nutrients and gases takes place here--
mainly O2 and CO2. It’s a critical part of the circulation.
4) Venules- Blood collects here from the capillaries.
5) Veins- Blood collects here from the venules, and then it is delivered to the heart.The
veins are a passageway to the heart, and to the atria.

Distribution of the Blood in the Circulation:

- ~84% of blood is located in the Systemic Circulation. Most of the blood is present
here as it has the function of supporting the system’s organs. Arteries contain 13% of
the blood, while arterioles and capillaries contain 7%.
- ~16% is located within the heart or the pulmonary circulation: ~9% of this is within the
pulmonary circulation, and ~7% within the heart.
- 64% is present within veins and venules
- Note: The large percentage of the blood is present in veins and venules, indicating
that they’re important as a storage site for the blood- they store it, and it can be
released into the circulation when necessary to boost cardiac output. This
emphasises their function beside delivering blood to the pulmonary circulation and
the atria.

Cross-Sectional Areas of Systemic Circulation Blood Vessels:

Note: The cross-sectional area is the sum of the diameters of all vessels of a certain
type.

(Unit of measurement in cm^2)

- Aorta: 2.5
- Small arteries: 20
- Arterioles: 40
- Capillaries: 2500
- Venules: 250
 - Small veins: 80
- Venae cavae: 8

- The large capillary area is explained by their importance to the microcirculation,

thereby leading to an extensive network of capillaries).
- The larger cross sectional area of veins leads to the conclusion that veins are more
numerous in the body than arteries, as well as having larger diameters. This
cross-sectional area also emphasises the fact that veins act as a storage site for
blood, along with venules.
- The arteries' area is relatively small, and they provide high arterial pressure blood
flow to the body’s tissue.

The involvement of velocity in cross-sectional area:

- Velocity of blood flow is related to the cross-sectional area of the body’s blood
vessels.
- The volume of blood that moves, per minute, to the different parts of the circulation is
more or less the same. However, if you calculate the velocity, it differs, and is
inversely related to the cross section.
- Representative equation: v = F/A. Volumetric blood flow over the cross
sectional area gives the velocity.
- Ex: since the capillaries have the largest cross sectional area, they have the smallest
velocity (0.3 mm/s). This is important since it has to be relatively slow, since that’s a
property that makes sense for its microcirculatory properties. The large arteries,
however, have a very fast velocity of nearly 30 cm/s.
- Note: The capillaries are fairly short structures, and blood spends a relatively short
amount of seconds within them. This duration is still enough to move the gases and
exchange nutrients.

Blood Pressure:

- It is the parameter by which blood is pushed through the circulation. It is generated

by the heart’s contraction.
- BP is measured as the force exerted by the blood against the interior of the vessel
wall.
- It is conventionally measured by millimeters of mercury (the height of mercury) above
atmospheric pressure, since the mercury manometer has been used as the standard
reference for measuring pressure. As pressure increases, it pushes the mercury up
the column, and therefore we are able to read it.
 Normal BP in Different Circulatory Sys Areas When A
Person Is Lying Down Horizontally:

- Note that since this is a horizontal position we’re excluding the effects of gravity.

- The Left Ventricle: Systolically: rises to 120 mm Hg, Diastolically: 0 mm Hg.

- The Aorta: Systolically: 120 mm Mg, Diastolically: 80 mm Hg. Note that it doesn’t
drop to zero here, since the blood vessel has elasticity which is responsible for the
maintenance of blood pressure during the systole. Also note that according to the
graph, as we move down the systemic circulation, BP decreases.
- In veins it’s around 20 mm Hg.
- In the right ventricle: Sys: 20/30 mmHg, Dia: 0 mm Hg
- In the Pulmonary artery: Sys: ~30 mm Hg, doesn’t drop to 0 either. Dia: ~15 mm Hg.

Question for self: why is blood pressure lower in the right ventricle than the left?
A: The pulmonary circulation offers far less resistance to blood flow than the systemic
circulation, so it doesn’t require as much pressure to push blood through it. In the systemic
circulation, the resistance mostly rises from the arteries and arterioles. In the systemic one,
the capillaries’ cross sectional diameter is so large that they, too, offer considerably lower
resistance.

Hemodynamic Rules:

Ohm’s Law: The flow (measured by ml/s) through the vessel can be calculated by the
following formula.

In other words: Blood flow is determined by the vessel’s pressure gradient (typically P1
(beginning of the vessel) should be higher while P2 should be lower) and the resistance,
which is offered by blood’s friction against the vessel wall and influenced by the blood’s
viscosity.

F = delta P (pressure gradient)/R (resistance).

Character of Blood Flow:

- In small diameter blood vessels lined with smooth muscles, the blood moves in
streamed lines. It has a laminar direction and movement. The velocity layer is
 parabolic: this means that layers of blood situated near the walls move slower,
meanwhile central layers move faster. In smooth muscles, blood flow is
laminated, in lines, and has a parabolic nature.
- Q: Why do we have this parabolic nature of blood movement? A: Its because the
layers of blood near the walls are essentially adhered to the walls and practically
don’t move. The layers after the ones by the wall move relatively slower because
they slide against the first layer (the ones adhered to the wall), and the middle layer
is fastest because of its considerable distance from the vessel walls.
- Note: this laminar flow also explains the fact that veins can store the blood, seeing as
the blood near the walls can practically be in an unmoving state-- when restriction
takes place, though it can put out more blood into the circulation, thereby increasing
cardiac output.
- Blood turbulence is an alternative way of blood flow. It is in contrast to the laminar
movement of blood, and the layers mix with each other. It is chaotic and doesn’t
move in a streamlined manner. This increases vascular resistance. This doesn’t take
place in small, smooth vessels.
- Blood’s tendency towards turbulence can be measured using Reynold’s number
(Re).
- Re = v (mean velocity of blood flow) x d (vessel diameter) x p (density) / η (eta)
(viscosity).
- Note that due to their larger diameter and higher velocity of blood movement,
arteries tend to be more likely to experience blood turbulence (average Re of
about 200 - 400) especially at the sites of changes of diameter and at the
sites of arterial bending. Note: The proximal pulmonary artery is notably
susceptible to turbulence, where Re can rise to several thousands. Also
remember that turbulence affects resistance.

- 1 Peripheral Resistance unit (PRU) is when the difference in pressure

between two points is 1 mm Hg and the difference in flow is 1 ml/sec.
- Conductance: it is the inverse variable of resistance. Conductance =
1/resistance. It describes how easily blood flows through a certain
vessel.
 Poiseuille’s Law. It states that blood flow is proportional to the
pressure gradient^4 and inversely proportional to the viscosity.
In other words, it indicates that the conductance is proportional
to the diameter^4.

Note: Viscosity is inversely proportional to Q (the blood flow).

Effect of Vessel Diameter on Blood Flow:

- Blood flow depends on the diameter of the blood vessel. It’s important to note this as
it informs us that changing a vessel’s diameter can have a huge consequential effect
on the amount of blood flow to specific tissues or organs. This quality can be seen in
arterioles, which, due to their smooth muscular layer, tend to have the ability to dilate.

-
- Note the parabolic nature of blood flow: in larger diameter vessels, the blood flow is
faster the further it grows from the arterial walls. But in smaller vessels, the layers are
closer to the walls than in large ones, rendering the blood flow slower.
- Note: when metabolism is large in uncertain tissues, blood flow is increased and
vessels dilate to accommodate it.
Vascular Resistances: A, in series, and B, in parallel

1) When vessels are arranged in series, the blood flow in each of the vessels is the
same and the total resistance to blood flow is equal to the sum of the resistance of
each vessel.
- Ex: R(total) = R1+ R2+ R3+ R4….

2) For blood vessels arranged in parallel, the total blood flow is expressed inversely.
- Ex: 1/R(total) = 1/R2 + 1/R3+ 1/R4….

The Effect of Hematocrit on Blood Viscosity:

- Hematocrit (the percentage of blood that is RBCs) determines the blood viscosity
.The more RBCs, the more viscous the blood. The more viscous, the more resistance
increases.
- The viscosity of normal blood is when the hematocrit is about 4, when hematocrit is
at 40. Viscosity of water is at 1, and plasma is 2.
- Polycythemia is a condition in which there is an increased viscosity of blood due to
an increased amount of RBC, thereby increasing the resistance (and also leading to
some issues such as blood clotting.

Effects of Pressure on Vascular Resistance and Tissue Blood

Flow:

Reminder: Ohm's law of fluid flow states that flow (Q) is equal to the pressure gradient (ΔP)
divided by resistance (R): Q = ΔP/R.
 - When mean arterial pressure increases, the blood flow also increases proportionally,
but it doesn’t follow Ohm’s law exactly because it doesn’t do so in a linear manner.
- Instead, there’s a flattening of the curve later on. This is caused because of the local
control and regulation (i.e, autoregulation) based on the demand of blood flow by the
local tissue.
- However, in a passive blood vessel without autoregulation, the graph shows a more
linear line, following Ohm’s law. However, the presence of a passive vessel in the first
place isn’t normal, since blood vessels are typically autoregulated to adapt to the
metabolic needs of body tissue.

Vascular Distensibility and Vascular Compliance:

Vascular distensibility: increase in vol/increase in pressure x original volume

Vascular compliance: increase in volume/increase in pressure

- Vascular Distensibility: Fractional increase of the volume when the pressure

increases.
- Vascular Compliance: Absolute increase of the volume when the pressure increases
- Notes: veins have better vd and vc than arteries for their blood storage function.
Venous system has considerable vc and vd, while the arterial system has a relative
amount but not as much.

Arterial Pressure Pulsation:

- Arterial pressure has a pulsating nature.

- Although arteries’ distensibility is less than that of veins, it is the reason blood
pressure is maintained during the diastolic period.
- Pulse pressure: the stroke volume/arterial compliance. It is the difference in pressure
between the systolic and the diastolic points.
- Pulse pressure can change during certain pathologies like arteriosclerosis and aortic
stenosis.
- Blood pressure also changes with age. The systolic and diastolic blood pressure
tends to change with age. Additionally, the kidney has a role to play in the
maintenance of the blood pressure.
- Note: the heart spends more time in the diastole than in the systole.
 LECTURE 3.

Veins and their functions:

- Provide passageways to the heart.

- Have a higher relative number than arteries, and relatively large diameters
- Have pronounced distensibility and compliance/capacity.
- These features are responsible for the veins’ ability to store blood
- Veins have well developed smooth muscle layers which allow for venous constriction
and relaxation. They can thereby store large or small quantities of blood, and when
necessary, release a large amount of returned blood to the heart. This in turn leads to
the increase of cardiac output.
- Therefore, veins play a big role in regulating cardiac output and cardiac function

Venous Pressures:

- The large veins converge unto the right atrium, and the pressure at the right atrium is
called the central venous pressure.
- Usually, CVP at rest is around 0 mm Hg, which is equal to atmospheric pressure.
- NOTE: This can change when venous return increases, as a result of, for example,
blood displacement; in such cases, CVP would increase in the right atrium. A notable
increase is around 5, 6, or maybe even 8 mm Hg.
- It can increase to 20 or 30 mm Hg under very abnormal conditions, or pathological
conditions, such as cardiac failure. This might signify the heart’s inability to pump
enough blood, or the compromise of the ability to pump blood in general.
- However, moderate increase of atrial pressure indicates an intensive circulation, or a
larger venous return response, and the increase in atrial pressure prompts the heart
to increase cardiac output.
- Right atrial pressure can decrease to around -3 to -5 mm Hg. This usually indicates
that the heart is working very intensely, and it also indicates that there might be a
decrease of venous return, such as hemolysis, which might decrease CVP.

Compression points that tend to collapse the veins:

 - Arteries and arterioles offer the most resistance of blood flow, but veins on the other
hand offer relatively little resistance.
- Still, there is relatively some resistance there, usually present because of the veins’
abilities to bend and compress. Ex: veins entering the thoracic/abdominal cavity can
bend and partially collapse. This is, for example, because of the bend of the ribs.
Also, in the abdomen, they can bend around the organs.
- As a result, veins have the capacity for distortion, which offers resistance to the blood
flow.

Gravitational Pressure in Venous System:

- When considering venous blood flow, we spoke about humans in horizontal

positions, which excludes the gravitational effect, and the weight doesn’t affect the
blood pressure much.
- On the other hand, being in an upright position gives the blood weight, as it would be
pushing down on blood vessels.
- In the case of veins, this would generate pressure that opposes the blood flow from
the veins to the direction of the hearts.
- At the level of the feet, the standing human’s veins generate a pressure of around 90
mm Hg.
- Pressure is different at different levels. Ex: 40 mm Hg at the knees, 22 mm Hg in the
abdomen.
- It’s important to discuss how the system can overcome the gravitational flow of blood.

.
Venous valves of the leg:

- Veins consist of valves that open in the direction of the blood movement to the heart.
- These veins open in the direction facing the heart but resist backflow away from it.
- We also have skeletal muscle surrounding these blood vessels. Their contraction
generates venous compression, which propels blood in the direction of the heart.
- The valves maintain the blood in place, preventing backflow.
- The venous pump is very effective as a result of all of this, and can overcome the
gravitational effects on blood.
- In pathologies, the valves can be compromised in some cases, which causes the
venous pump to be incapable of working properly, which can lead to edema in feet
(i.e fluid filled swelling). This could be deadly in severe cases.
- TLDR: The importance of the valve/pump system is to manage the effects of gravity
on blood flow and redirect blood to the heart.
- On the other hand, in the arterial system, blood’s weight increases arterial pressure
and it pushes down the blood with a higher strength through the arteries and
arterioles.

Specific Blood Reservoirs:

- As we know, one of the veins’ primary functions is the storage of blood.

- The prominent storage locations are:
1) Large abdominal veins
2) Liver
3) Spleen: Note: interestingly, can store not only liquid blood, but blood in the “pulp”
formation, where it can store RBCs, and can release them upon loss of blood volume
as a result of things like hemorrhages (an escape of blood from a ruptured blood
vessel.). This release occurs as a result of the actions of the sympathetic nervous
system, which promotes the squeezing of the veins and pulp, forcing the erythrocytes
into the circulation.
4) Venous plexus beneath the skin

- Q: When is it necessary to increase cardiac output?

- A: during situations such as hemorrhages and also during intensive periods of
physical activity, wherein veins constrict and release more blood into the circulation,
which increases cardiac output and in turn blood flow to skeletal muscles increases
to meet their need.
- Additionally, transfusion of blood can occur without major changes to arterial blood
pressure since a considerable amount of blood can be stored within the veins due to
distensibility and compliance, since they can extend to put away that transfused
blood.
Microcirculation:

-
- Responsible for the exchange of nutrients, gases, and metabolic byproducts.
- It consists of the arterioles (which consist of a relatively small diameter) with a very
well developed smooth muscle layer, and capillaries.
- The arteries that originate from the heart branch 8, 9 times and as a result the
diameter changes, yielding arterioles. After 4 or 5 divisions, these arterioles become
small arterioles, which then yield capillaries.
- Capillaries lack smooth muscle, and they are the site where the exchange of
nutrients and gases takes place. Their length is relatively small (few mms), and the
blood flow is relatively slow with very fast diffusion. Since the diffusion is very fast,
the blood has enough time for the exchange to occur.
- Diffusion is very fast because the capillaries contain special tissues that facilitate
diffusion through their walls: additionally, oxygen and CO2 can diffuse through the
bilipid layer of cells.
- Reminder: Diffusion is the movement of molecules across a concentration gradient.
Due to heat agitation and the chaotic movement of molecules as a result of their heat
kinetical energy, they are able to move along the concentration gradient.
- Note: hydrophilic substances move through the pores present in the capillaries,
which hydrophobic substances can move through the bilipid layer.
- Though capillaries don’t have smooth muscles, they have precapillary sphincters,
which is a layer of smooth muscle that allows the opening and closure of capillaries.
- Note that: blood flow is directed to tissue according to tissue need. This happens
because the arterioles and precapillary sphincters can cause changes to the
diameter of blood vessels. When metabolic need is high, smooth muscles are
relaxed, leading to the dilation of arterioles and precapillary sphincters, allowing the
 diameter to increase and direct more blood flow to the specific tissue. On the other
hand, the opposite is true: when the metabolic need is low, they constrict, lowering
blood flow.

The Structure of the Capillary wall:

- Differs from other blood vessels because they are composed of a single layer of
endothelial cells.
- They also have a basement membrane, and as seen on the diagram, an “intercellular
cleft” or space, which provides channels for diffusion. The diameter is about 70-80
angstrom (one angstrom = 0.1 nanometre), which is wide enough to allow the entry
of ions and medium sized molecules like glucose. However, they do not provide
passage to larger substances like proteins, and very few proteins can filter through
the capillary walls. Therefore, only plasma can filter through the capillary wall.
- O2 and CO2 can diffuse through the lipid layer and require no intercellular cleft since
they are lipid soluble.
 - Note: Different capillaries have slightly different clefts: for example, in the brain,
capillaries are fused to each other, and therefore have very few intercellular clefts.
Alternatively, in the liver, intercellular clefts are very prominents with a large diameter:
the same is the case in the kidney, within the glomerulus. In the kidney, the
endothelial cells also have additional channels that allow more fluid diffusion.
- Note: the presence of caveolae within capillary walls, which are vesicles that perform
endo and exocytosis. Within caveolae, we find a special protein called Caveolin,
which is responsible for facilitating endocytosis.

Blood Flow in Capillaries:

- Note: Blood flow is intermittent (occuring in irregular intervals) in capillaries (as in, it
is not continuous, and undergoes vasomotion: the intermittent contraction of
arterioles and precapillary sphincters). However, because of the large number of
capillaries, it evens out into a regular blood flow since it averages out in the end.
Therefore, despite vasomotion, capillaries have a steady flow because their large
number evens out irregularities, since at any given moment where some precapillary
sphincters may be contracting, others may be relaxing)

Diffusion of fluid molecules and dissolved substances between

the capillary and interstitial fluid spaces:

- The exchange of materials occurs through diffusion.

- Capillary vascular walls have high permeability, which allows nutrient flow along a
concentration gradient. Nutrients reach the interstitium and enter the cells from there.

Structure of the Interstitium:

 - It is the area between cells, and it makes up about 40% of the body.
- During diffusion, nutrients and exchanged substances pass the interstitium before
entering the cells.
- Note: two types of tissue are within the interstitium; collagen fibres (relatively large,
with a sizable diameter) and proteoglycan filaments (which are very small and thin).
- Note: Interstitial fluid is the same as the plasma, except interstitial fluid has a very low
concentration of proteins. It is essentially plasma without proteins. Additionally,it has
a gel-like consistency. Generally, free fluid is rare in the interstitium: we only have
rivulets of free fluid that move between parts of the interstitium to other parts, but
mostly the interstitial fluid maintains a gel-like form due to the proteoglycan filaments
that are bound to fluids coming from the capillaries,
- The gel-like consistency is actually very diffusible, and nutrients and ions can fuse
here nearly as fast as in regular fluid, and so it does not hinder diffusion. Thereby, we
can consider it a “fluid” of sorts since it still allows fast diffusion.

Fluid Pressure & Colloid Osmotic Pressure Forces at the

Capillary Membrane:

- Fluid moves through the capillaries while being exposed to different types of
pressure, including:
1) Capillary pressure: (hydrostatic pressure; pushes fluid through the membrane
into the interstitium)
2) Interstitial fluid pressure (Pif): (can be pos or neg, depending on the area. Ex:
it is negative in the subcutaneous area, and helps move the fluids from the
capillary into the interstitium.)
3) Plasma colloid osmotic pressure (IIp): (is generated by proteins in plasma;
pushes fluid from the outside into the inside)
4) Interstitial fluid colloid osmotic pressure (IIif): (generated by the low
concentration of proteins that can penetrate through the endothelial plasma
membrane/the intercellular cleft)

- Q: What is net filtration?

- There are forces that push the fluid out the capillaries, and forces that force the fluid
back in. They are summated through NFP, which is the summation of the four forces
mentioned before (the “Starling” forces, named after the scientist Ernest Starling).

- NFP (net filtration pressure) = Pc - Pif - IIp - IIif

- Filtration/Filtration rate = Kf (filtration coefficient) x NFP
 NOTE: The filtration coefficient characterises the capillaries’ capacity to allow fluid
movement through the endothelial walls, and it depends on capillary branching and
the number of intercellular clefts. Usually, the filtration coefficient is around 2 ml per
minute.
Q- What does Starling equilibrium mean?

- It means that the amount of fluid filtered through the arterial end of the
capillary is the same amount moved back towards the venous end of the
capillaries. This occurs because on the arterial end, we have high hydrostatic
pressure which pushes fluid through the wall, while on the other hand, we
have low hydrostatic pressure and BP at the venous end coupled with
relatively high (28 mm Hg) plasma colloid osmotic pressure which pushed the
fluid back into the capillary. TLDR: if you consider both forces at the either
end of the capillary, we’;; find there’s very little filtration, and that if we average
the two opposite forces out, the total net force is nearly 0 (it’s around 0.3 mm
Hg)
- NOTE: The small amount of fluid that does excessively seep into the
interstitium is moved onto the lymphatic system
- NOTE: this also explains why diffusion is mainly relied upon for nutrient and
gas exchange instead of relying on the mere movement of fluid to do so.

The Lymphatic System:

- Also called the accessory circulation pathway or the scavenger passway.

- It allows the excessive fluid leaving capillaries due to the quasi-equilibrium state to be
absorbed-- in case of lymphatic system malfunction, the excess fluid would develop
conditions like edema.
- Note: the presence of lymphatic channels that separate into the thoracic duct (lymph
accumulation from the lower and left part of the body) and the right lymphatic duct
(lymph accumulation from the right part of the body).
- From these ducts, the lymph moves into the venous system, joining the general
circulation.

- Q- What is the function of the lymphatic system?

A: (The movement of excessive interstitial fluid back into the circulation, as well as
moving the small number of proteins that escape the plasma through the intercellular
clefts in the capillary walls back into the circulation via veins.)
A2: (The presence of lymphatic nodes (little sacs of tissue wherein different lymphatic
vessels converge) contain large amounts of lymphocytes and macrophages, and
they have a critical role in immune response against infection. This is because when
viruses and bacteria penetrate through the skin, they usually move to the lymphatic
system rather than the circulation, where the present amount of lymphocytes and
macrophages can attack and deal with the invaders.
Structure of Lymphatic Capillaries:

- Site of fluid absorption.

- They consist of endothelial cells, containing little flaps which overlap each other, as
well as “anchoring filaments” which attach the endothelial cells to the surrounding
cells.
- The flaps can open and allow fluid penetration through the endothelial cells and into
the lymphatic capillaries. When closed, they do not allow backflow.
- Remember that: Lymphatic fluid is made up of mostly absorbed interstitial fluid
(which, as stated, is like a low-protein version of plasma) as well as absorbed
proteins)
- NOTE: The lymphatic system has a special role in the intestines. There, it moves
large amounts of lipids from the point of absorption. Thereby, we can say that the
lymphatic system also assists in moving lipids as an additional function in the specific
case of intestines.

- NOTE: The lymphatic vessels contain valves which allow a unidirectional flow of fluid
(in the direction of veins).
- We can find smooth muscles within large lymphatic vesicles; they contract and act as
a sort of “lymphatic pump” to move in the direction of the veins.
- Even in regular lymphatic capillaries, we can note the presence of myofibrils (actin
and myosin fibres), which assist in contraction and thereby fluid movement into the
large lymphatic vessels, and then the venous system.
 END OF LECTURE.

LECTURE 4.

Flow of Current in Chest Around Partially Depolarised Heart:

- The Electrocardiogram (ECG) is a tool used to record the electrical signals of the
heart, and this can be done when the heart is partially depolarised (i.e: when
electrical signals propagate through the heart).

- The diagram shows the heart-- the ventricle, specifically -- in partial depolarisation. In
this case, the electrical signal propagates through the purkinje fibres, passing
through the IV septum, and depolarising it. Thereby, the fibres’ surface is charged
negatively, and the interior is charged positively.
- The apex of the ventricle, on the other hand, is still polarised, as the signal hasn’t
reached it yet, and so the surface of its fibres are charged positively.
- When the heart is partly depolarised, like in cases such as these, the potential
differences generated are created between different parts of the heart. As a result,
the currents flow around the heart, but also upon the surface of the body/chest.
- When electrical currents carried by ions flow, electrical potential is generated on the
surface of the body and within it.
- Therefore, placing electrodes on the chest and then connecting it to an
electrocardiogram can record electrical activity/potential.
 - Q: why should the heart be only partially depolarised, and not fully so, in order for the
ECG to get a read?
- A: ECG calculates the differences in electrical activity, not absolute voltage, so a
completely depolarized or polarised (as in during a total diastolic period) wouldn’t be
recorded.

Normal Electrocardiogram:

- ECGs are read using the letters “PQRST”.

- First it begins with a P wave, followed by QRS waves, and then ending with a T
wave- these letters repeat as a result of cardiac rhythmicity.
- The P wave is caused by the depolarisation of the atria. It is followed by a flat
interval, wherein the entire atrium is depolarised.
- The QRS wave is caused by ventricular depolarisation.
- The ST period is caused by entire ventricular depolarisation.
- The T wave is caused by ventricular repolarization.
- NOTE: There is a wave signifying the repolarisation of atria, but it is obscured by the
QRS wave
- The PR interval (period from P->R) is around 160 millisecs. This duration is how long
the atrium is contracted.
- The duration between the Q to T wave (Q-T Interval) is around 250 millisecs. In other
words, that’s how long the ventricles are contracted.
- There are two kinds of waves: waves generated through depolarisation, and waves
generated through repolarisation.
Recording Depolarisation (A,B) and Repolarization waves
(C,D):

- Note on the diagram that the two electrodes are placed on areas of the different
charges- the first electrode is placed in an area where the intracellular space is
entirely positively charged with the surface being negatively charged where the
electron potential flows through the muscle fibre. On the other hand, the reverse is
true for the second electrode.
- This generates a difference in electrical potential between the two areas on the
electrode, which is represented on the ECG graph: the upwards rise begins as the
depolarisation starts, and it reaches zero as it continues to the other electrode,
meaning there is no difference in electrical potential between the two electrodes
anymore.
- This is the basic concept of the AB (depolarization) wave.
- As for the CD wave:
- The process of repolarization begins as the internal environment of the cell begins to
grow negative, and the outside surface begins to grow more positive. During the C
phase, the cell is still now completely repolarized. This time, the ECG illustrates a
negative graph in the opposite direction.
 - In the CD phase, the entire muscle fibre is wholly repolarised, leaving no potential
difference and deflecting the graph back to zero again.

Monophasic Action Potentials and Electrocardiogram:

- The upper graph represents the action potentials in ventricular muscle, and we can
see this because of the provided characteristics (long ap duration, presence of a
prominence plateau, etc)
- The lower graph represents a ventricular depolarization- repolarization segment on
the ECG.
- (NOTE TO SELF: I was confused as to why T waves are positive on the ECG if
they’re repolarization waves. I googled it and it turns out it’s because there’s a double
negative of direction and charge, which makes them appear positive. Still kind of
confused about that TBH. Another source says it’s because the first ventricular cells
to depolarise are also the first to repolarise. Wack! Anyway I’ll look into it later.)
- Note that the QRS phase corresponds to the depolarisation phase on the upper
graoh, and the T wave corresponds to the AP depolarization phase on the T phase.
Most importantly, the plateau corresponds to the flat segment (S-T segment).

Conventional Arrangement of Electrodes to Record Standard

Electrocardiogram:

- Standard bipolar limb leads show the conventional arrangements of ECG electrode
placements.
- There are three leads.
- Lead 1- one electrode connected to the right hand, and the other on the left hand.
- Lead 2- one electrode connected to the right hand, and the other to the left foot.
- Lead 3- one electrode connected to the left hand, and the other to the left foot.
 - Other leads can be taught, like chest leads (positive leads on the chest and negative
ones on the limbs) or unipolar limb leads (one electrode is connected to one limb,
and another to three(?!?!) limbs)
- Einthoven’s triangle (shown on the graph) presents the points where the heart is
electrically connected to the limbs.

Heart Electrical Activity & Vectors-

- Remember that a vector is a variable with a direction and length (aka magnitude)
 - Vectors can help characterise cardiac activity. They calculate the average electrical
activity drop set by cardiac activity.
- The arrow on the figure below signifies the positive direction of electrical potential
drop, and the length signifies the magnitude of the drop.

-
- The vector is generated when the ventricle undergoes depolarisation, and its
direction is conventionally measured relative to the horizontal line (which is
considered 0 degrees.
- In the particular graph shown above, the direction is 59 degrees.
- In normal circumstances, when the ventricle is depolarised, the instantaneous mean
vector’s directional angle is around 59 degrees.
- These vectors can be built via ECG, and their direction changes during pathologies,
i.e. if the heart is displaced or something of the sort.
- Vectorial EGGs analyse heart activity in great detail.

Vectorial Analysis of Cardiac Activity:

 - We record the ECG on 3 different leads typically, and draw the deflection magnitude
along those leads.
- The arrow length tells us the magnitude of the deflection along each lead.
- If we draw perpendicular lines between those arrows (those striped lines), we may be
able to calculate the heart activity’s vectors, either instantaneously in the moment or
the average vector of re/depolarisation.
- TLDR: Vectors correspond to cardiac activity which is calculated from the voltage
deflection across different leads. The potential differences are recorded and
measured along the axis, and then the vectors are calculated.
- NOTE: blue lines represent the axises. Lead I is 0 degrees, Lead II is 60, and Lead III
is 120.

Mean Electrical Axis in Ventricles from Electrocardiographic

Leads:

- The average/mean vector can be calculated using the net total deflection by
gathering up all the other deflections and then measuring and drawing them upon
their corresponding axes. (Ex: drawing the vector for lead i on the lead i axis, for lead
iii on the lead iii axis, etc). (note: only the positive/upward deflection, we should
disregard the negative deflection, as seen in the graph for lead iii).
- Then, from each vector, we must draw a perpendicular line-- where the two
perpendicular lines meet is where the final vector should be drawn, giving us the
mean vector which is pointed at a 59 degree angle.
- Use of these vectors is very efficient when identifying cardiac pathologies, like
arrhythmias, anatomical displacements, etc.
Right Bundle Branch Block in the Ventricle:

- In some cases, the right purkinje bundle is blocked when the AP (actional potential)
generation is slowed down. Due to this slowing down, the vector’s direction and
magnitude will be changed.
- We can calculate the drop using the leads and the perpendiculars drawn between
them.
- In this pathology, the vector’s angle is 100 degrees, different from the normal 59.

A low-vol ECG caused by previous MI:

 - We can get information simply by observing ECG voltages, even without vectorial
analysis.
- Normally, the amplitude of different leads on the ECG reaches at least a few
millivolts, but in the case above, it decreases very much, to about .5/.6 millivolts. This
indicates that some of the cardiac muscle is weakened. In this case, this is caused by
a previous MI-- so some parts of the fibre do not function and do not generate strong
electrical currents.
- Another reason for the low voltage is the accumulation of cardiac fluid shunts the flow
of the current.

Effects of a Current Injury on the ECG:

- Some injuries to the heart, perhaps because of cardiac infarction or other causes of
damage to the heart muscle, caused by ischemia or anoxia, muscle fibres become
permanently depolarised due to lack of adequate nutrition.
- Muscle fibres that are permanently depolarised cause an electrical potential
difference between different parts of the heart. Ex: during a diastolic period in a
ventricle, when all areas should show no difference in electrical charge, the damaged
area would, generating a difference.
- The injury and subsequent electrical difference causes the vector to point in different
directions.

Cardiac Arrhythmias:
 - Cardiac Arrhythmias are abnormalities in heart rhythm.
- Some causes include:
1) SA node abnormalities
2) Pacemaker function shifting,
3) Blockages in certain cardiac points that prevent impulse spread
4) Abnormal pathways of impulse transmission
5) Spontaneous generation of spurious impulses in (nearly) any part of the heart

Abnormal Sinus Rhythms:

- Tachycardia: high frequency of heart contraction, anything < 100 bpm. Could be
caused via fever (since rising temperature affects heart rate), effects on sympathetic
nervous system, SA node damage, etc
- Bradycardia: decreased frequency of heart contraction, anything > 60 bmp. Could be
due to parasympathetic NS abnormalities and or SA node pathologies.

Main types of arrhythmias:

- Sinus arrhythmia
- Sinoatrial block :
● develops when SA node signals are blocked from propagation, causing the
pacemaker activity to shift to AV node, and decreasing rhythm. In this case,
the P wave is absent, as it is caused by atrial depolarisation)
- Atrioventricular block
● has different forms:1st, 2nd, and 3rd degree. 1st degree has a delay of
excitation spread from atria to ventricles, causing an increase of the period
between the p wave and the qrs complex. 2nd degree constitutes complete
brief blockages of signal spread from atria to ventricles, blocking ventricular
contraction. 3rd degree consists of long blockages of total signal spread from
atria to ventricles. In this case, ventricles contract at a lower frequency than
atria
- Interventricular blockage:
● When purkinje fibres are blocked, changing the amplitude of the PQRS
complex, resulting in intermittent increases and decreases.This usually
occurs during tachycardia, because the quick frequency might make it hard
for the purkinje fibres to exit their refractory periods, making it so that every
other contraction or so in entirely skipped.
- Premature contractions:
● Occur as a result of activities originating outside of the sinus node. Can occur
in the atria, ventricles, or AV nodes. Can be caused by different factors like
mechanical irritation, ischemia, inflammation, or because of non-SA node
signals (if it occurs in the atrium), which causes a shorter period between the
 P and QRS complex. Premature contractions can occur from time to time in
healthy individuals, but frequent occurrences indicate pathology.
- Paroxysmal tachycardia
● High freq contraction of atria or ventricles, originates outside the SA node.
Can also originate in the AV node. Characterised by circular movement of
activity and constant excitation of the initial sites of activity. Could be caused
by intoxication, ischemia, inflammation, etc. If tachycardia develops in atria or
AV sites, it is not deadly and can happen in healthy folks on rare occasions.
Very fatal in ventricles though, which leads us into...
- Fibrillation:
● Chaotic contraction of muscle fibres, leading to improper contraction of, say,
atria, leading to improper pumping of blood. In minutes, can lead to loss of
consciousness and death, can be developed from Paroxysmal tachycardia;
characterised by different direction of electrical circulation in ventricles and
chaotic contraction, and can be caused due to increased cardiac volume,
decreased electrical signal propagation, or the decrease of refractory periods.
● Not present in healthy individuals as electrical propagation continues down
the conductive pathway and the impulse does not repeat due to the presence
of the refractory period. Increased heart volume may change this, since the
pathways become longer and some fibres exit the refractory period quickly,
among other reasons. Atrial fibrillation is not too deadly, however, and is
easily survivable.
- Cardiac arrest
● Electrical signal generation in the heart stops entirely. Caused by either
ischemia, or anoxia. Could be caused by improperly administered anesthesia

LECTURE 5

Humoral and Nervous Regulation of Blood Circulation

- One of the fundamental capabilities of the circulation is directing the flow of blood
based on metabolic need.
- Blood flow and exchange occurs such that functions like delivering O2 and nutrients
can be maintained, as well as removing CO2 and H.
- Maintaining the proper concentrations of ions and transporting hormones to different
tissues are also important functions of the circulation.
- NOTE: While it is standard that blood flow to certain tissues is regulated based on
the metabolic needs and/or requirements of the aforementioned tissue, there are
 exceptions. Ex: the skin, where blood flow is also a means of thermal regulation, if
needed. Ex2: the kidney, where blood flow is directed for filtration and removal of
metabolic byproducts.
- Knowing that the two main states of the heart are either being at rest or working, note
that at rest we have lower blood flow towards skeletal muscles, at around 750 ml per
minute. While involved in intensive exercise, however, the blood flow can increase to
up to 25 times more.
- The liver also gains a lot of cardiac output, as it is one of the largest solid organs in
the body.
- Q: why regulate blood at all? Why not just distribute the maximum amount of cardiac
output to each tissue/organ?
- A: The heart is incapable of doing so and maintaining maximal demands from all
tissue organs. Therefore, it requires regulation, leading to the regulatory system only
distributing blood where it’s needed for efficacy.
- Regulation distributes blood flow exactly as it is needed, providing neither more nor
less blood than is necessary to a specific tissue.

The Two Phases of Local Blood Flow:

- Local blood flow contains two main phases: acute (takes seconds or minutes, can
occur very quickly), and long term (may take, as the name suggests, a longer period
to redirect blood flow; perhaps due to higher metabolic needs from an organ)
- Ex: If a person exercises on a daily basis, long term control regulation might occur.
- Local blood control is mainly humoral, with the nervous system playing a more minor
role.
- NOTE: Two basic theories exist concerning blood flow regulation: the vasodilator
theory and the oxygen lack theory.
- Vasodilator theory: States that according to metabolic need, vasodilators (ex: CO2,
adenosine phosphate, histamine, hydrogen ions) are released, causing the blood
vessels (specifically meta arterioles and capillary sphincters) to dilate more, therefore
delivering more blood to tissue.
- NOTE: Adenosine is especially important when it comes to the vasodilators
previously listed. It’s important in the heart, skeletal muscles, and so on. Though
other substances like lactic acid and histamine have their own important roles.
- Oxygen lack theory: States that the decrease of oxygen specifically affects the
smooth muscles of metarterioles and precapillary sphincters such that they become
relaxed, causing an increase in blood flow.
- NOTE: Most likely both of them are at play at varying levels depending on the organ
in question. We know for sure that oxygen concentration has a direct effect on
smooth muscles, but we also know that oxygen concentration does also depend on
vasodilators. It seems that a decreased concentration of other nutrients (glucose,
amino acids, etc) also causes the relaxation in smooth muscles, though there’s less
evidence for this.
Specific Examples of Acute “Metabolic” Local Blood Flow
Control:

- Occlusion: the blockage or closing of a blood vessel or hollow organ.

- Reactive Hyperemia: Occurs as a result of occlusion in a certain blood vessel and

then the subsequent removal of that occlusion, which leads to an increased delivery
of blood flow to compensate for flow not received during the occlusion. Ex: occluding
the skeletal muscles (as shown on the graph), removing the occlusion from the artery
makes the blood flow increase significantly above the average blood flow the tissue
would be receiving normally had the artery never been occluded in the first place.
- Active Hyperemia: Occurs as a result of increased tissue activity (in the diagram, for
example, as a result of increased skeletal muscular activity), which in turn leads to
higher metabolism, which in turn leads to greater metabolic demands and greater
loss of concentration of substances like O2 and, finally, greater blood supply as a
result.

Effects of different levels of APD on blood flow through muscle:

- Reminder: Ohm’s Law of flow, which indicates that increased arterial pressure
gradient causes an increased blood flow, isn’t perfectly linear due to the effects of
autoregulation. This is because local mechanisms essentially shut down
unnecessary increases in blood flow, even if BP is high, and increase resistance (or
decrease compliance) to maintain regular blood flow despite increasing BP.
- Autoregulation occurs via increasing O2 concentration and the washing out of
vasodilators.
 - Basically, autoregulation plays by the rules of local control, and responds to
metabolic needs rather than BP.
- This principle is important and allows for the proper redistribution of blood and for
maintaining normal cardiac activity, not forcing the heart to pump more than it needs.

Nitric Oxide and Blood Vessel Dilation:

- When blood flow increases in skeletal muscles, for example (there’s a focus on
upstream circulation here in the lecture), the arteries that deliver blood there
experience an increase in blood velocity, which causes what we call “shear stress”
which affects the endothelial cells, deforming them.
- This deformation causes the production of NO, which occurs through the interaction
of O2 with the amino acid L-Arginine, with the help of the enzyme eNOS (endothelial
nitric acid synthase).
- Then, the eNO diffuses through the endothelial cells and reaches the smooth
muscles, where it changes cGTP to cGMP, which activates protein kinase G (?)
which causes smooth muscle relaxation.
- NOTE: Endothelial cells produce endothelin, which has more or less the opposite
effect on blood vessels, and causes constriction. It’s important during vascular
damage, as it constricts the vessel, preventing blood loss. It works alongside blood
coagulation.
Long-term Blood Flow Regulation:

- Long-term regulation, as opposed to acute regulation, can occur over the period of
days, weeks, or even months.
- Ex: if skeletal muscles are engaged in consistent physical exercise, angiogenesis
(the production of new blood vessels) occurs
- Angiogenesis is a long term solution for meeting chronic metabolic needs.
- Low O2 concentration seems to trigger the synthesis of growth factors.
- Four types of growth factors: Vascular endothelial growth factor (VEGF), fibroblast
growth factor (FGF), platelet derived growth factor (PDGF), and angiogenin. They’re
all polypeptides which function on special blood vessels. They promote the
proliferation of endothelial cells and formation of new blood vessels.
- Another phenomenon that occurs during chronic nutrient demand is the opening of
collateral blood vessels, which might be closed in normal cases but opened when
there is high demand, especially during long term demand, but can also open during
acute demand.

Vascular remodeling in response to a chronic increase in blood

pressure & flow:

- Let’s say that we have increased muscular skeletal blood flow, which is associated
with increased arterial pressure.
- Note: remodelling takes time, perhaps months.
 - Inward eutrophic remodelling: in the case of certain blood vessels that supply organs
w/o a demand for high blood flow (ex: intestines). Characterised by increased
thickness of vessel wall and decreased lumen size, adapted to withstand high
pressure.
- Hypertrophic remodeling: Characterised by thickening of the vascular wall and the
increase of diameter. Can withstand high BP, can prevent rupture.
- Outward remodeling: In organs with chronically high blood flow, the diameter of the
artery’s lumen increases.Can be seen in skeletal muscle.
- Outward hypertrophic remodeling: Usually seen in veins and venules. Characterised
by the increase of the diameter as well as the increase of thickness of vascular walls.
- NOTE: If the demand decreases chronically, this may all be reversed.
- NOTE: Remodelling and angiogenesis are the two main ways of chronic/long term
blood flow control.

Autonomic Nervous System:

- Its main role here is the autonomous pumping activity of the heart, the redistribution
of blood along different parts of the circulation, and maintaining arterial pressure.
AKA: PRP (pumping, redistribution, pressure).
- The sympathetic part of the NS is very important, as it innervates blood vessels and
has a vasomotor function (causing or relating to the constriction or dilatation of blood
vessels). Notably, it has a vasoconstrictor function.
- NOTE: They innervate all blood vessels except capillaries.
- The peripheral sympathetic NS develops from the thoracic and lumbar segments of
the spinal cord.
- Two pathways to vascular smooth muscles exist: sympathetic nerves from the
sympathetic ganglion, and other sympathetic nerves that go through the spinal nerve
and then reach the blood vessels located at the skeletal muscles and the skin.
 - Special centers located in the medulla and the caudal pons are responsible for the
regulation of sympathetic nerves.
- NOTE: These areas have vasodilator and vasoconstrictor areas. The latter are
associated with SNS while the former is associated with PSNS.
- These vasomotor centers also have an effect on the heart. Activating them through
the SNS affects the frequency of heartbeats and the strength of heart pumps; it also
makes action potentials propagate faster.
- PSNS does not innervate any blood vessels at all, and its only direct circulatory
innervation is the heart (vagus nerve)
- PSNS also has a limited distribution of fibres it innervates, like the SA and AV nodes.
Has the opposite effect as the SNS on the heart.
- A very important function of the NS is the maintenance of arterial pressure--
increasing or decreasing it when necessary.
- Increasing BP like during stressful periods or during threats, to boost capability.
- Mediating ABP occurs through the baroreceptor system.
- It’s located in arteries, in all the thoracic cage/neck arteries, with an especially high
concentration in carotid sinuses and the aorta.
- Method of function: if AP increases above normal, the receptors are activated, and
through CNIX (glossopharyngeal) and CNX (vagus), the afferent signals returns to
the brain stem, and suppress the sympathetic NS’ effect and the effects of
vasoconstriction if BP is too high. If it drops, on the other hand, the opposite
happens, making blood pressure rise.
- Basically baroreceptors play an important role in maintaining normal AP.
- Note: The baroreceptor system is an example of a “negative feedback” system, or a
buffer system.

Control of Arterial Pressure by the Carotid & Aortic

Chemoreceptors-

- Chemoreceptors are found in the carotid sinus and aorta, which respond to O2 and
CO2 concentration.
- Drop in O2 and increase in CO2 (or vice versa) can be used as a measure of blood
pressure, as this increases heart activity.
- Baroreceptors have a higher role in regulating blood pressure- chemoreceptors have
more of a role in regulating the intensity of respiration.
- Atrial and pulmonary artery reflexes regulate arterial pressure: they’re called low
pressure receptors which respond to low levels of BP and activate specifically during
blood transfusions, when volume increases significantly. In this case, they decrease
sympathetic tonus and try to redirect blood pressure to its normal range. They’re less
important than baroreceptors as well.
- NOTE: During the ischemic response of the CNS, significant/critical drops of BP, the
lack of nutrients to the vasomotor centres, the sympathetic centers activate with
 intensity, which dramatically tries to increase BP as a last ditch effort to maintain
normal BP.
- NOTE: The somatic nervous system, too, has a role, not just the autonomic one- for
example, abdominal muscles contract when the SNS is activated, squeezing
abdominal cavity veins and displacing blood into the system, which increases BP.

LECTURE 6

COLOUR GUIDE:

Me being annoyed.

Cardiac Output & Venous Return-

Reminder:

- Cardiac output is the quantity of blood pumped into the aorta each minute by the
heart. (Note: the minimum level of cardiac output is 5 l/min, and life cannot be
sustained if it drops below critical level. Sympathetic activated affects the kidney at
times in such cases, resulting in the kidneys absorbing more water, thereby
decreasing blood volume and increasing cardiac output back to a sustainable range.)
- Circulatory shock is a condition which can occur as a result of critical loss of cardiac
output. It means bodily tissues and organs’ functions are compromised. CS can lead
to death.
- Venous return is the quantity of blood flowing from the veins into the right atrium each
minute. (Note: At equilibrium, venous return and cardiac output are equal. At times
venous return might exceed cardiac output, but this is quickly balanced out into
equilibrium again.)

Effects of Age on Cardiac Output:

 - Cardiac Index = cardiac output/m^2
- Cardiac index is at a maximum during early growth, becoming optimal around the
ages of 10-15.
- Cardiac output decreases from there with age as a result of changes in metabolism,
as the metabolic requirements of organs decrease, leading to decreased flow.

Frank-Starling Law of the Heart:

- States that increased quantities of blood flow into the heart cause the walls of heart
chambers to stretch. As a result, the cardiac muscle contracts with increased force,
emptying out extra blood that has entered from the systemic circulation.
- In simple words, the increase of venous return causes the increase of cardiac output.
- This law relies on the basic property of striated muscles which states that stretching
them causes the contraction force to be stronger.
- Ex: skeletal muscles in high activity, needs more blood flow → vessels dilates,
increases venous return → myocardial muscles stretch, causing them to contract
more powerfully and release more blood per contraction → cardiac output
increased.
- Note: this is considered acute regulation of blood flow.

Long-Term Cardiac Output Varies Inversely with Total

Peripheral Resistance When Arterial Pressure Is Unchanged:
 - (Ohm’s law) Cardiac output = arterial pressure/total peripheral resistance.
- There are cases which chronically reduce cardiac output-- for example, the
amputation of limbs, which would drastically decrease the demand for blood by the
body. Also, the same occurs in conditions like hypothyroidism (a condition wherein
thyroid doesn't create and release enough thyroid hormone into the bloodstream--
thyroid is the hormone which regulates how fast calories are burned, and therefore
controls the rate of body metabolism). Cardiac output is lower here with a higher total
peripheral resistance.
- On the other hand, in situations where there is a chronic need for a higher amount of
cardiac output (ex: beriberi, hyperthyroidism), the cardiac output increases notably
due to the dilation of blood vessels and the subsequent venous return, and peripheral
resistance decreases.
- Note: in cases such as these, cardiac output and venous return equilibrium will be
disrupted, but only momentarily until Frank-Starling’s law comes into place and they
return to equilibrium once more.

Cardiac output curves for the normal heart and for

hypoeffective & hypereffective hearts:

- Reminder: cardiac output must be maintained at its minimal level lest the individual
dies. Sympathetic functions, renal functions, and hormonal functions act towards
regulating cardiac output.
 - Normal Circumstances: A heart under normal circumstances might have a cardiac
output of about 4-5 l/min, and this amount can increase to 10-ish l/min as well during
periods of physical activity.
- (Note: Sympathetic activity isn’t heavily involved during normal cardiac output. Also,
the plateau shown on the graph symbolizes the limit to which the level of cardiac
output can be maintained without further strain).
- Hypereffective heart: Extending from the maximum normal amount of cardiac output
all the way up to around 25 l/min, sometimes 30 - 40l/min. Sympathetic NS activity is
notable here, increasing the force and frequency of the contractions, therefore
pushing cardiac to its limit.
- Hypoeffective heart: Is an unsustainable condition, usually around 2 l/min of CO.
Occurs during cardiac shock, cardiac failure, etc.

Autonomic NS Maintains Normal Arterial Pressure:

- Recall Frank-Starling’s law and how it causes equilibrium between CO and VR.
- Note that in order to maintain such conditions, arterial pressure must also be
regulated to a normal level (or a slightly higher level at times). The Autonomic NS
helps with this.
- The red line on the graph represents an experiment on an animal where it is injected
with dinitrophenol, a vasodilating drug. This causes an increase in CO, while ABP is
steady. However, if the ANS is compromised (specifically the sympathetic NS), ABP
decreases, and cardiac output is also reduced.
- TLDR: In order for Frank-Starling’s law to be maintained, ABP needs to be
maintained as well, and it is usually maintained by the SNS.

Factors that affect venous return:

 - Right atrial pressure, exerting a backward force on the veins to impede blood flow
from the veins into the right atrium.
- Degree of filling of the systemic circulation (measured by mean systemic filling
pressure), which forces the systems blood toward the heart
- Resistance to blood flow between peripheral vessels and the right atrium.

Venous Return Curve:

- Takes place primarily from the vena cavae, enters right atrium, and increases when
atrial pressure equals the mean systemic filling pressure (~7-8 mm Hg)

Mean Circulatory Filling Pressure & Mean Systemic Filling

Pressure:

- Without blood flow, pressures everywhere in the circulation become equal. This
equilibrated pressure level is called the mean circulatory filling pressure.
- Mean systemic filling pressure is the measure of blood pressure after the blood flow
has been stopped by clamping the large blood vessels at the heart. This way, the
pressures in the systemic circulation can be measured independently from the
pulmonary circulation ones.
- These pressures are generated when blood pumping stops-- more precisely, by the
resulting tightness in blood vessels when the heart stops beating.
Effects of changes in total blood volume on the mean
circulatory filling pressure:

- Just note that filling pressure is influenced by the tightness of blood vessels. So to
speak, consider that it increases the stronger the tightness of blood vessels gets,
such as under strong sympathetic stimulation.

Venous Return:

- We can calculate venous pressure via the following formula:

- VR = (Psf - PRA)/(RVR)
- Psf = mean systemic filling pressure, PRA = right atrial pressure, RVR = resistance
of veins and arterioles, which is the pathway creating resistance of blood flow to the
right atrium.
- It can be thought of as a sort of restatement of Ohm’s law. Can also be used to
calculate cardiac output since cardiac output is usually the same as venous return.

Venous Return Curves Depicting the Effect of Altering the

Resistance of Venous Return:
 - Resistance decreasing = more venous return = more cardiac output

Cardiac Output, Venous Return, and Right Atrial Pressure:

- This graph just demonstrates that the increases in venous return equal the
increases in cardiac output, as seen on the intersections on the blue and red
lines. It shows an increase of venous return (say, due to extensive physical
activity), followed by equilibrium.
- Basically this is just another restatement of Frank-Starling’s law. Again. Why
is this chapter so repetitive with a million graphs?
Effects of muscle exercise on blood flow in the calf of a leg
during strong rhythmical contraction:

- Graph shows increase in blood flow during periods of physical activity within skeletal
muscles.
- Notably, the increase has a pulse like nature due to the contraction of blood vessels.

Changes in CO, VR, and Right Atrial Pressure With Onset of

Strenuous Exercise:

- Wow look what we have here. If you guessed “another annoying reconfirmation of
Frank-Starling’s law”, you’re right!
- Basically it’s also a reaffirmation of the last graph: the black lines represent CO and
VR and how they reach equilibrium under normal circumstances. (Point A)
 🙄
- Red lines show increased CO and VR due to physical activity. And wow guess what
law brings them back to equilibrium again . (Frank-Starling’s law)
- If I have to write another point about FS’s law I’ll commit homicide.

Coronary Blood Supply:

- Coronary blood supply provides blood supply to the heart.

- RCA and LCA supply the myocardial muscles with blood. RCA → right atrium, right
ventricle (anterior side), LCA → light atrium, left ventricle, right ventricle (posterior
side)
- Flow is pulse-like/rhythmic here as well.
- In a systole, blood vessels constrict = decreased blood flow. In a diastole, blood
vessels relax = increased blood flow.

Diagram of the epicardial, intramuscular, and subendocardial

coronary vasculature:

- Note the presence of peripheral epicardial coronary arteries, and how they dip into
the myocardial.
- Note the subendocardial arteries/plexus, which provides inflow of arterial branches
deeper into the myocardium and subendocardium.
- Note the smaller branches of capillaries and arterioles.
- Especially note that the subendocardial plexus is especially vulnerable in terms of
myocardial contraction, as it compresses arterial blood to a considerable extent and
may be harmful if the individual is inclined towards conditions like ischemia.
- 1/3rd of the death count in the western world is due to ischemic diseases, and
practically most old people have some sort of disruption in their circulation.
- Ischemia usually occurs due to atherosclerosis (accumulation of cholesterol around
endothelial cells, developing plaques which also accumulated platelets, erythrocytes,
etc, developing blood clots which occlude blood vessels, perhaps leading to acute
ischemia)
- Atherosclerosis may occur due to dietary problems, lack of exercise, lipid digestion
issues, etc.
 - A thrombus is a blood clot- a moving thrombus which travels across the circulation to
other locations is called an embolism. Both thrombi and emboli can cause acute
ischemia.
- Usually mild occlusions only have a mild effect, while complete occlusions are
eventually fatal and/or lead to the death of specific muscle fibres, and/or circulatory
shock.
- Note: during mild occlusion cases, the opening of collateral pathways can
compensate for blood flow. It does take time to establish proper blood flow through
collateral pathways though-- days or even weeks. However, over time, complete
recovery can occur due to them, especially if they work in conjunction with
hypertrophy.

Systolic stretch in an area of ischemic cardiac muscle:

- Image displays what happens during MI (myocardial infarc.), or when cardiac muscle
function is lost.
- Note the presence of a systolic stretch in the ventricular wall, because muscle fibres
cannot contract, causing them to bulge. This causes CO to drop, leading to cardiac
failure and possibly even cardiac shock.

Small and Large Areas of Coronary Ischemia:

 - Figure shows that mild ischemia causes a patch of non-functional/injured muscle
fibre which is depolarised, leading to an injury current, which can be seen on ECGs.
- In such cases, collateral blood vessels may take over and cause tissue recovery,
causing them to become repolarised.
- On the other hand, severe cases may result in completely dead fibres that have no
chance of recovery. These dead fibres, however, can be replaced by fibrous tissue
overtime. As a result, the cardiac wall can more or less maintain its intact shape, and
generate pressure necessary for maintaining cardiac output.
- Overtime, muscular hypertrophy takes place to compensate for the dead tissue in
that region as well.
- Note: However, the deficit shows itself usually during periods of physical activity,
because this ischemia causes an overall decrease of cardiac reserve (amount by
which the heart can increase its cardiac output-- normally it can increase by 4-5 times
its regular extent. In post-MI hearts, the increase can barely get up to around 40-45%
of its usual amount).

LECTURE 7

RBCs:

- Also called erythrocytes.

- Functionally important because they transport the protein hemoglobin which carries
the oxygen from the lungs to the tissue.
- Additionally, they contain the enzymes carbonic anhydrase, which catalyze the
reversible reaction between CO2 and water to form carbonic acid, H2CO3.
- Hemoglobin also has a very important acid-base buffer function, making RBC natural
buffers within the blood. They maintain blood pH very well.
- Hemoglobin concentration: 34 grams/100 mls of RBCs, and this is the maximum
concentration which RBCs can contain.
 - This allows for the transportation of 20 mls of oxygen per 100 mls of blood during
normal concentration.
- RBCs are produced in the bone marrow postnatally, but in the embryonic period
they’re first produced in the yolk sac, and then the liver, lymphatic nodes, and spleen
during mid-gestation, and then they begin to develop in BM during latter gestation.

Relative rates of RBC production in BM of different bones at

different ages:

- The graph shows RBC production in the BM of different bones.

- Usually RBCs are produced in all bones during the early postnatal period.
- Then, however, the large bones of the lower limbs stop producing RBCs.
- Vertebral and sternal bones as well as ribs continue the production of RBCs,
however.

Formation of multiple diff. Blood cells from pluripotent

hematopoietic stem cells in BM:
- Pluripotent stem cells give rise to all sorts of blood cells, including leukocytes.
- Differentiating commits blood cells into certain lines. Ex: CFU (colony forming
units), like CFU-Erythrocytes, committed stem cells which produce
erythrocytes.
- The life cycle of a RBC:
-
1) Proerythroblast- (has nucleus, ER, and golgi complex-- no
hemoglobin)
2) Basophilic erythroblast
3) Polychromatophilic erythroblast
4) Orthochromatic erythroblast
5) Reticulocyte- (high conc. Of hemoglobin, released from BM into
circulation and become RBCs in a couple days)
6) Erythrocyte- (diameter of about 8 micrometers, thickness of 2.5
micromes at thick parts, 1 micrometre in thin parts; biconcave shape
with high elasticity)

- NOTE: Bit by bit, the nucleus begins to disappear as well as the golgi complex and
ER throughout the development of erythrocytes. Meanwhile, the concentration of
hemoglobin increases.
- NOTE: During pathological conditions, RBCs may become fragile and break down.
- The maturation of RBCs requires: Folic acid and vitamin B12 (cobalamin). In the
case of vitamin B12, gastric chambers’ intrinsic factors allow for the binding and
subsequent absorption of B12- this is why the disruption of GI function can have a
notable effect of RBC production/maturation. This could be one of the reasons for
anemia.
Tissue Oxygenation is the Most Essential Regulator of RBC
Production:

- RBC production depends on body needs-- specifically on oxygen needs.

- Hypoxia increases RBC production, which happens as the hormone erythropoietin is
released from the kidney from the cells within the interstitium. It has an effect on BM
and increases RBC production. It takes a couple days for the effects of erythropoietin
(EPO) to work as it takes time as it takes some time for pluripotent stem cells to
develop down the RBC lineage, but generally erythropoietin is massively effective.
- Q: How does hypoxia occur?
- A: high altitude, anemia, low hemoglobin, cardiac failure, pulmonary disease, etc.
- Hypoxia may lead to subsequent polycythemia (an increase in the number of RBCs
in blood).
- Regular hematocrit= 40-45. Polycythemia hematocrit= up to 60-70.
- Polycythemia can either be as a physiological response (high altitude) or a
pathological response (unnaturally low hemoglobin).
- EPO can increase in response to stress hormones such as epinephrine and
norepinephrine, during periods of stress of physical strain.

Anemia:

- Anemia is the deficiency of hemoglobin in blood.

-
- Microcytic anemia: rbcs small, hemoglobin conc. Is low. Caused by chronic blood
loss, which disrupts synthesis of hemoglobin because iron uptake isn’t sufficient
enough to maintain proper synthesis. Usually is also hypochromic, causing colour to
be lighter due to the lack of hemoglobin.
 - Sickle cell anemia: inherited disease wherein hypoxic conditions result in defective
hemoglobin which changes the shape of erythroblasts and causes breakdown
- Megaloblastic anemia: caused by the disruption of rbc maturation, which might be as
a result of malabsorption of vitamins b12 and maybe b9 (folic acid). Results in large
sized cells, immature and very fragile. They break down easily while flowing through
the circulation, causing RBC loss, causing anemia.
- Aplastic anemia: caused by destruction of bone marrow due to chemical or x ray
radiation exposure.
- Erythroblastosis fetalis: a result of an embryo with rh+ blood within a pregnant parent
with rh- blood. This results in antibodies being generated-- they diffuse through to the
embryo and begin destroying its RBCs.

Leukocytes (WBCs):

- Mediators of immunity in the blood.

- Two types of immunity- adaptive and innate.
- If WBC production is suppressed, constantly-present microbes will penetrate into the
body and eventually lead to death.
- Platelets are also relevant to the immune system, though they’re really more cell
fragments than proper cells. They’re present in high concentrations (1 microlitre has
around ~300k platelets). They’re associated with blood coagulation.
- Note: megakaryocytes have cell fragments which break off of them-- those are
platelets.
- Monocytes are an immature type of leukocytes. They penetrate different tissues and
change into macrophages, highly phagocytic cells. They can be found in different
types of tissue: cutaneous tissue, underneath the oral, nasal surface,etc-- areas of
environmental exposure that can be easily penetrated by microbes. Macrophages
easily digest them. They’re part of the first line of defense against infections.
- Reticuloendothelial system/monocyte-macrophage system: is the total combination of
monocytes, mobile macrophages, fixed tissue macrophages, some specialised
endothelial cells in the bm, spleen, and lymph nodes.
- Lymphocytes are important for acquired immunity.
- Inflammation: tissue response to damage. A defensive reaction directed towards
recovery and protection from damage; can be caused by infectious or mechanical
damage. Leukocytes enhance inflammation, especially the granulocytes.
- During inflammation, blood vessels dilate and become more permeable. Proteins
flow into the interstitium, which provokes fluid clogging; this results in the release of
substances like histamines, heparin, lipokines, and cytokines (they act in vessel
dilation and immune activity, increasing both). The innate immune system
participates in this, but so does the adaptive system. The resulting effect is
accumulating macrophages and neutrophils and antibodies in the damaged area. All
of these accumulations cause tissue swelling.
- Inflammation is good because it's a signifier of immune defense and healing--
however, chronic inflammation can be very bad, as it can damage healthy tissue via
provoking autoimmune mechanisms which may attack healthy tissues as well.
Defensive reaction of body to injury/infection called
inflammation:

- Different cells respond to the concentration gradient of different substances; in other

words, they move into areas due to “chemotaxis” (movement of a motile cell in a
direction corresponding to a gradient of increasing or decreasing concentration of a
particular substance). The substances in question could be the ones that promote
inflammation or substances related to immune response such as
cytokines/lymphokines, etc. They all attract phagocytes.

-
- Graph shows neutrophil migration to infected area.
- First they bind to the surface of endothelial cells, and then they exit through
diapedesis (the passage of blood cells through the intact walls of the capillaries,
typically accompanying inflammation).
- NOTE: The gathering of different immune cells is a huge part of inflammation and a
main factor.

Control of BM production of granulocytes and

monocyte-macrophages in response to multiple growth factors:
 - Activated macrophages can stimulate granulocyte-monocyte production in BM by
releasing some factors. Ex: TNF (tumor necrosis factor), IL-1 (interleukin-1), GM-CSF
(granulocyte-monocyte colony stimulating factor), G-CSF, and M-CSF.

What is immunity?

- The human ability to resist almost all types of organisms and toxins that tend to
damage the body.

TLDR: phagocytes, destruction of swallowed objects in stomach acid, the barrier of the skin,
complement system in blood.

Adaptive Immunity & Antibody formation and sensitized

lymphocytes by a lymph node in response to antigens:

- Cell mediated (by T cells) or humoral (by B cells).

- Lymphocytes are produced from pluripotent stem cells in BM, from the common
lymphoid progenitor cell.
- T cells develop in BM and mature in the thymus and B cells develop in the BM and
mature in the lymph nodes.
- Lymphocytes recognise antigen (a compound of an infectious agent, ex: a protein ,a
polysaccharide (at least 8k molec weight).
- Antigens have special regions called “epitopes” (the part of an antigen molecule to
which an antibody attaches itself).
- Attachments to lymphocytes cause their proliferation.
- Different types of T and B cells can recognise different types of antigens. This is
because the genes have a mosaic characteristics, which mix and interact in different
ways- as a result, different B and T cells can produce different genomes, therefore
producing different antibodies and/or receptors on the surface of T cells. They can
basically recognise an endless amount of lymphocytes, producing activated
antibodies and/or cytotoxic T cells.
- Macrophages phagocytose microbes, break them down in pieces, and sometimes
present those pieces to B cells (specifically membrane-surface B cells)
- This causes B cell proliferation and releasing antibodies into the circulation.
- The activation of the complement system helps antibodies perform their functions: it’s
a supportive system of enzymes.
- Note: he sort of talks about agglutination and how it might lead to cell autolysis?
- Recall: antibodies are macroproteins with two ends: one end is variable, recognises
antigen, and one end is invariable; interacts with different membrane surfaces,
promotes agglutination, etc.
- Activated T cells do not produce antibodies but they have proteins like antibodies on
their surface, because they can recognise antibodies.
- T cell activation occurs when they are presented with antigens by APCs (antigen
presenting cells). Ex: dendritic cells.
- Histocompatibility Complexes are proteins which bind to antigens and are presented
to T cells, causing activation.
- Different types of T cells: T helper, cytotoxic, and suppressant cells.
- Helper T cells release lymphokines (hormone like substances), which promote
immune strengthening. Acquired immunity is suppressed without them.
- Suppressor T cells level down the immune system, on the other hand.,
- Cytotoxic T cells directly attack infectious agents. They tend to be within tissues
rather than within the circulation mostly.
Time course of the antibody response in the circulating blood to
a primary injection of antigen and to a secondary injection
several weeks later:

- (Note: this graph is B cell-related, but the info can basically be applied to T cells as
well)
- 1st we have the primary response- B cells activate, proliferate, and begin antibody
production, though at a low level. Usually the disease does end up developing during
primary responses/first encounters.
- On the other hand, the following exposure is when “Memory B cells” have already
been developed for the specific antigen-- therefore, the secondary exposure leads to
a far stronger immune response, producing many more antibodies and lymphocytes.
Usually the disease doesn’t develop (or not as strongly).
- This is the primary method of immunization.

Regulation of The Immune System:

- T helper cells release lymphokines and promote immunity.

- T lymphocytes require MHC for antigen presentation-- B cells do not require them
because B cells can bind to the antigen. However, they do need to interact with
helper T cells.
- Plasma B cells create antibodies, of which there are 5 main types-- IgM, IgG, IgA,
IgD and IgE. (DAMGE)
- IgG has a high concentration (about 75%)
- IgE is valuable during allergic responses.
- IgM is responsible for the primary response.
- Cytotoxic T cells are activated by antigens, usually pathological ones but sometimes
even benign ones.
Direct Destruction of An Invading Cell by CTT cells:

- They contain antibody-like proteins on their surface which recognise antigen, binding
cells which display them.
- Basically they punch pores into the cellular membrane and inject them with cytotoxic
substances and digestive enzymes, destroying the cells.
- CT T cells are detrimental during implantation at times since transplanted tissue
contains antigens.

Allergy & Hypersensitivity:

- Two types of allergies: E type/Atopic allergies & Activated T-cell allergy

(delayed-reaction allergy)