BIOL 243


The science that is concerned with the function of the living
organism and its parts, and of the physical and chemical processes involved.

Pathophysiology is
the study of disordered body functions

A Complex Society of Differentiated Cells

Cells: the basic
structural and functional unit (~ 100 trillion)�But ~1,000
trillion bacteria in the body Tissues: 4 basic: muscles,
epithelial, nervous, connective Organs: e.g. brain, heart,
kidneys, liver, etc. (all in the trunk) The trunk could also be
thought of as the torso Organ systems:(e.g.
cardiovascular, urinary, etc.)

~8 anatomical but ~11 physiological systems

Some anatomical systems have multiple physiological systems within them
1.Nervous system/ motor & sensory
(1)2.Endocrine (2)3.Muscle/skeletal (3,
4)4.GI/major glands(5)5.Cardio/pulmonary (6,
7)6.Immune/lymphatic (8)7.Urinary/reproductive (9,
10)8.Integumentary (11)

Nervous system, sensory & motor components

Gather & process inside/outside information, and directs muscles
to contract or glands (endocrine and exocrine) to respond.
All tissues are innervated except: epithelia such
as outer layer of skin, nails, hair. Glands are innervatedMostly made
of neurons and glia


Provide 1) blood circulation, 2) oxygenation and CO2 removal, 3)
nutrients in and out of each organ, 4) temp control.
All tissues are vascularized except: outer layer
of skin, hyaline cartilage, cornea. Mostly made of connective tissue,
epithelium, and muscle (both striated and smooth)
When this becomes vascularised it is a sign of
inflammation or degeneration

GI/Major Glands

?GI/major glandsMechanical and chemical processing of food,
adsorption of nutrients, elimination of by-products, location of the
largest microbial colony in the body.

Mostly made of epithelium
and connective tissue, smooth muscle and lots of neurons


Functionally �similar� to the nervous system, provides fast and slow
chemical communication and control of many major functions in the
body. Mostly made of
epithelium in the form of glands


Provide filtration and excretion of toxic chemicals from blood,
regulates fluid volume. Insure reproduction, under the control of
nervous and endocrine systems
Mostly made of connective tissue, some nervous
tissue, epithelium and smooth muscle


General mechanical functions such as structure and mobility of the
body as a whole.
Mostly made of muscle and connective tissue, no epithelium!


Mechanical protection of every surface of the body. Epithelium on the
outside (skin, but also nails, horns, etc), mucosa on the inside
(mouth, etc.), endothelium inside other organs (blood vessels), glands
(sweat glands, liver, etc.).
Mostly made of epithelium and connective tissue,
some smooth muscle


General and local defense from pathogens, immune surveillance of
every organ. Lymphatic support the immune system and helps the CV
system to carry out extra fluid. The brain is immune-privileged
(microglia). Mostly made of specialized connective tissue
Lymphatic system helps drain fluid from other
parts of the body

Connective tissue

95% of connective tissue is made of an inter cellular matrix whereas
other tissues are made 95% by cells

Basic histology:

the 4 types of tissues & how they are interconnected

Central Nervous System vs Peripheral Nervous System

Overall anatomy of the 2 system: �CNS is brain and spinal cord,
encased in bone (skull and spine). �PNS is everything else, ganglia,
local neurons in many organs (G.I.)
CNS is everything that is encased by bone
Everything that lies outside is known as the PNS

functions CNS

Split into 3 divisions

(starts in the periphery)� vision, hearing, touch, taste, smell, andsomatosensory
(Brain)� process information, creation of memory.
�MotorDivision (goes to the
periphery)� respond to and move about in our
environment.�1. contraction of skeletal muscle�2.
contraction of smooth muscle �3. secretion from selected glands
�1&2 are motor functions, 3 is
secretion� 1 voluntary motor function, 2&3 are
autonomic function

Autonomic Nervous System = subconscious

A. Controls the visceral functions of the body e.g.
blood pressure, GI motility and secretion, etc. Not as fast as the
motor system, the Aut. NS acts within
seconds.B. Resides in nuclei
in the hypothalamus, brain stem, and spinal cord, etc..C.
Activated by visceral reflexes. Sensory signals from
visceral organs ?autonomic ganglia ?CNS ?subconscious reflex responses
to the visceral organs.D. Limbic cortex (voluntary) can also
influence functions

Autonomic Nervous System

Accelerator & Brake FunctionFight or flight response
Sympathetic Nervous System (SNS) Accelerator for cardiovascular
and respiratory systems (increase in arterial pressure, heart rate and
contractility, blood flow to muscles, blood glucose, metabolic rate,
muscle strength, mental activity, blood coagulation, etc). Brake
for gastrointestinal tract(decrease peristalsis, secretion, etc.)
Parasympathetic System (PSNS) Accelerator for
gastrointestinal tract Brake for cardiovascular and respiratory systems

Autonomic Nervous System Parasympathetic Division

Parasympathetic fibers leave cranial nerves III, VII, IX, andX &
Sacral nerves
About 75 percent of all parasympathetic nerve
fibers are in the 2 vagi(X) nerves
Pre-and post ganglionic fibers: the preganglionic
neurons are very long; the postganglionic neurons are short and
located in the wall of the organ (except for the head).

Autonomic Nervous System
Sympathetic Division

Spinal nerves go to ?�2 paravertebral sympathetic chains of
ganglia ?�Pre-ganglionic neuron�Series of visceral ganglia
(Celiac, etc.)�Post-ganglionic neurons to organs�Except:
adrenal medulla

Anatomy of the Sympathetic System

In both sympathetic and parasympathetic pathways PRE-ganglionic
neurons ALWAYS make a synapse with a POST-ganglionic neuron
One exception: Preganglionic sympathetic
nerve go UNINTERRUPTED to the two adrenal medullae.These cells
are derived from nervous tissue, they are the postganglionic nerve
that secrete epinephrine and norepinephrine.

Organization of the Autonomic Nervous System - Recap -

Parasympathetic ganglia are located in the effector
tissues�Parasympathetic pathways have long preganglionic and
short postganglionic fibers
�Sympathetic ganglia are located close to the spinal cord.
�Sympathetic pathways have short preganglionic fibers and
long postganglionic fibers

Characteristics of Sympathetic andParasympathetic Function

ALL preganglionic neurons are cholinergicin both the sympathetic and
the parasympathetic nervous systems�Postganglionic sympathetic
nerves are adrenergic ?release norepinephrineat their nerve endings
(except for sweat glands, pilo erector muscles and select blood
vessels which are cholinergic)
Postganglionic parasympathetic nerves are
cholinergic ?release acetylcholine at their nerve endings

Sympathetic and Parasympathetic neurotransmitter

Norepinephrine and epinephrine are synthesized from the amino acid
tyrosine� tyrosine ?DOPA ?dopamine ?nor-epi ?Epi in the adrenal medulla
�Neutralized by: 1) re-uptake, 2) diffusion, 3)
degradation by monoamine oxidase �Seconds
�In the blood stream (Epi from adrenal),
degradation by the liver takes minutes�Acetylcholine is synthesized
in the nerve ending by acetyl CoA and choline
�Neutralized by: 1) Acetylcholinesterase (AChE hydrolysis)

Characteristics of Sympathetic andParasympathetic Function

Cholinergic Neurotransmitters

Parasympathetic nerves release acetylcholine.� acetylcholine
excites two types of receptors nicotinic and muscarinic.�
nicotinic receptors are found in synapses between the pre-and
post-ganglionic neurons and at the neuromuscular junction.
Ligand-gated ion channels

Stress Response

Mass sympathetic discharge �increase in arterial pressure, heart rate
and contractility, blood flow to muscles, blood glucose, metabolic
rate, muscle strength, mental activity, blood coagulation.
�Prepares the body for vigorous activity need to
deal with a life-threatening situation.
�AKA -the fight or flightresponse.

Effect of the Autonomic Nervous System on the Organs

Eye- Sympathetic --pupillary dilation.- Parasympathetic
--pupillary constriction and accommodation (focusing) of the
lens. Glands of the body- Sympathetic stimulates
the sweat glands.- Parasympathetic stimulate the nasal,
lacrimal, salivary, and G.I. glands
Heart�Sympathetic increases the rate and
contractility. �Parasympathetic decreases heart rate.
Blood vessels�Sympathetic causes
vasoconstriction.�Parasympathetic causes some
vasodilation. G.I. tract- Sympathetic has very
little effect.- Parasympathetic stimulates overall activity
including G.I. smooth muscle

Sympathetic and Parasympathetic �Tone�

�The basal rate of activity of each system.
�This background activity allows for an increase
or decrease in activity by a single system. �sympathetic tone
normally causes about a 50% vasoconstriction.�increasing or
decreasing �tone� can change vessel diameter.
�parasympathetic tone provides background G.I. activity.

Cardia c structu
r e an
d function

A. Plumbing: Pulmonary and systemic circuits
B. Cardiac anatomy and histology (cardiac muscle
and Ventricular Purkinje fibers) C. Cardiac cycle:
Systole, diastole, volume, pressure, etc. D. Electrical
Activity- Wiring of the heart- Physiology of the
electrical activityThe Normal ElectrocardiogramCommon arrhythmias

Cardia c structu
re an d function

Two important definitions:

ARTERY: any of the muscular-walled
tubes, carrying mainly oxygenated blood away
from the heart to
other body parts.

VEIN: thinner
walled tubes carrying mainly oxygen-depleted blood
towards the heart.

E x c
e pt: in the pulmonary circulation
these features are inverted

Cardiac structure and function

A. Plumbing: Pulmonary and systemic circuitsB. Cardiac anatomy
and histology (cardiac muscle and Ventricular Purkinje fibers)C.
Cardiac cycle: Systole, diastole, volume, pressure, etc.D.
Electrical Activity
Wiring of the heart Physiology of
the electrical activity The Normal Electrocardiogram
Common arrhythmias

Two important definitions:

ARTERY: any of the muscular-walled
tubes, carrying mainly oxygenated blood away from the heart
to other body parts.

VEIN: thinner walled tubes carrying mainly
oxygen-depleted blood towards the heart.

Except: in the pulmonary circulation these features
are inverted

Some anatomy of the vessels

ARTERY: any of the muscular-walled
tubes, carrying mainly oxygenated blood away from the heart
to other body parts.

VEIN: thinner walled tubes carrying mainly
oxygen-depleted blood towards the heart.

Cardiac muscle histology

Syncytium = low resistance intercalated disks � many cells
functionally making 2 �beating units�: atrial and
ventricular units

Cardiac muscle histology

2 tissue type: muscle and conductive

Circulation, overall plumbing

Aorta blood is pumped out
Atria and ventricles separated by two valves
Arteries are separated by another one valve each
Blood and arteries are typically going side by side
most of time go with veins
If not going with veins arteries are deep in the
tissue while veins are typically superficial can be see veins not arteries
Arteries have to be deep because damage is catastrophic
At the tip of the organ arteries will become
smaller arteries, capillary then vein

Circulation, overall plumbing

Two Circuits: Systemic and Pulmonary
Left heart aorta coming out
Aorta then divides to head and body circuits
In either case there will be arterioles that will
become capillaries and venuoles
Everything will eventually flow back into big and
larger veins which will go to the right atrium and the right heart
(This is oxygen depleted) has to go through the lungs to become oxygenated
Pulmonary artery carry non-oxygenated pulmonary
vein carries oxygenated blood
Blood always red just different shades
Looks blue in veins because theres tissue between
eyes and blood
Pulmonary and systemic pressure is very different
Dr measures systemic pressure
Pulmonary lower because circuit is smaller goes
between heart lungs and back
Capillaries of blood are very thin so don�t need a
lot of pressure to work
Parallel circuits are all those within the body
So if blood flow stops in one area the rest are fine
In series shutdown causes downstream failure


A-V valves: the tricuspid and
mitral valves
Semilunar valves: the aortic and pulmonary artery valves
Prevent backflow Open and closes
Between atria and ventricle there are these valves
They all have muscle chordae tendenae
Tendons attached to the valve
In the ventricle high pressure valves may go back
to the atria (Backflow) attached to base of ventricle to stop this
backflow from ventricle to atrium
Aortic and pulmonary valve all have three sides no
papilary or chordae tendenae
They withstand a lot of presssure (pressure from
aorta back to the left ventricle, pulmonary artery back to right
aorta) Mitral � Has two tips

Cardiac cycle

Systole � ventricular muscle stimulated by action potential and
contracting Diastole � ventricular muscle reestablishing
Na+/K+/Ca++ gradient and is relaxing As the rate increase,
systole remains ~the same, but diastole get significantly shorter �
too fast, not filling At 72bpm, cardiac cycle is ~0.83sec
(60/72). How much is at 180bpm?
The time ventricles stay contracted is about .3 sec
at 180bpm not much time to refill

(left) Cardiac cycle

Red lline at the the bottom is the filling period
Left ventricle goes from 50ml to 120 ml of blood
Meaning even at end of systole there is still about
50ml left in the ventricle
Between 110 and 120ml small notch due to atria
squeezing last bit of blood into the ventricle so the pressure goes
up a little bit
After this mitral valve closes, this is the one
between left atrium and left ventricle
Left ventricle is full valves shut closed passively
(Due to pressure and volume inside left ventricle)
C - D: At about 80mm hg the aortic valve now opens,
volume going back to 50ml little bit of higher pressure that then
drops because the ventricle is empty and the aortic valve closes
because the pressure of the blood is now in the aorta
Opens due to ventricle squeezing, now closing
because of the load
At this point the volume, ventricles are half empty
volume back to 50ml, aortic valve is closed, ventricle is relaxing so
pressure is dropping, flow blood is going in from the atrium to the
ventricle as in low pressure the mitral valve opens. Blood flows from
left atrium.

Cardiac cycle, summary

Most ventricles filling is passive, atria work
as primer pumps to add the last ~20% of blood Ventr. are
full (~130mL, end-diastolic volume) Isometric contraction of Vs
surpass the pressure of the aorta and pulm. artery Only
~60% of blood is ejected from the left ventricle at the end of the
systole (stroke volume) (~50mL left, end-systolic volume)
Ventricles relax and back pressure form arteries close the
semilunar valves back, diastole begins. Atria and
ventricles are filling again In healthy hearts,
end-systolic volume goes to 10-20mL, and end-diastolic volume goes
to 180mL, doubling the Stroke Vol.

Cardiac cycle

Different events in the cardiac cycle

Frank-Starling Mechanism

Within physiological limits, the heart pumps all the blood that
returns to it (venous return).
Peripheral arterioles, capillaries, and
venules can contract and relax and control local blood flow.
More heart muscle is stretched during filling � more force of
contraction and � more blood pumped into the aorta. This
stretching causes the actin and myosin filaments to be at a more
optimal length of overlap for force generation. Common to
all skeletal muscle
The circulatory system is not a set of steel tubes
Arteries contract and veins dilate
Heart can adapt to a variety of pumping needs automatically
Amount of blood running or sleeping different
Can double or triple blood pump
Stretching of the heart creates more powerful force

Electrical Activity of the Heart

Mass vs metabolism ? animal surface
Smaller animals need increase output but can�t increase heart
volume (Stroke volume)

Electrical Activity of the Heart

Blood circulation relies on: Self-generate rhythmical
impulse to initiate repeated contraction of the heart muscle
Have the atria empty first into ventricles Propagate
signal from atria to ventricles Have all portions of the
ventricles to contract almost simultaneously

Electrical Activity of the Heart

Sinus Node

Strip of specialized cardiac cells connected to atrial
muscle Acts as pacemaker because membrane leaks Na+. Resting
potential: -55 to -60mV (surrounding cells are at -90) When
membrane potential reaches -40 mV, slow Ca++ channels open causing
full-blown action potential After 100-150msec Ca++ channels
close and K+ channels open more thus returning membrane potential to

Rhythmical Discharge of Sinus Nodal Fiber

Molecular aspects or cardiac contraction

When the full potential of the purkinje cells is completed
Calcium enters via the t-tubules and there is contraction
Then calcium goes out and k goes in to reestablish
resting potential

Internodal Pathways

Transmits impulse between the 2 nodes = throughout atria
3 branches, anterior, middle, and posterior internodal
pathways Anterior interatrial band (Bachmann) carries
impulses to left atrium.

A-V Node

Delays cardiac impulse (0.09s) � atria can empty into
ventricles before they pump Final delay AV
bundle (0.04s) Total of 0.16s before the excitatory signal
finally reaches the contracting muscle of the ventricles.
Delay due to very low number of gap junctions

A-V Bundle

One-way conduction through the bundles.
One-way conducting path between: A-V node � A-V bundle
Divides into left and right branches Transmission time
between A-V bundles and last of ventricular fibers is 0.06s (QRS
time) � FAST!
Two sides
Once electrical stimulus crosses av bundle
Crosses fibre tissue between the isolate between atria
and ventricles
Then the ventricles have to beat as fast as possible
all together

Cardiac Conduction Pathways

Stimulus begins in the sinoatrial (S-A) node

Internodal pathway to atrioventricular (A-V) node
Impulse delayed in A-V node and bundle
(allows atria to contract before ventricles)

A-V bundle takes impulse into ventricles (one way!)

Left and right bundles of Purkinje fibers take impulses to all
parts of ventricles
Ventricle conduction is FAST; many gap junctions at
intercalated disks

Purkinje System

Fibers lead from A-V node through A-V bundle into
Ventricles Fast conduction; many gap junctions at
intercalated disks (~150-fold faster than AV bundle) Few
sarcomeres and muscle fibrils, they don�t contract

Speed of conduction of cardiac impulse

Ventricles contraction last 0.3sec
Long enough to empty them

Main Arrival Times
S-A Node 0.00 sec
A-V Node 0.03 sec
A-V Bundle 0.12 sec
Ventricular Septum 0.16 sec

Sinus Node is Cardiac Pacemaker

Normal rate of discharge:
sinus node 70-80/min.; A-V node -
40-60/min.; Purkinje fibers - 15-40/min. Sinus
node is pacemaker because of its faster discharge rate

Ectopic Pacemaker

This is a portion of the heart with a more rapid
discharge than the sinus node. Or can occur when
transmission from sinus node through the A-V node is blocked (A-V
block). During sudden onset of A-V block, sinus node
discharge does not get through: Atria beat at normal rate, and
Purkinje system take over for the ventricles Delay in pickup of the
heart beat by Purkinje cells cause the �Stokes-Adams� syndrome.
Patient faints during delay


Atrial syncytium (�primer�-pump) Ventricular
syncytium Fibrous insulator exists between atrium and
ventricle (why?) The heart�s fibrous skeleton serves as
an electrical insulator between the atria and
ventricles to ensure that there is a pause between atrial
contraction and ventricular contraction so that the ventricles have
the opportunity to fill with blood before they contract

Innervation of the heart

Normal rate 70bpm up to 200bpm or more Between bpm and
more volume, output can increase 3-4 fold Vagi afferent to
atria mainly. Decrease ~30%, bpm mainly Sympathetic nerves
to ventricles, increase in both bpm and contractile strength.

Parasympathetic Effects on Heart Rate

Parasympathetic (vagal) nerves, which release acetylcholine at
their endings, innervate S-A node and A-V junctional fibers proximal
to A-V node. Causes hyperpolarization because of increased
K+ permeability in response to acetylcholine. This causes
decreased transmission of impulses maybe temporarily stopping heart
Ventricular escape occurs if nodes become silent (ectopic
pacemaker, e.g. Purkinje take over)
SA node is the main pacemaker of the heart
Acetylcholine hyperpolarises the cells of the nodes
Resting potential of around -55mv leaky sodium
channels bring the membrane potential up to -40mv triggering cascade
of ion flow and polarisation
Acetylcholine hyperpolarises bringing down to -65mv
increasing potassium permeability
Causes transmission impulse to slow down
Incase of strong parasympathetic impulse there could
even be stopping of sa impulse
Either the av node or purkinje nodes will take over,
beating heart at a much slower pace

Sympathetic Effects on Heart rate

Releases norepinephrine at sympathetic ending Causes
increased sinus node discharge Increases rate of conduction
of impulse Increases force of contraction in atria and
ventricles Norepinephrine stimulates ? -1
adrenergic R, � increase of Na-Ca permeability �
more positive resting potential

Depolarization and Repolarization Waves

No potential is recorded when the ventricular muscle
is either completely depolarized or repolarized.
Cardiac impulse spreads currents into the
tissues around the heart, including the surface of the body.
Electrodes are placed on the skin on opposite sides of the
heart Electrical potentials can be recorded
Because theres only one electrically driven organ in the chest
Putting electrodes on the surface theres enough current coming to
skin to be recorded

Normal EKG

Atrial depolarisation:
Qrs complex: Ventricular depolarisation interval
between the two is .16 seconds
Ventricles are now contracting
After that that there is a longer repolarisation
R-R interval is the BPM
P wave is atria depolarisation which is just before
ventricular depolarisation
After there is ventricular repolarisation meaning
the current is going silent in the ventricles
The atrial T will be in the qrs but is covered by
ventricular depol
EKG traces the elctric impulse through the purkinje
cells and the nodes doesn�t record what happens in the muscles

EKG Concepts

The P-R interval on the electrocardiogram = 0.16 sec
0.16 second = time between the beginning of atrial contraction
and the beginning of ventricular contraction. The Q-T
interval = 0.35 sec 0.35 sec = time of ventricular

EKG Concepts

The P wave immediately precedes atrial contraction.
The QRS complex immediately precedes ventricular
contraction. The ventricles remain contracted until a few
milliseconds after the end of the T repolarization wave.
The atria remain contracted until they are repolarized, but an
atrial repolarization wave (Atrial T) is obscured by the ventricular
QRS wave.
Fast depol followed by slow repol
Ventricle will remain a little bit more contracted
than the ventricle t wave

Heart Rate Calculation

R-R interval = 0.83 sec
Heart rate = (60 sec)/(0.83 sec) = 72 beats/min

Flow of Electrical Currents in the Chest Around the Heart

Ventricular depolarization starts at the ventricular septum and
the endocardial surfaces of the heart. The average current
flow occurs with negativity toward the base of the
heart and with positivity toward the apex.
At the very end of depolarization the current reverses from
1/100 second and flows toward the outer walls of the ventricles near
the base (S wave).

Bipolar Limb Leads

Einthoven�s Law states that the electrical potential of any
limb equals the sum of the other two (+ and - signs of leads
must be observed). If lead I = 0.5 mV, Lead III = 0.7 mV,
then Lead II = 0.5 + 0.7 = 1.2 mV.

Causes of Cardiac Arrythmias

Abnormal rhythmicity of the pacemaker
Ectopic pacemaker (AV node, Purkinje fibers)
Blocks at different points in the transmission of
the cardiac impulse
Abnormal pathways of transmission in the heart
Spontaneous generation of abnormal impulses from any
part of the heart
Ec: SA node not working properly, lead to arrhythmia

Abnormal Sinus Rhythms

Tachycardia means a fast heart rate usually <100
beats/min. Caused by: Increased body temperature (18
bpm/per degree Celsius) Sympathetic stimulation (fear)
Decreased volume (dehydration, blood loss) Toxic
conditions of the heart (certain drugs) Weakening of the
heart (old age, etc.)

Abnormal Sinus Rhythms

Bradycardia means a slow heart rate usually >60
beats/min. Caused by: Athlete, larger than normal
stroke volume Decreased body temperature
Parasympathetic stimulation (carotid sinus syndrome � pressure
of the neck) Toxic/drug

Sinoatrial Block

Impulses from S-A node are blocked. Atria are
still This causes cessation of P waves.
A-V node becomes new pacemaker (usually)

AtrioVentricular Block

Impulses through A-V node and A-V bundle are slowed down
(>0.2sec) due to: Can occur when transmission from
SA node through the A-V node is blocked (A-V block) (AV and
purkinje) During sudden onset of A-V block, sinus node discharge
does not get through: Atria beat at normal rate, and purkinje
system take over for the ventricles. Delay in pickup of the heart
beat by purkinje cells cause the �Stokes-Adams� syndrome. Patient
faints during delay.

AtrioVentricular Block

Ventricles spontaneously establish their own signal distal to
the block, usually AV node or AV bundle Atria can be at
100bpm and Ventricles can be at 40bpm
Stokes adams syndrome; ventricular escape

Ventricular Fibrillation

Some parts of ventricle contract while others relax, thus
little blood flows out of the heart. No coordinated contraction
Caused by electrical shock or cardiac (Purkinje) ischemia
FATAL! Impulses stimulate randomly different parts of the
ventricles, circling back and never stopping Ischemia:
heart attack

Ventricular Fibrillation

Caused by circus movements If pathway
is long (dilated heart) � refractory period
ended If conduction velocity is decreased
(blockade of Purkinje system, ischemia of muscle, and high
K+ levels) If refractory period is shortened

Ventricular DE-fibrillation

Fibrillation can be caused by 60-Cycle Alternating
Current. 1000 volts direct current is applied for a few
thousandths of a second. All parts of the heart become
refractory and remain quiescent for 3-5 seconds until new pacemaker
is established. If used later than one minute after
fibrillation, the heart is too weak to defibrillate and may have to
be hand-pumped.

Atrial Fibrillation

Atrial fibrillation most often occurs without
ventricular fibrillation (remember the fibrous ring?). Most
frequent cause is atrial enlargement due to A-V valve
disfunction. Long pathway of conduction � circus
movements. Efficiency of ventricular pumping is decreased
20-30 percent.
Irregular, fast heart rate occurs because of
irregular arrival of cardiac impulse at the A-V node. No P
wave, irregular spacing Atria not as important as
ventricles for blood pumping Ventricles establish irregular

Atrial Flutter

Single large impulse wave travels around atria in one
direction Atria contracts at 200-350 beats/min A-V
node will not pass signal until 0.35 sec elapses after the previous
signal Therefore, atria may beat 2 or 3 times as rapidly as
the ventricle

Cardiac Arrest

FATAL! Usually because of hypoxic
conditions in the heart, sometimes during surgery
Needs prolonged CPR to reestablish a rhythm Pacemaker
(if arrest under surgery)

Major functions of
circulatory system

Transporting nutrients to the tissues
Transporting waste products away from the
tissues Transporting hormones In
general to maintain homeostasis and temperature of all tissues

Cardiac structure and function

Two important definitions:

ARTERY: any of the muscular-walled
tubes, carrying mainly oxygenated blood away from the heart
to other body parts.

VEIN: thinner walled tubes carrying mainly
oxygen-depleted blood towards the heart.

Except: in the pulmonary circulation these features
are inverted

Some anatomy of the vessels

ARTERY: any of the muscular-walled
tubes, carrying mainly oxygenated blood away from the heart
to other body parts.

VEIN: thinner walled tubes carrying mainly
oxygen-depleted blood towards the heart.

Circulation, overall plumbing

2-pump system: Pulmonary and systemic circuits
2-chamber system: atria prime, ventricles push blood
around the body

What are the components
of the circulatory system?

Expanded view of just the heart
This is the amount of blood typically present in each
compartment of the circ system
5L/min at 70bpm
60% in veins, act as blood reservour for the whole system

Function of the aorta and large arteries

Transports enough blood to ALL tissues under high pressure (100mmHg)
High flow volume
High velocity of the blood
Transport down to capillaries
Aorta approx 2.5cm in diameter high pressure and velocity
Left ventricle more powerful


Strong muscular wall Control site for blood flow
Constrict to almost ZERO flow (e.g. gut if running)
Relax to increase flow several fold (in the leg muscles)
Overall = Major resistance site of the circulation
Site where blood flow can be controlled for each organ
Small arteries can control outward blood flux to organ


Very thin wall Major site of water and solute
between blood and tissues
Largest volume of circulatory system
Three types of capillary walls: continuous,
fenestrated, sinusoid
Chemical, gas exchange
Largest volume in the circulation
Not all the same
Dependent on the type of organ they are located

Erythrocytes in capillaries

5-9 microns
Some can be smaller than size of red blood cell
Red cells squeeze through in line
Basement membrane made by connective tissue



Only gas and small molecules (glucose, amino acids, etc.) pass.
Most organs and tissues
Passes larger molecules (proteins, lipid particles).
Endocrine glands, liver, intestines, pancreas, and
the glomeruli of the kidney.
Allow entire cells to pass.
Bone marrow, lymph nodes
Intercellular cleft where solutes etc can go through
Typically present in most tissue
Looser as there are larger gaps

Venules and large veins

Once blood reaches the capillaries
Waste products now entering the capillaries
Will go to veins and venules

Blood distribution

Blood distribution
~80% in systemic circulation
~20% heart and pulmonary circulation
~64% in veins
~20% arteries and arterioles, capillaries
~16% heart, pulmonary vessels
Don�t need to remember exact numbers

Capillaries have the largest total
cross-sectional area

Because flow is continuous the velocity of blood flow (v) is
inversely proportional to vascular cross-sectional area (A)
Aorta fastest flow
Cap biggest sectional area so has the lowest flow,
reflected by measure speed of the flow

Aorta has the highest velocity of blood flow

Velocity of blood flow is the speed at
which blood flows in the circulation (mm/sec)

Basic Theory of Circulatory Function

Blood flow to tissues is controlled in relation to
tissue needs. Local tissue need can increase to
20-30 fold from resting. Heart output only
4-7 fold: arterioles, capillaries, and venules
monitor local needs and can open or shut down circulation (digestion
vs running)
Cardiac output is mainly controlled by local
tissue flow More return = more pumping
Arterial pressure is independent of either
local blood flow control or cardiac output control It needs
to regulate the circulation of the entire organism If an
organ needs more blood, another will have less
Three main req for blood circ
Blood flow is controlled locally by local tissue
Heart will pump as much blood as it receives
Reception depends on the local control which will have
veins as buffer of total volume

There are dramatic variations in tissue blood flow in the
human body

Different tissues have dramatic difference in blood flow
All of this variation is controlled locally

What is blood flow?

Blood flow is the quantity of blood that passes a given
point in the circulation in a given period of time
Unit of blood flow is usually expressed as milliliters (ml)
or Liters (L) per minute Overall flow in the circulation of
an adult is ~5 liters/min which is the cardiac output
(70mL each beat x 70bpm) Amount
of blood passing through a given tissue in a unit in time

Determinants of blood flow

Flow (F) through a blood vessel is determined by the Ohm�s
law: 1) The pressure
difference (D P
or P1-P2) between the two ends of the vessel 2)
Resistance (R) of the vessel
Differential pressure between two points required for flow

Characteristics of blood flow in a vessel

Laminar flow: Blood usually flows in
streamlines with each layer of blood remaining the same
distance from the wall
When laminar flow occurs, the velocity of blood in the center of
the vessel is greater than that toward the outer edge creating a
parabolic profile Center is faster because of
successive layers with less friction on the previous (the first
being on the vascular wall). True for any fluid in a tube
Resistance caused by blood flowing into a vessel Typically flow
within vascular system is laminar The blood layers at the centre of
the tube have highest velocity

What are some causes of turbulent blood flow?

Causes of turbulent blood flow (Think of a river!)
High velocities Sharp turns
Rough surfaces Obstruction, such as the rapid
narrowing of blood vessels
Laminar flow is silent, whereas turbulent flow
tend to cause murmurs Murmurs or bruits
are important in diagnosing vessel stenosis, vessel shunts, and
cardiac valvular lesions
Laminar flow norm for many vessels
For others like the aorta there is turbulent flow
-Lot more friction in this

What are some causes of turbulent blood flow?

This flow applies only to arteries
In veins flow is slow so no turbulence

Effect of Wall Stress on Blood Vessels

The wall of the artery will start making slight bubble to side which
gets worse with time
-They always progress, if you turbulent flow in the
area of aneurysm pushes artery wall further out wall will become thinner
-If ruptures you die within minutes, arteriole blood
goes out under pressure
Rough surfaces
-- cholesterol plaques restriction that will become
less smooth
-Causes turbulent flow, restricts blood flow

Parallel resistance in the circulation

System in series resistance of the system increases, collective
increase in resistance with each organ in series
Resistance decreases in parallel series with each
additional organ
- Facilitate overall circulation

What is conductance

More often talk about conductance opposite of resistance how easy the
blood flows
Increases resistance decreases conduction

What is the effect of changing vessel diameter on blood flow?

Conductance is very sensitive to change in diameter of vessel
The conductance of a vessel increases in proportion to
the fourth power of the diameter.
A small increase in diameter will have a big impact in
how easily blood flows
Most of the blood near surface in a smaller vessel
increasing friction and higher resistance
Increasing diameter the more layer you have away from
the wall lower resistance

Why is conductance important?

- 2/3 of conductance is due to small arterioles (Diameter between 3
and 30 microns)
-Capable of increasing their diameter up to 4 fold =
256 � fold increase in blood flow
-Small changes in diameter = big changes in flow up or
down Arterioles have most of the muscles, therefore
increase or decrease there diameter most power in changing local
resistance of blood flow

Viscosity effect blood flow

Hematocrit mainly effect viscosity more cells, more friction
Normal anemia polycythemia
Measured by reynolds number
Mostly due to amount of red cells in the blood
Typically hematocrit is 42% in male and 38% in female
Measured by centrufuging blood amount of cells packed
at bottom of tube
Impacts viscosity

Veins are very distensible

Their about 8 fold more than arteries for the same amount of pressure applied
Veins provide reservoir function for storing large
volume of blood
They provide reservoir function for
storing large volume of blood

Veins are more distensible than arteries

Arteries have thicker walls = less distensible
Veins have thinner walls allowing for greater distensibility

Vascular Capacitance

Vascular capacitance is the total quantity of blood
that can be stored in a given portion of the circulation for each
Capacitance ~ Distensibility x volume (e.g
capacitance of a small vein ~ large artery because of the
difference in volume) The capacitance of veins is 24 times
that of arteries (8X more distensible, 3X more volume = 24
fold) Vascular compliance = Increase in volume
Increase in pressure

Volume-pressure Relationships in the Circulation

Any given change in volume within the arterial
tree results in larger increases in pressure than in
veins When veins are constricted a large
volume of blood are transferred to the heart thereby
increasing cardiac output Hemorrhage can be
compensated (partially) Transfusion (lots of drinking)
don�t affect pressure much
Veins can compensate for increasing amounts of volume
maintaining steady blood pressure

Delayed Compliance (Stress-Relaxation) of Vessels

Increase in blood volume in a segment causes immediate
elastic distention of the vein (e.g. transfusion)
Followed by smooth muscle relaxation, pressure drop (e.g.
hemorrhage) And vice versa
Increase in volume (Transfusion) sharp increase in pressure
Followed by relaxation of the veins and arteries
compensating for that increase in pressure
In decreased volume pressure goes down compensated by
subsequent constriction
Physiology is all about maintaining homeostasis

Blood Pressure Profile in the Circulatory System

High pressures in the arterial tree Low pressures in
the venous side of the circulation Large pressure drop
across the arteriolar-capillary junction

Blood Pressure Profile in the Circulatory System

Blood Pressure Profile in the Circulatory System


What are arterial pulsations?

The height of the pressure pulse is the systolic pressure
(120 mmHg), while the lowest point is the diastolic
pressure (80 mmHg). The difference between
systolic and diastolic pressure is called the
pulse pressure (40 mmHg)
Sharp increase due to opening of aortic valve
Sharp incisura due to the closing of the aortic valve
Gentle slope result of aortic elasticity going down,
going back to normal size

MAIN factors that effect pulse pressure

How much blood is getting out
And how elastic are the arterioles

Arterial pulsations � peripheral circulation

Arteries have compliance and distensibility The
intensity of pulsations becomes progressively less in the smaller
arteries At the capillary level almost no pulsation =
continuous flow
Farther you get from blood down to the capillary the
elastic tissue is going to decrease the arteriole pulsation down to
the capillary where you almost have continous flow

Pressure pulse contours in arteriosclerosis

Arteriosclerosis -- decreases compliance of
arterial tree (rigid); thus leading to increase in pulse
Arteries are more rigid
There may be difference that can be measured in aortic pulsation

Pressure pulse contours in aortic stenosis

Aortic stenosis - aortic valve opening is reduced
Low blood flow through the aortic valve � Low systolic
pressure = low pulse pressure

Overall Objectives

Distensibility and compliance Factors affecting pulse
pressure How blood pressure is measured clinically
Functional characteristics of the veins

Vascular system is DISTENSIBLE

Accommodate pulsatile nature of circulation -> smooth flow

Pressure pulse contours in patent ductus arteriosus

Patent ductus arteriosus � some blood flows back to the
pulmonary artery through a duct. Associated with
low diastolic pressure and high
systolic pressure, net result very high pulse pressure

Patent ductus arteriosus in aortic regurgitation

Aortic regurgitation � absent or defective aortic valve
Backward flow of blood through the aortic valve. Low
diastolic and high systolic pressure leads to high pulse pressure
No incisura (closing of the aortic valve

Blood Pressure Profile in the Circulatory System

Just enough pressure/speed in the capillaries to �push liquid
out� and exchange nutrients

What is blood pressure?

Blood pressure is the force exerted by the blood
against any unit area of vessel wall
Measured in millimeters of mercury (mmHg). A
pressure of 100 mmHg means the force of blood was sufficient to push
a column of mercury 100mm high Low pressures are sometimes
reported in units of mm of water. 1mmHg =
13.6 mm of water
Force exerted on vessel wall within the arteries
mmHg because its been that way since the 1900
In pulmonary circ some time measure in mmH2O, little bt
more accurate than mercury
Low pressures sometimes reported in mmH2O

Measurement of Systolic and Diastolic Pressures

Korotkoff sounds
Insertion of needle in artery most accurate but
Auscultatory method is (was) the most commonly used method
for measuring systolic and diastolic pressures at the antecubital
artery by compressing the brachial artery Not the most
practical measure 1 Uses the sounds to measure the diastole and
systolic blood pressure Inflated cuff squeezes brachial artery Most
of the time now this process is automated no sound listening

Measurement of Systolic and Diastolic Pressures

Arm at same level of heart When cuff pressure =
systolic pressure � tapping sounds in the
antecubital artery disappear; As the cuff pressure
reaches diastolic pressure � muffled sounds and then
Korotkoff sounds disappear Why sound?
Either sitting or laying
The arm has to be at the same level as the heart
Inflated cuff to 200mmhg way above probably systolic press
Deflated to 0
Sounds first appear at about the systolic disappear
around the diastolic pressure
When there is no more resistance from the cuff stopping
the blood
Why sound? Turbulent flow caused by
squeezing of the cuff, creating the sound disappears when artery is
opened again laminar flow

Blood pressure raises with age Why?

Mean blood pressure NOT the average between systolic and diastolic,
closer to diastolic. Why?
~60% time in diastole and ~40% time in systole, except
at high bpm rate (Remember why?)
Artherosclerosis arteries begin to get harder and less
elastic the pressure from the ventricle will stay in the artery at
the same time
The mean is not necessarily the average
Change when high bpm diastole gets shorter the mean
blood pressure will go up


passageways for flow of blood to the heart temporary
storage of blood 60% of blood is in veins � very compliant
= reservoir

regulate cardiac output
Flow from capillaries back to the right heart
Temp reservoir of blood

Blood Reservoir Function of Veins

The spleen, liver, large abdominal veins and the venous plexus
under the skin also serve as reservoirs
Together, these reservoir can contain (and release) ~1L of blood
or 20% of the total Under various physiological
conditions (e.g. dehydration, hemorrhage) veins constrict and blood
is transferred into arterial system to maintain arterial pressure
-> venous pump
20% can be stored and used when necessary
Spends more time in veins than overal circulation
Dehydration or overhydration veins will either
constrict or relax for this system
Venous pump can pump blood into circ or keep more in
venous circuit

Central venous pressure

�or right atrial pressure is zero
regulated by: (1) strength of the
right ventricle � blood into the lungs

(2) flow from the peripheral veins into the right atrium.
Factors that increase CVP:
-increased blood volume
-More liquid volume
-increased venous tone
-Less bed volume
-dilation of arterioles
-More blood flow to the veins
-decreased right cardiac function
-More blood stagnation
Influence how much pressure is in the right atrial pressure
If the right heart is not stronger enough defect in
cardiac function there is stagnation of the blood or backflow from
atria into the veins
Sometimes in older or obese people slight
discolouration of the legs due to backflow

Effect of gravitational pressure on venous pressure

Any compression causes resistance to flow in
large peripheral veins Pregnancy, large tumors, abdominal
obesity, or excessive fluid (�ascites�) in the abdominal cavity =
swollen legs
Hydrostatic pressure = Weight of blood in the vessels cause
venous pressures to be as high as +90 mmHg
Any compression can cause additional problems with the
flow of the veins
Hiking for a long time hands get swollen because there
is compression point in the ribcage
Low blood pressure in the veins small constrictions
cause problems

Venous Valves and �Venous Pump�

Venous pump: moving and tightening of muscles
squeezes blood in one direction due to valves = actual lower leg
pressure ~20mmHg Soldier fainting due to loss of liquid
under +90mmHg pressure in legs Long flights!!
Veins in the lower legs or heart veins have valves
important to keep blood flow one directional
Hydrostatic pressure pools in the legs
Sitting on veins elderly and people with problems in
legs should move as often as possible to continue circulation

Varicose veins

The venous valves and pump maintain a relatively low venous
pressure in the legs Faulty venous valves lead to varicose
veins � 30% population, 2X women. Obesity, not enough
exercise, leg trauma, pregnancy, and a family history Lower
return, fluid leakage, edema, brown discoloration of ankles
Therapy � compression stocking, exercise, stripping.
When there are faulty valves it can lead to varicose veins
Fluid leakage in lower legs
Discolouration around ankle and the foot
Stripping � veins cut above and below the vein and
removed from the leg, new veins will then form

Overall Objectives

Structure and function of the microcirculation How
solutes and fluids are exchanged in capillaries What
determines net fluid movement across capillaries

Blood Pressure Profile in the Circulatory System

Capillaries have highesst permeability
Have huge total area delicate small endothelial walls
Mostly no elastic fibre or muscles

Function of the microcirculation

�whole point� of the cardio-pulmo-circulatory system
Important in the transport of nutrients to tissues Site
of waste product removal Over 10 billion capillaries with
surface area of 500-700 m2 perform function of solute and fluid
Each organ can have enough blood for survival

Structure of Capillary Wall

Arterioles� smooth muscle and sphincters provide control of
local circulation Capillaries are made of unicellular layer
of endothelial cells surrounded by a basement membrane
Diameter of capillaries is 4 to 9 microns (diameter of red
cells: 7.7microns!) Venules have few smooth muscle cells
but much lower pressure
Metartierioles short cut between arteries and veins
incase local circulation has to be shutdown
Each cap has a single smooth muscle cell which makes
pre capillary sphincter which regulates the flow, SM provides local
control of the circulation
Venules � muscle cells will increase when veins get wider


Blood flow in the capillaries is continuous. BUT:
There is intermittent contraction of the arterioles,
metarterioles, and precapillary sphincters � In INDIVIDUAL
capillaries, flow only happens every few seconds or minutes
Low local O2 level means longer and more frequent opening
On AVERAGE, across millions of capillaries, the flow is nearly

EM Structure of Capillary Wall

Fen � allows protein passage

Molecular size affects passage of molecules across the
capillary wall

The width of capillary intercellular slit pores is 6
to 7 nanometers (60-70 �) � albumin is ~100� The
permeability of the capillary pores for different
substances varies according to their molecular
diameters The capillaries in different tissues have
extreme differences in their permeabilities
Brain: lowest permeability, �tight junctions� only
small molecules. Blood-Brain-Barrier or BBB
Liver: large pores, proteins and lipid particles go
through rapidly (from digestion)
GI capillary membranes: are midway in size most
substances, but not proteins
BBB only allow small molecules to go through, problem
in brain disease treatment

Relative Permeability of Muscle Capillary Pores to
Different-sized Molecules

Perm related to the size and hydrophobicity of the molecule

Interstitium and
Interstitial Fluid

1/6th of body volume is between
Cells and it�s called interstitium;
fluid in this space is called

interstitial fluid (~12L)
Two major components are collagen fibers
and proteoglycan filaments (coiled molecules composed of
98% hyaluronic acid) Collagen provides resistance to
tension Proteoglycans provide resistance to compression
Most fluid in interstitium is ge
l (fluid proteoglycan mixtures); very little free


Structurally heterogeneous family of proteins
with extensive posttranslational modification with
sulfated sugar chains �
retains lots of water Central protein core with O-linked
glycosaminoglycan side-chains Aggrecan, Brevican,
Biglycan, Versican, Glypican, and others
Multifunctional proteins: sponge for water; stabilize
ligand�receptor interactions; store growth factors; activate (or
dampen) various signaling cascades; etc.

Interstitial Fluid

Fluid is generated by filtration and diffusion from the
capillaries � similar to serum but almost no proteins Water
and ions are trapped by proteoglycans = GEL Water, ion, gas
diffusion >95% of free flow ~1%
of interstitium makes pockets of �free fluid� liquid, which can
increase significantly in case of EDEMA
When fluid comes out of cap it gets sucked by
proteoglycans and stays in this gel state
95% of the water acts as free water
Binding of water to proto glycan doesn�t limit water movement

How do solutes and fluids cross the capillary wall?

Most important means by which substances are
transferred to
interstitial fluid is by diffusion

(thermal motion)

Lipid soluble substances diffuse directly through
cell membrane of capillaries (I.E. CO2, O2)
Water soluble substances such as H2O, Na+, Cl-, glucose,
cross capillary walls via intercellular clefts
Concentration differences across capillary drive diffusion
(e.g O2, CO2) including drugs!
Fluid and substances moving out of cap by diffusion

Determinants of net fluid movement across capillaries

Two main forces act in balance:

1: hydrostatic pressure (Pc) from inside and
outside the capillary membrane. 2: osmotic pressure
caused by the proteins inside and outside the
capillaries. lymphatic system returns to the circulation the
small amounts of excess fluid and protein that leak to the
interstitial space � rhythmically squeeze fluid to the
main circulation Pressure carried by
arterials, from inside cap to the outside On the inside/outside of
the cap same with the osmotic, two opposing forces

What are the determinants of net fluid movement across capillaries?

OUTWARD Capillary hydrostatic pressure
(Pc) - through the capillary membrane � from blood pressure
and gravity
INWARD Interstitial ( hydrostatic ) fluid
pressure (Pif)- opposes Pc
INWARD plasma colloid osmotic
pressure (?p) � keeps fluids in OUTWARD
interstitial fluid colloid osmotic pressure (?if) � pull
fluid out
Four forces are the starling forces

What are the determinants of net fluid movement across capillaries?

If NET filtration pressure is POSITVE liquid moves
out If NET Starling forces are negative,
liquid moves in

Determinants of net fluid movement across capillaries

NFP is slightly positive under �normal� conditions (~20 mm Hg
in most tissues but ~60 mm Hg in kidney) Different tissues
have ? capillary bed and ? number and size of the pores in each
capillary = capillary filtration coefficient (Kf)
Different filtration properties in different tissues

Capillary Filtration Coefficient

Extreme differences in permeabilities of the capillary in
different tissues � coefficient varies >100-fold among the
different tissues. Very small in brain and muscle
Moderate in subcutaneous tissue, Large in the
intestine, Extremely large in the liver and glomerulus of the
kidney, bone marrow Concentration of protein in the
interstitial fluid of muscles is about 1.5 g/dl; in subcutaneous
tissue, 2 g/dl; in intestine, 4 g/dl; and in liver, 6 g/dl.

Interstitial fluid
hydrostatic pressure

Interstitial fluid
hydrostatic pressure,
negative (-2mm Hg) BUT: tissues that are surrounded by
capsules (e.g. brain, kidney, liver, eye), the Pif is slightly
positive (+10 mm Hg)
Overall , interstitial fluid colloid
pressure - promotes filtration by causing osmosis of fluid
outward ~-3mm Hg Lymphatics remove excess liquid, thus
lowering pressure

Plasma colloid osmotic pressure

Plasma colloid osmotic pressure - opposes filtration
Only the molecules or ions that do NOT pass
through the pores exert osmotic pressure = ~28 mm Hg
Proteins exert 19 mm Hg of this pressure (80% albumin)
9 mm Hg is caused by the Donnan effect�
sodium, potassium, and other cations bound to the plasma
proteins. Liver disease or prolonged starvation (no
protein diet), cause edema
Not enough protein in circ causing liquid to seap out

Interstitial Fluid Colloid Osmotic Pressure

Proteins exert ~8 mm Hg of this pressure Proteoglycans
from connective tissues Ions bound to them

Approximate average forces at arterial end

Under normal conditions complete equilibrium exists

More venous capillaries and more permeable than the
arterial ends = more inward movement of fluid
A slight positive pressure, necessary for
formation of interstitial fluid, remains
The remaining fluid flows into the lymph vessels and returns to
the circulating blood.

Too much Pc and or too little
p p

Abdominal edema for lack of protein in the diet
(extreme starvation, liver disease)
Lower limbs edema for circulation defects (heart,
abdominal compression, etc.)

Lymphatic System

An accessory route by which fluid and protein (Lymph) flow from
interstitial spaces back to the blood
Larger duct is thoracic duct, joins left
internal jugular subclavian veins One tenth of the fluid
enters the lymphatic capillaries (120 mL/h = 2-3L/day)
Important in preventing edema Major route for
absorption of nutrients from the GI tract Plays important
role in the immune system

Within physiological limits, any increase of filtration
(Sterling forces) is absorbed by the lymphatics.
Whatever isnt reentering circ through venous end will be
picked up by this
Lipids enter in the lymphatic system

Lymph composition

Protein concentration in the interstitial fluid of
most tissues averages about 200 mg/mL
Lymph formed in the liver has ~600mg/mL of protein
Lymph formed in the intestines has ~ 300 to 400mg/mL.
Two thirds of all lymph normally is derived from
the liver and intestines Very rich in fat (from digestion)
� milky aspect Larger particles, such as
bacteria and lymphocytes
Lymph from liver is whitish due to fat content
No erythrocytes
Will be clear

Lymphatic microcirculation

Activity of the lymphatic pump
-Lymphatics have loose endothelial cells, gaps between them
-Lymphatic capillaries are dead ends
-Gaps form unidirectional (inward) valves
-Smooth muscle filaments in lymph
vessel cause them to contract
Sm helps lymph moving through lymphatics

External forces influencing the Lymphatic System

Local smooth muscle compression and valves make
flow possible.
External factor intermittently compresses
lymph vessels such as: Contraction of surrounding
skeletal muscles;
Movement of the parts of the body;
Pulsations of arteries adjacent to the
Compression of the tissues by objects outside the
External factor constantly compresses lymph
vessels Edema, bandage, etc., will block lymphatic
as well
Constant pressure internal or external will block the lymphatics
Intermittent compression

Recap: Lymphatic System

Overflow mechanism� to return excess proteins and excess fluid
volume from the tissue spaces to the circulation. Lymphatic
system controls: (1) protein concentration, (2) the volume and (3)
the pressure of the interstitial fluid. More protein and
more fluid = more interstitial volume and pressure � increased
return of protein and fluid by the lymphatic system = balance.
Hugely important in function of the immune system

Local Control of Blood Flow

Each tissue controls its own blood flow in proportion to
its needs Tissue needs include
1) Delivery of oxygen to tissues
2) Delivery of nutrients such
as glucose, amino acids, etc.
3) Removal of carbon dioxide, hydrogen and other
metabolites from the tissues
4) Transport various hormones
and other substances to different tissues
Flow is closely related to metabolic rate of
tissues and other special needs/functions (e.g. cooling through the
skin, kidney filtration, etc.) This keeps the heart�s work
at a minimum
THE NS doesn�t control blood delivery in each tissue
controlled locally

Variations in Tissue Blood Flow

70ml stroke volume of left ventricle times 70

Variations in Tissue Blood Flow

K g shut off during exercise

Acute and chronic control of blood flow

Acute or short term � seconds to hours Rapid
vasodilation (or constriction) of the arterioles, metarterioles, and
precapillary sphincters Chronic or long term � days to
months increase or decrease in the physical sizes and
numbers of blood vessels supplying the tissues.
Chronic more anatomical more blood vessels invading the tissues

Short-term Control of Blood Flow

Increase in tissue metabolism lead to
increases in blood flow (how much depends on the tissue)
Decrease in oxygen availability to tissues
increases tissue blood flow (altitude, pneumonia, CO poisoning,
etc.) Two major theories for local blood flow
control 1) The vasodilator theory 2) Oxygen demand

Vasodilator Theory for Blood Flow Control

Increase in metabolism causes the production of Nitric Oxide*
(NO) Adenosine and ADP compounds (From ATP), CO2, Lactic acid,
Histamine, K+ ions, H+ ions Leakage of once or more of
these chemicals outside the cells will cause vasodilation
Increase in met increases production of vasodilators
Active mechanism of increasing local blood flow

Oxygen (nutrient) demand Theory

Precapillary sphincters open/close cycles regulate
flow � Vasomotion
More oxygen, sphincters closed
Less oxygen, sphincters open

Problem: can smooth muscle sense what tissue needs?

Passive mechanism: lack of oxygen relaxes smooth muscle

Active and reactive hyperemia

A combination of
vasodilator substances, lack of oxygen and other nutrients is
probably at work in the short term control of blood flow

Humoral (acute) Regulation of Blood Flow


Norepinephrine and epinephrine (sympathetic action)
from nerve terminal and adrenal gland

Angiotensin II constrict the small arterioles and kidney

Vasopressin VERY potent, AKA antidiuretic hor?mone


Vasodilator agents

Bradykinin (inflammation, skin, GI tract)


Histamine, from Mast cells, allergic reaction,


Nitric oxide

Short-term Control of Blood Flow

Decrease of glucose, some amino acids, and/or lipids also
causes vasodilation Thiamine, niacin, and riboflavin (B
group) also cause vasodilation

A combination of
vasodilator substances, lack of oxygen and other nutrients is
probably at work in the short term control of blood flow
At the end of the intense metabolic activity, too much
oxygen and other nutrients arrive � vasodilators are �washes out� �
return to normal blood flow

Special cases

Kidney: tubulo-glomerular feedback, the composition
of the fluid in the early distal tubule is detected by the
macula densa � blood flow and filtration are reduced
Brain: the concentrations of carbon dioxide and
hydrogen ions play prominent roles because neuronal excitability
depends on these components
Skin: blood flow control is linked to body
temperature regulation through the sympathetic nerves

Autoregulation of Blood Flow During Changes in
Arterial Pressure

Myogenic (acute control): sudden stretch of
small blood vessels causes the smooth muscle of the vessel to contract

Metabolic: too much oxygen and too many other nutrients
Sudden change in bp causes little change in blood flow

Long-term Regulation of Blood Flow

Long-term local blood flow regulation occurs by changing the
degree of vascularity of tissues (size and
number of vessels)
Days to weeks, more extensive and more rapid in
young animals than older ones
Long-term regulatory mechanisms which control blood
flow are more effective than acute mechanism
Oxygen is an important stimulus for regulating tissue
It works both ways!!

Exercise increases number of capillaries

What is Angiogenesis?

The growth of new blood vessels Angiogenesis occurs in
response to angiogenic factors released from
1) Ischemic Tissue
2) Rapidly growing tissue
3) Tissue with high metabolic rates
Most angiogenic factors are small peptides
such as Vascular endothelial cell growth factors (VEGF),
fibroblast growth factor (FGF), and angiogen.

How new capillaries form

Membrane basement dissolve New endothelial cells
invade the tissue as solid �cords� toward the source of angiogenic
factors �Cords� hollow to become tubes Tubes keep
developing and some of them are eventually covered in smooth muscle
cells Definite arterioles, capillaries and venules are
formed Vascularization reaches maximum level of blood
flow need NOT average need (think of athletes) Angiostatin,
Endostatin, and other factors BLOCK and reverse angiogenesis
Used as anticancer?

Vascular remodeling

In most tissues, small blockage (e.g. physical damage) results
in new arteries-capillaries-veins within days to weeks � depends on
size Process usually restores full functionality
Vascular remodeling sustain normal growth (and athletes)
By age of 60 � small coronaries can be blocked and are replaced
with �collaterals� � no symptoms If a larger one is blocked
� heart attack!!! Vascular remodeling also occurs in
vascular walls � saphenous vein (From
leg) implanted for a coronary artery bypass will thicken
its wall in months are become �artery-like� Vascular
remodeling is reversible

Tissue remodelling

Tissue remodelling is the reorganisation or renovation of existing tissue
TR results in the dynamic eq of a tissue such as in bone remodelling
Bone remodelling is a lifelong process -> reshaping
or replacement of bone following fractures but occurs during the
entire life to meet demands of mechanical loading

Autonomic Nervous System control of the circulation

Sympathetic nervous system is important in control
of circulation
Exit through thoracic and lumbar nerves � sympathetic
chain � directly or indirectly to the vasculature

Parasympathetic nervous system is important in regulating
heart function
Mainly the vagus, directly to the heart � Ach to slow
down HR

Heart receives BOTH innervations

Veins and arteries only receive sympathetic innervation

Sympathetic Innervation of Blood Vessels

Sympathetic nerve fibers
innervate all vessels except
capillaries (No muscle to innervate)
Innervation of small arteries and
arterioles allow sympathetic nerves to
constrict � increase vascular resistance
� decrease flow
Large veins are also sympathetically innervated �
decrease volume and increase return � more
pumping (faster& stronger beats)
Sympathetic go directly to the heart rate
increasing the heart rate and enhancing its
strength and volume of
pumping Little to nil parasympathetic innervation to

Sympathetic Vasoconstrictor System

Vasoconstrictor fibers (and a few �dilator) are distributed
throughout all segments of the circulation Distribution is
greater in kidneys, gut, spleen, and skin Less potent in
coronary circulation, brain, and muscle

The Vasomotor Center (VMC)

The VMC transmits impulses downward through the cord to almost
all blood vessels VMC is located bilaterally in the
reticular substance of the medulla and the lower third of the
pons The VMC is composed of a
vasoconstrictor area, vasodilator
area, and sensory area Many higher centers
of the brain such as the hypothalamus and
cortex can exert powerful excitatory or inhibitory
effects on the VMC

Parasympathetic Effects on Heart Rate

Parasympathetic (vagal) nerves, release
acetylcholine at their endings, innervate
S-A node and A-V node.
Causes hyperpolarization � increased K+
permeability. � causes decreased heart rate
maybe temporarily stopping heart rate.

Sympathetic Effects on Heart rate

Releases norepinephrine at sympathetic
ending Causes increased SA node
discharge Increases rate of conduction of
impulse Increases force of contraction in
atria and ventricles

Functions of The Vasomotor Center

Vasoconstrictor area transmits signals
continuously to sympathetic nerve fibers �
sympathetic vasoconstrictor tone.
Block of the vasomotor tone makes average pressure
drop in half Norepinephrine, sympathetic neurotransmitter,
transiently brings pressure back Why
Destroyed by the liver within a few minutes

Sympathetic control of arterial pressure

The nervous system via the vasomotor center (VMC) can increase
arterial pressure (AP) within seconds by:
-Constricting almost all
arterioles of the body which increases total
peripheral resistance (TPR)
-Constricting large vessels
of the circulation thereby increasing venous return and
cardiac output (Frank-Sterling)
-Directly increases cardiac output by
increasing heart rate and contractility
Rapid increases in arterial pressure can occur
during exercise or with fright

VMC affects vessel function via neurotransmitters

The neurotransmitter for the vasoconstrictor
nerves is norepinephrine acting on alpha
adrenergic receptors
Adrenal medulla secretes epinephrine and
norepinephrine which constricts blood vessels via alpha
adrenergic receptors. Systemic effect: �
Epinephrine also dilate vessels through a potent Beta
2 adrenergic receptor. E.g. muscle,
lungs, etc. �and don�t forget the local control
by O2, etc.

Blood pressure is controlled by receptors

What are the positive and negative feedback
reflex mechanisms to maintain the normal arterial pressure?
Baroreceptors Chemoreceptors
Low-pressure receptors

All located outside the brain
Baro and chemo
-All in the periphery
-Communicate with brain to give response

Rapid regulation of blood pressure

The nervous signals

(a) increase the force of heart pumping,

(b) cause contraction of the large
venous reservoirs to provide more blood to the heart,

(c) cause generalized constriction of the
arterioles in many tissues � increase resistance � increase pressure.
Over more prolonged periods�hours and days�the
kidneys play an additional major role in pressure
control both by secreting pressure-controlling hormones and by
regulating the blood volume.

Anatomy of the Baroreceptors

Located in the walls of the carotid bifurcation called the
carotid sinus and in the walls of the aortic arch
, a small number in many other large arteries
Hering�s nerve and vagus are the afferent nerves to the CNS
Located in circle of carotid and aortic wall
Sense bp
Communnicate back through the herings nerve

The Arterial Baroreceptor Reflex

Important in short term regulation of arterial
pressure � negative feedback Reflex is
initiated by stretch receptors called baroreceptors or
pressoreceptors located in carotid sinus and
aortic arch A rise in pressure
stretches baroreceptors and causes them to signals to the VMC.
Negative feedback signals are sent to the
circulation to reduce AP back to normal
Mostly for negative feedback
Pressure to high sense readjust
In essence stretch receptors
(Receptor of pressure)
Increasing bp will stretch these in the arteries send
stim to the cns so that can reduce or increase the bp depending on signal
More they stretch more frequently they send signals to
the vasomotor center

Baroreceptors respond to
changes in arterial pressure

Carotid sinus baroreceptors respond to pressures between
60 and 180 mmHg (most sensitive ~100mmHg)
Baroreceptors respond to changes in arterial
pressure -> not
constant pressure As
pressure increases, impulses from carotid sinus
increase ->
1) Inhibition of the vasoconstriction ->
decreased blood return
2) Activation of the vagal center -> slow down
of heart
�and vice-versa as pressure decreases
Important to maintain blood pressure during changes in
body posture

Sitting -> standing
Range of sensitivity
Have optimal sensitivety between 60 � 180 mmhg
AS pressure increase send impulse from carotid sinus to CNS

Baroreceptors reduce daily variations in arterial pressure

Oppose either increases or decreases in arterial pressure ->
reducing daily variations in arterial pressure

Not important in the long-term regulation of the pressure
Pretty tightly controlled bp second by second during
different activities
If baro receptor nerves were cut then the pressure fluctuates
Denervation removes most of the control
Normal animal has very narrow bp range denervated broad range
Acute control
At some point baroreceptors stop signaling around 160bp

Carotid and Aortic Chemoreceptors

Sensitive to low oxygen,
high CO 2 , or
high H+ ion Located in
carotid bodies and on the arch of the
aorta Activation (below 80mmHg) results in
excitation of the vasomotor center Stimulated
also by very low pressure (= low O2 and high CO2)
More important in respiratory control
Located same place as baro
Different sense range to baro receptors
Below 80 there are different concentrations of chemicals
ionic change
Stim by low pressure where low oxygen

Atrial and pulmonary artery reflexes

If pres in atria to low
Increase hr contractivity

Other Reflexes

Baroreceptors, the chemoreceptors, and atrial low-pressure
receptors do most of the control. But:
Bainbridge reflex: Stretch of atria sends signals
to VMC via vagal afferents to increase heart rate and contractility.
Prevents damming of blood in veins atria and pulmonary
Abdominal compression reflex: low pressure �
abdominal muscles contraction � compression abdominal venous
reservoirs � helping to translocate blood out of the abdominal
vascular reservoirs toward the heart (increase return �
Skeletal muscles contract during exercise, they
compress blood vessels throughout the body � translocation of blood
from the peripheral vessels into the heart and lungs

CNS Ischemic Response

CNS Ischemic response is activated in response to cerebral
ischemia = low enough pressure to cause lack of O2 and buildup of
CO2, lactic acid Greatest activation occurs at pressures of
15-20 mmHg (almost dead) Vasomotor center stimulation ->
increasing arterial pressure CNS ischemic response is the
most powerful (last resort) activators of the sympathetic
vasoconstrictor system
Last resort of low bp response
Powerful mechanism

The kidneys have a dominant role in long term pressure control

Plays a dominant role in long term pressure control As
extracellular fluid volume increases -> arterial pressure
increases. Regulation of the blood volume and


blood flow to the skeletal muscles 2. coronary
artery blood flow to the heart. 3. cardiac output
control during exercise 4. heart attacks

Muscle blood flow during exercise

A.Resting blood flow = 3 to 4 ml/min/100 gm muscle.
Vasomotion, few opened capillaries
B.Can increase? 20-50 fold during heavy exercise ->
all capillaries are opened
C.Muscle makes up a large portion of body mass ->
great effect on O2 consumption and CO2 production
D.Heart output raises only 3-4 fold, rest is vasodilation.

Exercise and Muscle Blood Flow

Blood flow occurs only between contractions.
During weight lifting, almost always closed ->
pain, burning sensation within seconds
Blood flow wont go up and down in spikes with contraction
If the muscle doesn�t relax it will start having burning sensation

Short-term Control of Blood Flow

A combination of:

Vasodilator substances (NO, Adenosine, CO2,
Lactic acid, Histamine, etc.)

Lack of oxygen and other nutrients
(very fast in muscle activity)�

Sympathetic stimulation both local
(to local arterioles and veins) and systemic (through
adrenal medulla) � local vasodilation, systemic vasoconstriction
Local control
Muscle makes more lactic acid under these conditions
Sympathetic stim will constrict vessels all over the
place and vasodilate locally

Sympathetic regulation during exercise

Veins -> overall constricted
20-40% increase in blood pressure
Veins due to adrenaline and noradrenaline

Effects of arterial pressure on flow

20-40% increase in blood pressure
Higher blood pressure -> increase local flow several
fold More pressure = larger (stretched) vessels
BP increase depends on exercise: �hammering� vs
Hammering doesn�t result in any large opening of big
muscles compared to swimming
Higher bp in hammering

Effects of venous pressure on blood flow

Heart filling pressure increases from the
sympathetic stimulation that contracts the veins (and other
capacitative parts of the circulation) (Frank Sterling)
Tensing of the abdominal and other skeletal muscles of the body
compresses many of the internal vessels � venous
pump In a healthy heart, central venous pressure (0
mmHg) hardly increases
Because the heart will be able to keep up with the extra
work and keep up with it so bp will remain the same

Long-term Control of Blood Flow

Muscles have myoglobin similar to haemoglobin (Tetramer can bind 4 or
more molecules)
Myo is a monomer can only bind one molecule
At different oxygen pressures in the lungs there is
different saturations myo vs haemo
Myoglobin able to pull oxygen from red cell higher affinity
Muscles have reserve oxygen when capilaries are shut down

More myoglobin which has more affinity for 02

Coronary arteries

3 main arteries (2 Left + 1 right) lie on the surface of
the heart, plus minor branches Smaller arteries penetrate
deep into the myocardium Coronary flow = 225 ml/min = 5% of
heart output No significant nutrition from blood inside
Used to pinponit what each branch of coronary artery is
feeding (the heart %)

Coronary arteries and veins

75% of blood goes back to the right atrium by coronary
sinus (Left arteries) ~20% from right side goes
back through anterior cardiac veins ~5%
through small Thebesian veins
Collecting everything the left coronary artery is providing
Veins follow the arteries then diverge in branching

Changes in coronary flow during the cardiac cycle

Blood flow falls during ventricular contraction � opposite as
other tissues � why? Much less in right ventricle because
of its strength
Because of the muscle contraction

Structure of the wall of the heart

Muscle: Endomysium, Epimysium, Perimysium

Nerve: epineurium perineurium endoneurium
Endocardium layer of endothelial cells on a basement
membrane cover heart inner surface
Pericardium fibrous connective tissue two layer inside
pericardial little bit of fluid allowing pump to move mithout
effecting anything else

Changes in coronary flow during the cardiac cycle

Epicardial side and sub endocardial side
Fed through these branches
Difference in pressure between these depending on whether
the heart is sytole or diastole

Control of coronary flow

Local control is similar to muscle (O2, adenosine, CO2, NO,
etc.) but much faster and flexible Nervous stimuli
Mainly affects epicardial flow (a, constriction)
Little effect of parasympathetic (Ach).

b sympathetic subendocardial flow (dilation)

not very powerful, overridden by metabolic factors
This type of control is usually overiden by metabolic

Energy supply for heart

Necessary for beating & moving ions (Ca++, Na+, K+, Cl-,
etc) in and out of the membranes
Fed state: Fat metabolism + O2 = Krebs cycle -
70% 30% comes from glucose -> Glycolysis
(no O2) - little capacity � no glycogen
Fasting state: Lactic acid and
Ketone bodies (e.g., acetoacetate)
Ischemia or Hypoxia (coronary stenosis or blockage)
-> use of glucose -> lactic acid as
metabolite -> chest pain

ischemic heart disease

Results of ischemic heart disease
1/3 of all deaths due to ischemic heart
disease 45% of all deaths are cardiovascular (only 22%

Types of Ischemic Heart Disease
1.Acute -> coronary occlusion or
fibrillation of the heart
2.Progressive -> weakening of the
heart pumping over decades

Risk factors for ischemic heard disease

Risk factors for ischemic heart disease

Causes of Atherosclerosis

1.Start as endothelial damage
2.Subintimal deposit of cholesterol and fats
3.Restriction, uneven surface (turbulent flow)
4.Local necrosis
5.Fibrous repair & Calcification
6.Reduced lumen of many arteries (heart, brain, kidneys)
7.Acute occlusion of a coronary artery
(brain, kidney)

Results of ischemic heart disease

Angina pectoris

Pain in the sternum, left arm, shoulder, neck and
face (same embryologic origin of sensory nerves)
Likely due to increased glycolysis and lactic acid
or other pain-promoting products (histamine, kinins, etc,)
Exacerbated by exercise, emotion, cold, full stomach
Diagnosed by stress test on treadmill
Comes and goes not classical heart attack
Pain origin seems to be increased glycolysis
Less oxygen comes to heart more lactic acid produced
Heart needs more blood supply and if arteries are blocked
then this will make it worse (exercise)
All conditions that make heart work harder, worsen the angina
Monitor with ecg to monitor seriousness of angina

Results of occlusion

Thrombus due to endothelial damage -> local
blood clot -> occlusion
Embolus -> blood cloth enters the circulation
-> coronary embolism Embolus can also go to lungs,
kidney, etc, End result will depend on occluded artery
Remodeling delays/avoids complete occlusion
If the clot is big enough it will completely occlude the artery
If it detatches will become embolus
- Can have embolism in other parts of the body
- If bigger trunk of the artery is occluded can have deadly
myocardial infraction

Myocardial infarction (MI)

Chronic obstruction by atherosclerosis
Acute coronary thrombus or embolus
Acute coronary spasm
blood flow stops -> Local vasodilation
2.small amounts of collateral blood begin to seep into the
infarcted area
3. -> infarction of the area with
stagnant blood
4.No oxygen in, no catabolites out -> tissue death
5.subendocardial (deep) muscle more active, less oxygen
-> most damaged (Less blood supply)
Typically no symptoms until 70-80% of artery is occluded
90 � 95 even mild stress will cause the pain
Backup of blood seeping into the muscle, endothelial in
absence of oxygen will start to separate
All little arterioles will open,

Treatment for ischemic heart disease

Coronary bypass (1 to 5 succesful)
Coronary artery angioplasty
If you don�t die from myocardial infarction
Take leg vein replace blocked artery
- Introduction of small balloon
Guide probe to aorta and to the coronary artery guided by
x-ray imaging
Inflate the balloon compress plaques
Put in a titanium net that will stay in place once inflated
by balloon
Covered by endothelium after 2 weeks
If you have 90 occluded arteries in heart you may have the
same in other organs

Causes of death after MI

Decreased cardiac output �systolic stretch
Pulmonary edema -> increased capillary pressures
in the lungs -> no gas exchange Fibrillation
Erratic electric current can renter the cycle -> circus
movements Powerful sympathetic stimulation
excessive dilation -> erratic current Local rupture
of the heart -> blood into the pericardial space -> tamponade
-> compression of the heart from the outside
Left ventricle will have most consequence
Tissue without blood flow will partly die
With less stroke volume heart power there will be backflow
through the pulmonary circuit
The right ventricle will pump enough
Left wont clear the lungs accumulation of blood in lung
Pulmonary edema lower gas exchange
When you have enlarged heart and more surface area for
electric impulse to circulate you may start to have circus movement
Heart is not pumping enough lung subjected to edema
Less Gas Exchange
When worse there is fibrilation of the ventricles at that
point there is no actual pumping of blood in the circulation, if
patient doesn�t die there may be rupture of the heart more rare
significant damage and thinning may not happen in the first hour but
may happen
-Most serious event
-Most of the blood in left ventricle will accumulate in the
pericardium which isnt elastic, heart will be compressed by own blood
-End up with cardiac tamponade heart now can�t beat due to
external compression

RBC Size and Shape

Biconcave discs 7.7 x 2.5 microns (around) and
~1 micron (center)
Average volume 90-95 micrometers3 At ~100fL
each, they pack ~ 33pgr of hemoglobin each Abundant
membranes allows deformation to squeeze through capillaries
No nucleus
Remember the number 7.7
Like a deflated ballon lot of membrane not a lot of content
Brings haem closer to surface optimise gas exchange
Abundant membrane means it is flexible
Can go through capillaries thinner than its size no problem
If it has nuclear not necessarily mammalian

RBC Count and Indices

Men: 5.2M (� 0.3) / mm3 Women: 4.7M (� 0.3) / mm3
- RBC counts is increased at higher altitudes
- RBC counts is decreased in anemias (~10% less hemoglobin
than normal)

Red Blood Cells (Erythrocytes)

Carry hemoglobin, which carries O2 to the tissues
Contain carbonic anhydrase, which catalyzes the reaction:
CO2 + H2O -> H2CO3
- allows large amounts of CO2 to be carried in solution as HCO3-
Hemoglobin is an excellent acid-base buffer

Hemoglobin and Hematocrit

Normal hemoglobin concentration is 34gr per 100 ml of packed
cells Normal hematocrit (�packed cell volume�) is 40-45%
(slightly lower in women) Thus normal hemoglobin is 14-15 g
per 100 ml of blood (34 X 0.42 = 14)
O 2 carrying
capacity is 1.34 mL /gr Hgb, or 19-20 mL O2 / 100 ml blood
(15 X 1.34 = 20)
Try to remember these numbers
10% less than 34 around 30 is called anemia
Remember anemia

Sites of Erythropoiesis

First few weeks of gestation � yolk sac Mid-trimester
� Liver (+ spleen, lymph nodes) Last month of gestation
through adulthood � Bone marrow
Where the RBC are generally made
1st 7 years made everywhere
Tibia and femur stop making it


Pluripotent hematopoietic stem cells give rise
sequentially to committed stem cells and mature cells
Driven by Growth inducers (factors; e.g.
interleukin-3) Differentiation inducers
Hematopoiesis responds to changing conditions Hypoxia:
erythropoiesis Infection / inflammation: WBC production
Diff tells cell type what it should become then growth
stimulates the multiplication and cell division of these
White cells respond mostly to infection

Blood Cell Lineages

All cells made in bone marrow of different bones
Don�t need to know schematic
Pluripotent in bone marrow make the lineage


Basophilic in the beginning stained shows golgi and er contains lot
of protein tends to stain in basophilic way
Lose all components apart from cytoplasmic enzymes and reticulocytes
-Have a little bit of ER, pretty rare to find
-Once mature reticulocytes they enter from bone marrow to
circulation through the fenestrated capillaries

Regulation of Red Cell Mass

Red blood cell mass is regulated within a narrow range to:
Maintain adequate oxygen carrying capacity Avoid
excessive blood viscosity
Demand for erythropoiesis (altitude, anemia, lung
disease) in increased, or � bone marrow is
damaged (Chemotherapy, radiations) ->
More bone marrow will become hyperplastic, -> If
extreme, extramedullary hematopoiesis may

Tissue O 2 and Erythropoietin

Key to stimulate bone marrow to make more red blood cells

Erythropoietin (EPO)

Circulating hormone Glycoprotein, MW 34,000Da
(fibroblast cells in kidney) ~90% express by kidney
(adult), some by liver (fetal, perinatal) Expressed by
fibroblast-like interstitial cells Typical levels = 10
mU/mL (up to 10,000 mU/mL) in severe anemias recombinant
human erythropoietin (rhEPO) can be used as therapy
(anemias, kidney disease) As doping agent to increase
endurance (cycling, etc.)

Erythropoietin bound to its receptor

Used to identify interactions and necessary functions

Response to Hypoxia

Erythropoietin is expressed within minutes to hours after low
oxygen (e.g.altitude) ~ 5 days before new circulating
reticulocytes are identified Erythropoietin�
drives production of proerythroblasts from HSCs
accelerates their maturation into RBCs Can increase RBC
production up to 10-fold Erythropoietin remains high until
normal tissue oxygenation is restored.
Accelerates maturation
Half life of a few days until normal oxygenation is reached

RBC Senescence & Destruction

RBC life span is ~120 days (remember) Though lacking a
nucleus, mitochondria, and endoplasmic reticulum, RBCs have enzymes
that can metabolize glucose and make small amounts of ATP. These
enzymes� Maintain membrane pliability Support ion
transport Keep iron in the ferrous form (rather than
ferric) Inhibit protein oxidation As enzymes deplete
with age, RBCs become fragile and rupture in small passages, often
in the spleen spaces between the structural trabeculae of
the red pulp, are only 3 micrometers wide
Membrane will become weaker and easier to rupture
Loss of elasticity means they can burst in thin capillaries

Formation of Hemoglobin

Occurs from proerythroblast through reticulocyte stage
Reticulocytes retain a small amount of endoplasmic reticulum and
mRNA, supporting continued hemoglobin synthesis Two
distinct globin chains (each with its individual heme molecule)
combine to form hemoglobin

Types of Globin Chains

Several types of globin chains resulting from gene duplication
� ?, ?, ?, ?; MW ~ 16,000 Predominant form in adults is
Hemoglobin A, with 2 ? and 2 ? chains; MW 64,458

Hemoglobin Structural Units

Each globin chain is associated with one heme group containing
one atom of iron Each of the four iron atoms can bind
loosely with one molecule (2 atoms) of oxygen
Thus each hemoglobin molecule can transport 8 oxygen

Oxygen Binding to Hemoglobin

Must be loosely bound � binding in higher O2 concentration,
releasing in lower concentration Binds loosely with one of
the coordination bonds of iron Carried as molecular oxygen
(not as ionic oxygen) Easily exchange in tissues,
myoglobin, fetal hemoglobin Binding of O2 to HB shows
positive cooperativity
When rbc reach tissues will exchange with myoglobin which
has higher affinity or fetal haemoglobin both of these have higher
affinity than haemoglobin a

Cooperativity of HG

Deoxy-hemoglobin (no oxygen attached) has low affinity
for oxygen When the first O2
binds to the first heme, the oxygen affinity
increases, The second O2 to bind more easily, and the third
and fourth even more easily. (Because of resulting conformational
change). The oxygen affinity of 3-oxy-hemoglobin is ~300
times greater than that of deoxy-hemoglobin. This behavior
leads the affinity curve of hemoglobin to be sigmoidal, rather than
hyperbolic The same cooperativity allows hemoglobin to
lose oxygen faster as fewer oxygen molecules are
More oxygen in haemoglobin then greater affinity
This is inverse in unloading oxygen in tissues

Iron Metabolism

Iron is a key component of hemoglobin, myoglobin, and other
enzymes (cytochromes, peroxidase, catalase, etc.) Thus iron
stores are critically regulated Absorbed through the small
intestine, binds in plasma to apotransferrin , to
form transferrin and carried around Released
to various tissues and reticuloendothelial cells
of the bone marrow (HG) Total body iron ~ 4 � 5 g
65% in hemoglobin 4% in myoglobin 1% in
intracellular heme compounds 0.1% associated with
circulating transferrin 15 � 30% stored mainly as
ferritin in RES
Apo means only or alone or not loaded
Enzyme without any cofactors or binding molecules

Iron Balance

Stored in cells cytoplasm, by apoferritin (460kDa) to form
ferritin. Maximal absorption of a few mg per day, modulated
over 5 � 6-fold range based on body stores Daily iron loss
of ~ 0.6 mg/day in men (GI) or ~1.3 mg/day in women (GI and
menses) With an average life span of ~120 days, red cells are
destroyed in the spleen and in liver
Apoferretin without iron, ferritin with iron
Can aquire and loose iron especially through intestine or
through blood loss

Life of the RBC

With an average life span of ~120 days, red cells are destroyed
in the spleen and in liver Cell membrane becomes fragile
(no nucleus) and in narrow capillaries (3micron) of the red pulp of
the spleen they rupture. Hemoglobin is phagocytized by
Kupffer cells of the liver and macrophages of the spleen and bone

Degradation of Hemoglobin

Iron is released back to transferrin in the blood to support
erythropoiesis or be stored as ferritin Macrophages convert
the porphyrin portion, stepwise, into bilirubin, which is released
into the blood and secreted by the liver into the bile
Turning color of the bruise!


deficiency (10% or more) of hemoglobin in the
blood 1) Too few RBCs (with
normal amount of haemoglobin) 2) Too little hemoglobin
in the cells

Circulatory Effects of Anemia

- Decreased blood viscosity � more return
- Decreased O2 - carrying capacity
Increased cardiac output (BPM)
Feeling tired, shortness of breath, Rapid
HR, decreased exercise capacity Pale skin and mucosae
Viscosity goes with circulating cell amount
Lower cell amount decreases viscosity and leads to
decreased oxygen carrying capacity
So the heart beats faster to counteract it

Loss of blood

Any acute or chronic hemorrhage In the first few
hours blood volume is restored (drinking or
I.V.) In the next few days plasma is
restores = proteins and ion, nutrients, etc. First
reticulocytes appear In the next few
weeks RBC are normal count
Chronic blood loss can lead to iron deficiency, with
hypochromic, microcytic anemia.
Hypochromic not as coloured red cells
Microcytic smaller than normal RBC

Vitamin B 12 and Folic Acid

Vitamin B 12 and
folate are needed to make thymidine triphosphate (thus,
DNA) RBC are among the rapidly reproducing cells � affected
by lack of these vitamins
Deficiency of Vitamin B 12
- From animal products, dietary deficiency
in strict vegans
- Atrophic gastric mucosa � no intrinsic factor
� no B12
- Causes pernicious anemia

Deficiency of Folic acid
-Folic acid is present in green
vegetables, some fruits, and meats
-Destroyed by cooking

Megaloblastic Anemia B12 and folate deficiency

Formation of large, fragile,
misshapen cells, which rupture
easily Hyper-segmented neutrophils (nucleous)
Megaloblastic different shape, size some reticulocytes and
are very fragile due to weakended cell wall
Neutrophils � typically have nucleus composed by 2 - 4
parts and in this case hypersegmented this one has 7 - 9 different
blobs of dna making a single nucleus

Aplastic Anemia (aplastic =
failure to develop)

Bone marrow failure Radiation
Chemotherapy Chemical toxins Auto-immune
Idiopathic (unknown) Loss of RBCs
but also white cells and
platelets Supported by
transfusions or treated by bone marrow

Hemolytic Anemia

Normal RBC number but very fragile, short
Hereditary condition causing fragility
- Hereditary spherocytosis (spheroidal
cells, jaundice, splenomegaly).
splenomegaly: enlargement of the spleen
- up to 5 genes, of proteins that allow for cell flexibility
- 50% cases arise form mutation in ankyrin-1 (ANK1)

Immune-mediated destruction
- Erythroblastosis fetalis
- Rh-positive RBCs in the fetus are attacked by antibodies
from an Rh-negative mother (when fetal and maternal blood come in contact)
Genetic disease
Low cell count, jaundis
-Red cell destroyed in the spleen more hemoglobin being
metabolised colour of skin goes yellow
-Splenomegaly because the spleen is busy destroying those RBC
-RBC more spherical than usual disk shape

Sickle cell anemia

0.3 to 1% of west African (and African American)
Sickle hemoglobin: hemoglobin S
Glutamic acid 6 to Valine (E6V)
- Single point mutation ^
Homo- or heterozygote (one or both alleles)
Hemoglobin of homozygous individuals (�VV�)
forms elongated crystals when exposed to low
-> hemolysis, vascular occlusion
-> death
IF homo than two Valine than two glutamic acids
If exposed to low oxygen, haemoglobin will start to
aggregate forming needles that destroy the RBC

Sickle cell anemia protects from Malaria

Homozygous deadly
Cells clump together and form embolism that can cause issues
Advantage of the heterozygote

Polycythemia (More cells than normal)

Secondary (RBC + ~30%; 6-7 million/mm3)
- Chronic hypoxemia (heart or lung disease)
- Physiologic polycythemia

- Living at 4000 - 5,000m (Andes, Himalayas)
- Markedly enhanced exercise capacity at altitude
Polycythemia Vera (primary,
uncommon, slow cancer) Clonal abnormality causing
excessive proliferation Usually all lineages (white cells
and platelets) 7- 8 million RBCs / mm3; Hematocrit
Not as bad
More rbc in higher altitudes because they need more oxygen
Mutation increasing wbc and rbc
Almost twice as many cells as normal

Polycythemia & Circulation

Hyper-viscosity, up to 3-fold normal (10 x
water) Heart attack or stroke, clotting,
Increased viscosity decreases venous return
The venous plexus under the skin becomes engorged with
slow-moving, de-saturated blood, producing a ruddy complexion with a
bluish tint to the skin
Clotting is more common, heart attack and stroke
Splenomegaly means the spleen has to work harder to destroy rbc
Edema also common
Rare but pretty dangerous

Hemostasis: Prevention of Blood Loss

Vascular constriction (not in capillary) Formation of
a platelet plug Formation of a blood clot Healing
of vascular damage + re-canalization
Synonymous of clotting
Basement membrane rich in collagen, 50% by endothelial rest
by fibroblast connective tissue around capillary
Vascular spasm followed by platelet plugs that grab to the collagen

Vascular Constriction after damage

Myogenic spasm (cut vs crush) arterioles and veins
Local autocoid* factors from damaged tissues and platelets, will
help the constriction Nervous reflexes (Arterioles,
venules), same Smaller vessels: thromboxane A2 released by
platelets Formation of platelets
Autacoid = fancy name for local factor or
hormone not named or not identified
Crush of the veins and arteries make a lot more collagen
and cells die around injury will make more vascular constriction
Clean wont stop the blood flow
During crush a lot more tissue damage around the vessels in
a way helpful for repair faster haemostasis

Platelets (Thrombocytes)

1- 4 �m discs Released by fragmentation of
megakaryocytes 150-300,000 per �L Half-life in blood
of 8-12 days
Platelets also called thrombo help stopping blod
Small fragments, come from fragmentation of megakaryocytes
- live in the bone marrow come from lineage
Blast means precursor cell
Cyte means cells
Megakaryotes will have cytoplasmic extensions from which
plates will come off
Platelet pieces of cytoplasm from megakaryocytes
Platelets smaller than rbc a lot fewer as well

Platelet Properties

Contractile capabilities (clot retraction) actin,
myosin, thrombosthenin Residual ER and Golgi
synthesize enzymes, prostaglandins, fibrin-stabilizing
factor, store Ca++, etc. Still produce some
Repels intact endothelium
Adheres to injured endothelium and exposed collagen
Assume irregular forms, swell
Adhere to collagen
Local platelets aggregate other platelets
Fragments of cytoplasm contain actin myosin proteins that
can contract the platelet

Key Steps in Blood Clotting (after platelet plug)

>50 components affect blood coagulation have been
found in the blood and in the tissues
Some that promote coagulation = procoagulants

Others that inhibit coagulation =
anticoagulants .
Blood clotting happens after platelet plug which doesn�t
stop the flow completely

Clot Formation and Progression

Begins in 15- 20 seconds in severe vascular trauma
Occlusive clot within minutes unless very large
vascular defect 20-60 minutes: Clot retraction 1-
2 weeks Invasion by fibroblasts Restoring of
damaged area Organization into fibrous tissue
Remember this schematic
Fibrinogen is converted to fibrin by thrombin
And thrombin comes from prothrombin
Basic mechanism

Effector Proteins for Clotting

Prothrombin ? 2 globulin, MW 68,700Da;
1.5mg/1mL in plasma Synthesis in liver (continuously)
Cleaved by ProThrombin activator to thrombin,
MW 33,700Da
Fibrinogen MW 340,000Da; 10-70 mg/mL in
plasma Synthesized in the liver (continuously)
Usually intravascular; can extravasate with increased vascular
permeability (inflammation)
Serious liver disease will decrease the bodies coagulation capacity

Key Steps in Blood Clotting (Coagulation)

Final goal is to have cross linked 3d fibrin fibres
Comes from stabilisation of bibrin fibrin fibres individual
Comes from fibrin monomers and help from calcium
Fibrin comes from fibrinogen cleavage
Thrombin cleaves fibrinogen to make it fibrin, also
activates fibrin stabilising factor which will cross link fibrin fibers
Thrombin doesn�t circulate as thrombin
Circulates as prothrombin which needs PT activator
something that cleaves it to make it active
Calcium is always necessary to this mechanism
Citric acid is used in the blood test tube to stop coagualtion

Fibrin Production

Thrombin (weak protease) cleaves four small peptides from
� fibrin monomer � spontaneous polymerization

Long fibers form clot reticulum
Fibrin stabilizing factor (Factor XIII)
Activated by thrombin
Covalent cross-linking of fibrin monomers
Clot is composed of a meshwork of fibrin fibers running in
all directions and entrapping blood cells, platelets, and plasma
Fibrinogen becomes monomer that triggers spontaneous fibrin polymerisation
Forming long fibres stabilised by cross linking fibrin monomers

Fibrin Production

Clot Retraction

Platelets bind to multiple fibrin fibers contract via
actin, myosin,
thrombosthenin Begins within 20-60
minutes Platelets release more fibrin-stabilizing factor
(XIII) Clot tightens, expressing serum, and closing the
vascular defect � stiches!
Serum is the plasma minus fibrinogen and thrombin

How do you stop coagulation from diffusing away?

Fibrin fibers bind 85-90% of thrombin and
localize it to the clot -> stopping diffusion of
clotting Antithrombin III (protease inhibitor) combines
with the remainder thrombin and inactivates it over 12-20 minutes
-> stopping diffusion of clotting

Disseminated Intravascular Coagulation (DIC)

Occurs in the setting of massive tissue damage or sepsis
Wide-spread coagulation in small vessels Manifested as
bleeding from multiple sites because of depletion of clotting
factors Catastrophic, deadly
If there is no antithrombin
Massive tissue damage there can be widespread coagulation
which is typically catastrophic
Symptoms is bleeding from multiple points
As the clotting agents have been used so there is bleeding

Clot Lysis

Plasminogen is trapped in the clot Over several days,
injured tissues release tissue plasminogen activator (tPA)
Plasminogen (inactive form) is activated to plasmin by
plasminogen activator, a protease resembling trypsin
Plasmin digests fibrin fibers and several other clotting
factors Often results in re-opening millions of small
repaired blood vessels

Clinically Useful Anticoagulants

Heparin Works rapidly, generally used
acutely Degraded in hours by Heparinase
Coumarins Deplete active vitamin K ?
deplete active prothrombin, factors VII, IX, X Slower
acting (days); used chronically

In vitro Anti-coagulation
Siliconized containers prevent activation of factor VII and platelets
Heparin � used in blood collection, heart-lung and kidney machines
Calcium chelators (citrate, EDTA) used in blood collection,
blood storage

Causes of Excessive Bleeding

Severe hepatic disease � no pro-thrombin or
fibrinogen, or the other 50 factors! Vitamin K
deficiency Hemophilia (Deficiency of factor VIII or IX)
Low platelet count (thrombocytopenia)
All coagulation factors made in the liver

Vitamin K

Produced by the intestinal bacteria � always there!
Essential to carboxylate glutamic acid in five
important clotting factors: prothrombin and factors VII,
IX, X, and protein C
Fat-soluble: malabsorption of fats can lead to
deficiency (lack of bile production)
Warfarin (blocks recycle of Vit K � used as rat
poison and now blood thinner


Hemophilia A � Deficiency of factor VIII 85% of
hemophilia cases 1 / 10,000 males Hemophilia B �
Deficiency of factor IX 15% of cases About 1 /
60,000 males Both genes are on the X chromosome -> males
only get one copy -> severe sympthoms Clinically:
Bleeding after minor trauma, large bruises, pain & swelling of
joints, nosebleeds, blood in the urine, etc.


Low numbers of platelets Bleeding from small venules
or capillaries Petechaiae, thrombocytopenic
purpura Often idiopathic (no known cause)
< 50,000 platelets / �L � usually modest bleeding
< 10,000 platelets / �L � life-threatening
Treated with blood (platelet) infusions
Splenectomy in autoimmune forms


Purpose of Respiratory System

exchange O 2 and remove
CO 2
We�ll discuss: Some anatomy
and histology of respiratory system
Mechanics of ventilation

Anatomy of the respiratory system

Upper respiratory ways Bronchial tree 2 lungs
(with the alveolae) Pulmonary vein and arteries
Capillaries Innervation both sympathetic, and
parasympathetic (vagus)

Upper respiratory tract

Nose: the air is 1) warmed, 2) humidified, 3)
primary filter for large particles, dust, pollen, etc. By
turbulent precipitation large
particles (>6micron) stick to mucus,
removed by cilia in upper respiratory tract.
Particles <1micron reach the walls of the
alveoli and adhere to the alveolar fluid (cigarette
smoke, viruses)

Upper respiratory tract

Mucus and Cilia

Cigarette smoke particles ~0.3micron. Almost all
reach the alveoli, removed by alveolar macrophages (dust cells)
Non-respiratory epithelium is kept moist by
goblet cells � mucus Covered with
ciliated epithelium (~200 cilia/cell)

Beating of the cilia is always toward the
pharynx Eventually solid particles are swallowed or

Cough and sneeze

Slight amounts of foreign matters in bronchi and trachea,
irritate and initiate the cough reflex
Cough reflex: ~2-3 L of air are rapidly
inspired. Epiglottis and the vocal cords close
Abdominal muscles (and all other expiratory
muscle) contract forcefully. The pressure in the lungs
rises rapidly to >100mmHg. Vocal cords and the
epiglottis suddenly open widely, Air is expelled at
velocities <120kph
Sneeze is similar reflex expect that: 1) it starts
when the upper respiratory components are irritated, 2) uvula is
depressed, air passes rapidly through the nose

Trachea, Bronchi, and Bronchioles

Multiple C-shaped rings of hyaline
cartilage keep the trachea OPEN
(not collapsing) Cartilage decreases in the bronchi and
disappear in the bronchioles (<1.5mm in diameter) Where
no cartilage plates are present, the walls are composed mainly of
smooth muscle Bronchioles are almost entirely smooth
muscle, Bronchioles become respiratory bronchioles (only a
few muscle fibers)

Cell Types in Alveoli

Alveoli Epithelial Cells Type 1 cells (epithelial
proper) Type II cells (Clara cells) (surfactant)
Capillary Endothelial Cells Fibroblasts
Macrophages Mast Cells
Type 1 make the inside surface of the alveoli
Type 2 stick out from the alveoli, secrete surfacant
Basement membrane with endothelial cells
-Made by fibroblasts

Structure of the Alveoli

Type 2 pneumocyte
-Foaming cytoplasm produce surfacant
-Each arm composed of two layers of endothelial cells and in
between there are capillaries
-Right is cross section of lung
-Bronchiole open into alveolar duct

Structures in the pulmonary system

Structure anatomy of pulmonary system
Epithelium is only down with alveoli
-Thick to thin
-Has to be gradient goblet and ciliated go
together in upper layers and structure of resp tree
-Goblet cells replace by clara cells

Anatomy of the Respiratory System

Pleural membrane: 2 membranes of connective tissue
between rib cage and lung
Serous fluid between lung, pleura, ribs. Provides
lubrication allows lung to move along pleura.
Together, pleura and fluid provide suction to keep the lungs
open. Lungs have no �ligaments�:
they remain open and in place by the negative pressure provided by
the serous fluid between the pleural membranes.
Lymphatics ensure slight negative pressure to keep
everything in place


Piercing of the pleural cavity causes air to enter the space, loss of
negative pressure, collapsed lung

Spontaneous pneumothorax:
collapsed lung without any apparent cause, such as a traumatic
injury to the chest or a known lung disease.
Most times, a small rupture of the lung ruptures, causing the
air to leak into the pleura.

Connective tissue disorder, smoking, deep diving or high
altitude can be the cause

Mechanics of the Respiratory System

Lungs surrounded by chest wall:
Bones: Ribs & Sternum
Thoracic vertebrae -> Several muscles
Intercostal muscles (Internal, External),
Diaphragm, sternocleidomastoid, anterior serrati, scalene, abdominals

Mechanics of Respiration
inspiration at rest

Muscles of Respiration
Mainly diaphragm
Abdominals help with expiration

Mechanics of Respiration
inspiration under effort

Muscles of Respiration
Diaphragm, sternocleidomastoid, anterior serrati, scaleni, abdominals

Mechanics of Respiration expiration

Resting -> Passive process, mostly elasticity
of the lungs and rib cage Expiration Effort
-> muscle driven -> abdominal and internal intercostals
Muscles that elevate the chest cage are classified as
inspiratory, Muscles that depress the chest cage are classified as

Movement of Air in and Out of Lungs

Compliance of the lungs

The extent to which the lungs will expand for each unit
increase in transpulmonary pressure

200 ml/cm H 2 0
(lungs alone, no rib cage)
(1 cm H20 ~ 0.7 mmHg)

110 ml/cm H 2 0
(lungs alone, + rib cage)
Resistance to inflation grows to a maximum as the cage expands
Determined by elastic forces Lung tissue
(elastin and collagen) Surface tension
(fluid-air) due to the presence of SURFACTANT

Compliance of the lungs

Work of the inspiration can be divided into three fractions:
(1) to expand the lungs against the lung and chest
elastic forces = compliance or elastic work;
(2) to overcome the surface tension of the
lung = tissue resistance work;
(3) to overcome airway resistance to movement of air
= airway resistance work
During quiet respiration, 3 to 5 percent of
the total body energy is required for pulmonary ventilation.
During heavy exercise, the amount of energy
required can increase many fold � sustainable for few minutes

Surface tension

Attraction of water molecules at air-water interface
Will result in collapse of alveoli Prevented by
surfactant Secreted by type II (Clara) cells in the
lungs Detergent-like substance -> Interferes with
hydrogen-bonding between H2O molecules Reduces surface
tension at the alveolar � air interface -> alveolae remain open
& reduces effort required by the respiratory muscles to expand
the lungs.

Pulmonary Surfactant

Several phospholipids, proteins, and ions. Especially by
dipalmitoyl phosphatidylcholine, surfactant
apoproteins , and
calcium ions .
Surface tension in the alveoli is inversely affected by the
radius of the alveolus -> the smaller the
alveolus, the more difficult is to keep it open
Small premature babies, have small alveoli (25% size adult)
Surfactant secretion starts between the 6th and 8th months of gestation.
= Small alveoli + no surfactant -> collapse ->
respiratory distress syndrome of the newborn.

Lung Volumes = spirometry

Pulmonary Volumes

Volumes vs Capacity
Pulmonary volumes are the individual volumes
Pulmonary capacities are the sum of
individual volumes

Inspiratory Capacity (IC)

IC: the maximum amount of air that can be
inspired following a normal expiration

Vital Capacity (VC)

VC: the maximum amount of air that can be
expired following a maximal inspiration

Functional Residual Capacity (FRC)

FRC: the amount of air remaining in the lungs
following a normal expiration.

Total Lung Capacity (TLC)

TLC: the amount of air in the lungs at the end of a maximal inspiration.

Minute Ventilation

Minute ventilation: Total amount of air moved in and
out of respiratory system per minute Respiratory
rate or frequency: Number of breaths taken per
minute At rest: ~12 breaths X 0.5L each =
6L/min Up to: ~45 breaths X 4.5L each =

Dead space

Dead space: Part of respiratory system where gas
exchange does not take place
Typically anatomical = physiological dead space
in healthy individual

Alveolar Ventilation

Alveolar ventilation: How much air per minute enters the parts
of the respiratory system in which gas exchange takes place
At rest: ~12 breaths X 0.5L each = 6L/min Because of
the dead space: At rest: ~12 breaths X 0.35L each =

Control of Bronchiolar Diameter

Nervous ( weak) Sympathetic b2
receptors -> relax and dilate � run! Parasympathetic
(irritation by gas, infection, smoke etc.) Acetylcholine
-> constrict Humoral (
significant) Histamine (mast cells),
slow reactive substance of anaphylaxis ->
Constrict norepinephrine and epinephrine (b agonists) ->
relax and dilate � run!

Common diseases

Pneumonia:. Fever, cough, chest pain, difficulty
breathing, etc,
Causes: infection of the alveoli caused by
bacteria, viruses, or fungi
Therapy: Antibiotics

Emphysema is a lung condition that causes shortness
of breath.
Causes: heavy smoking and pollution, genetics
(alpha-1-antitrypsin deficiency) Inner walls of
the alveoli weaken and rupture -> larger air spaces ->
lower overall surface During expiration, big alveoli don't
work properly and old air remains in, leaving no room for fresh,
oxygen-rich air to enter.

Pulmonary circulation

Trachea, bronchi, receive systemic circulation
(high O2 and high pressure) Lungs, pulmonary circulation
(high CO2 and low pressure) Pulmonary circulation: Very
short Divides into left/right branches Thinner wall than aorta (1/3)
Large diameter Large lymphatic network


Blood volume in the pulmonary circulation
~ 450 mL (~9% total blood volume) ~70mL are in the
capillary bed The higher the systemic
return, the higher the flow in the pulmonary
circulation Left circulation is 9X larger,
large effects on right side
Left heart failure (e.g. aortic stenosis) can back
up blood into the pulmonary circulation ->
pulmonary edema Increase in left atrial
pressure >30mmHg -> engorge pulmonary capillaries No
surrounding tissue -> alveolar capillaries are delicate,

Blood Pressure Profile in the Circulatory System



Hydrostatic Effects on Blood Flow

Pulmonary Edema

Fluid accumulation in pulmonary interstitial space -> around capillaries

1.Increase in pulmonary venous and capillary
pressure (left sided heart failure, mitral valve stenosis) ?
outward ^ force -> more dead space

2. Increased capillary membrane permeability (damage
to associated with infections, noxious gases (chlorine, sulfur dioxide).
3.Decrease in plasma osmotic pressure (liver
failure). � inward force

4. High-altitude pulmonary edema (HAPE)
pulmonary hypertentsion

Symptoms: acute edema
Extreme shortness of breath � feeling of suffocation
Wheezing, cough, tachycardia Cold, sweaty skin, blueish
lips, etc.

Pleural Effusion

Chronic excessive fluid production ->

collection of fluid in pleural space. Caused by lymphatic
obstruction (tumor), heart failure, reduced plasma osmotic
pressure, infection/inflammation of capillary membranes causing
increased permeability

Physical principles
driving gas exchange

Diffusion to concentration gradient &
partial pressure of gas. Normal air
composition: Nitrogen ~79%, Oxygen
~21%, CO2, helium, etc. <1%
Solubility & MW of the gas: for example, CO2 20
times as soluble as O2 (more polar than O2) The
cross-sectional area of the fluid (direct) &
the distance through which the gas must diffuse
(inverse) Solubility is inverse of the temperature

Physical Principles of Gas Exchange

O2 and CO2 are highly soluble in
lipids -> are highly soluble in cell membranes

Diffusion through the tissues almost equal to
the diffusion of gases in water

Respiratory Unit (where the gas
exchange occurs)

Cross-sectional view of alveolar walls and their vascular supply.

Diffusion of gas through the respiratory membrane.

Note the diffusion barriers present:
Alveolar epithelium (pneumocyte I)
Epithelial basement membrane
Interstitial space
Capillary basement membrane
Capillary endothelium
Capillaries here are ~5micron diameter
Red cells 7.7 micron diameter -> Not much plasma to dilute gas
Mean filtration pressure ~+1mmHg -> slow
outward flow -> compensated by lymphatics
Some fluid is removed by evaporation

Factors that determine gas
exchange in vivo

1)The thickness (Distance) of
the membrane(s) = 0.2-0.6micron, but edema, fibrosis,
inflammation, etc. may change it = worse
2)The surface area of the
membrane, (70m2) but emphysema will decrease it = worse
3)The partial pressure
difference of the gas between the two sides of the membrane.
4)Solubility of the gas (Fixed, CO2 is ~20X
more soluble than O2)
5)MW of the gas, body
temperature (Both fixed)

Exchange of Oxygen in Lungs

In a healthy lung, O 2
and CO2 diffuse rapidly enough so RBC has plenty of time
to take up/saturate with O2.

20 breaths/min = 1 each 3 secs

Uptake of Oxygen in Lungs

A small degree of anatomical shunt in the bronchial
circulation -> some venous blood is
not exposed to lung air Goes back directly to
left ventricle (~2%) is poorly oxygenated When this
�shunt� blood mixes with the oxygenated blood from the alveolar
capillaries, the PO2 fall to about 95 mmHg.

Diffusion of O2 and CO2 at the Tissue

The normal intracellular PO2 ranges from 5 mm Hg to 40
mm Hg.
Average ~ 23 mm Hg Only 1-3 mm Hg
of O2 pressure is required for full support cell
life. Intracellular PO2 of 23 mm Hg provides a large safety
The normal intracellular PCO2 ranges from 45 to 46mm

CO2 transport

Regulation of Respiration

The ultimate goal of respiration is to maintain proper concentrations
of O 2 , CO 2 , and H+ ions in the tissues.
Basic rhythm in the respiratory center in the
brain stem - automatic Central
�integrate signals
�gather information
�Muscles (more breathing)

Central regulation of Respiration

Ventilation is normally involuntary and automatic, but can be overridden

Yawning, laughing, sighing, talking, whistling, burping,
vomiting, sneezing, straining, etc.

Central regulation of Respiration

Dorsal respiratory group initiate inspiration
(ramp fashion -2 secs on, 3 secs off). Slow
inspiration and no gasp
Pneumotaxic center controls the
�switch-off� point of the inspiratory ramp � limit
inspiration time � increase rate
Ventral respiratory group of
neurons causes powerful expiratory signals to the abdominal muscles
during very heavy expiration

Lung receptors

Stretch Receptors � communicate to pneumotaxic center
�Located in smooth muscle of large and small airways
�Minimize work of breathing by inhibiting large tidal volumes:
trigger Hering -Breuer reflex
� inhibition at large or fast inflation
�Protective effect on lungs
J receptors (juxtaposition to the pulmonary
�Located alveolar wall, interstitium
�Stimulation causes rapid shallow breathing (tachypnea)
�Lung disease and edema (pulmonary congestion)

Other Reflexes

Arterial Chemoreceptors Hyperpnea, increased blood
pressure Peripheral mechanoreceptors Muscles of
respiration as well as skeletal muscles, joints and tendons
Adjust ventilation to elevated workloads

Chemical Control of Respiration

Excess CO 2 or excess
hydrogen ions in the blood mainly act directly on the
respiratory center (soluble, passes into CNS freely)
Oxygen, acts almost entirely on peripheral
chemoreceptors located in the carotid and
aortic bodies

Chemoreceptors and Control of Respiration


Carotid body-bifurcation of the carotids
� responds to oxygen (greatest Po2<100 mmHg)
� responds to carbon dioxide and hydrogen ion
� less powerful but more rapid than central stimulation

Respiration During Exercise

Increase in respiration results from signals
transmitted directly to the respiratory center at the same
time that signals go to the body muscles to cause muscle
contraction. It appears that anticipatory increase is a �learned� response
O2, CO2, and hydrogen ion concentrations control final
adjustment of respiration

Other Factors to Influence Respiration

Sleep apnea, 10 seconds of apnea 300 -
500 times each night. Older obese people
Surgery to remove excess tissue/fat
(uvulo-palato-pharyngo- plasty )
nasal ventilation with continuous positive
airway pressure (CPAP)
Overdosage with anesthetics or narcotics.
Brain edema
Periodic breathing in several disease (Cheyne-Stokes
breathing, etc.). Often at the end of life


General function of GI system

Provide the body with supply of water, electrolytes, vitamins,
and nutrients
Introduction of the food and water & movement through
the alimentary tract; Digestion of the food by mixing with
digestive juices Absorption of water and various digestive
products including electrolytes, vitamins, etc. Circulate
the absorbed substances by a specific anatomical arrangement of the
intestine-liver complex Controls of all these functions by
local, nervous, and hormonal systems.

Alimentary Tract

Autonomic Nervous System Parasympathetic Division

Parasympathetic fibers leave cranial nerves III, VII, IX,
and X & Sacral nerves
About 75 percent of all parasympathetic nerve fibers are in the
2 vagi (X) nerves
Pre- and post ganglionic fibers: the
preganglionic neurons are very long; the
postganglionic neurons are short and located in the
wall of the organ (except for the head).

Autonomic Nervous System Sympathetic Division

Pre-ganglionic neuron -> 2 paravertebral
sympathetic chains of ganglia Series of
visceral ganglia (Celiac, superior
and inferior mesenteric)
Post-ganglionic neurons, from ganglia to organs

Characteristics of Sympathetic and Parasympathetic Function


Preganglionic efferent neurons - acetylcholine
Postganglionic efferent neurons
-Parasympathetic NS � acetylcholine - excitatory
-Sympathetic NS � norepinephrine - Inhibitory
Enteric nervous system
-Excitatory - acetylcholine, substance P, serotonin
-Inhibitory - VIP, NO, many others

Typical cross section of the gut wall

1.Overall outer layer (Serosa, mesothelium)
2.Muscle layers (2)
3.Connective tissue (submucosa)
5.Lumen of the organ (where food-bolus-chyme-feces is)

Typical cross section of the gut wall

Typical cross section of the gut wall

Gastrointestinal Smooth Muscle

2 layers: longitudinal outside,
circular underneath Smooth muscle fibers:
200 to 500 micrometers in length and 2 to 10 micrometers in
diameter, arranged in bundles of hundreds to
thousands Fibers are interconnected with many gap
junctions -> syncytium
Connections are fiber-to-fiber and
bundle-to-bundle -> branching lattice of smooth
muscle bundles
Stimulus generated in one muscle fiber can be
transmitted to many Muscle contractions
spread few mm to many cm and beyond
Gastrointestinal tract, bile ducts, ureters, uterus, and many
blood vessels
Connections exist between the
longitudinal and circular layers as well

Special features of smooth muscle

Smooth muscle:
Can operate over large range of lengths (60 - 75%
shortening possible) Is very energy efficient
(O 2 consumption is ~ 1 % of same weight of
skeletal muscle at same tension!) Can maintain
force for long periods (hours, days, weeks) Stimulus cab
be myogenic (spontaneously active)
Strength equivalent to that of skeletal muscle
Stress-relaxation and reverse stress-relaxation.
Always maintains the right pressure Activated by endocrine,
paracrine, CNS, PNS stimuli

Slow waves and Spike Potentials

Muscle layers are excited by almost continual
slow, intrinsic electrical activity 2 basic types:
slow waves and (2)
spikes , In addition, voltage
of the resting membrane potential of the smooth muscle can change
to different levels

Slow Waves

Rhythmical changes in membrane potential caused by
variations in sodium conductance � not real action potential

-Rate of 3-12/min depending on tract and status
-Originate from pacemaker cells - Interstitial cells of
-Cajal cells located between the 2 muscle layers

Variable amplitude
-Affected by nervous / hormonal stimuli
-Promote the appearance of intermittent spike potentials,
-The spike potentials underly the muscle contraction.

Spike Potentials

True action potentials -> smooth muscle
-When slow waves reach threshold (-40 mV)
-The higher the slow wave potential rises, the greater the
frequency of the spike potentials,

Voltage dependent Ca ++
-Ca++ channels opening � contraction (Na+ in neurons)
-Ca++ entry necessary for contraction

-The spike potentials last 10-20ms,
significantly longer than potential in
nerve fibers (<1ms)

Depolarization and hyperpolarization

Normal resting conditions, membrane potential ~-56 millivolts,

depolarization of the membrane, the
muscle fibers become more excitable. 1)
stretching of the muscle, (2)
stimulation by acetylcholine released
from the endings of parasympathetic nerves, and
(3) stimulation by several specific gastrointestinal
hormones .
hyperpolarization , the fibers
become less excitable. 1) Effect of
norepinephrine or
2) sympathetic nerves or local

Neural Control of GI Tract

Extrinsic Control - Autonomic nervous system
-Parasympathetic - mainly stimulates (Ach)
-Sympathetic - mainly inhibits (NE)

Intrinsic Control - Enteric nervous system
-Myenteric (Auerbach�s) plexus
-Submucosal (Meissner�s) plexus

500 Million neurons (Spinal cord only 100M)
Controls movement and secretion

Enteric Nervous System (ENS)

Location - gut wall from esophagus to anus Composition
- cell bodies, axons, dendrites Innervation - gut cells,
sensory nerves, other neurons Integration - can occur
entirely within ENS
- can function in concert with ANS
Transmitters - many excitatory and inhibitory

Enteric Nervous System
Location and connectivity


Enteric Nervous System
Myenteric Plexus Auerbach�s

Function - controls
local GI motility
-Stimulatory influences -
Increase tonic contraction (tone) Increase
contraction frequency / intensity (? propulsion)
-Inhibitory influences
Secretes VIP (vasoactive intestinal
polypeptide) Decreased Sphincter tone (relax) -
pyloric sphincter, ileocecal sphincter, etc. � food

Enteric Nervous System
Submucosal Plexus

Location - Mucosal layer from esophagus to
Function � local control
Glandular Secretion Absorption Contraction of
muscularis mucosa

Sensory Afferent Neurons

Cell bodies in the gut or DRGs
Stimulation of afferent neurons
-Distention of gut wall
-Non-specific irritation of gut mucosa
-Specific chemical stimuli (fat, acid, etc.)

Response - can excite or inhibit
-Intestinal movements
-Intestinal secretions

Gastrointestinal Reflexes

Local (within Enteric Nervous System)
-Afferent fibers from gut terminate in ENS
-Affect (+ or -) secretion, peristalsis, mixing movements
GI � �Long loop�
-Section A Gut -> prevertebral ganglia ->
Section B gut
-Gastro-colic -> Activate colon evacuation
-Entero-gastric -> Inhibit stomach motility/secretion
-Colono -ileal -> I
nhibit emptying of ileal content into the colon

Gastrointestinal Movements

Peristalsis � move the food A contractile
ring appears around the gut and then moves forward Driven
by Myenteric Plexus Peristalsis also
occurs in the bile ducts, glandular ducts, ureters, and many other
smooth muscle tubes of the body

Rhythmic segmentation � mix the food, without
advancing � stationary ring

Propulsive Movements - Peristalsis

Stimuli that initiate peristalsis
-Local distension
-Irritation of gut epithelium
-Parasympathetic nervous system

-�Law of the Gut� -> peristalsis moves downstream
-Myenteric plexus required
-Congenital absence of plexus - no peristalsis
-Atropine (blocks Ach receptors) - (Down) peristalsis

GI (Splanchnic*) Circulation

Organs and Components - GI tract, spleen, pancreas, and
liver Feed Arteries
-Celiac artery - stomach, spleen
-Superior Mesenteric Artery -
Small intestine, pancreas, proximal colon
-Inferior Mesentery Artery �
rest of the colon

Venous drainage (to the liver, in series)
-Portal vein � liver sinusoids � hepatic vein
-Reticuloendothelial cells remove bacteria
-~1/3 nutrients removed and stored in liver

Arterial supply to gut

Stomach: celiac artery
Upper part of intestine: superior
Lower part of the colon: inferior
mesenteric Very muscular arterial walls �
greatly reduce circulation
Villi circulation: highly developed, fenestrated

Hepatic Portal System

Portal circulation: 2 organs in series:
Intestine -> liver
Portal system also used for hypothalamus to anterior
pituitary. ~75% blood that enters the liver is portal
Hepatic portal circulation: all the blood that
passes through the gut, spleen, and
pancreas flows directly into the liver Hepatic
veins -> empty into the inferior vena cava of the general

Intestinal Portal system

Reticuloendothelial cells that line the liver
sinusoids can remove bacteria and other particulate
matter immediately
Nonfat, water-soluble nutrients (e.g. sugars, amino
acids) flow into the lover
Lipids go to the intestinal lymphatics and reach
the systemic circulation by the thoracic duct � bypassing the

Control of Gut Blood Flow

Blood flow proportional to local activity
-Meal causes increase blood flow (2-3 fold) for 3-6 hr

Causes of activity-induced blood flow
-Vasodilator hormones - gastrin, secretin, CCK
-Vasodilator kinins
-Low oxygen (high adenosine)

Nervous control of blood flow
-Parasympathetic - ? gut activity � ? blood flow
-Sympathetic decrease flow and activity
-Also veins constriction increase central return to heart
-shutoff of gastrointestinal and other splanchnic blood flow for
short periods during heavy exercise

Chewing (mastication)

Breaks cells (especially vegetable) - breaks
indigestible cellulose Increases surface
area & decreases particle
size -> key to maximize enzymatic attack
Mixes food with saliva
-Begins digestion of starches (a-amylase, lingual lipase)
-Becomes softer and warmer -> Lubricates for swallowing ->
called bolus
Unchewed meat and vegetables are not digested, but cheese,
fish, eggs do not need to be chewed to be digested Prepares
and stimulate the rest of the GI tract to start
�working� (balance hunger and satiety)

Nervous Control of Chewing

Innervation -
-5th cranial nerve innervates muscles of mastication
-Controlled by nuclei in brain stem

Reflex mechanism � mostly unconscious
-Food in mouth -> muscles of mastication
relax -> jaw drops -> stretch
reflex -> rebound contraction -> pushes food against
lining of mouth -> repeat
-Tongue and cheeks center the
food under the teeth and mix it
-Integrated with brain cortex, reflex and
pattern can be changes (loss of teeth, dental appliances, etc.)
-Start and stop and mostly conscious

Swallowing (deglutition)

Three stages -

Voluntary - initiates swallowing process
Pharyngeal - passage of food through pharynx into
esophagus (involuntary)
Esophageal - passage of food from pharynx to
stomach (involuntary)

Swallowing (deglutition)

Bolus stimulates epithelial swallowing
receptor areas all around the opening of the pharynx
Respiration is stopped The soft
palate is pulled upward to close the posterior nares
The epiglottis and vocal cords are closed.
First 2-3cm of the esophagus, upper esophageal
sphincter relaxes. Peristalsis of the
bolus in the esophagus begins All ends in less than
2 seconds

Esophageal Stage of Swallowing

Primary peristalsis - continuation of pharyngeal
peristalsis � in 5-8 secs the food is in the stomach � done!
Secondary peristalsis � things that are harder to
-Induced by distention - food slow to arrive or
swallowing head down (common to other mammals)
-Repeats until bolus is cleared
Upper esophagus - striated muscle ->
partly voluntary Cannot occur after vagotomy Lower
esophagus - smooth muscle -> completely
involuntary Can occur after vagotomy � Enteric
nervous system

High resting pressures of Esophageal


Disorders of Swallowing (Dysphagia)

Symptoms: Coughing or choking when eating or
drinking; Sensation that food is stuck in your throat or chest
Nervous system disease: stroke, multiple sclerosis,
Amyotrophic lateral sclerosis, etc.
Muscular diseases - myasthenia gravis, polio,
Anesthesia - aspiration of stomach contents.

Gastro-Esophageal Reflux Disease (GERD)
Heartburn/acid indigestion (1/10 people) � Backwash
of acid, pepsin, and bile into esophagus Can lead to:
-Ulcer of the epithelium
-stricture of esophagus (scar tissue)
-Barrett�s esophagus (pre-cancer)

Gastric anatomy

-The top of the stomach touches the diaphragm
-2 sphincters: gastro-esophageal and pylorus
-The walls contain three layers of smooth
muscle: longitudinal, circular, and inner oblique (diagonal)
-The wall has folds that provide more room
during filling
-Divided in fundus, body and antrum or
proximal and distal
-Max volume ~1.5L but 3-4L are not uncommon

Motility of the stomach

2 types of waves: peristalsis (strong) segmentation (weak)
-20% peristaltic � mix and push chyme into duodenum
-80% segmentation � gently mix the chyme
Food is mixed, ground, and liquefied to form the chyme
When no contractions, solid food stays up,
liquid food moves to the pylorus -> duodenum
Bolus now infused with stomach contents and called chyme

Regulation of Gastric Emptying

Driven by signals from stomach (+) and
intestine (+++) Chyme must enter duodenum
at proper rate
Intestinal mucosa receptors - stimulated by
high volume, change in
osmolarity, too much acid,
fat, and protein
Fat/proteins - CCK release
increases gastric distensibility which decreases gastric
Acid - decreases gastric emptying (in 20-40s) via
intrinsic neural reflex when pH <3.5 � 4
Decrease contractions (Pyloric pump) increase
pyloric tone -> decrease gastric emptying

Slow digestion is key to extract all nutrients from food

Migrating Motility Complexes

Only liquids(ish) pass the pyloris What happens to
indigestible solids (rocks, tooth, etc.)
Either pass between meals (Migrating Motor
Complex � a stronger peristaltic pattern)
Purpose - (housekeeping function). Sweeps
undigested residue toward colon to maintain low bacterial
counts in upper intestine. Most coordinated,
rapid peristalsis. Occurs between meals.
-Takes ~90 min to go from stomach to colon
-Mediated by motilin and Enteric NS

Anatomy of small intestine 3-5m long, 2-3cm diameter

3 sections: duodenum, jejunum, and ileum.


Duodenum, 20cm, receives chyme from the
stomach, digestive juices from the
pancreas, and the liver
(bile). It has Brunner's glands, produce a
mucus-rich alkaline secretion
containing HCO3-. � neutralize the acids contained in chyme.

Mixing and preparing for absorption


~2m long, has well developed villi, absorbs
the main products of digestion (sugars, amino acids, and fatty
acids) � into the bloodstream. Mainly


~2.5m long, well developed villi. It absorbs remaining
nutrients + vitamin B12 and bile acids. Complete
absorption The ileum joins to the cecum at the
ileocecal junction.

Anatomy of small intestine

Lumen can move and contract for better absorption
Microvilli projections of cell membrane
Thin wall and large lumen

Small Intestine Motility

Motility contributes to digestion and absorption
-Mixing chyme with digestive to achieve optimal
exposure to villi of the mucosa
-Propulsion of chyme always in an aboral direction
-Net movement ~1-2 cm/min -> 3-5h
from the pylorus to the ileocecal valve.

Ileocecal Junction

Functions as a valve and a sphincter
Valvular function -
prevents backflow into small intestine. 90 degree angle improves
valve efficiency

Sphincter function -
regulates movement of ileal contents into large intestine.
Regulates how much chyme is going to become feaces

Large Intestine

No digestive enzymes produces but water, salt, and vitamin B12
absorption Propels fecal material to rectum
Undigested food + mucus + bacteria = feces

Gut microbiota ( microbiome)

Site of largest bacterial colony in body �
�gut microbiome�
Dysregulation of the gut flora has been correlated
with a host of inflammatory, autoimmune and nervous conditions
Established by ~1 year of age, keep changing with time and
diet Bacterial fermentation of
carbohydrates, short chain fatty acids, urea cycling, etc.
Produce vitamins (B group, K), gas,
acetic and butyric acids but little
absorption � NOT the large intestine�s job
Large intestine is to dry up food and make feces

Large Intestine

5 sections � color coded

Ascending colon including the
cecum and appendix
2. Transverse colon including the
colic flexures
Descending colon
Sigmoid colon � the s-shaped
region of the large intestine
Rectum + anus

Taeniae coli

three bands of smooth muscle � shorter that the colon itself
-> colon becomes sacculated


bulges caused by contraction of taeniae coli. Small
intestine doesn�t have definite shape LI does Held by ligaments

Large Intestine

Mucosa � The thick mucosa has deep crypts, but
there are no villi. The epithelium is formed of columnar
absorptive cells with a striated border, many goblet
cells Practically no villi (no food absorption) but many
crypts of Lieberkuhn, numerous goblet cells (lots of mucus!).

Innervation and movements of Large Intestine

Myenteric plexus - concentrated beneath teniae
Parasympathetic and Sympathetic inputs
External anal sphincter - pudendal nerves
Feedback control of the ileocecal sphincter for stretch,
irritants, etc.

Typically sluggish movement

Haustral Contractions - combined contractions of
the circular and teniae coli cause the unstimulated portion
to bulge outward into sacs called
Mixing movements facilitate fluid and electrolyte
absorption (minimal propulsion) They appear and disappear
every 30-60s
8-12 hours to move the content from ileum to rectum

Mass Movements

Propulsive movements of intense peristalsis

Move feces to rectum and stimulate defecation
Entire colon to sigmoid colon or rectum
Occurrence typically once or twice a day, series
lasting 10-30 min. (1-2 min each) Often after the morning
coffee! Reflexes � smell, sight, noise

gastrocolic reflex (distention of stomach)

duodenocolic reflex (distention of duodenum)

Ulcerative colitis frequently has mass movements that persist
almost all the time!


Final process of digestion � few times a day to few times a
week Rectum is empty most of the time
anus closed by internal (smooth
muscle) and external (striated muscle - voluntary)
sphincters When mass
movement forces feces into rectum -> s
tretch responses initiate defecation reflex
Humans and �house trained� animals can defer
There are two levels of control
-Intrinsic reflex
-Spinal cord reflex

Intrinsic Defecation Reflex

< Mediated by myenteric NS, is initiated when
feces enters rectum via mass movements
< Rectal distention initiates
afferent signals -> descending and sigmoid
colon, and rectum. This causes positive feedback
loop -> contractions that force feces
toward anus.
< Internal anal sphincter relaxes and if
external anal sphincter is voluntarily relaxed, defecation occurs.

Defecation Reflex - Spinal Cord

Rectal distention also initiates the
parasympathetic reflex and greatly
intensifies it
Afferent signals go to sacral cord
and back by parasympathetic fibers in pelvic
nerves. Also coordinate taking a
deep breath, closure of the
glottis, and contraction of the abdominal
In both modalities, higher centers help by
initiating a deep breath, closure of glottis, and
increased abdominal pressure = V
alsalva maneuver

List of GI Sphincters

Upper esophageal sphincter (pharyngoesophageal) Lower
esophageal sphincter (gastroesophageal) Pyloric sphincter
(gastroduodenal) Ileocecal valve/sphincter Internal
anal sphincter External anal sphincter

List of Reflexes

Peristaltic Reflex:
- stretch intestine -> proximal contraction, distal relaxation.

Gastro-ileal Reflex: (gastroenteric)

- gastric distention relaxes ileocecal sphincter -> chyme advances

Entero-gastric Reflex:
- from duodenum to decrease gastric emptying -> chyme slows

Intestino -intestinal
- over-distention or injury of bowel segment causes entire bowel
to relax.

Gastro - and
Duodeno -colic
- distention of stomach/duodenum initiates mass movements ->
chyme or feces advance

Defecation Reflex:
- rectal distention initiates defecation -> feces advance.

GI secretory functions

Glands: Masses of
epithelial cells Synthesize something to
be released
Exocrine= on a surface (inside or outside the
body), with a duct
Endocrine = in the bloodstream, no secretory ducts,
products are called hormones Driven, in part, by
submucosal plexus
Glands are muscles of epithelial tissue which synthesize products

GI-associated Glands

Function of secretion:

Digestion of food - Digestive
Lubrication and protection of the mucosa -

Location of the glands

Within the epithelium � goblet cells
Within the wall of the GI tract � e.g. gastric
Outside the GI � Salivary, liver, pancreas

Morphology of glands

Control of Secretions

Local - tactile, distention, irritation
Reflex - nervous input (which system?)
Hormonal - G.I. hormones
Most of secretion controlled at the local level
Nervous input � Parasympathetic system
Sympathetic tends to decrease secretion increases in certain situations

Daily Secretion of Intestinal Juices

Intestinal secretion is about 7L 99% is reabsorbed by time it reaches
the rectum

Mucus Composition - Properties

Thick secretion that is mainly water, electrolytes and
glycoproteins, lysozyme. Used in other system
organs respiratory, urogenital Essential for digestion
because - Thick & Resistant to digestion = surface
protectant Low resistance = good lubrication of surface Self
adherent to food, surfaces, keeps particles (e.g. feces) together
Buffering capacity across a wide range of pHs

Serous fluid Properties

Mostly water and protein, contains amylase, typical of the parotid gland

Salivary Glands

Parotid � Serous type, largest, make amylase, ~20%
of saliva, Mumps affect parotids
Submandibular � mix serous-mucus,
~70% saliva,
Sublingual � mucous gland, ~10%
saliva, ducts opens under the tongue 800 to 1,000 minor
salivary glands located throughout the oral cavity
within the submucosa � mainly mucous secretion


Formation and Secretion of Saliva

Two Stages - -Acini - primary secretion
similar to plasma. -Water, proteins, ions -Salivary Ducts - modified
as it passes through ducts, K+ and HCO3- are secreted there
Ionic composition depends upon rate of
secretion. Resting composition is: -Na+ - 0.1 x
plasma -Cl- - 0.15 x plasma -K+ - 7 x plasma HCO-3 - 3 x
plasma Max secretion tends to have concentration more similar
to plasma

Parasympathetic regulation of salivary secretion

Esophageal secretion

Receives a constant supply of saliva
Compound mucosal glands to protect
from bolus Secretion increases
- Rough foreign material from mouth
- Acid from stomach

Functions of Stomach

Short-term storage reservoir for
food Secretion of intrinsic factor
allows Vit. B12 absorption
Chemical and enzymatic digestion
is initiated, particularly of proteins.
�Liquefaction� of bolus into chyme
Slow release into the small intestine for further

Stimulation of Acid Secretion

Basal secretion (pH @ 2.0) few mL /hour between meals
Response to meal -
- Cephalic - 30% - sight, smell, taste, etc.
-> Vagus
- Gastric - 60% - distension, peptides, ->
Meisnner�s plexus, gastrin, vagus
- Intestinal - 10% - chyme in the duodenum ->
gastric secretion

Gastric Secretions

Surface mucus cells

Columnar cells secrete large amount of viscid mucus -> 1mm thick
Mucus is alkaline and contains K+ buffers local
acidity of the HCl
Stomach does not absorb nutrients, too much mucus

Aspirin suppress production of prostaglandin (PGE2)
-> decrease mucus
Large doses of NSAID, sensitive people -> damages epithelium

Pyloric Gland

Too much aspirin lowers the amount of mucus
Gastric ulcers

Gastric (oxyntic) Gland

Four cell types -

Mucous neck cells - top
- mucus = mucin + bicarb + K+
- Prostaglandin help protection
Generate cells of stomach surface

Parietal cells - middle
- HCl
- intrinsic factor

ECL cells

Peptic cells (chief cells) - bottom
- pepsinogen
- rennin
- Lipase
80% of stomach

Parietal Cell

HCl is formed at the villus-like membranes of the canaliculi
which are continuous with the lumen H taken from water
combined with co2 to make bicarb And the cl comes straight from the
serum that will combine hcl The venous blood out of the stomach is
slightly more alkaline then the rest of the blood

Gastric Acid

Three major functions -
-Bacteriostatic (but Helicobacter pylori lives in
the stomach)
-Converts pepsinogen to pepsin
-Begins protein digestion (by unfolding them)

Regulation of parietal cells

Gastric secretion is stimulated by neural, paracrine and
endocrine mechanisms
-Acetylcholine - HCl secretion
- mucus, pepsinogen, and gastrin
-Histamine - HCl secretion
-Gastrin - HCl secretion (secreted by the pyloric glands)
Pepsinogen inactive form of protein digester pepsin

HCL production

Protein degradation in stomach ->amino
G-cells (pyloric glands) stimulation by aa ->
Gastrin reaches the ECL
(enterochromaffin) cells via blood ECL
cells release histamine next to the
parietal cells
Histamine stimulates parietal cells to
produce HCL

Epithelia renewal in the stomach

Surface mucus cells live 3-5 days and then renewed
Parietal cells live 5-6 months Peptic cells live 2-3

Helicobacter pylori

pylori found in 95% patients with Duodenal Ulcer
and 100% patients with Gastric Ulcer.
Gram negative bacterium Marshall and Warren were
awarded the 2005 Nobel Prize in Physiology or Medicine.
High urease activity
- high NH 4 + activity
- can withstand acid environment -> alkaline �shied� or �aura�
Treatment of gastric ulcers is mainly to use antibiotics to kill
the bacteria


Pepsinogen is the inactive form of pepsin -
-Acid converts pepsinogen (42.5kDa) to pepsin
-Pepsin (35 kDa) converts more pepsinogen to pepsin
- proteolytic enzyme
- optimal pH 1.8 - 3.5
- irreversibly inactivated >pH 6

Pepsinogen Secretion
Two signals stimulate secretion
-Vagal stimulation mediated by ??
-Direct response to gastric acid
Regulated by parasympathetic

Why doesn�t the stomach digest itself?

The gastric mucosa has a physiological and an
anatomical basis to prevent back-leak of H+
-Physiological - Thick layer of mucus
-Anatomical - cell membranes and tight junctions
between cells

Integrity of Mucosal Barrier

Secretions of Small Intestine

Brunner�s - Compound mucus gland in duodenum
Secrete an alkaline mucus. Brings chyme pH up &
protect mucosa from acid Stimulated by local irritation -
Crypts of Lieberk�hn � between the base of the
villi in small intestine mostly secrete water-like fluid pH
8.0 - 1800 mL/day Fluid is reabsorbed here and in the
Enterocytes � small amount of digestive enzymes �
peptidase and sucrase, maltase, lactase -> complete the digestion
initiated by pancreas
Goblet cells all around secrete mucus

Crypts of Lieberkuhn�s

Secretions of Large Intestine

Increase by strong parasympathetic
Crypts of Lieberk�hn � but no villi in
large intestine!
Fluid with HCO 3
- from remaining cells Stimulated by
direct tactile stimulation Large amount of
mucus from goblet cells
Roll and hold fecal matter together
Protects from irritation and from bacterial
Diarrhea � secretion of large quantities of
mucus + water +
ions From intense
irritation by acids, bacteria, toxins, insoluble salts
(MgSO4), etc. -> quick and effective
removal of irritant


As acidic chyme enters the small intestine the
pancreas provides:
Bicarbonate solution to prevent damage to duodenal
Digestive enzymes for all food �polimers� -
proteins, fats, and starch

Internal Structure of Pancreas

< Compound gland with structure similar to
salivary gland
< Acini - grape-like clusters of cells that store and secrete digestive enzymes
< Ducts - secrete bicarbonate

Intercalated ducts - receive secretions from acini

Intralobular ducts - receive fluid from intercalated ducts

Regulation of Pancreatic Secretion

Secretion of fluid and HCO 3
- is mainly dependent upon amount of
acid entering duodenum Secretion of
enzymes is mainly dependent upon amount of
fat and protein entering duodenum

Pancreatic Secretion by Secretin

Secretin (27 aa), secreted by
S-cells in duodenum and jejunum, secreted at pH
<4.5 (max of pH 3.0). Stimulates releases of large
quantities of fluid + HCO 3
- -> Chyme returns to neutral
H 2 CO
3 enters the blood and is expired by the
First hormone to be identified (1902) by Bayliss
and Starling (Frank-Starling and Starling forces,

Pancreatic Secretion by CCK

Cholecystokinin (�Move the gallbladder�) or CCK (33
aa), secreted by I-cells in duodenum and jejunum,
secreted in response to peptides and fatty acids in
the chyme. Large quantities of enzymes
-> Content of the chyme is digested in various nutrients
Discovered in 1905, exists in many forms
(CCK58, CCK33, CCK22 and CCK8. CCK58, etc.)

Other functions: mediate satiety,
increases anxiety, CCK-4 (WMDF) induces panic attacks, hallucinogenic

Enzymes for Protein & DNA Digestion

Enzymes for Carbohydrate & lipid Digestion

Pancreatic lipase fat -> fatty acids +
monoglycerides Phospholipase - phospholipids ->fatty
acid Cholesterol esterase - cholesterol esters -> fatty

All enzymes are secreted in excess. Enzyme secretion

must be reduced to 10-15% of normal to cause problem.

Why Doesn�t the Pancreas Digest Itself?

Why Doesn�t the Pancreas Digest Itself?

Trypsin Inhibitor

Bicarbonate Neutralizes Acid Chyme

Secretin induced bicarbonate secretion &
neutralizes acid chyme creating optimal conditions (pH = 7-8) for
digestive enzymes - Secretin - acts to open Cl- channels
and thus increase secretion of bicarbonate.


Inflammation of pancreas ->Autodigestion
Symptoms � Upper abdominal pain that radiates to the back and
worsen with eating, fever, nausea, vomiting Chronic
pancreatitis � also: loosing weight, steatorrhea
-Alcohol/smoking- most common cause in adults
-cystic fibrosis - most common cause in children
Acute pancreatitis �
-gallstones - most common cause
-Surgery, duct blockage, trauma,
-Infection, injury, pancreatic cancer

Pancreatic cancer

Spreads rapidly, detected late, mostly fatal Symptoms
� Upper abdominal pain that radiates to the back loss of appetite
and weight, depression, diabetes, fatigue, etc Risk factors
� Family history, chronic pancreatitis, obesity, old age,
smoking Notable people lost to pancreatic cancer: Steve Jobs,
Aretha Franklin, Luciano Pavarotti, many others

Liver secretion

Bile � Generated by hepatocytes into bile
canaliculi, progressively concentrated as it moves to the
terminal bile, hepatic, and
common hepatic ducts.
When the chyme reaches the duodenum, the gallbladder contracts
and sphincter or Oddi relaxes � Parasympathetic and CCK
(most potent stimulus)


Bile - dark green brownish fluid
Continuously produced but stored
in the gallbladder between meals and concentrated 5-10 fold
97% water, ~1% salts (Cholic*, taurocholic,
lithocholic acids, etc.,); 0.2% bilirubin; 0.51% cholesterol, fatty
acids, and lecithin; and inorganic salts
Bile salts are recovered by the ileum (>90%)
and recycled by the liver
1-2gr of cholesterol is used to make bile salts
each day
Cholesterol gallstones are common when bile is
concentrated too much

Bile function

Bile acids help emulsify the fats in the diet
� better attack by lipases and
absorption from the villi Also helps
absorbing Vitamins A, D, E, K Vehicle for
excretion of excess bilirubin (hemoglobin
degradation) Lipids then go into the lymphatic

Basis for Digestion - Hydrolysis

Digestion involves the breakdown or hydrolysis
(addition of water) of nutrients to smaller molecules that can be
absorbed in small intestine
Carbohydrate-monosaccharides Proteins - di-peptides and
amino acids Lipids - 3 free fatty acids + glycerol

No digestion = no absorption

Basis for Digestion - Hydrolysis

Digestible nutrients

Carbohydrates: mostly from plants,
sucrose, lactose, starches, some glycogen, little pectin, dextrin,
etc. Not cellulose! ~3.75 to 4cal/gr
Proteins: several sources, animals
and vegetal. Plant protein don�t have enough of the
ALL essential amino acids (arginine, histidine, isoleucine, leucine,
lysine, methionine, phenylalanine, threonine, tryptophan, and
valine) Pregnant, breastfeeding, developing/growing, heavy
activities, illness, etc. require some animal proteins (milk,
cheese, eggs). Human need ~0.5g/kg/day, heavy exercise
Fats: animal and
vegetal, ~8.8 to
Cholesterol is an animal product, not in

Types of Digestion

Luminal or cavital digestion -
-occurs in lumen of GI tract
-enzymes from salivary glands, stomach, pancreas
-pancreatic enzymes do most of the work
Membrane or contact digestion -
-enzymes on brush border of enterocytes
Intracellular digestion -
-di and tri-peptides

Digestive Enzymes by location

Digestion of Carbohydrates

Starch digestion -
-Begins with a-amylase in saliva (5% digestion in
mouth, up to 40% while not mixed in the stomach) to
maltose (Gluc-O-gluc)
-Continues in small intestine with pancreatic
a-amylase and is virtually done in the upper jejunum (<1hr)
-Final digestion to monosaccharides occurs at brush border
- Enterocytes

Lactose and sucrose - digestion only occurs at
brush border

Digestion of Carbohydrates

Digestion of Proteins

< Digestion of proteins to AA occurs:

Stomach - pepsin (can digests
Small intestine - trypsin,
chymotrypsin, elastase, carboxypeptidase
Brush border - oligopeptidases, dipeptidases
Cytoplasm of mucosal cells � di-
>99% of proteins ingested are adsorbed as single
amino acids
*Collagen (tendons, ligaments, fascia, etc.) needs to be
digested first to access other proteins in meat Collagen
made of 55% of glycine, proline and hydroxyproline, only ~7% of
Arg/Lys that can be cleaved by trypsin Pepsin only provides
10-20% total digestion due to short time of action (chyme going into

Activation/Destruction of Proteases

Proteolytic enzymes are activated and destroyed very
-Enterokinase activates trypsinogen
-Trypsin is autocatalytic
-Trypsin activates other proenzymes
-Proteolytic enzymes digest themselves

Why so many proteolytic enzymes?

Mostly because of the large variety of amino acids
Proteins are folded (fats and carbohydrates are
not) � folding limits accessibility to substrate, specific recognition
sequences help
Different proteases have different specificities:
some very low (Trypsin digests at R or K, but TEV at ENLYFQ\S�)

Digestion of Triglycerides

Starts in the mouth with small amount of
lingual lipases (<10%) Lipids are
hydrophobic! Micelles need to be broken down by
bile salts � emulsification Emulsification
happens in small intestine by lecithin � the
smaller the drop, the better

Digestion of Triglycerides

>90% digestion happens in the first half of intestine
Pancreatic lipase -> triglyceride -> Glycerol + 3X free
fatty acids Cholesterol is mostly assumed as ester
Cholesterol esterase, produce cholesterol and free fatty acids
-> absorbed separately

Sites of Absorption

Stomach - ethanol, NSAIDs, aspirin
Duodenum and Jejunum - nutrients, vitamins, various
ions, some water and electrolytes
Ileum - bile salts and vitamin B12
Colon - water and electrolytes
Rectum - drugs such as steroids and

How much can we digest?

Under normal conditions, we can absorb 250gr
of carbohydrates (1000 cal.), 50gr amino
acids (200 cal.), 90gr of fat (800 cal.)
= 2000cal. + 7-8 L of fluid. Actual capacity of the
intestine is 5-10 times more for nutrients � evolutionary adaptation
to �intermittent� food

Anatomical Basis for Absorption

Total surface area of small intestine is >300m
2 Small intestine - 4-5 m long
Folds of Kerckring 3-fold Villi - 10-fold
Microvilli - 20-fold

Folds of
, Circular folds, Valvulae conniventes

Anatomical Basis for Absorption

Microvilli vs cilia

Life Cycle of Enterocytes

Villi maintain a self-renewing population of epithelial cells
with a 3 to 6-day turnover. Cell types in villus include:
secretory cells, endocrine cells, goblet cells, and mature
absorptive epithelial cells. Cells in enterocyte lineage
divide and differentiate as they migrate up crypts,
becoming mature absorptive cells. Enterocytes are
shed into lumen to become part of ingesta to be
digested and absorbed.

100 million cells per day

30-50 g protein

Absorptive Pathway of Nutrients

Nutrients must cross 7 barriers to be absorbed by blood or
lymph 1.Glycocalyx 2.Apical cell membrane 3.Cytoplasm of enterocyte
4.Basolateral cell membrane 5.Intercellular space 6.Basement
membrane 7.Wall of capillary or lymph vessel

Water Movement in Small Intestine

Water moves into or out of gut lumen by diffusion with osmotic
forces �
-Hypotonic chyme - water is absorbed
-Hypertonic chyme - water enters intestine
Between cells = paracellular pathway Through cells =
transcellular pathway

Fluid Entering and Exiting the Gut

Intestinal Sodium Balance

>99% of the sodium is reabsorbed by the intestine
Daily cycle
-Diet - 5-8 g/day
-S.I. secretion - 20-30 g/day
-Intestinal absorption - 25-35 g/day
-Excretion in feces - 0.1 g/day
Decreased absorption of sodium can lead to rapid sodium
depletion and death - e.g. diarrhea Cholera, patient dies
because of dehydration 50% death without therapy
1% death with proper hydration therapy

Sodium Absorption drives Water Absorption

Sodium is actively �pumped� by epithelial
cells (enterocytes) of small intestine. Sodium uptake
creates negative electrical potential in gut lumen,
that provides gradient for chloride uptake.
Water follows sodium and
chloride in accordance with osmotic forces.
Aldosterone (adrenal cortex) increases Na+
reabsorption (and Cl- and H2O) and K+ secretion in S.I. and

Sodium Absorption in Small Intestine

Sodium is absorbed across apical cell membrane by 4 mechanisms -

Diffusion - through water-filled channels
Co-transport - with AA and glucose (S)
Co-transport - with Cl- 4.
Counter-transport - in exchange for H+

bicarbonate ions + H+ ->form carbonic acid
(H2CO3), � dissociates to form water and carbon dioxide
Additional Cl- follows electrical gradient created by absorption of Na+

Other ion absorption

ions - actively absorbed from the duodenum,
Amount of calcium ion absorption is controlled by the daily need
of the body for calcium.
Parathyroid hormone secreted by the parathyroid glands, and
vitamin D control intake and secretion
Iron, p
otassium, magnesium,
phosphate, and other ions can also be actively
absorbed through the intestinal mucosa. In general, the
monovalent ions (Na+, Cl-, etc.) are absorbed with
ease and in great quantities. Bivalent ions (Mg++,
Ca++, etc.) are normally absorbed in only small amounts but used in
smaller amout

Absorption of Carbohydrates

Glucose and galactose - secondary active
transport with Na+
-compete for membrane carrier (Sodium/glucose cotransporter 1, SGLUT-1)
-energy from Na+ - K+ ATPase

Fructose - facilitated diffusion (fructose
transporter, GLUT-5)
-does not require energy
-requires concentration gradient

Protein Digestion and Absorption

Basic Steps of Lipid Absorption

Emulsification - large aggregates of dietary
triglyceride are broken down -> micelle formation
Enzymatic digestion � lipases yield glycerol and
fatty acids that can diffuse into enterocyte because they are
soluble in the cell membrane
Reconstitution of triglyceride in the smooth ER and
chylomicron formation (aka HDL, LDL, VLDL, etc.)
Chylomicron are lipoprotein particles made of
triglycerides (85�92%), phospholipids (6�12%), cholesterol (1�3%),
and proteins (1�2%).

Chylomicrons - Life Cycle

Colon Absorption

Liquid - >1.5L of chyme pass the ileocecal valve
each day, it can absorb 5-8L -> less than 100 milliliters of
fluid in the feces excess appears in the feces as
Na+ and Cl- go in, H2CO-
go out to buffer acids from fermentation First
half absorbing colon, second half storage
Colon flora can digest small amount of
cellulose -> glucose + various gases. Also,
vitamin K, B12, thiamine, riboflavin, are
Feces: 30 percent
dead bacteria
, 10 percent
, 20 percent
matter some protein, and 30 percent
food, remains of digestive juices, dead epithelial
cells. The brown color of feces is
caused by
stercobilin and
, derivatives of bilirubin.
Odor comes form indole, skatole, mercaptans, and
hydrogen sulfide, can vary from individual, food, fermentation type


Sensory signals (afferent signals)
Originate in pharynx, esophagus, and upper small intestine.
Afferent signals transmitted via vagal and sympathetic
Motor impulses (efferent signals) To
upper GI tract via 7th, 9th, 10th, and 12th
cranial nerves. To lower GI tract via
vagal and sympathetic nerves To
diaphragm and abdominal muscles via spinal

The vomiting (emesis) process

Nausea - sensation often a prodrome of vomiting
conscious recognition irritative impulses coming from
the gastrointestinal tract impulses that originate in the
lower brain associated with motion sickness,

Antiperistalsis (opposite direction of
peristalsis) Can begin as low as ileum. Prelude to
vomiting Pushes GI contents into duodenum This
distension excites the vomiting act

1.Deep breath
2.Gastro-esophageal sphincter opens
3.Glottis closes
4.Elevation of soft palate (closes nares)
5.Contraction of diaphragm (a downward motion) and abdominal muscles
increases pressure in stomach.
6.Upper esophageal sphincter relaxes
7.GI contents is forced out mouth

Abnormalities of Carbohydrate Assimilation

Lactose Intolerance - acquired lactase deficiency -
most common

Symptoms - abdominal cramps, bloating, diarrhea,
and flatulence
Diagnosis - feed lactose - look for glucose in
Cause - absence of brush border lactase
Prevalence: 80% blacks and Hispanics, 90% Asians,
15-20% white Europeans
Treatment � avoid milk, drink predigested milk
(lactose free milk) or take calcium supplements

Lack of glucose / galactose carrier - rare
diagnosed at birth feed fructose

Abnormalities of Protein absorption

Pancreatic insufficiency -
-pancreatitis or cystic fibrosis
-decreased absorption -> high nitrogen in stool

Congenital absence of trypsin
-no trypsin - no other proteolytic enzymes
-protein malabsorption

-cannot absorb neutral amino acids, e.g., tryptophan
-neutral amino acids can still be absorbed as di- and tri- peptides


Diseases that result in decreased absorption
even when food is well digested are often classified as
�sprue� -> steatorrhea

sprue - also called celiac
disease- allergic to gluten (small protein in wheat,
rye, barley)- destroys microvilli and, when severe, villi

Tropical sprue - bacterium (many different
types)- treated with antibacterial agents

Motility disorders - moving through too
Absorption disorder � e.g. short gut syndrome,
congenital or by resection of parts of small intestine.
Results -> Impaired absorption of proteins,
carbohydrates, calcium, vitamin K, folic acid, and vitamin B12 also
occurs -> demineralization of the bones, defective coagulation,
anemias, etc.

Celiac disease

Autoimmune disease, 1 in 100 worldwide. Hereditary,
1:10 in families When gluten is introduced, a strong immune
response � Enterocytes and villi
in the small intestine are damaged and destroyed � severe
decrease of absorbing surface! In
classical celiac disease, patients have symptoms
of malabsorption, diarrhea, steatorrhea, and weight loss or growth
failure in children. Pain, iron-deficiency anemia, chronic fatigue,
and other GI symptoms. Cure � gluten-free diet

Gluten are a family of proteins

with unique viscoelastic and adhesive properties, which give
dough its elasticity, helping it rise and keep its
shape and giving the final product a chewy texture.


Slow movement of feces through the large
intestine Not enough fibers in the diet,
constrictions in the large intestine � tumors,
malformations of the enteric NS, adhesions,
segmental spasms, etc. Too much
constipation eventually triggers liquid secretion and diarrhea,
followed by more constipation, etc. Drink more, eat more
fibers, stool softeners, laxatives, etc.


Diarrhea is the third leading cause of death by disease worldwide
- 5-8 million children per year worldwide
- 250,000 hospital visits in US
8 million office visits in US

Types of diarrhea

Infectious diarrhea - Bacteria, virus, parasites,
etc. large quantities of water are secreted - Cholera toxin
directly stimulates excessive secretion of electrolytes and fluid �
loss of 5-6L of water and ion in one day can kill � therapy, water
and ions (+antibiotics)
Motility related diarrhea � Psychogenic (anxiety)
excessive sympathetic and parasympathetic stimulation, vagotomy,
diabetic neuropathy
Osmotic diarrhea (malabsorption) pancreatic
disease, Celiac disease, lactose intolerance, short bowel syndrome,
Inflammatory diarrhea - autoimmune diseases
(Crohn�s disease, ulcerative colitis)
Dysentery if blood is present in the stool

Obstruction in GI tract

From 1. cancer, 2. fibrotic
constriction resulting from ulceration or from peritoneal adhesions,
3. spasm of a segment of the gut, and 4.
segmental paralysis Obstruction
at pylorus
Acidic vomitus � can lead to metabolic
alkalosis Obstruction below duodenum
Neutral or basic vomitus
Usually little change in whole body acid-base status
Obstruction at distal large intestine
Severe constipation can cause vomiting when contents of small
intestine accumulate


Chronic liver disease in which normal liver cells are damaged
and replaced by scar tissue.
-Excessive alcohol intake is most common cause of
cirrhosis, accumulation of fat within hepatocytes. Fatty liver leads
to steatohepatitis.
-Steatohepatitis is fatty liver accompanied by
inflammation, which leads to scarring of liver and cirrhosis.
hepatitis - A, and E spread with
food and water -> acute and mild disease
-B, C, D, with contact with infected sample or
person -> acute or chronic sever disease - cirrhosis, liver
failure, and liver cancer

Complications of Cirrhosis

Complications of cirrhosis include:
-Jaundice (yellow skin caused by bilirubin retention)
-Ascites (fluid accumulation in abdomen)
-Peripheral edema
-Portal hypertension
-Blood coagulation abnormalities
-Spontaneous bacterial peritonitis � fewer
Kupffer's cells
-Hepatic encephalopathy (ammonia, drugs, and other
toxins are not cleared and enter the BBB -> abnormal
neurotransmission -> neurological symptoms develop
-Coma and death