BIPN 102 Spring 2011 GO notes5

BIPN 102 Spring 2011 GO notes5 - Go
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Notes
1
 Teaching
Assistant
 Jag
Go
 
 MAM
PHYS
2
NOTES
(SPRING
2011)
 TABLE
OF
CONTENTS
 
 LECTURE
1/MARCH
28,
2011……………………………………………………………………....Page
2
 LECTURE
2/MARCH
30,
2011……………………………………………………………………….Page
6
 LECTURE
3/APRIL
1,
2011………………………………………………………………………....Page
11
 LECTURE
4/APRIL
4,
2011………………………………………………………………………....Page
17
 LECTURE
5/APRIL
6,
2011………………………………………………………………………....Page
21
 LECTURE
7/APRIL
11,
2011……………………………………………………………………….Page
24
 LECTURE
8/APRIL
13,
2011……………………………………………………………………….Page
27
 LECTURE
9/APRIL
15,
2011……………………………………………………………………….Page
31
 LECTURE
10/APRIL
18,
2011…………….……………………………………………………….Page
37
 LECTURE
11/APRIL
20,
2011…………….……………………………………………………….Page
41
 LECTURE
12/APRIL
25,
2011…………….……………………………………………………….Page
49
 LECTURE
13/APRIL
27,
2011…………….……………………………………………………….Page
51
 LECTURE
14/APRIL
29,
2011…………….……………………………………………………….Page
55
 LECTURE
15/MAY
2,
2011………………………………………………………………………….Page
60
 LECTURE
16/MAY
4,
2011………………………………………………………………………….Page
62
 LECTURE
17/MAY
6,
2011………………………………………………………………………….Page
66
 LECTURE
18/MAY
9,
2011………………………………………………………………………….Page
68
 LECTURE
19/MAY
11,
2011……………………………………………………………………….Page
68
 LECTURE
20/MAY
13,
2011……………………………………………………………………….Page
72
 LECTURE
21/MAY
16,
2011……………………………………………………………………….Page
77
 LECTURE
22/MAY
18,
2011……………………………………………………………………….Page
80
 LECTURE
23/MAY
23,
2011……………………………………………………………………….Page
84
 LECTURE
24/MAY
25,
2011……………………………………………………………………….Page
89
 LECTURE
25/MAY
27,
2011……………………………………………………………………….Page
92
 LECTURE
26/JUNE
1,
2011…………………..………………………………………………….....Page
96
 LECTURE
27/JUNE
3,
2011…………………..…………………………………………………….Page
99
 Notice
that
I
am
going
to
just
copy
and
paste
the
rest
of
my
notes
for
the
last
lecture.

 I
have
talked
to
Dr.
Fortes
and
he
hasn’t
decided
yet
whether
to
skip
muscle
 physiology
and
talk
about
repro
physiology
for
the
last
lecture.

Either
way,
we
are
 pretty
behind,
so
we
wouldn’t
be
able
to
complete
either
of
them
with
great
detail.

 For
the
sake
of
thoroughness
my
notes
should
cover
anything.

Thanks
for
a
great
 quarter.



 
 
 
 
 
 
 ‐Jag
 
 Go
Notes
2
 
 Hi
guys,
welcome
to
BIPN
102,Spring
2011.

These
are
my
own
lecture
notes
for
this
 course.

This
file
should
typically
be
updated
once
a
week,
most
likely
by
Sunday
 evenings.

These
notes
will
not
only
include
the
topics
in
presented
in
lecture,
but
 will
often
elaborate
upon
them
based
on
my
knowledge
as
well
as
outside
sources
of
 information
(I
may
also
just
copy
and
paste
stuff
from
my
old
lecture
notes
and
a
 former
head
TA
Chris
Childers
who
had
some
cooler
illustrations).

Sorry,
 sometimes
I
may
just
get
a
little
lazy
but
at
least
I
cited
him.

As
a
note,
physiology
is
 often
a
complex
and
dynamic
subject;
therefore,
in
order
to
fully
understand
the
 material,
I
have
often
found
that
detailed
explanation
and
examples
are
warranted
 in
order
to
understand
the
“big
picture”.

Please
do
not
try
to
memorize
physiology,
 instead
try
to
intuitively
analyze
situations
based
on
the
principles
shown.


 Thanks,
‐
Jag.
 
 BIPN
102
PA
George
Fortes
 1st
Midterm
–
Friday,
April
22th
20%
 2nd
Midterm
–
Friday
May
20th
20%
 Final
Exam
Wednesday
June
8th
3‐6pm
60%
 
 Podcast.ucsd.edu
 Webct.ucsd.edu
 
 March
28,
2011
 
 Introduction
+
Overview
 Functional
Anatomy
and
Histology
of
the
Respiratory
System
 Ventilation
 Poiseuille’s
equation
 Boyle’s
law
 Mechanics
 Inspiration
and
Expiration
 Surface
tension
 Law
of
LaPlace
 
 Suggested
chapter
readings
–
Silverthorn
17,
and
WEST
1,
2,
7
 Also
review
–
cardiovascular,
autonomic,
endocrine
action,
smooth
muscle,
and
 membrane
transport
systems
 
 
 RESPIRATORY
SYSTEM
OVERVIEW:
 • FIG
17‐1
 
 There
are
4
major
functions
of
the
respiratory
system
 1. Exchange
of
gasses
btw
the
atmosphere
and
the
blood
 2. Homeostatic
regulation
of
blood
pH
 Go
Notes
3
 3. Vocalization
 4. Metabolic
reactions
(for
cellular
respiration)
 
 
 There
are
two
types
of
respiration.
 1. Cellular
respiration
–
which
includes
the
oxidative
phosphorylation
and
the
 electron
transport
chain
 2. The
one
we’re
concerned
with
is
the
gas
exchange
between
the
external
and
 internal
environments

 a. Of
which
there
are
three
key
gas
exchanges
that
have
to
occur
 i. Exchange
between
the
atmosphere
and
the
lung
(ventilation)
 ii. Exchange
of
gasses
from
the
lung
to
the
blood
(diffusion)
 iii. Exchange
of
gasses
from
the
blood
to
the
tissues
(diffusion)
 b. (more
on
these
to
come)
 
 There
are
a
multitude
of
challenges
posed
to
these
processes.
 1. Physical
gas
exchange
between
the
atmosphere
and
the
“dead
end”
structure
 of
the
lung.

Usually
when
materials
are
exchanged
with
our
surroundings,
 they
enter
one
way
and
exit
another.

However
the
specific
challenge
with
the
 lung
results
in
a
fractioning
and
mixing
of
“fresh”
and
“stale”
air.
 a. Exchange
I
–
atmosphere
to
the
lung
–
utilizes
PRESSURE
gradients
in
 order
to
drive
air
into
and
out
of
the
lung
 2. Gas
exchange
between
the
air
in
the
alveoli
with
gas
in
the
blood
 a. Exchange
II
–
alveoli
to
blood
–
driven
by
CONCENTRATION
gradients
 but
mediated
by
the
principles
of
diffusion
(solubility,
thickness,
conc
 dif….)
 b. This
is
a
complex
process
as
diffusion
of
the
gasses
across
the
alveoli
 walls
must
be
sufficiently
fast
enough
to
exceed
the
rate
of
blood
flow
 (perfusion)
 i. Diffusion/perfusion
mismatch
will
cause
problems
of
 inefficient
gas
exchange
 ii. What
affects
perfusion
and
how
fast
is
it?


 1. Recall
that
the
average
resting
cardiac
output
(CO)
is
 about
5L/min.

Because
the
systemic
and
pulmonary
 circuits
are
in
series,
the
amount
of
blood
flow
through
 the
left
heart
must
equal
the
blood
flow
through
the
 right
heart.

But
the
pulmonary
circuit
is
much,
much
 shorter
than
the
systemic
circuit.

Therefore
blood
flow
 through
the
lungs
is
extremely
fast.
 2. At
rest,
the
time
for
a
red
blood
cell
to
flow
through
a
 pulmonary
capillary
is
0.75s.

During
exercise
the
same
 blood
cell
would
only
take
0.25s
to
pass
through.

 Therefore
exchange
II
or
diffusion
–
must
be
sufficiently
 faster
than
those
times,
or
not
enough
oxygen
will
be
 supplied.
 3. Gas
exchange
between
the
blood
and
the
tissues
 Go
Notes
4
 a. Exchange
III
–
blood
to
cells
–
again
driven
by
concentration
gradients
 and
principles
of
diffusion
 
 
 Gas
Transport
 ‐ gasses
generally
have
low
solubilities
in
H20
(ex
–
soda’s
easily
loses
its
 carbonation
once
opened.

This
is
because
the
pressure
keeping
the
CO2
in,
is
 removed
once
opened)
 ‐ CO2
is
20x
more
soluble
in
water
at
body
temperature,
than
O2
 ‐ Solubility
decreases
with
increasing
temperature
based
on
general
 thermodynamics
 ‐ These
serve
as
major
obstacles
for
gas
transportation
and
requires
additional
 mechanisms
beyond
diffusion
 ‐ How
solved?
 o For
O2
–
Hemoglobin
(Hb)
–
98%
of
all
O2
in
the
blood
is
hemoglobin
 bound
in
order
to
overcome
the
lack
of
O2
solubility
in
blood
 o For
CO2
–
when
CO2
is
combined
with
H2O
is
forms
H2CO3.

Which
 will
dissociate
into
H+
and
HCO3‐
(main
buffer)
 As
a
result,
the
regulation
of
extracellular
pH
is
largely
 controlled
by
the
respiratory
system!
 
 Regulation
 ‐ The
processes
are
highly
autonomically
regulated
 ‐ Ie
during
exercise,
O2
consumption
increases
and
respiration
increases
 accordingly

 ‐ O2
and
CO2
are
therefore
highly
regulated
within
tight
parameters
 
 ANATOMY:
 
 *FIG
17‐2
a‐b
 
 1. Upper
airways
/
Upper
respiratory
tract
 a. Composed
of
the
nasal
and
oral
cavities,
the
pharynx,
and
the
larynx
 (glottis
and
vocal
chords)
 i. The
larynx
moves
up
and
down
(during
swallowing
and
 manually)
in
order
to
close/open
the
glottis
 ii. Val
Salva
Maneuver
–
pushing
against
a
closed
glottis
‐>
 generates
an
increase
in
abdominal
and
thoracic
pressure.
 1. This
occurs
while
attempting
to
create
a
bowel
 movement
as
well
as
right
before
the
expulsion
phase
of
 a
cough
 2. Lower
respiratory
tract

 a. Composed
of
the
trachea,
the
bronchi,
2°
and
3°
bronchi,
bronchioles,
 and
the
alveoli
 
 In
addition,
the
respiratory
system
is
also
distinguished
into
two
zones.
 Go
Notes
5
 1. Conducting
zone
–
includes
the
upper
respiratory
tract
and
the
airways
of
the
 lower
respiratory
tract
 a. This
zone
is
only
used
for
the
purpose
of
conduction;
ie
where
there
is
 no
gas
exchange
and
therefore
no
alveoli
 2. Respiratory
zone
–
where
gas
exchange
actually
occurs.
 a. Ie
the
respiratory
bronchioles
and
the
terminal
bronchioles
which
 empty
into
bunches
of
alveoli
 
 Lungs
 ‐ Left
lung
–
slightly
smaller
than
that
of
the
right
lung
 o Why?
Because
of
the
space
taken
up
by
the
heart
 o Two
lobes
–
the
superior
and
inferior
lobes
 ‐ Right
lung
–
larger

 o Three
lobes
–
Superior,
middle,
and
inferior
lobes
 o Has
a
much
steeper
primary
bronchus
 Foreign
objects
inhaled
(mostly
by
kids…like
marbles
and
 stuff)
are
most
likely
to
be
found
in
the
right
lung
rather
than
 left
 
 Muscles
 ‐ Inspiratory
muscles
 o Diaphragm
–
the
main
inspiratory
muscle
 It
is
dome
shaped
at
rest,
but
flattens
when
contracted
 The
flattening
of
the
diaphragm
increases
the
volume
(↑V)
of
 the
thorax,
which
by
boyle’s
law
will
decrease
the
pressure
 (↓P).

Air
will
flow
in
as
a
result
from
high
pressure
to
low
 pressure.
 o External
intercostals
–
lift
the
ribcage
up
and
out
(like
a
bucket
 handle)
which
↑V
of
thorax
and
↓P
 o Sternocleidomastoid
–
from
the
sternum
and
the
clavicle
to
the
 mastoid
process
at
back
of
jaw.

Lifts
the
ribcage
up
↑V
of
thorax
and
 ↓P.

ONLY
DURING
FORCED
INSPIRATION.
 o Scalenes
–
from
the
clavicle,
1st,
and
2nd,
rib
to
the
mastoid.
Lifts
the
 ribcage
up
↑V
of
thorax
and
↓P.

ONLY
DURING
FORCED
 INSPIRATION.
 ‐ Expiratory
muscles
 o Note:
the
elasticity
of
the
lungs
and
the
natural
bowing
of
the
ribs
will
 decrease
the
V
and
increase
the
P
of
the
lungs
in
order
to
expel
air.

 Therefore
exhalation
is
a
passive
process
at
rest,
in
order
to
conserve
 energy.

However
during
intense
exercise
and
manual
forced
 expiration
we
would
use
the
following…
 o Abdominals
–
which
inc
the
P
of
the
abdomen,
which
will
dec
the
V
of
 the
thorax,
which
increases
the
P
of
the
thorax
 o Internal
intercostals
–
bow/depresses
the
ribs
which
will
dec
the
V
of
 the
thorax,
which
increases
the
P
of
the
thorax
 Go
Notes
6
 
 HISTOLOGY
 *FIG
17‐5
 
 Airways
are
lined
with
two
types
of
cells,
which
comprise
the
mucociliary
escalator
 1. Goblet
cells
–
which
secrete
mucus
 a. The
mucus
will
trap
inhaled
particulates,
bacteria,
dust
 2. Simple
ciliated
columnar
epithelium
–
cilia
move
in
sync
 a. Cilia
move
the
mucus
with
trapped
particles
upwards
towards
the
 pharynx
where
it
will
be
swallowed
and
digested.
 
 Cilia
can
be
inhibited
by
cold,
smog,
and
smoke.
 ‐ cold
–
increases
the
propensity
for
sickness
because
viruses
and
bacteria
are
 less
likely
to
be
captured
 ‐ smoke
–
extended
paralysis
of
the
cilia
means
that
mucus
has
to
be
violently
 expelled
by
coughing
‐>
“smoker’s
cough”
 
 *FIG
17‐2f

Lung
Lobule
 
 ‐ Throughout
the
upper
airways
(trachea
to
secondary
or
tertiary
bronchi)
there
 are
cartilaginous
rings.
Cartilage
functions
to
keep
airways
open
(radius
of
the
 airways
cannot
be
changed
by
muscle
contractions;
it
can,
however,
change
as
 a
result
of
inflammation/edema)

 ‐ But
once
you
reach
the
intermediate
bronchioles
(division
11
and
12)
the
 cartilage
disappears,
and
is
instead
replaced
by
circular
smooth
muscle
 (similar
to
arterioles)
which
can
likewise
constrict
and
dilate
 (bronchoconstriction
and
bronchodilation).
 ‐ Respiratory
bronchioles
have
some
alveoli
(start
of
respiratory
zone)
 ‐ Terminal
bronchioles
which
empty
into
alveolar
sacs
 ‐ Alveoli
–
are
hemispheres
(half
bubbles)
which
are
composed
of
flattened
cells
 o Encompass
a
huge
surface
area
(tennis
court
to
basketball
court)
 which
is
essentially
exposed
to
the
atmosphere.
 
 
 March
30,,
2011
 
 Anatomy
cont.
 Ventilation

+
Mechanics
of
breathing
 Boyle’s
Law
 Poiseuille’s
Law
 Pressure
Pip,
Palv,
Ptp
 Lung
Inflation
curves,
role
of
surface
tension
 Lung
surfactant:
DPPC
 Law
of
LaPlace
 Go
Notes
7
 Lung
Volumes
and
Capacities
 Spirometry
 
 ANATOMY
cont.
 
 *Fig
17‐2f
cont.
 
 ‐ within
the
alveolar
sacs
are
an
abundance
of
elastin
fibers
which
contribute
 the
elasticity
of
the
lungs
 ‐ Chronic
Obstructive
Pulmonary
Disease
(COPD)
like
emphysema
are
due
to
 the
degradation
of
these
elastin
fibers.

As
a
result,
the
lungs
lose
the
ability
 to
passively
recoil
and
expiration
will
mandate
the
usage
of
the
abs
and
 internal
intercostals
for
active
expiration
 ‐ Opposite
to
that
of
COPD,
exposure
and
chronic
inhalation
of
coal
dust,
 smoke
or
ash
can
result
in
an
inflammatory
response
which
can
also
 compromise
ventilation.

These
inorganic
particles
cannot
be
phagocytized
 by
macrophages
(immune
cells).

In
an
effort
to
increase
their
effectiveness
 the
macrophages
release
cytokines,
which
recruit
fibroblasts
which
deposit
 inelastic
fibers
(like
scar
tissue).

These
fibers
greatly
increase
elasticity
to
 the
point
that
is
difficult
to
inflate
the
alveolar
sacs.

“Fibrosis”
is
the
key
 restrictive
disease
which
will
be
discussed
later.
 
 *Fig
17‐4
branching
of
airways
 Name

 
 
 Trachea
 Primary
Bronchi

 
 Smaller
Bronchi

 
 Bronchioles

 
 Alveoli

 
 Division
 Diameter
 How
Many?
 Cross‐Sectional
 Area
 0

 
 1
 15‐22

 1

 2.5
 10‐15
 2
 
 2‐11
 1‐10
 4
‐>
1x104
 
 12‐23
 0.5‐1
 
2x104
‐>
8x107
 100
‐>
5x103

 24
 0.3
 3‐6
x
108
 >1
x
108
 
 Branching
of
airways
 ‐ as
one
goes
down
the
subdivisions

 o #
of
airways
increases
 o radius
decreases
 o enormous
increase
in
cross
sectional
area
 ‐ what
does
the
increase
in
cross
sectional
area
do?
 o First
lets
look
at
what
happens
when
we
do
the
opposite,
decrease
the
 cross
sectional
are.

For
example,
if
we
partially
placed
our
thumb
on
a
 flowing
hose.

The
decrease
in
cross
sectional
area
will
increase
the
 Go
Notes
8
 o o o o velocity
of
flow.

But
in
the
lungs,
the
TOTAL
cross
sectional
area
 increases,
so
flow
decreases
by
Bernoulli’s
principle.



 Flow
rate
=
cross
sectional
area
x
velocity
 In
the
trachea,
the
cross
sectional
area
is
smallest
=
highest
overall
 flow
 Through
the
smaller
bronchioles
flow
is
driven
by
diffusion
rather
 than
bulk
flow
=
slowest
(due
to
bernoulli’s)
 But
if
we
looked
merely
at
flow
through
a
given
airway
it
is
smallest
 through
intermediate
bronchi.

Why?

Because
of
the
decrease
in
 resistance
(compared
to
trachea)
and
it
does
not
have
a
huge
amount
 of
cross
sectional
area
(compared
to
smaller
bronchioles).
 
 Back
to
the
lung
lobule
anatomy
*Fig
17‐2f
 ‐ There
is
a
significant
lymphatic
network
to
facilitate
the
immune
system
as
 well
as
to
absorb
the
filtrate.
 o Remember
Starling’s
law
of
ultrafiltration
from
Mam
Phys
1?
 o You
don’t
need
to
use
it
in
this
course,
but
do
remember
that
a
 significant
amount
of
plasma
is
filtrated
across
the
capillary
wall
due
 to
hydrostatic
and
oncotic
pressures…
Without
the
lymphatic
system
 to
drain
the
excessive
filtrate
the
lungs
would
fill
with
fluid.
 ‐ In
addition,
there
are
two
types
of
circulation
 o 1.

Pulmonary
circuit
which
carries
unoxygenated
blood
from
the
right
 heart
via
pulmonary
arteries

‐>
capillaries
for
gas
exchange
‐>
 oxygenated
blood
leaving
the
lungs
via
the
pulmonary
vein
to
the
left
 heart
 o 2.

The
lung
also
has
to
receive
systemic
circulation
from
the
aorta
to
 provide
cells
with
gasses,
nutrients,
and
waste
removal.

This
occurs
 via
the
bronchial
arteries
and
veins.
 
 Autonomic
innervation
 ‐ Parasympathetic
(PS)
innervation
via
the
vagus
nerve.
 o Contains
both
motor
(to
diaphragm)
and
G‐protein
coupled
R
(to
 bronchioles
for
bronchoconstriction…think
they’re
M3AChR’s)
+
(unto
 mAChR’s
for
increased
mucus
secretion).
 o When
the
PS
is
activated
there
is
an
increase
in
bronchoconstriction
 and
increase
in
mucus
secretion.



 ‐ Sympathetic
–
NONE
(well
directly)
 o Instead,
when
the
sympathetic
is
activate,
the
adrenal
medulla
is
 activated
and
will
secrete
mostly
epi
and
some
NE.

These
hormones
 need
to
travel
throughout
the
circulatory
system
and
then
it
can
act
 upon
Beta‐2
adrenergic
R
of
the
lungs.
 o Activation
of
the
Beta‐2
adr
R’s
will
increase
bronchodilation
 o Example:

Asthma
is
characterized
by
abnormal
constriction
and
 inflammation
of
the
bronchiolar
smooth
muscle.

This
situation
will
 decrease
the
radius
of
the
lumen
thus
increasing
resistance.
 Go
Notes
9
 Major
rescue
inhalers
utilize
Beta
2
agonists
in
order
to
 increase
bronchodilation
 Also
sometimes
they
carry
epi‐pens
for
emergencies
 Epi‐pens
are
also
used
for
severe
allergic
rxns,
as
systemic
 shock
will
typically
cause
massive
bronchoconstriction
 
 *Fig
17‐2
g
and
h
 Alveoli

 ‐




½
bubbles
which
range
in
diameter
 ‐ two
types
of
cells
 o 1.
Type
I
alveolar
cells
–
flattened
cells
(similar
to
epithelial
cells
with
 tight
jxns)
which
are
specialized
for
gas
efficient
gas
exchange
by
 thinness
and
maximal
surface
area
 o 2.

Type
II
alveolar
cells
–
secreting
cell
which
synthesize
and
secrete
 lung
surfactant
via
exocytosis
 ‐ notice
that
the
distance
btw
the
alveolar
air
to
plasma
interface
is
only
1.6um
 thick.

Short
distance
is
essential
for
rapid
diffusion
of
gasses.
 ‐ Surfactant?
 o It
acts
upon
surface
tension
and
disrupts
it
 o Active
ingredient
(DPPC)
works
like
a
detergent
in
order
to
decrease
 surface
tension
allowing
the
alveoli
to
inflate
(More
on
this
later
‐>
 LaPlace)
 o Type
II’s
don’t
mature
until
the
7th
month
(I
think
27th
week),
 therefore
if
born
premature
to
this,
babies
will
require
supplementary
 surfactant
in
order
to
be
able
to
breath.

In
general
the
27th
week
is
 the
magic
mark
for
increased
survivability
of
preemies.


 
 Surface
Tension
 ‐ water
molecules
tend
to
form
lattices
in
which
there
are
a
number
of
dipole‐ dipole
interactions
and
hydrogen
bonding.


 ‐ At
the
surface
of
water
molecules,
there
is
a
large
force,
which
pulls
them
 down.
 o This
is
why
water
has
a
meniscus
in
a
tube.
 o Why
does
water
bead
up
on
waxed
cars?

To
minimize
the
surface
 area
touching
the
fatty
wax.
 ‐ A
sphere
is
the
minimal
surface
area
per
given
volume.
 o The
smaller
the
bubble
=>
the
greater
the
pressure
 They
are
more
susceptible
to
collapse
 o The
larger
the
bubble
=>
lower
pressure
 More
stable
 o If
one
connected
two
balloon
of
varying
sizes,
which
one
will
collapse
 and
empty
into
the
other?
 The
small
one
will
collapse
due
to
the
greater
pressure,
 emptying
into
the
larger
one
 This
can
be
seen
if
you
look
at
dishwater
bubbles.

They’re
 extremely
dynamic
and
constantly
fuse
 Go
Notes
10
 
 Law
of
LaPlace
 ‐ Pressure
=
4T
/
r
(full
bubbles
with
two
air
water
surfaces;
therefore
double
 the
P)

 ‐ For
our
purposes,
alveoli
are
half
bubbles,
P
=
2T
/
r
 o T
=
surface
tension,
r
=
radius
 ‐ So
again,
this
formula
confirms
the
fact
that
smaller
bubbles
have
higher
P
 
 
 ‐ Does
this
mean
that
smaller
alveoli
are
more
likely
to
collapse?
 o NO!
‐>
because
of
the
presence
on
lung
surfactant.
 DPPC
serves
to
decrease
the
term
T
 It
breaks
the
hydrogen
bonding
between
 water
molecules
as
it
has
a
polar
 region
and
2
hydrophobic
tails
 *Fig
17‐13
 DPPC
itself
is
more
concentrated
 in
smaller
alveoli
then
in
 larger
ones
 So
it
equalizes
 pressure
among
 alveoli
of
varying
sizes
 
 *Fig
17‐2d
 Lungs
and
thoracic
cavity
cross
section
 ‐ The
Left
lung
–
is
smaller
and
is
composed
on
only
two
lobes
(superior
and
 inferior)
due
to
volume
taken
up
by
the
heart
 ‐ The
Right
lung
–
is
larger,
with
three
lobes
(superior,
middle,
inferior)
and
 has
a
steeper
primary
bronchus
 ‐ All
thoracic
organs
are
encompassed
in
membranous
sacs
 o For
the
heart
=
pericardium
 o For
the
lungs
=
pleural
membrane
 One
side
of
the
membrane
is
attached
to
the
thoracic
wall
and
 the
other
is
attached
to
the
lungs
 o Each
are
closed
cavities
w/
some
lubricating
fluid
(a
couple
of
 millileters)
 The
pleural
fluid
primarily
has
two
main
functions
 • 1.

Cohesion
–
provides
forces
which
keep
the
walls
 connected
(think
when
two
glass
slides
have
water
in
 between
them)
 • 2.

Lubrication
–
decreases
friction
between
the
 movement
of
the
wall
and
the
movement
of
the
lungs.
 
 *Fig
17‐3
 pleural
space
=
balloon
 ‐ There
are
two
opposing
forces,
which
act
upon
the
intrapleural
space
(IP)
 Go
Notes
11
 ‐ o The
ribs
are
shaped
in
such
a
way
that
they
want
to
“bow”
outwards
 o The
lungs,
or
more
specifically
their
elasticity,
wants
to
collapse
 o ‐>
Therefore
these
two
opposing
forces
on
the
IP
create
NEGATIVE
 pressure
(always!).


 If
by
some
accident
(stabbing,
breaking
a
rib
through
the
pleura,
violent
 cough
or
gsw),
the
IP
space
is
exposed
to
the
atmosphere,
air
will
flow
down
 its
pressure
gradient
into
the
intrapleural
space.

This
air
will
overcome
the
 cohesive
forces
of
the
pleural
fluid,
and
the
lung
will
collapse
=
 PNEUMOTHORAX
*Fig
17‐12
 o Treat
by
sealing
opening,
use
needle
one
way
valve
to
decrease
air
in
 the
IP
during
inhalations.
 
 
 April
1,
2011
 
 Ok
so
I’m
not
going
to
front.

Uhm
I
didn’t
go
to
today’s
lecture
because
during
 Fridays
I
have
a
scheduling
conflict
with
one
of
my
grad
classes.

However,
being
 that
this
is
my
5th
time
TAing
this
course
(ie
have
heard
this
lecture
5
times
before),
 I
can
more
or
less
guess
as
to
what
Dr.
Fortes
presented.

For
example,
he
may
have
 done
the
balloon
prop,
presented
lung
inflation
curves,
etc.
etc.

So
rest
assured
the
 material
I
present,
will
more
or
less
contain
all
the
information
pertinent
to
this
 lecture.

Feel
free
to
email
me
(adgo@ucsd.edu)
if
I
jump
ahead
or
fall
behind
on
 these
notes
and
I
can/will
adjust
adjust
them
accordingly.

Thanks,

 ‐
Jag
 
 Ventilation
cont.
 Poiseuille’s
equation
 Lung
inflation
curves
 Compliance
 Surface
tension
 Lung
surfactant
 Law
of
LaPlace
 Spirometry
 
 Lung
Volumes
and
Capacities
 Forced
Expiration
tests
 Total
and
Alveolar
ventilation
 
 Boyle’s
Law
 ‐ PV
=
nRT
 o so
at
constant
T,

P1V1=P2V2
 
 How
many
ways
are
there
to
inflate
a
balloon?
 1. Blow
into
it
like
a
ventilator
 2. Or
decrease
the
pressure
of
the
surrounding
areas
of
the
balloon.
 Go
Notes
12
 a. This
is
more
efficient
for
our
purposes.

Balloon
prop
=
pull
on
the
 syringe
‐>
increase
pleural
volume
‐>
decreases
pleural
pressure
‐>
 balloon
expands
(V
inc)
‐>
the
pressure
inside
the
balloon
decreases
‐ >
air
flows
from
high
P
(atmosphere)
to
lower
P
(balloon).
 
 *Fig
17‐9
Ventilation
mechanics
 • part
one
the
diaphragm
and
ext
intercostals
contract
which
increase
the
 volume
to
the
thorax.

Because
the
thorax
is
connected
to
the
pleural
 membrane…
 • ↑VIP
‐>
↓PIP
‐>
↑PTP
‐>
↑Valv
‐>
↓Palv
‐>
air
flows
from
high
P
(atm)
to
low
P
 (alv)
 • What
is
PTP?
 o PTP
=
Palv
–
PIP
 o Its
always
positive
 o ALWAYS!!!
 
 Poiseuille’s
equation
 ‐ all
flow
equations
are
analogous
to
Ohm’s
law
 ‐ Flow
=
driving
force/resistance
 o I
=
ΔV/R
 ‐ But
physiologists
utilize
conductance
(G)
 o G
=
1/R
 ‐ Poiseuille’s

 o Flow
(Q)
=
ΔP
π
r2/
8
η
l
 o Where
r
=
radius,
η
=
viscosity,
and
l
=
length
 o Therefore,
r
=
8
η
l
/
π
r2
 
 Lung
inflation
curve
 
 
 
 TLC
‐
 b
 
 
 
 
Vol
 a
 c
 

 
 
 

RV
‐
 
 
 
 
 ‐10
 ‐20
 
 P
in
cmH2O
 
 Compliance
is
the
ability
of
an
object
to
be
deformed.
 Go
Notes
13
 ‐ ‐ ‐ Essentially,
it
is
the
change
in
volume
per
given
change
in
P.

Compliance

=
 ΔV/ΔP
 ‐
a
plastic
bag
has
higher
compliance
than
say
a
brick…
 At
low
pressures,
it
is
compliance
is
naturally
low
(this
is
intuitive,
it
harder
 to
initiate
inflation
of
a
balloon,
but
once
it
is
started
it
become
much
easier)
 If
compliance
is
too
high,
there
is
essentially
no
elasticity
(the
ability
to
 return
to
normal
shape/volume
after
deformation
(ie.
Notice
that
a
plastic
 grocery
bag
will
not
deflate
on
its
own
after
inflation.)
 
 o If
compliance
is
too
high,
manual
effort
(via
contraction
of
abs)
is
 necessary
in
order
to
expel
air.
 
 Lung
curves
–
refer
to
above
graph…
 a. Normal
lung
inflation.


 a. Notice
that
compliance
(slope)
is
low
at
the
beginning
(hard
to
initiate
 inflation
of
a
balloon),
it
increases
dramatically
at
‐10mmHg,
and
 decreases
again
at
the
end
(right
before
a
balloon
will
pop)
 b. Lung
inflated
with
saline
 c. Lung
inflated
with
air
POST‐saline
 
 ‐ What
happens
from
a
‐>
b?
 o Repeat
a,
but
with
saline
instead
of
just
air
 o Increase
in
compliance
due
to
the
elimination
of
the
air
water
 interface.

There
is
no
more
surface
tension
between
the
surface
 tension/cohesion
of
the
H2O
molecules.
 Why
do
we
need
an
air‐H2O
interface
to
begin
with?
 • Gasses
cannot
just
dissolve
from
the
air
to
the
blood
 • Diffusion
requires
it
to
first
dissolve
into
the
alveolar
 liquid,
and
then
from
there
it
can
dissolve
into
the
blood
 
 ‐ What
happens
from
b
‐>
c
 o The
lungs
were
drained
of
saline
and
re‐inflated
with
air.
 o All
of
a
sudden
there
is
a
large
decrease
in
compliance.

(moreso
than
 the
normal
inflation
curve).
 o So
what
changed?
‐>
there
must
have
been
something
that
washed
out
 with
the
saline
in
the
previous
experiment.
 o What
was
washed
out?

‐>
the
lung
surfactant
was
removed
when
the
 saline
was
washed
out.
 The
active
ingredient
in
lung
surfactant
was
Dipalmitoyl
 phosphatidyl
Choling
(DPPC).
 Remember
that
the
lung
surfactant
is
secreted
by
type
II
 alveolar
cells.

Those
are
not
mature
until
the
7th
month
(28th
 week)
of
pregnancy.


 • If
DPPC
is
insufficient
‐>
infant
respiratory
distress
 syndrome.

These
“preemies”
require
artificial
DPPC
in
 order
to
survive.
 tercostals (Sternocleidomastoids, Scalenes) al Intercostals) Go
Notes
14
 
 
 r rib is behind insertion of lower rib, contraction ! lifts and pushes out ribs This
graph
is
also
another
way
of
looking
at
the
P
volume
graphs.
 
 
 ases volume of This
graphically
shows
that
FRC
or
 n functional
residual
capacity
of
the
lung
 is
the
pt
in
which
the
bowing
of
the
 of the chest
wall
and
the
elastic
recoil
of
the
 f the lungs
balance
at
atmospheric
P.
 onary pressure 
 d pleura, P(alv) Note:
cm
in
H20
is
easier
to
measure
 ! decrase rather
than
Hg
columns.

To
convert
 approximately
1
mmHg
=
1.34
cm
H2O
 
 t to be 
 lume change for 
 
 
 low (this makes 
 on is hard at the 
 easier) (to be discussed 
 
 *Fig
17‐11
Pressure
changes
during
resting
breathing
 ‐ Inspiration
 !"#$"%&" o The
diaphragm
contracts
causing
PIP
to
decrease
from
‐3
to
even
more
 negative
numbers.
(B1
‐>
B2)
 o The
decrease
in
PIP
will
decrease
the
Palv
from
0
to
‐1
mmHg
(A1
‐>
A2)
 o At
time
=
1
sec,

air
has
been
flowing
into
the
alveoli
from
the
 atmosphere
because
of
the
negative
P
in
the
alveoli.

However
as
that
 air
is
flowing
in,
we’re
increasing
the
amount
of
molecules
in
the
 alveoli,
so
the
Palv
starts
to
rise
from
A2
‐>
A3
(but
still
negative)
 o Because
Palv
is
still
negative,
relative
to
atmosphere,
air
will
continue
 to
flow
into
the
alveoli
(from
250ml
to
500ml
inspired)
 o At
A3,
the
amount
of
air
added
increased
the
alveolar
pressure,
 counteracting
the
decrease
in
pressure
caused
by
the
stretching
of
the
 thorax
and
alveoli.

At
this
point
the
Palv
=
Patm,
and
air
no
longer
flows
 in.

 ‐ Expiration
 o Also
at
A3,
if
you
start
to
relax
your
diaphragm,
the
lungs
are
allowed
 to
passively
recoil.
 o This
increase
the
IP
pressure
B2
‐>
B3
(‐6
to
‐3),
the
Palv
increases
 above
atmospheric
(A3
‐>
A4
‐>
A5),
and
air
is
expired
from
C2
‐>
C3.
 ‐ Why
is
there
a
difference
between
the
PIP
range
from
‐3
to
‐6
and
the
Palv
 range
from
0
to
±1?


 Go
Notes
15
 o Because
a
lot
of
the
work
in
stretching
the
thorax
has
to
fight
the
 elasticity
of
the
lung
 
 Flow
rate
of
air
as
a
fxn
of
effort.
 ‐ Physiologists
conducted
two
experiments.
 o 1.

Inspire
maximally
to
reach
TLC,
then
blow
out
as
fast
as
possible.

 They
then
measured
the
flow
 Initially
flow
was
fast
because
of
the
↑PIP/↑Palv
 However
at
middle
to
lower
lung
volumes
the
flow
decreased
 to
a
stable
flow
rate
 o 2.

After
a
normal,
tidal,
inspiration
‐>
expire
normally.

Measure
flow.
 Flow
was
identical
in
medium/lower
lung
volumes
to
that
of
 the
first
experiment.
 ‐ The
result
was
they
concluded
that
at
medium/low
lung
volumes,
flow
is
 INDEPENDENT
of
effort.
 ‐ This
baffled
the
researchers
because
by
Poiseuille’s
law
(Q
=
ΔP
π
r4/
8
η
l)
 flow
should
increase
with
increased
effort/pressure
 o So
why
is
the
flow
identical?
 o It
turns
out,
that
with
increasing
effort
the
resistance
to
air
flow
 increases
as
well
 o The
resistance
is
increasing,
because
of
compression
of
the
airways
 due
to
more
force
being
generated.
 
 
 
 The
following
figure
illustrates
this
process
well.
 
 *Fig
7‐18
West
book
 Dynamic
Compression


 ‐
Occurs
under
normal
physiological
 conditions



 ‐
Basic
idea:
Poiseuille’s
law
predicts
 that
increased
effort
(forced
 expiration)
will
increase
the
flow
of
 air
out
of
the
lungs

 ‐
What
we
actually
find
is
that
after
a
 maximal
point,
flow
becomes
 independent
of
effort


 ‐
Why
does
this
occur?
Increased
 pressure
causes
collapse
of
the
 airways
increasing
resistance
and

 decreasing
flow.

Additional
effort
 only
increases
resistance.


 ‐
Now
you
can
look
at
graph
D;
this
shows
that
increased
effort
for
expiration
‐>
 Go
Notes
16
 decrease
volume
in
thorax
‐>
increase
 pressure
in
thorax
‐>
collapses
airways
‐ >
flow
becomes
independent
of
effort

 ‐
Typically
this
is
not
a
problem
for
most
 individuals.


 ‐
But,
in
patients
with
emphysema,
a
loss
 of
elastic
fibers
increases
compliance
 and
decreases
the
rigidity
of
the
 bronchioles

 ‐
When
a
patient
with
emphysema
takes
a
deep
breath,
the
increased
pressure
can
 collapse
the
bronchioles
and
actually
make
it
more
difficult
to
expel
air!
 
 *Fig
17‐8
Spirometry
 
 Tidal
Volume
–
resting
inspiration
and
expiration
(~500ml)

 Inspiratory
Reserve
Volume
–
maximum
inspiration
(~3L)

 Expiratory
Reserve
Volume
–
maximal
expiration
(~1100ml)


 Residual
volume
–
air
left
in
your
lung
even
after
maximal
expiration
(~1200ml)

 Lung
Capacities
–
combinations
of
two
or
more
volumes

 Inspiratory
Capacity
=
IRV
+
TV

 Functional
Residual
Capacity
=
ERV
+
RV

=
point
at
which
no
muscles
are
 
 Contracted,
no
air
is
moving,
and
Palv
=
Pbronchioles
=
Patm.
 Vital
Capacity
=
IRV
+
TV
+
ERV
=
maximum
amount
of
air
that
can
be
moved
in
and
 
 out
of
your
lungs
 Total
Lung
Capacity
=
IRV
+
TV
+
ERV
+
RV

 

 How
do
we
measure
RV?

 ‐ Dilution
techniques
(using
an
inert
gas)
 ‐ Measure
initial
and
final
concentrations
of
a
radioactively
labeled
gas
or
 helium
and
then
use…
V1C1
=
V2C2

 
 Lung
diseases
(in
regards
to
ventilation
problems
there
are
2
major
categories,
but
 many
others
that
don’t
affect
ventilation)
 1. Restrictive
diseases
 a. Marked
by
a
decreased
ability
to
inflate
the
lung
 b. Examples
include
no
surfactant,
fibrosis
 c. ↓compliance,
therefore
↑elasticity
 2. Obstructive
diseases
 a. Marked
primarily
by
an
increased
resistance
to
air
flow
 b. Examples
include
COPD
(chronic
bronchitis
and/or
emphysema),
and
 asthma
 c. In
the
case
of
emphysema,
there
is
↑compliance.

Proteases
destroy
 alveoli
(↓
surface
area
for
gas
exchange,
hindering
diffusion)
and
also
 destroy
elastin
fibers
(↓elasticity).
 Go
Notes
17
 i. In
this
case
the
increase
in
resistance
to
airflow
is
not
during
 inhalation
but
rather
exhalation.

Because
the
elastin
is
 destroyed
(in
alveoli
as
well
as
airways)
these
individuals
have
 to
manually/actively
exhale.

The
generation
of
force
results
in
 a
tendency
for
their
airways
to
collapse
=
dynamic
 compression
of
the
airways
(discussed
more
next
time).
 ii. Dynamic
compression
results
in
retention
of
air
because
they
 essentially
can’t
get
air
out.

If
that
“stale”
air
cannot
escape,
it
 becomes
increasingly
harder
to
ventilate
“fresh”
air
into
the
 lungs.


 iii. To
decrease
the
possibility
of
dynamic
compression
individuals
 with
emphysema
often
take
very
shallow
breaths,
and
exhale
 very
slowly.

Because
they
take
shallow
breaths
they
do
not
 have
to
exhale
as
much
volume,
and
do
so
slowly
as
to
 minimize
their
effort.
 d. For
bronchitis
(inflammation
of
the
bronchioles)
and
asthma
 (inflammation
and
bronchoconstriction)
the
lumen
of
the
bronchioles
 decreases
thus
increasing
resistance
for
both
inhalation
and
 exhalation.

 
 
 April
4,
2011
 
 Spirometry
(cont)
 
 Abnormalities
in
volumes
and
capacities
 
 Forced
expiration
tests
 Dalton’s
Law
 Alveolar
Gas
equation
 Total
ventilation
 Alveolar
ventilation
 Effects
of
dead
space
 
 Obstructive

 ‐ Pneumonia,
asthma,
COPD,
bronchitis,
emphysema,
esophageal
cancer

 ‐ Often
associated
with
constriction
of
the
bronchioles,
inflammation
and
 secretion
of
mucous
in
lumen
of
the
conducting
zone

 ‐ Loss
of
elastic
fibers
causes
increase
compliance
and
retention
of
air
in
the
 lungs
–
increases
RV!

 ‐ It’s
hard
to
get
air
out
because
of…

 o 1.
Loss
of
elastic
fibers
prevents
recoil

 o 2.
Obstruction
of
the
airways
(esophageal
cancer)
à
decrease
radius
 ‐>
decrease
flux
(Poiseuille’s
law)

 ‐ Decreased
vital
capacity
(mostly
because
of
decreased
ERV)

 ‐ Chronic
smoking
can
lead
to
an
obstructive
pulmonary
disease…

 o Increased
irritation
‐>
bronchitis,
increased
secretions,
paralysis
of
 Go
Notes
18
 o o the
mucociliary
escalator
‐>
COPD
‐>
emphysema

 Also,
cigarette
smoke
stimulates
proteases
in
the
lung
‐>
decreases
 elastic
fiber
and
eventually
decreases
overall
alveolar
surface
area

 Combined
these
effects
cause
increased
compliance,
decrease
 surface
areas,
increased
residual
volume
and
can
exacerbate
 dynamic
compression
of
the
airways!

 Restrictive
 ‐ Impede
proper
inflation
of
the
lung

 ‐ Decrease
compliance

 ‐ Usually
caused
be
accumulation
of
inorganic
material
in
the
alveoli
(chalk
dust,
 coal
dust
etc.)

 ‐ This
inorganic
material
is
consumed
by
macrophages
but
can
not
be
digested
 causing
the
recruitment
of
fibroblasts
which
deposit
collagen
fibers
(leading
 to
“fibrosis”)

 ‐ Collagen
fibers
are
very
inelastic
decreasing
the
compliance
of
the
lung
(very
 hard
to
get
air
into
the
lung)

 ‐ This
will
decrease
total
lung
capacity,
decrease
inspiratory
reserve
volume
and
 decrease
vital
capacity

 

 FEV/FVC

 ‐ Take
a
maximum
inspiration
‐>
TLC

 ‐ Blow
out
as
fast
as
you
can!

 o Measure
the
volume
of
air
that
comes
out
in
1
second
(FEV1)

 o Total
Volume
Expired
=
FVC
(same
as
vital
capacity
for
all
intensive
 purposes)

 ‐ Normal
person,
FEV/FVC
~0.8

 ‐ For
obstructive
diseases…

 o FEV1/FVC
<0.8
(as
low
as
0.3)
because
 of…

 o The
loss
of
elastic
fibers
which
 makes
the
lung
more
difficult
to
 recoil
(emphysema)
 o Dynamic
compression
or
restriction
 of
the
airways
(bronchitis,
asthma
 and
emphysema)

 o Also,
TLC
and
RV
will
increase
for
 individuals
with
advanced
 emphysema
because
of
the
increase
 compliance
(think
of
a
plastic
bag;
 it’s
really
easy
to
get
air
in
but
really
difficult
to
get
air
out)

 ‐ For
restrictive
diseases…

 o TLC
decreases
because
of
decreased
compliance
(due
to
collagen
 fiber
inelasticity,
therefore
graph
starts
lower)

 o Collagen
fibers
increase
the
recoil
of
the
lung
and
therefore
allow
 patients
to
exhale
very
quickly

 o (FEV1/FVC
>0.8,
as
high
as
0.9)

 Go
Notes
19
 
 Dalton’s
Law
(of
partial
pressures)
 ‐ Patm
=
sum
of
the
partial
pressures
of
each
constituent
gas
 ‐ Patm
=
PN2
+
PO2
+
PCO2….
 ‐ 1
atmosphere
is
equal
to
760
mmHg
at
sea
level
 
 How
to
calculate
the
partial
P
of
a
particular
gas?
 ‐ If
you
know
the
fraction
of
the
gas
and
the
Patm
you
can
extrapolate
and
 calculate
the
partial
pressure
 ‐ In
dry
air,
N2
=
79%,
O2
=
21%
(actually
20.93%),
and
CO2
=
.03%
(can
 round
to
0)
 ‐ These
percentages
do
NOT
change
w/
altitude,
only
Patm
does
 ‐ So
for
example
PO2
=
760
x
.21
=
160mmHg
 
 • What
about
high
altitude?


 o Atmospheric
pressure
decreases
drastically

 o The
air
is
mixed
in
the
same
proportions
/
fractions
(0.21
oxygen,
 0.79
nitrogen)

 o The
partial
pressures
are
decreased
proportional
to
atmospheric
 pressure
(i.e.
if
atmospheric
pressure
was
cut
in
half,
the
partial
 pressure
of
oxygen
would
also
cut
in
half)

 o This
is
why
cabins
have
to
be
pressured
on
airplanes…
(more
later…)

 
 • What
about
going
below
sea
level?

 o Death
valley
for
example


 o Too
small
of
a
distance
to
effect
pressures
significantly

 
 • But
what
about
going
below
the
water?

 o For
every
10
meters
you
go
down…
increase
pressure
by
1
 atmosphere
(14psi)

 o Perspective:
tires
on
your
car
are
~
3atm
(equivalent
of
20
meters
 below
water)

 o As
you
dive…
gasses
(nitrogen)
dissolve
into
your
blood
stream
 because
of
the
high
pressure;
as
you
rise,
if
you
come
up
too
 quickly,
the
nitrogen
bubbles
will
come
out
of
solution
and
cause
 bubbles
in
your
blood
(The
Bends!)

 o Hyperbaric
chambers
generate
pressures
>
3atm
 
 But
the
air
in
the
respiratory
system
is
not
dry
air.

Instead,
it
is
saturated
with
 100%
H2O.
 ‐ The
solubility
of
H2O
within
air
is
dependant
upon
temperature.

(higher
 temp
‐>
higher
solubility)
 ‐ At
body
temp,
37°C,
100%
saturation
is
approximately
a
PH2O
of
47mmHg

 o As
soon
as
air
enters
the
airways
it
is
fully
humidified
and
brought
 up
to
37°C
 Go
Notes
20
 ‐ ‐ ‐ 
 The
presence
of
H2O
dilutes
the
concentration
of
the
other
gasses.
 But
since
the
Patm
=
P1
+
P2
+
P3
+
PH20
we
can
simply
subtract
PH2O
in
order
to
 calculate
the
gasses
 So
the
PIO2
=
(Patm
–
PH2O)
x
%O2
 o Inspired
PO2
=
(Patm
–
PH2O)
x
fraction
O2

 (760
–
47)
x
.21
=
150mmHg
 ‐ 
 When
air
gets
to
the
respiratory
zone,
O2
is
diffusing
out
of
alveoli
and
CO2
is
being
 added.
 ‐ There
is
steady
of
state
of
diffusional
movements
which
are
matched
with
 external
ventilation
 ‐ PAO2
(alveolar)
=
100mmHg
at
sea
level
 ‐ PACO2
=
40mmHg
 ‐ But
what
we
breath
in
is
PIO2
=
150mmHg
(calculated
above)
 o How
does
it
go
from
150mmHg
to
100mmHg
(next
lecture)?
 ‐ Alveolar
air
is
essentially
in
equilibration
of
blood
arterial
concentrations
 o PaO2
(arteriole)
=
100mmHg
and
PaCO2
(arteriole)
=
40mmHg
 
 *Fig
17‐15
as
alveolar
ventilation
increase
Alveolar
PO2
increases
and
PCO2
 decreases.
 ‐ Normal
ventilation
=
4.2
L/min
 ‐ If
hypoventilating,
<4.2
L/min
‐>
PO2
decreases
and
PCO2
increases
 ‐ If
hyperventilating,
>4.2L/min
‐>
PO2
increases
and
PCO2
decreases
 
 As
we
shall
see,
CO2
reacts
with
H2O
and
creates
H2CO3
‐>
which
dissociates
into
 H+
and
HCO3‐

 ‐ CO2
creates
an
acid
 ‐ Soda
pop
are
drinks
which
are
carbonated
in
order
to
balance
the
sugary
 content
with
acid
 ‐ HCO3‐
is
the
main
extracellular
buffer
which
maintains
pH
at
normal
 physiological
level
of
7.4
(more
on
this
later)
 o If
we
hyperventilate,
we
shift
the
equilibrium
(by
law
of
mass
 action)
of
this
reaction
which
removes
H+
and
thus
raises
pH
 o Hypoventilation,
will
induce
the
opposite,
retention
of
CO2
shifts
 equilibrium
right‐ward
‐>
causing
the
formation
of
H+
thus
 lowering
pH
 o [CO2]
is
a
major
regulator
of
pH
 
 Which
can
be
changed
via
lungs
(fast)
or
kidney
fxn
(slow)
 
 In
alveoli,
O2
is
contantly
being
replaced
w/
CO2
 ‐ Essentially,
PCO2
↑,
while
PO2
↓
 ‐ This
is
a
dynamic
exchange
which
reaches
equilibration
 ‐ Essentially
it
depends
on
the
rate
at
which
O2
is
being
utilized
and
the
rate
in
 which
CO2
is
produced.
 Go
Notes
21
 ‐ We
calculate
it
via
the
alveolar
gas
equation…
 o Answers
how
a
PIO2
of
150mmHg
becomes
a
PAO2100mmHg
in
the
 arterial
circulation.
 
 Alveolar
gas
equation:
 ‐ PAO2
=
PIO2
–
(PaCO2/R)
 ‐ Alveolar
O2
=
inspired
O2
–
(arterial
CO2/respiratoy
quotient)
 ‐ R
=
respiratory
quotient
or
respiratory
exchange
ratio
(RER)

 o Depends
on
metabolism
 o =
CO2
produced
/
O2
consumed
 o is
a
general
indication
of
metabolism
 for
carbs
=
1
 for
fats
=
.7
 for
proteins
=
.84
‐
.9
 for
mixed
diets
=
.8
 ‐ For
normal
values
PAO2
=
150mmHg
–
(40mmHg/0.8)
=
100mmHg
 ‐ Remember
that
arterial
blood
is
in
equilibrium
w/
alveolar
air
 
 April
6,
2011
 
 Vtotal
 Dead
Space
(anatomic
vs
physiological)
 Valv
 Gas
exchange
 Fick’s
 Diffusion
Limited
gas
exchange
 Perfusion
limited
gas
exchange
 V/Q
Matching
 Properties
of
pulmonary
arterioles
and
bronchioles
 
 Total
Ventilation:
 Vtot
(L/min)
=
Vtidal
x
frequency
 ‐ on
average,
a
tidal
V
of
500ml
and
a
frequency
of
12
breaths/min
=
6L/min
 ‐ this
equation
is
very
much
similar
to
the
cardiac
output
equation
from
 mamphys
1
(CO
=
stroke
volume
x
heart
rate)
 ‐ but
remember
that
the
alveoli
do
not
receive
all
of
this
total
ventilation
 because
of
dead
space
‐>
Alveolar
ventilation
equation
(below)
 
 Alveolar
Ventilation:
 Valv
(l/min)
=
(Vtidal
–
Vdead)
x
frequency
 ‐ on
average
dead
space
is
equal
to
150ml
 ‐ so
(500
–
150)
x
12
=
4.2L/min
 
 *Fig
17‐14
 1. 


Right
after
a
tidal
inspiration
–
of
the
tidal
volume
of
500ml,
350ml
of
fresh
 Go
Notes
22
 air
makes
it
to
the
alveoli
and
150ml
of
“fresh”
air
occupies
the
dead
space.
 2. 


Exhale
500ml,
a
tidal
volume
–
the
first
exhaled
150ml
is
the
fresh
air
that
 occupied
the
dead
space.

Next,
350ml
of
stale
air
exits.

Think
about
this
 logically,
the
150ml
of
fresh
air
that
exits
is
one
of
the
major
reasons
in
which
 CPR/rescue
breathing
works.

The
350ml
of
stale
air,
also
contributes
to
the
 success
of
CPR/rescue
breathing
but
we’ll
discuss
this
later
when
we
talk
 about
chemoreceptor
reflexes
 3. 


At
the
end
of
a
tidal
expiration,
the
dead
space
is
occupied
with
stale
air
that
 just
left
the
alveoli
in
the
previous
step.
 4. 


Inhale
500ml
of
fresh
air
–
150
ml
of
stale
air
that
occupied
the
airways
is
 forced
into
the
alveoli
and
350
ml
of
reaches
the
alveoli
where
it
mixes
with
 the
2200ml
of
stale
air
that
previously
occupied
it.

The
combination
of
 2350ml
of
stale
air
and
350ml
of
fresh
air
adds
CO2
and
dilutes
O2
of
the
 fresh
air
(that’s
why
PIO2
=
150mmHg
and
PAO2
=
100mmHg).

In
addition,
 now
the
dead
space
is
occupied
by
150ml
of
fresh
air.
 5. 


“rinse
and
repeat”
 
 Both
Vtotal
and
Valveolar
can
increase/decrease
by
simply
changing
the
Vtidal
or
 frequency.
 ‐ although
cardiac
output
can
increase
5
or
6
fold
 ‐ the
ventilation
can
be
increased
25‐30
fold
 
 If
you
take
in
less
air
than
in
your
dead
space,
‐>
no
exchange
with
the
outside
and
it
 will
eventually
lead
to
asphyxiation
 ‐ Snorkeling
example
(LISTEN
TO
PODCAST
IF
EXPLANATION
INSUFFICIENT)
 o The
effect
of
a
snorkel
generally
increases
the
dead
space
 o In
order
to
maintain
the
same
alveolar
ventilation
one
has
to
 increase
the
tidal
volume
or
increase
the
respiration
rate
 ‐ Story
time
(bad‐guy
bamboo
analogy)
 o Bad
dude
or
hero
wants
to
hide
from
people
who
want
to
kill
him
 o He
hides
at
the
bottom
of
a
lake/pond
and
uses
a
hollowed
out
 bamboo
tube
to
breath
through
 o But
bamboo
tube
seriously
increases
his
dead
space.
 o If
he
breathes
in
the
tube,
and
out
through
the
water
bad
people
see
 bubbles
‐>
dead.
But
if
he
breathes
in
through
one
tube,
and
out
 through
another
he’s
safe
 o Essentially,
if
the
tube
is
greater
than
or
close
to
his
vitally
capacity
 he,
will
only
exchange
air
between
the
outside
and
the
tube.

No
 fresh
air
gets
to
the
alveoli.
 
 Anatomic
dead
space
=
is
what
naturally
comprises
our
airways
 Physiologic
dead
space
=
should
normally
equal
our
anatomic
dead
space.

However,

 
 there
are
certain
situations
in
which
the
physiological
dead
space
can
 increase

due
to
a
pulmonary
embolism
or
emphysema
which
essentially
 destroys
surface
area
thus
minimizing
exchange.

 
 Go
Notes
23
 
Henry’s
Law
 ‐ calculation
of
partial
pressure
of
a
gas
in
a
liquid
 ‐ [gas]
=
Pgas
x
Solubilitygas
in
liq
 ‐ Different
gasses
have
different
solubilities
within
liquids
 o Ie
CO2
is
20x
more
soluble
in
H2O
than
O2
 So
at
PaO2
100mmHg
of
O2
=
concentration
=
100
 But
PaCO2
=
40mmHg
x
20solubility
=
concentration
=
800
 
 *Fig
17‐15
as
alveolar
ventilation
increase
Alveolar
PO2
increases
and
PCO2
 decreases.
 ‐ Normal
ventilation
=
4.2
L/min
 ‐ If
hypoventilating,
<4.2
L/min
‐>
PO2
decreases
and
PCO2
increases
 ‐ If
hyperventilating,
>4.2L/min
‐>
PO2
increases
and
PCO2
decreases
 
 Fick’s
law
of
diffusion
 ‐ 


Flux
=
(ΔP
x
Area
x
D)
/
Thickness

 ‐ 


D
=
(Dcoeff
*
Solubility)
/
(Molecular
Weight^1/2)

 ‐ Area,
D
&
Thickness
are
sometimes
grouped
together
to
be
called
the
 “diffusion
capacity
of
the
lung
=
DL”
 ‐ Which
terms
can
change?
 o ΔP
if
concentrations
change
(like
at
high
altitude)
or
via
 hypo/hyper
ventilation
 o area
–
can
change
via
exercise
(increased
pulmonary
blood
 pressure
can
open
up
additional
capillary
beds
which
were
closed
 at
rest)
,
diseases
like
emphysema
(disease
destroys
alveolar
 surface
are
decreasing
area
of
exchange),
or
blocked
airways
of
 blood
vessels
(thus
decreasing
SA).
 o Thickness
‐

mostly
in
pathological
situationlike
increase
fluid
in
 the
lung
(via
pulmonary
edema
caused
by
increased
filtration
 pressure
due
to
LH
failure
or
widespread
pulmonary
 vasoconstriction)
or
via
pulmonary
hypertension.

In
addition
 fibrosis
can
add
scar/fibrous
tissue
from
chronic
inflammation
 (asbestos
poisoning,
coal
dust,
chalk
dust,
smoking).
 
 
 April
8,
2011
 
 MOVIE
 
 
 
 
 
 
 
 Go
Notes
24
 
 April
11,
2011
 Gas
exchange
 Diffusion
limited
+
perfusion
limited
gas
exchange
 Properties
of
pulmonary
circulation
 Local
and
autonomic
factors
that
regulate
bronchioles
and
arterioles
 V/Q
matching
 Effects
of
gravity
on
V/Q
 ‐‐‐‐‐‐‐‐‐0‐‐‐‐‐‐‐‐‐‐
 gas
transport
 Hb‐O2
association
curve
 
 *Fig
18‐3
gasses
diffuse
down
their
partial
pressure
gradient
at
alveoli
and
cells.
 ‐ In
lungs
 o Alveoli
have
a
PAO2
of
100mmHg
and
a
PACO2
of
40mmHg
 o Quickly
equilibrates
with
arterial
gas
levels
 o O2
diffuses
into
capillaries
due
to
gradient
(100‐>40mmHg)
and
 CO2
diffuses
into
alveoli
(46
‐>
40mmHg)
 o ARTERIAL
BLOOD
=
100mmHg
of
O2
and
40mmHg
of
CO2
 ‐ At
tissues
 o Tissues
have
a
PO2
of
40mmHg
and
a
PCO2
of
46mmHg
due
to
 cellular
respiration
 o Rapidly
equilibrate
again
 o O2
diffuses
into
tissues
due
to
gradient
(100mmHg
‐>
40mmHg
in
 soma)
and
CO2
diffuses
into
capillaries
(46mmHg
‐>
40mmHg)
 o VENOUS
BLOOD
=
40mmHg
of
O2
and
46mmHg
of
CO2.
 ‐ NOTICE
=
that
these
are
mixed
values
 o In
the
lung
there
are
varying
degrees
of
perfusion
hence
varying
 degrees
of
exchange.

When
all
of
the
pulmonary
veins
reconvene
at
 the
left
atrium,
the
average
is
100mmHg
of
O2
and
40mmHg
of
CO2
 o In
the
tissues,
varying
tissues
have
varying
metabolism
and
 therefore
produce
more
(muscle)
or
less
(bone)
CO2
and
use
O2,
 respectively.
But
when
they
all
reconvene
in
the
systemic
venous
 vessels,
the
mized
venous
blood
has
a
concentration
of
40mmHg
of
 O2
and
46mmHg
of
CO2.
 ‐ As
for
which
gas
diffuses
faster?
 o Δ60
mmHg
for
O2
and
Δ6
mmHg
for
CO2
 o but
remember
that
CO2
is
20x
more
soluble
 diffusion
is
slower
slower
for
O2
than
CO2
 o because
of
these
differential
rates
of
diffusion,
a
hypoventilated
 person
will
exhibit
hypoxia
symptoms
before
hypercapnia
 symptoms.
 ‐ Nitrous
oxide
(N2O)

 Go
Notes
25
 o o o o o 
 ‐ Oxygen

 o o o o o o o o (don’t
confuse
with
nitric
 oxide)
–
anesthetic
 properties,
“laughing

gas”

 
Added
to
the
alveoli
at
a
 partial
pressure
of
 100mmHg

 Diffusion
will
occur
until
the
 partial
pressure
equilibrates
 with
that
in
the
capillary

 Equilibrates
very
rapidly

 Why?
Diffuses
into
the
water,
 does
not
bind
hemoglobin,
 does
not
undergo
any
 metabolic
reactions
in
the
 plasma

 Normal
partial
pressure
of
oxygen
at
sea
level
is
~
100mmHg
(in

 alveoli)

 PO2
of
mixed
blood
is
40mmHg
at
the
beginning
of
the
capillary
 (which
is
why
the
graph
doesn’t
start
at
the
origin!)

 Why
does
it
equilibrate
 slower
than
that
of
N2O?


 Binds
hemoglobin

 Partial
pressure
is
a
 measure
of
freely
 dissolved
gas
 (oxygen
bound
to
 hemoglobin
is
not
 dissolved
therefore
 doesn’t
count
 Hemoglobin
acts
as
a
 “sink”
for
oxygen

 Also,
the
initial
 gradient
for
oxygen
 is
smaller
(60mmHg
as
opposed
to
100mmHg
for
N2O)

 At
rest
there
is
plenty
of
time
for
complete
equilibration
of
oxygen
 (equilibrates
in
less
than
¼
of
a
second)

 Even
at
maximum
exercise
(where
the
time
in
the
capillary
 decreases
to
¼
second)
oxygen
can
still
equilibrate
(barely…)

 TIP:
DRAW
A
VERTICAL
LINE
AT
.25
SECONDS
TO
ILLUSTRATE
 MAXIMAL
EXERCISE

 Oxygen
is
perfusion
limited
at
resting
and
exercising
conditions
 There
can
be
abnormalities
in
oxygen
exchange…
 o Thicker
membrane
(pulmonary
edema),
decrease
in
surface
 area
(emphysema)
will
all
decrease
the
rate
of
equilibration
 Go
Notes
26
 o o o Not
a
problem
at
resting
conditions,
but
at
exercise
they
 may
start
to
have
problems…

 In
very
advanced
lung
diseases
(advanced
emphysema,
fibrosis),
 even
at
rest,
oxygen
concentrations
won’t
equilibrate
(grossly
 abnormal)
For
these
people,
even
very
basic
functions
(going
to
 bathroom,
typing
shoelaces
etc.)
they
will
be
very
out
of
breath.
 When
the
gas
can’t
equilibrate
entirely
before
the
blood
leaves
the
 capillary
–
“diffusion
limited”

 When
the
gas
can
equilibrate
entirely
before
the
blood
leaves
the
 capillary
–
“perfusion
limited”

 
 ‐ CO
(Carbon
Monoxide)

 o Very
dangerous,
toxic,
because
it
binds
hemoglobin
with
a
much
 higher
affinity
than
oxygen

 o Hemoglobin
acts
as
a
sink
for
CO
and
until
all
of
the
subunits
of
 hemoglobin
are
saturated,
the
partial
pressure
won’t
increase
 (hence
the
very
low
slope
of
the
graph)

 o Diffusion
limited
(always!)

 
 **The
slope
of
a
graph
=
diffusion
capacity!

 ‐ Perfusion
Limited
=
N2O,
O2
(rest
and
exercise),
Abnormal
O2
(rest),
CO2

 ‐ Diffusion
Limited
=
CO,
Abnormal
O2
(exercising),
Grossly
Abnormal
(always)

 **Train
analogy
(look
online!)
 
 High
Altitude
‐
O2

 ‐ Alveolar
PO2
has
decreases
to
 50mmHg,
massively
decreases
 the
driving
force

 ‐ Takes
almost
half
a
second
to
 equilibrate
oxygen
in
normal
 conditions

 ‐ Exercising
at
altitude
is
dangerous
 because
oxygen
equilibration,
 even
for
normal
individuals,
will
 not
reach
completion
(big
 problem
for
mountain
climbers)

 
 Gas
exchange
depends
both
on
diffusion
as
well
as
blood
flow
 ‐ the
rate
limiting
steps
–
sets
the
reaction
pace
 ‐ normal
conditions
diffusion
is
sufficiently
fast.

Essentially
the
system
cannot
 absorb
more
O2
even
if
we
increased
diffusion.

Why?

The
concentration
 gradients
already
equilibrate
before
we
get
to
that
point.

 ‐ Instead
it
is
considered
perfusion
limited.

Why?

Because
if
we
increased
 perfusion
to
0.25
s
we
could
potentially
pick
up
3x
more
O2
overall.
 
 Go
Notes
27
 
 April
13,
2011
 
 Properties
of
pulmonary
circulation
 Autonomic
and
local
regulation
of
bronchioles
and
arterioles
 ‐ systemic
vs
pulmonary
 V/Q
matching

 Effect
of
gravity
on
V/Q
 ‐‐‐‐‐‐‐‐o‐‐‐‐‐‐‐‐
 gas
transport
 HB‐O2
association
curve
 Modulation
of
Hb
affinity
for
O2
 CO2
transport
 Carbonic
anhydrase
rxn
and
Cl‐/HCO3‐
exchange
 
 Remember
from
mamphys
1
that
there
are
multiple
differences
between
the
 systemic
and
pulmonary
cardiovascular
circuits.
 ‐ The
right
ventricle
is
much
weaker
than
that
of
the
left
heart.
 o Obviously
the
the
myocardium
of
the
right
ventricle
is
smaller
than
 that
of
the
left
ventricle
 ‐ The
left
ventricle/systemic
circuit
has
a
much
higher
systolic
pressure
and
a
 much
longer
circuit
in
total.

(blood
has
to
go
to
far
regions
including
the
 brain
(against
gravity
and
the
distal
peripheral
limbs).
 o As
a
result
the
mean
arterial
pressure
(MAP)
in
systemic
is
90‐ 100mmHg
(120/80
systolic/diastolic)

 ‐ But
the
right
pulmonary
circuit
only
needs
to
travel
a
couple
of
inches
to
the
 left
and
right
lungs
and
then
back
again.
 o This
circuit
is
very
low
pressure,
low
resistance
 o In
the
pulmonary
circuit
(MAP)
is
15mmHg
(25/8
sys/dias)
 o The
pressure
is
only
1/6th
of
the
systemic
pressures.
 
 So
we
would
normally
think
that
the
 higher
the
R
of
a
given
circuit,
the
more
 pressure
is
needed
to
overcome
that
 pressure.

Like
a
positive
correlation
 trend.


 
 But
if
we
solely
look
at
the
pulmonary
 circuit,
with
R
and
P
plotted,
its
different
 than
what
we
would
expect.

Next
Page!
 
 
 
 
 
 Go
Notes
28
 Why
is
that
with
increasing
pulmonary
 pressure,
the
resistance
of
the
circuit
 decreases?
 
 R
 ‐

At
rest
some
blood
vessels
within
the
 lungs
are
collapsed.

As
we
increase
 blood
pressure
it
will
forcibly
open
up
 more
avenues
(recruitment)
and
 increase
the
diameter
of
the
already
 open
arterioles
(distension)!
 
 P
 
 Smooth
muscle
dilation
or
constriction.
 ‐ The
systemic
arterioles,
bronchioles,
and
pulmonary
arterioles
are
all
made
 of
smooth
muscle
which
is
subject
to
autonomic
(parasymp
and
symp)
 control.
 ‐ However,
in
addition
to
those
control
mechanism
they
are
also
subject
to
 local
regulators
of
constriction/dilation.
 ‐ I
will
attempt
to
illustrate
these
local
control
mechanisms
in
the
context
of
 ↓ O2,
↑ CO2,
and
↓ pH.

(notice
that
these
things
all
typically
occur
 concurrently
together
as
a
result
of
metabolism.

The
opposite
of
those
↑O2,
 ↓CO2,
↑pH
will
elicit
opposite
effects.)
 o First
let’s
look
at
what
happens
in
response
to
those
factors
in
the
 systemic
arterioles
(which
includes
brain
arterioles).
 All
of
these
factors
are
indications
of
a
highly
metabolic
tissue.

 Take
for
example
an
active
muscle,
which
will
use
a
lot
of
O2,
 produce
a
lot
of
CO2,
which
will
decrease
the
pH.
 An
active
tissue
like
that
needs
more
O2,
so
the
arterioles
will
 dilate
‐>
more
O2
delivery
to
that
region!
 o Now
if
the
↓O2,
↑CO2,
and
↓pH
are
in
the
alveoli,
the
pulmonary
 arterioles
will
do
the
opposite
compared
to
the
systemic
arterioles
 above.
 In
the
alveoli,
all
of
these
factors
are
indicative
of
good
gas
 exchange
but
limited
ventilation.


 Now
remember
that
the
whole
point
of
pulmonary
circulation
 is
to
send
de‐oxygenated
blood
of
high
CO2
and
low
pH
to
be
 re‐oxygenated.

 But
those
signs
tell
us
that,
this
particular
alveoli
is
not
 ventilated.
 Why
send
blood
to
an
alveoliif
there
is
a
SMALLER
gradient
for
 diffusion
into
the
alveoli
 ‐>
the
pulmonary
arteriole
constricts
thus
“shunting”
blood
to
 a
better
ventilated
region
of
the
lung.
 
 
 Go
Notes
29
 o If
we
look
at
what
the
pulmonary
bronchioles
are
doing…
 ↓O2,
↑CO2,
and
↓pH
in
the
alveoli
will
result
in
 bronchodilation.
 Again,
same
as
above…these
signs
indicate
low
ventilation
 If
the
pulmonary
bronchioles
dilate
‐>
we
decrease
resistance


 -> more
ventilation
towards
that
particular
alveoli
 o DISCLAIMER:
 The
way
I
just
explained
these
mechanisms
was
in
a
 “teleological”
fashion.
 - As
in
“the
end
justifies
the
means”
 Do
understand
that
these
mechanisms
do
not
work
in
order
to
 achieve
this
or
correct
that,
they
are
designed
in
such
a
way
 that
they
are
mediated
by
the
unique
receptors
and
responsive
 paths
that
are
unique
to
the
smooth
muscle
that
comprises
the
 systemic
arterioles,
pulmonary
arterioles,
OR
pulmonary
 bronchioles.
 
 HACE
=
High
Altitude
Cerebral
Edema
 ‐ keeping
the
above
mechanisms
in
mind…
 ‐ Note
that
a
decreased
PO2
will
result
in
systemic
arteriole
vasodilation
 (including
brain
arterioles)
 ‐ A
high
altitude
mountain
climber
will
have
decreased
O2
because
1.

High
 altitude
=
lower
partial
pressure
of
O2.

And
2.

He’s
climbing
using
up
what
 little
O2
he
does
have
 o This
results
in
vasodilation
especially
in
the
brain
(because
it’s
a
uber
 high
metabolic
tissue)
 o The
increased
blood
flow
to
the
brain
results
in
increased
filtration
of
 fluid
into
the
brain.

(just
big
enough
to
exceed
the
rate
at
which
fluid
 is
drained
from
the
brain)
 o The
excess
fluid
(edema)
can
compress
the
brain
resulting
in
severe
 headaches,
nausea,
and
death.
=
BAD
 o Tx
=
take
them
back
down
+
supplemental
O2
 
 HAPE
=
High
Altitude
Pulmonary
Edema
 ‐ similar
to
above
 ‐ but
now
if
we
are
considering
the
pulmonary
arterioles
 ‐ they
constrict
in
response
to
low
O2
 ‐ widespread
pulmonary
constriction
increases
the
resistance
of
the
circuit
 ‐ this
results
in
increases
pulmonary
pressure
(pulmonary
hypertension)
 ‐ the
increased
pressure
also
increases
the
filtration
out
of
capillaries
resulting
 in
fluid
accumulation
in
the
lungs
 ‐ they
basically
will
asphyxiate
due
to
it
=
just
as
BAD
 ‐ Tx
=
supplemental
O2
 
 Go
Notes
30
 The
whole
point
of
these
local
mechanisms
is
to
match
V
(ventilation)
with
Q
 (perfusion).
 ‐ Optimally
V/Q
is
most
efficient
when
equal
to
1.
 1. What
if
V>>>Q

 a. As
in
there
is
essentially
no
blood
flow
due
to
a
clot
or
pulm.
 Embolism
 b. V/Q
>>>>1
 c. If
perfusion
stops,
the
blood
across
the
alveoli
wall
will
equilibrate
 fast
(remember
0.25s)
but
once
it
does
there
will
no
longer
be
a
 gradient
for
more
gas
diffusion
 d. But
the
alveoli
continue
to
exchange
gas
with
the
atmosphere.

As
a
 result
the
PAO2
and
PACO2
begin
to
equilibrate
with
the
PIO2
and
 PICO2.

(100‐>150
and
46
‐>
0
respectively)
 2. What
if
Q>>>V
 a. No
ventilation
due
to
blocked
airway
 b. V/Q
goes
to
zero.
 c. If
there
is
no
ventilation,
but
gas
exchange
continues
to
occur
the
 PAO2
and
PACO2
will
begin
to
approach
venous
blood.

(100
‐>
40
 and
40‐>46)
If
prolonged
the
PAO2
will
‐>
0
and
PACO2
‐>
∞
until
you
 die.
 
 
 
 
 
 
 
 
 
 
 
 
 *Figure
17‐16
(a‐c)
 The
whole
point
of
those
mechanisms
was
to
make
V/Q
=1.
 a. V/Q
=1
 b. V/Q
<
1
 i. Ventilation
to
a
specific
alveoli
decreases
due
to
some
 obstruction.

PAO2
decreases
and
PCO2
increases
 c. RESPONSE:
 i. If
V
cannot
be
increased
for
some
reason
(bronchioles
will
TRY
 to
dilate)….
The
arterioles
to
that
alveoli
will
constrict
thus
 shunting
blood
to
a
better
ventilated
alveoli.
 ALL
of
these
responses
are
dynamic
in
the
sense
that
there
are
multiple
responses
 all
throughout
the
lung.

So
minor
fluctuations
in
ventilation
or
perfusion
will
be
 somewhat
corrected
by
the
local
mechanisms.
 Go
Notes
31
 
 Dr.
Fortes
did
mention
what
potential
implications
would
occur
if
the
problem
was
 chronic
and
these
mechanisms
cannot
compensate.
 ‐ The
best
example
is
COPD.

So
recall
that
chronic
emphysema
and
chronic
 bronchitis
has
multiple
implications
regarding
less
diffusion,
less
ventilation,
 compliance,
FEV/FVC…..etc,
etc.
 ‐ All
of
these
symptoms
typically
all
cause
what?

↓ O2
 ‐ Since
its
chronic,
the
pulmonary
arterioles
will
be
chronically
 vasoconstricted.

Decrease
radius
‐>
increased
resistance
 ‐ The
right
heart
over
time
is
constantly
fighting
against
increased
resistance.

 As
a
result
the
right
heart
hypertrophies
(grows
bigger)
in
order
to
increase
 P
=
pulmonary
edema).
 In
time
the
heart
is
just
simply
overworked!

This
is
why
end‐stage
emphysema
or
 bronchitis
patients
die
of
heart
failure
or
pulm.
edema
rather
than
hypoxia.
 
 
 April
15,
2011
 
 I
am
usually
absent
during
Fridays
because
of
my
biomed
course.


So
again,
I
will
 just
copy
and
paste
lecture
notes
that
cover
the
material
that
I
hope
he
went
over.

 The
material
may
be
more
or
less
depending
on
how
much
time
Dr.
Fortes
had.

In
 addition,
it
may
be
sort
of
redundant
since
I
am
copying
and
pasting
from
multiple
 quarters
of
my
notes.
 ‐Jag
 
 
 What’s
the
effect
of
gravity
on
V/Q?
 ‐ Remember
that
both
the
 lungs
and
the
blood
have
 “weight”.

So
they
tend
 to
sink
down
to
the
 lowest
portion.
 ‐ BLOOD
=
blood
like
any
 other
flow
through
 system
follows
the
path
 of
least
resistance.
 o Therefore,
 perfusion
is
 higher
in
the
 bottom
of
the
lung
rather
than
the
top
because
it
doesn’t
have
to
 “fight”
gravity.
 ‐ VENTILATION
=
this
relationship
is
not
so
straightforward.

The
way
that
I
 personally
think
of
this
is…

Because
there
is
more
blood
in
the
bottom
of
the
 lung
than
the
top,
the
alveoli
at
the
bottom
of
the
lung
are
smaller
(due
to
 blood)
pre‐inspiration.


When
you
do
inspire,
the
net
difference
in
volume
 Go
Notes
32
 ‐ ‐ pre‐inspiration
to
post‐inspiration
is
greater.

Greater
volume
change
=
 greater
pressure
difference
=
more
bulk
air
flow.

But
if
we
look
at
the
top
 of
the
lung,
because
blood
does
not
compress
the
alveoli
they
already
pretty
 expanded
priorto
inspiration.

The
net
change
in
volume
(pre‐inspiration
to
 post‐expiration)
is
not
that
much.

So
because
their
volume
won’t
change
 much,
the
pressure
change
won’t
change
much
=
less
bulk
air
flow.
 If
they
are
both
affected
by
gravity
similarly,
why
do
the
slopes
differ?
 o Gravity
affects
blood
a
lot
more
(steep
slope)
than
it
affects
some
 partially
inflated
alveoli
(shallower
slope).
 So
looking
at
the
lines.
 o Q
>
V
at
the
bottom
of
the
lung
(V/Q
<
1)
 As
a
result
more
gas
exchange
occurs
than
ventilation
 The
PAO2
is
↓,
and
the
PCO2
is
↑
 Generally,
the
bronchioles
dilate
and
the
arterioles
constrict
in
 order
to
bring
V↑
and
Q↓
(remember
local
mechanisms
try
to
 make
V/Q
=1)
 o V
>
Q
at
the
top
of
the
lung
 More
ventilation
than
gas
exchange
 PAO2↑
and
PACO2↓
 General
arterial
dilation
(Q↑)
and
bronchiole
constriction
(V↓)
 
 *V/Q
relationship
plot
(at
3rd
rib
V/Q
=1)
 - describes
the
effect
of
gravity
of
the
lungs.
 Therefore
at
the
top
of
the
lung,
Pip
is
more
negative,
higher
Ptp
‐>
more
 expanded
alveoli
 – Therefore
less
ventilation
 At
bottom
of
the
lung
Pip
is
less
negative,
lower
Ptp
‐>
less
expanded
 alveoli
 For
perfusion,
blood
is
heavily
subject
to
the
force
of
gravity,
therefore
 there
is
much
more
perfusion
at
the
bottom
of
the
lung
compared
to
that
of
 the
top
of
the
lung
 
 V/Q
relationship
can
change
depending
local
constriction
or
dilatory
effects
 - At
bottom
of
the
lung
the
PaO2
may
be
less
than
100mmHg
because
of
more
 perfusion
than
ventilation
(PACO2
WILL
BE
HIGHER)
 – Arterioles
will
contrict
and
bronchioles
will
dilate
 - At
top
the
PO2
may
be
higher
and
CO2
will
be
less
 – Arterioles
will
dilate
and
bronchoconstriction
 
 During
exercise
the
sympathetic
response
does
not
only
effect
the
left
heart
but
will
 also
increase
the
contractility
of
the
right
heart.

Thus
increasing
pulmonary
 pressure
(which
can
better
withstand
the
effect
of
gravity)
and
the
result
will
be
 more
uniform
pressure
throughout
the
top
and
the
bottom
of
the
lungs.
 - Pulmonary
pressure
 - P
sys
=
25mmHg
 Go
Notes
33
 - Pdias
=
8mmHg
 
 Pulmonary
arterial
hypertension
can
occur
if
excessive
arterial
constriction
occurs.

 AS
pressure
rises
to
compete
against
the
higher
R
there
will
be
a
resulting
increase
 in
filtration
according
to
Starling’s
law
of
Ultra
Filtration.

=>
pulmonary
edema.
 
 - This
can
occur
in
high
altitude
mountain
climbers
(HAPE)
This
is
due
 to
vasoconstriction
due
to
low
O2
as
well
as
the
exercise.
 - Pulmonary
edema
also
occurs
if
the
left
ventricle
fails
or
left
heart
 failure.

If
the
left
Heart
cannot
maintain
normal
activity,
blood
will
 back
up
into
the
pulmonary
circuit.

This
will
increase
the
pressure
in
 the
venous
pulmonary
circuit,
the
pressure
will
back
up,
and
again
 filtration
into
the
lungs
will
occur
 - People
with
chronic
lung
disease
will
be
hypoxia
acclimated.

As
a
 result
they
too
will
have
increased
pulmonary
constriction
and
 therefore
pulmonary
hypertension.

Heart
has
to
work
harder
against
 the
increased
resistance.
 - High
altitude
mountain
sickness
–
vasodilation
in
the
systemic
 circulation.

Excess
blood
flow
in
the
brain
headache
‐>
migraine
 (HIGH
ALTITUDE
CEREBRAL
EDEMA,
HACE)
 ‐ the
gas
physically
dissolved
in
H2O
gives
the
PO2
 o O2
bound
to
hemoglobin
does
NOT
count
towards
PaO2
 o But
the
PaO2
does
determine
how
much
O2
is
bound
to
Hb.
 o Essentially,
O2
must
first
dissolve
in
H2O,
its
concentration
dissolved
 (PaO2)
then
determines
how
much
will
bind
to
Hb.
 Must
dissolve
in
H20
first.

Then
depending
on
concentration
 (PaO2)
it
will
then
diffuse
from
the
H2O
into
the
red
blood
cell
 where
it
will
bind
to
Hb.
 ‐ At
the
physiological
temperature
37°C,
the
solubility
of
O2
=
.003
ml/(100ml
 blood
x
mmHg
O2)
 o Remember
that
normal
arterial
PO2
is
100mmHg,
so
with
that
in
 mind,
the
solubility
of
O2
is
.3ml/100ml
blood.
Or
3ml/L
blood
 o In
mamphys
1,
we
taught
you
that
the
resting
cardiac
output
is
 5L/min.

So
about
15ml
of
O2
is
delivered
per
minute
(dissolved
in
 blood)!
 o But
resting
VO2
consumption
is
250ml/min!
 o Where
does
the
remaining
235ml
O2/min
(that
we
need
to
live
come
 from?)
Clearly,
dissolved
O2
is
not
enough
to
provide
us
life
(at
rest).
 o To
emphasize
that
inadequacy
of
dissolved
blood,
if
we
were
to
 maximally
exercise,
our
VO2max
is
3L
O2/min.
 Even
if
our
cardiac
output
increased
to
25L/min
that’s
only
 75ml
O2/min
dissolved!

What
about
the
remaining
2925ml
O2
 that
we
need?!*sarcasm*!?
 o The
answer
is….HEMOGLOBIN!
yay!
 (Hb)
is
really
concentrated
in
RBC’s.

It’s
about
5mM
 Go
Notes
34
 in
addition,
the
RBC
has
a
biconcave
disk
shape
which
 maximizes
the
surface
area
to
volume
ratio
=>

enhances
 diffusion
into
and
out
of
the
RBC
 
 Hemoglobin
(Hb)
 ‐ it’s
a
tetramer
with
2
α
chains
and
2
β
chains
 ‐ each
chain
has
a
porphyrin
ring/heme
group
 ‐ in
the
middle
of
the
heme
is
a
ferrous
ion
(Fe2+)
 o Ferric
(Fe3+)
will
not
be
functional
 o Known
as
met‐hemoglobin
(met‐Hb)
 If
oxidized
from
ferrous
to
ferric
‐>
brownish
color
(rust!)
 ‐ That
ferrous
ion
is
surrounded
by
a
ring
with
double
bonds!
 o That
pattern
of
double
bonds
will
absorb
light
in
specific
ways
 o When
O2
is
bound
to
the
heme,
there
is
a
slight
change
in
 conformation
and
the
heme
changes
color
to
a
CRIMSON
red
 o If
no
O2
is
bound,
and
its
just
the
heme
itself
=
BLUE/PURPLE
color.


 To
future
docs,
check
inside
of
lips
for
blue‐ish
color
=
great
 indicator
of
hypoxia.
 o But
heme
can
bind
to
carbon
monoxide
(CO)
too.

CO
is
a
dangerous
 “poison”
which
binds
to
heme
with
210
times
the
affinity
compared
to
 O2.

Competitively
binds
Hb.
 In
this
case,
Hb‐CO
results
in
a
cherry
red
color
 People
that
die
of
CO
poisoning
often
look
healthy
with
“rosy”
 cheeks
 ‐ Normal
Hb
is
14‐15g
/
100ml
blood
 o And
each
gram
binds
about
1.39ml
O2
 o So
by
using
similar
calculations
as
above
(1.39ml
O2
x
15g
x
10
x
 5L/min)
=
1.042L/min
AT
REST!
 o Much
more
than
the
250ml
that
we
need
at
rest.
 As
much
as
5.212L
at
a
cardiac
output
of
25L/min
(again
much
 grater
than
the
VO2max
of
3L/min)
 
 Now
there
is
existential
problem
via
the
dual
nature
of
Hb.
 1. First
of
all
it
needs
a
sufficiently
high
affinity
for
O2,
in
order
to
grab
it
 rapidly
at
the
alveoli!
 2. But,
the
affinity
cannot
be
too
high,
because
it
needs
to
be
able
to
 dissociate
from
O2
in
order
to
release/deliver
it
to
the
tissues
 
 
 Remember
from
chem
(101?)
that
affinity
for
basic
protein‐substrate
interactions
 are
defined
via
Kd
(dissociation
constants)
 ‐ these
Kd
binding
curves
are
typically
 hyperbolic

 o like
that
of
the
one
to
the
right!
 PO2
 Go
Notes
35
 o But
if
we
look
at
the
PO2
change
in
order
to
elicit
10%
binding
to
90%
 binding,
it
would
require
a
change
of
81
fold
in
O2
concentration
 
 But,
an
Hb‐O2
association
curve
does
not
look
like
that!
 ‐ Instead
it
is
sigmoidal…
due
to
a
intrinsic
property
=
co‐operativity
 ‐ Remember
that
Hb
is
a
tetramer.

Each
protein
can
bind
an
O2
molecule
 o Essentially
cooperativity
is…
 Once
one
single
molecule
of
O2
binds
to
a
subunit,
there
is
a
 conformational
change,
which
enhances
the
affinity
or
binding
 capability
of
the
remaining
(3)
unoccupied
subunits.


 When
the
second
O2
binds
it
enhances
the
remaining
2
 subunits.

And
so
on
and
so
on.
 Similar
to
either
“all
subunits
bound
or
none
bound”
 ‐ So
instead
of
the
hyperbolic
graph
(above),
the
Hb‐O2
association
curve
is
 sigmoidal.
 100%
 75%
 Hb‐O2%
 50%
 27
 40
 PO2
(mmHg)
 ‐ ‐ ‐ At
27mmHg
O2
–
50%
of
Hb
is
O2
bound
 At
40mmHg
O2
(venous
blood)
–
75%
is
bound
to
O2
 And
at
100mmHg
(inspired
air)
‐
~98%
is
bound
to
O2
 
 
 
 Fetal‐Hb
 ‐ instead
of
the
adult,
Hb‐fetal
 has
two
δ
chains
instead
of
two
 β’s
 ‐ Exchange
of
materials
from
 mother
to
fetus
occurs
via
the
 placenta
 100
 
 Go
Notes
36
 ‐ ‐ If
Hb
of
mother
and
fetus
have
similar
affinities
for
O2
than
they
will
 essentially
“compete”
equally
and
the
fetus
will
not
get
enough
O2
 Any
INCREASE
in
affinity
shifts
the
normal
curve
leftward,
and
any
 DECREASE
in
affinity
shifts
it
rightward.
 o In
other
words,
at
any
given
partial
pressure
of
O2
(say
20mmHg
for
 example),
a
higher
affinity
Hb
binds
more
O2
than
that
of
a
lower
 affinity
Hb.
 o Therefore,
the
fetus
will
be
able
to
grab
O2
from
its
mother’s
Hb
and
 will
have
sufficient
O2.
 
 Other
factors
which
affect
the
Hb‐O2%
saturation
curve.
 1. pH
=
↓pH
‐>
lower
affinity
(right
shift)
 2. temp
=
↑temp
‐>
lower
affinity
(right
shift)
 3. CO2
=
↑CO2
‐>
lower
affinity
(right
shift)
 4. Another
one
is
↑2,3DPG
>
lower
affinity
(right
shift)
 a. 2,3DPG
is
created
via
an
 isomerase
when
there
is
 a
decrease
in
PO2
 b. binds
to
the
middle
part
 of
all
four
subunits
of
Hb
 c. ‐>
helps
to
decrease
 affinity
therefore
 releasing
more
O2
to
the
 tissues
 AND
VICE
VERSA!
 ‐ note
that
most
of
those
happen
 together.
 o ↓pH,
↑temp,
↑CO2
–
are
 all
indications
of
a
highly
 metabolic
tissue
(active
 muscle
for
example)
 o ↑pH,
↓temp,
↓CO2
–
opposite
 
 
 Physiological
example
–
high
altitude
 ‐ at
high
altitude,
there
is
a
decrease
in
PO2
 ‐ Over
1‐2
days
the
increased
secretion
of
2,3
DPG
will
help
to
acclimate
 person
to
high
altitude
(many
more
acclimation
mechanisms
also
occur)
 ‐ Also
the
JGA
(juxta‐glomerular
apparatus
of
the
kidneys)
are
also
O2
 sensitive.
 o Under
stimulation
by
low
PO2
the
JGA
will
secrete
erythropoietin
 (EPO)

 o EPO
stimulates
the
bone
marrow
to
make
more
RBC’s
 o More
RBC’s
‐>
more
Hb
 Go
Notes
37
 
 
 o Note:
this
will
NOT
change
the
Hb‐O2%
saturation
curve
because
its
 percentage!
 Instead
it
will
increase
the
TOTAL
carrying
capacity
of
the
 blood
 April
18,
2011
 
 As
a
clarification
“dissolved”
O2
is
only
the
amount
of
O2
dissolved
in
the
plasma,
 NOT
bound
to
Hb
as
Hb‐O2.
 ‐ PO2
measure
only
that
which
is
dissolved
in
H2O
 ‐ The
amount
dissolved
(PO2)
then
determines
the
extent
of
binding
to
Hb.
 ‐ So
O2
must
dissolve
first
in
H2O,
then
the
concentration
in
O2
will
determine
 how
much
diffuses
into
the
RBC
and
binds
to
Hb.

The
events
are
causal.
 
 Carbon
Monoxide
(CO)
 ‐ is
a
competitive
substrate
for
Hb.
 ‐ It
binds
with
an
affinity
for
Hb
which
is
210x
greater
than
that
of
O2.
 ‐ It
also
exhibits
cooperativity!
 o Once
one
CO
binds
to
one
Hb
subunit
–
the
remaining
three
subunits
 have
an
greatly
enhanced
affinity
for
O2.
 o Because
of
the
greater
affinity,
once
CO
is
bound
it
is
extremely
hard
 to
release
the
remaining
O2.

They
essentially
become
trapped
and
are
 constantly
transported
with
the
blood.

=
but
almost
never
released.
Ie
 no
reverse
cooperativity.
 o The
graph
to
the
left
 illustrates
the
two
major
 problems
due
to
CO
 poisoning.
 o 1.

The
increased
affinity
 results
in
a
left
shift
 trapping
O2
 o 2.

The
CO
binding
is
 essentially
irreversible
 reducing
Hb‐O2
 o So,
what
little
O2
that
 does
bind
is
trapped
 under
normal
 physiological
PO2’s
 o Notice
that
this
graph
is
 for
50%
CO
poisoning.
 o If
it
was
25%
CO
poisoning
the
curve
would
reach
75%
Hb‐O2
sat.

 Why?

If
25%
is
bound
to
CO,
the
remaining
75%
will
be
bound
by
O2.

 Remember
this
is
an
Hb‐O2%
sat
graph.
 
 Go
Notes
38
 You
can
treat
CO
poisoning
by
subjecting
the
patient
to
a
hyperbaric
chamber.

In
 the
chamber
the
Patm
can
increase
up
to
3
fold.

So
at
Patm
of
~2100mmHg,
the
 solubility
of
O2
would
be
6.3ml/100ml
blood.

At
a
cardiac
output
of
5L/min
that’s
 315ml
O2
per
min
(just
above
the
250ml
VO2
rest).
 ‐ However,
although
this
works
well
in
theory
this
type
of
treatment
is
only
 feasible
if
the
amount
of
CO
poisoning
is
really
low
less
than
25%
(just
my
 opinion)
 ‐ My
rationale
for
that
is,
typically
we
can
survive
for
maybe
four
minutes
 without
O2.

So
unless
you
can
find
the
patient,
remove
them
from
the
CO
 environment,
keep
them
alive
in
transit
to
a
hospital
with
a
hyperbaric,
and
 put
them
in
it…All
within
four
minutes
‐>
they
might
have
a
chance.
 
 Another
application
of
hyperbaric
(more
feasible)
 ‐ Deep
sea
diving
 o As
one
delves
deeperinto
the
ocean
the
atmospheric
pressure
 increases
 o Every
10m
is
approximately
1
atm
 o So
‐20m
is
equal
to
3
atmospheres
 o As
that
pressure
increases
more
and
more
gasses
will
dissolve
into
 the
blood.

The
worst
of
which
is
N2.

At
high
pressures,
the
normal
 insolubility
of
N2
is
overcome
and
N2
diffuses
into
the
blood.
 o But
if
one
submerges
relatively
fast,
the
Patm
decreases
and
the
N2
 comes
out
of
solution.

This
is
fine
if
the
N2
is
coming
out
of
solution
in
 the
lungs
because
it
will
just
go
back
into
the
alveoli.

BUT,
if
it
is
 coming
out
of
solution
in
other
tissues
such
as
the
brain,
N2
bubbles
 will
form
in
the
blood
vessels
=
very
bad.
 o N2
bubbles
in
the
brain
will
result
in
nausea
and
headaches
=
which
 are
symptomatically
described
as
the
“bends”
 o Tx
=
use
a
hyperbaric
chamber
to
force
the
N2
back
into
solution
by
 increasing
Patm.

Slowly
lower
the
Patm
over
time
so
the
N2
is
more
 likely
to
diffuse
back
into
the
alveoli
for
expiration.
 o This
is
why
when
people
scuba
dive
with
a
tank,
21%O2
is
in
the
tank
 and
the
remaining
78%
balance
is
filled
using
helium
rather
than
 nitrogen.

Helium
is
super
insoluble
even
at
high
Patm.
 
 But
scuba
diving
using
a
tank
is
not
without
some
dangers
of
its
own.
 ‐ Recall
boyle’s
P1V1=P2V2
 ‐ If
you
are
breathing
using
a
tank
you
are
adding
gas
to
your
lungs

 ‐ The
increase
in
P
when
diving
also
reduces
the
volume
which
the
added
gas
 takes
up
 ‐ But
when
you
submerge,
one
has
to
expire
this
added
gas
as
you
ascend.

 Otherwise
the
decrease
in
P
will
result
in
an
increase
in
volume.

If
that
 volume
increase
exceeds
that
of
your
lungs,
the
lungs
can
expand
too
rapidly
 and
will
explode.
 
 *Figure
18‐13
 Go
Notes
39
 The
total
arterial
O2
content
of
the
blood
is
determined
by
the
amount
of
O2
 dissolved
in
the
blood
plus
the
amount
of
O2
bound
to
Hb.
 ‐ What
factors
change
PO2?
 o Air
composition
 o Ventilationalv
 Rate
depth
of
breathing
 Resistance
 Compliance
 Dead
space
(anatomical
+
physiological)
 o Diffusion
 o Perfusion
 ‐ And
Hb‐O2?
 o %
saturation
 affinity
changes
 o total
number
of
binding
sites
 hematocrit

 [Hb]
per
RBC
 
 There
are
multiple
types
of
anemia’s
which
can
also
affect
O2
content
 ‐ iron
deficiency
anemia
–
menstruating
women
with
low
iron
diet
 ‐ met‐Hb
=
Fe3+
rather
than
the
functional
Fe2+
 ‐ lack
of
vitamin
B12
which
is
necessary
for
proper
RBC
synthesis
=>
 pernicious
anemia
(will
discuss
this
later
in
digestion
and
absorption)
 ‐ sickle
cell
anemia
–
single
aa
switch
which
disrupts
proper
Hb
folding
‐>
 RBC’s
become
“sickle”
shaped
 
 CO2
transport!
 *Fig
18‐14
overview
 ‐ Again,
CO2
is
20x
more
soluble
in
water
than
O2.
 o But
solubility
is
also
insufficient
for
transport
throughout
the
blood
 ‐ CO2
spontaneously
reacts
with
water
 o CO2
+
H2O
↔
H2CO3
↔
H+
+HCO3‐
 Carbonic
acid
(H2CO3)
and
H+/HCO3‐
are
soluble
in
H2O
 Bicarbonate
HCO3‐
is
the
main
extracellular
pH
buffer
and
H+
 contributes
significantly
towards
acidicpH
 So
as
we
shall
see
CO2
and
ventilation
play
a
major
role
in
acid‐ base
balance
(next
midterm?)
 o However
this
reaction
is
usually
quite
slow
when
uncatalyzed
 ‐ Carbonic
Anhydrase
(CA)
is
an
enzyme,
which
catalyzes
the
rate
limiting
step
 of
the
above
reaction.


 o Fastest
enzyme
with
a
turnover
rate
of
1µs
 o It’s
present
in
many
places
like
the
RBC’s,
interstitial
cells
of
the
 kidneys,
the
CSF,
and
parietal
cells.
 o If
we
inhibit
the
CA
rxn
by
the
drug
acetazolamide
the
result
will
be
a
 retention
of
protons
thus
decreasing
the
pH.
 Go
Notes
40
 ‐ So
now
let’s
look
at
Figure
18‐14
closer
 o Venous
side
of
systemic
 vein!

 o The
tissues
produce
 CO2!

Which
can
freely
 diffuse
into/out
of
RBC’s
 Only
7%
of
CO2
 transport
is
in
 dissolved
CO2
 23%
of
CO2
is
 transported
 bound
to
Hb
=
this
 is
why
CO2
decreases
Hb‐O2
affinity
 As
CO2
diffuses
into
the
RBC
‐>
The
increase
in
CO2
will
drive
 the
reaction
to
towards
the
formation
of
the
products
 H+/HCO3‐
by
the
law
of
mass
action.
 • The
proton
will
bind
to
Hb
(along
the
negatively
 charged
aa’s)
=
also
explains
decreased
Hb‐O2
affinity
 with
↓pH
 • HCO3‐
(70%
CO2
xport)
must
be
transported
out
 because
it
takes
up
too
much
space.

It
has
to
be
 transported
in
exchange
for
another
negatively
charged
 ion
(Cl‐)
or
there
will
be
a
loss
of
charge
(Nernst
 potential).

FASTEST
antiport!
 Therefore,
systemic
veins
have
relatively
↑[HCO3‐]
(more
 basic)
and
↓[Cl‐]
 o Venous
side
of
pulmonary
vein!
 As
CO2
diffuses
 out
of
the
blood
 into
the
alveoli
 the
PCO2
 decreases
 This
will
 facilitate
the
 dissociation
of
 CO2
from
Hb
 which
will
then
 diffuse
into
the
plasma
 The
decrease
in
PCO2
will
also
shift
the
CA
reaction
towards
 the
formation
of
CO2
from
H+
and
HCO3‐.

H+
comes
from
the
 dissociation
from
Hb
HCO3‐
comes
from
the
rapidly
 exchanging
HCO3‐/Cl‐
antiport
 Therefore
the
plasma
has
↓[HCO3‐]
(more
acidic)
and
↑[Cl]
 o Notice
that
there
is
a
big
difference
between
chloride
concentrations
 between
a
systemic
artery
and
a
systemic
vein
=
called
a
chloride
shift
 Go
Notes
41
 [Cl‐]
systemic
artery
>
[Cl‐]
systemic
vein
 
 *Fig
18‐15
Summary
of
O2
and
CO2
exchange
and
transport.
 
 
 April
20,
2011
 
 Control
of
Respiration
 CNS
centers

 
 PONS
=
pneumotaxic
and
apneustic
centers
 
 MEDULLA
=
dorsal
resp.
group
(insp)
and
ventral
resp.
group
(exp)
 Autonomic
nerves

 
 VAGUS
(X)
and
glossopharyngeal
(IX)
 
 Motor
nerves
to
muscles:
Phrenic
innervates
diaphragm
 ChemoR
 
 Central
and
peripheral
 
 Reflexes
associated
 Other
reflexes
 
 *Fig
18‐17
Brainstem
centers
which
control
respiration
 
 MEDULLA
 1.


Dorsal
respiratory
group
(DRG)
 ‐ the
DRG
innervates
motor
neurons
of
the
phrenic
nuclei
(spinal
cord
C3‐C5)
 which
activate
the
inspiratory
muscles
 
 
 
 2.


Ventral
respiratory
group
(VRG)
 ‐ VRG
mostly
innervates
motor
neurons,
which
are
expiratory
(FORCED)
in
 nature.

It
also
innervates
the
FORCED
inspiratory
neurons
to
the
scalenes
 and
sternocleidomastoids.

And
lastly
it
innervates
the
upper
airways
 muscles
of
the
pharynx,
larynx,
and
tongue
muscles.
 
 The
DRG
and
VRG
–
are
the
main
centers,
which
generate
the
pattern
or
frequency
 of
breathing.

Technically
known
as
the
Central
pattern
generator
(CPG)
of
 breathing.



 ‐ notice:
They
determine
the
RATE/FREQUENCY
of
breathing!
 ‐ At
rest,
the
pattern
is
mostly
activate
DRG,
turn
DRG
off,
activate
DRG…
 because
the
VRG
is
usually
unnecessary
for
resting
expiration
 
 PONS
 1. The
rostral
or
superior
resp
center
in
the
pons
is
the
Pneumotaxic
center.
 a. When
stimulated
this
inhibits
inspiration
 Go
Notes
42
 b. It
is
especially
important
when
preventing
over‐inflation
of
the
lungs
 via
the
Hering‐Breuer
reflex,
especially
in
infants.

(adults
not
so
 much)
 2. The
caudal
or
inferior
center
of
the
pons
is
the
Apneustic
center.
 a. When
stimulated
‐>
apneusis
(a
type
of
gasping
inspiration)
 b. BIG
inspiration
followed
by
small
expiratory
efforts
 c. Often
seen
right
before
death
“like
last
one
or
two
breaths”

 
 LESION
studies.

Refer
to
my
diagram

 Again,
I
like
to
think
of
the
medulla
setting
the
rhythm
and
the
pons
setting
the
 depth
of
breathing
(keep
in
mind)
 
 A. If
you
sever
the
brainstem
at
A,
 above
the
pons
–
there
is
normal
 breathing
because
all
centers
still
 have
connections
w/
lungs.

But
 there
will
be
no
voluntary
 breathing
or
inputs
from
higher
 centers
for
emotion,
anger,
 anxiety
etc.
 B. If
sever
at
B,
the
pneumotaxic
is
 lost
so
there
is
no
inhibition
of
 breathing
‐>
abnormally
large
insp
but
rhythm
is
more
or
less
intact
(slightly
 slower
due
to
changing
tidal
volume)
 C. If
sever
at
C,
no
apneustic
either
‐>
significant
abnormal
depth
of
breathing
 a. Rhythym
could
be
faster
or
shorter
depending
on
tidal
volumes
 D. At
D,
the
DRG
and
VRG
are
lost.

No
innervation
to
lungs
=
no
breathing
 a. Pretty
much
dead
unless
you
have
tracheotomy
or
intubation
for
an
 external
respirator
 *Fig
18‐18

DRG
activity
during
quiet
breathing
 ‐ If
we
look
at
the
trace
of
neuronal
activity
by
the
phrenic
(which
the
DRG
 innervates)
there
is
a
positive
feedback
loop
during
inspiration
 ‐ The
rapid
recruitment
of
more
and
more
inspiratory
neurons
occurs
via
 “ramping”.

This
recruitment
ensures
a
smooth
gradual
contraction
of
the
 diaphragm
‐>
smooth
change
in
volume
‐>
smooth
change
in
P
‐>
smooth
 inspiration
 ‐ At
the
end
of
the
inspiratory
portion
there
is
a
sudden
decrease
in
phrenic
 activity
resulting
in
the
relaxation
of
the
diaphragm
‐>
the
lung
is
allowed
to
 passively
recoil
=
expiration
 ‐ Whenever
there
is
an
increase
in
frequency,
the
result
is
typically
at
the
 expense
of
the
passive
expiratory
phase.


 o But
another
possible
mechanism
is
the
activation
of
the
pneumotaxic
 center
in
order
to
shorten
inspiration
 
 *Fig
18‐16

Overall
regulation
of
inspiration
 Go
Notes
43
 • • • Emotions
and
voluntary
control
via
the
cortex
can
easily
feed
down
to
the
 medulla
and
pons
to
adjust
rate
and
depth
of
breathing
 o Fear,
anxiety,
arousal,
sadness
all
are
examples
in
which
the
limbic
 system
can
override
normal
respiration
 Central
chemoR’s
also
greatly
affect
ventilation
 o These
are
only
sensitive
to
CO2
 o In
the
medulla,
right
next
to
the
DRG
and
VRG.
 o Increased
CO2
‐>
increased
ventilation
 Peripheral
chemoR’s

 o Sensitive
to
CO2,
O2,
and
pH
 o ↑CO2,
↓O2,
and
↓pH
will
increase
ventilation
(vice
versa
too)
 o located
in
aortic
arches
and
carotid
bodies
(same
locations
as
the
 baroceptors
which
monitor
and
mediate
blood
pressure
homeostasis)
 
 CO2
is
the
main
stimulant
for
the
respiratory
drive

 ‐ central
chemoR
(only
CO2)
drives
about
70%
of
ventilation
 ‐ peripheral
chemoR
(for
CO2)
drive
about
10%
of
V
 ‐ O2
drive
is
usually
very
small
(20%)
unless
arterial
O2
drops
significantly
 low
to
about
80mmHg,
moreso
at
60mmHg
 ‐ Why
is
CO2
more
important
than
O2?
 o Because
PaCO2
is
more
likely
to
change
than
PaO2.

Remember
that
 due
to
the
contribution
of
Hb,
overall
O2
arterial
content
only
 fluctuates
between
98%
and
75%
O2
from
arterial
to
venous.
 o In
addition,
because
CO2
reacts
with
H20
to
form
acid,
it
has
major
 implications
on
pH
and
therefore
must
be
tightly
regulated.
 
 
 
 
 *Figure
18‐20
Central
chemoR’s
monitor
CO2
in
CSF
 ‐ Gasses
can
diffuse
across
the
blood
barrier
but
ions
like
H+
cannot
 ‐ If
plasma
CO2
increases
‐>
increased
diffusion
of
CO2
into
CSF.
 o In
the
CSF,
CA
will
form
H+
and
HCO3‐
 o That
proton
will
activate
the
central
chemoR’s
resulting
in
an
increase
 in
ventilation.
 ‐ Essentially,
they
are
activated
by
proton’s
as
an
indirect
measurement
of
 CO2.
 ‐ The
increases
in
ventilation
will
help
to
decrease
CO2
=
negative
feedback
 loop
 
 *Fig
18‐19
Glomus
cell
carotid
body
O2
sensor
 ‐ If
there
is
less
PaO2,
then
less
O2
will
diffuse
into
this
glomus.
 ‐ As
a
result
less
ATP
will
be
made
via
oxidative
phosphorylation.
 ‐ Less
ATP
will
result
in
the
closure
of
ATP‐K+
channels.
 ‐ Less
K+
leaking
out
of
the
cell
results
in
a
depolarization
of
the
cell
 Go
Notes
44
 ‐ ‐ ‐ V‐gated
Ca++
channels
open,
Ca++
influx,
exocytosis
of
neurotransmitters
 which
result
in
increased
ventilation
 Again,
negative
feedback
in
order
to
bring
O2
levels
back
up
 Not
really
active
unless
PaO2
is
below
80‐60mmHg
 
 *refer
to
online
figures
for
graphs
in
which
1.
PaCO2
stays
constant
or
2.
PaO2
stays
 constant
 ‐>
I’m
going
to
explain
the
same
concept
using
my
own
diagrams.
 
 CO2

 ‐ So
I
pulled
this
graph
off
of
a
med
textbook
and
 it’s
the
same
one
my
PI
uses
to
teach
the
med
 students
 ‐ In
addition
we
have
an
experiment
in
which
a
 bag
is
filled
with
100%
O2
and
a
volunteer
just
 breathes
into
and
out
of
it.

Because
the
initial
 PO2
in
the
bag
is
uber
high
the
O2
NEVER
gets
 low
enough
to
activate
the
peripheral
 chemoR’s.

Basically
he/she
just
breathes
in
 more
and
more
CO2.
 ‐ Again
O2
stays
high
constantly
but
the
inspired
 CO2
increases.
 ‐ On
this
particular
graph,
they
plotted
V
at
O%,
 2%,
4%,
and
6%
inspired
CO2.
 ‐ Notice
that
V
increases
by
4L
with
an
increase
 of
only
3mmHg
of
CO2.
 ‐ From
41
‐>
45mmHg
ventilation
increases
6L

 ‐ 
And
from
45
‐>
50
mmHg
there
is
a
HUGE
increase
to
31
L.


 ‐ The
increase
was
almost
linear.

So
much
so
that
an
overall
change
in
 12mmHg
of
increasing
CO2
made
ventilation
increase
over
5x.
 O2
 ‐ This
graph
from
a
paper
by
my
lab,
is
a
 little
bit
more
 complicated
than
the
one
on
webCT.

 ‐ I
will
post
the
paper
in
my
webCT

 folder
because
I
think
it
is
a
great
 review
for
the
control
of

 ventilation.

It
covers
everything

 from
the
pontine
and
medullary
 centers,
ramping
of
inspiratory
 neurons,
O2
+
PCO2
+
pH

 responses,
exercise
homeostasis,

 and
a
little
bit
of
neuroplasticity.
 ‐ Anywho.

Let’s
look
at
the
curve
labeled
 normocapnic
first!
 o In
this
particular
curve
the
 PaCO2
is
kept
constant
 Go
Notes
45
 regardless
of
V.

Requires
the
researcher
to
slowly
add
CO2
to
the
 inspired
air
as
ventilation
increases.


 o So
CO2
receptor
activity
is
kept
at
the
baseline
level
at
42mmHg
(close
 to
40mmHg).
 o Trace
the
curve
from
right
to
left.

Notice
that
the
ventilation
does
not
 start
to
increase
until
O2
becomes
less
than
80mmHg.

And
it
 increases
at
even
lower
levels
of
O2,
60mmHg.

Remember
that
O2
 chemoR
don’t
even
really
activate
until
PO2
is
80
or
60mmHg.
 o If
we
compare
it
to
the
previous
response
to
CO2
(last
page),
there
has
 to
be
a
40mmHg
decrease
in
O2
to
increase
ventilation
from
~7L/min
 to
maybe
15L/min.

(Recall
a
12mmHg
increase
in
CO2
increases
 ventilation
to
32L/min.
 o Again,
this
confirms
that
CO2
accounts
for
much
more
of
the
 ventilatory
drive
 ‐ Now
let’s
look
at
normal
conditions
=
poikilocapnic
curve.
 o Normally,
as
hyperventilation
occurs,
the
PaCO2
becomes
less
and
 less.

This
is
illustrated
by
this
curve
because
as
ventilation
increases,
 the
PaCO2
goes
from
42,
to
37,
to
35,
and
to
33.


 o So
what’s
happening?

As
PaO2
decreases
more
and
more
peripheral
 chemoR
are
being
activated
=>
increasing
ventilation.
 However,
that
increase
in
ventilation
results
in
a
decreasing
 PCO2.

Less
and
less
central
chemoR’s
are
being
activated.
 o So
although
ventilatory
drive
is
increasing
due
to
↓O2,
we’re
losing
 even
more
ventilatory
drive
because
CO2
receptors
are
less
active.
 ‐ The
hypercapnic
curve
–
has
the
highest
ventilation
because
both
the
O2
 chemoR’s
inc
V
and
the
CO2
chemoR’s
increase
V.
 Mountain
climber
example
of
poikilocapnia:
 ‐ At
high
altitude
there
is
a
decrease
in
PO2
 ‐ This
results
in
hyperventilation
‐>
which
decreases
ventilatory
drive
due
to
 CO2
↓
 ‐ So
the
loss
of
CO2
ventilatory
drive
will
pretty
much
negate
the
efforts
to
 increase
ventilation.
=>
harder
time
acclimating
to
hypoxia
=
susceptible
to
 longer
high
altitude
mountain
sickness.
 ‐ We
know
that
2,3
DPG
take
1‐2
days
+
EPO
secretion
maybe
2‐3
days
 ‐ How
can
we
acclimate
faster?
 o DRUGS!
yay
 o not
the
fun
drugs
you’re
thinking
of,
but
a
drug
called
acetazolamide.
 ‐ Acetazolamide
 o Inhibits
carbonic
anhydrase
reaction.
 o Remember
that
this
reaction
occurs
spontaneously
 So
there
is
ample
time
for
the
formation
of
H+
and
HCO3‐
as
 blood
moves
from
the
tissues
to
the
right
atrium.
 o But
where
the
inhibition
of
CA
really
matters
is
right
outside
the
 alveolar
wall.
 Go
Notes
46
 If
the
formation
of
CO2
from
HCO3‐/H+
is
slow
(longer
than
 0.75),
CO2
will
not
be
made
fast
enough
to
diffuse
into
the
 alveoli
for
expiration
 This
will
result
in
a
retention
of
CO2
‐>
which
via
the
central
 and
peripheral
chemoR’s
‐>
will
keep
the
ventilatory
drive
high
 =
↑
ventilation
 o There
are
additional
functions
of
acetazolamide
in
other
tissues
as
 well.

When
we
get
to
acid‐base
balance
you
will
see
that
the
CA
 reaction
also
occurs
in
the
kidneys
in
order
to
regulate
pH.
 Inhibiting
CA
there
will
result
in
a
net
excretion
of
HCO3‐
 (what
the
kidneys
would
normally
do
when
acclimating
to
 hypoxia)
but
the
drug
makes
it
happen
faster
 The
net
excretion
of
HCO3‐
will
result
in
a
net
retention
of
H+.


 The
protons
will
also
drive
ventilation
via
the
peripheral
 chemoR’s.
 
 Acclimatization
to
high
altitude:
 ‐ So
normally
the
low
PO2
will
induce
hyperventilation,
but
as
we
saw
from
 the
poikilocapnic
curve,
hyperventilation
will
also
decrease
the
CO2.

The
 decreased
CO2
will
result
in
a
loss
of
ventilatory
drive
via
the
central
and
 peripheral
chemoR’s
sensitive
to
CO2
 o Therefore
any
increase
in
ventilation
will
just
be
attenuated
due
to
a
 loss
of
afferent
CO2
input.


 ‐ *Fig
18‐20
 o this
figure
shows
that
the
central
chemoR’s
indirectly
detect
increased
 CO2
levels
via
the
H+
concentration.

The
proton
is
made
via
the
CA
 reaction
 o by
the
law
of
mass
action
the
decrease
in
CO2
(via
hyperventilation)
 will
typically
result
in
less
protons
being
made,
therefore
↓
chemoR
 stimulation.
 o How
is
this
accounted
for?

Over
1‐3
days
at
high
altitude
the
the
 epithelial
cells
of
the
blood
brain
barrier
begin
to
secrete
HCO3‐
 outwards
from
the
CSF.

Therefore
because
we
are
removing
more
of
 the
extracellular
buffer,
more
protons
are
free
to
activate
the
 chemoR’s
 o Essentially
now
we
have
the
normal
basal
level
of
CO2
ventilatory
 drive
(despite
hyperventilation),
in
addition
to
the
increased
 peripheral
drive
due
to
↓O2.

 
 In
summary,
the
ways
in
which
ventilatory
acclimatization
to
hypoxia
occurs
are:

 ‐

↑2,3
DPG
 ‐

↑Epo
which
increases
total
arterial
carrying
capacity
by
inc
Hb
 ‐

↓HCO3‐
concentration
in
the
CSF
(which
↓pH
in
the
CSF)
 ‐

There’s
also
a
bunch
of
neural
mechanisms,
which
enhance
the
plasticity
of
 chemoR
reflexes,
medullary
and
pontine
centers,
and
etc.
for
the
acclimatization
to
 Go
Notes
47
 hypoxia.

This
is
what
my
lab
deals
with.

So
again,
if
this
may
interest
you
come
talk
 to
me
about
a
BISP199.
 
 *Figure
18‐21

Chemoreflexes
due
to
plasma
CO2
 ‐ this
graph
is
pretty
self
explanatory
just
make
sure
to
note
the
negative
 feedback
loops.
 ‐ ↑CO2
‐>
↑activity
of
both
peripheral
and
central
chemoR
‐>
↑ventilation
 o 1.

↓CO2
on
peripheral
and
central
chemoR
(NEG
FEEDBACK)
 o 2.

↑O2
which
will
decrease
peripheral
chemoR
(NEG
FEEDBACK)
 Example
of
how
theses
loops
work
together
at
high
altitude
 • Cheyne‐Stokes
breathing

 • Typically
seen
while
a
person
is
at
high
altitude
and
sleeping
 o The
lack
of
consciousness
means
that
the
autonomic
processes
of
 these
chemoR
reflexes
is
driving
breathing
 • Type
of
breathing
is
a
period
in
which
hyperventilation
occurs
followed
by
a
 period
of
no
breathing
(apnea)
 o Why
is
this
occurring?
 The
low
O2
at
high
altitude
causes
increased
peripheral
 chemoR
activity
=>
hyperventilation
 However,
that
hyperventilation
will
decrease
CO2
to
the
point
 in
which
the
ventilatory
drive
is
lost
=>
no
breathing
 After
not
breathing
CO2
eventually
builds
up
again,
and
then
 the
cycle
repeats
 
 Other
respiratory
reflexes
 ‐ Cough
and
sneeze
reflex
 o Serve
to
expel
irritants
forcefully
from
the
respiratory
tract

 o If
in
upper
airways
=>
sneeze,
if
in
lower
ones
=>
cough
 ‐ In
addition,
there
are
stretch
reflexes
which
are
mediated
by
stretch
 receptors
in
the
lung
 o They
are
activated
once
volume
in
the
lung
reaches
a
specific
large
 volume
 o Serve
to
prohibit
overexpansion
of
thenzymatic
e
lung
(or
else
they
 can
pop
like
a
balloon)
 o Most
probable
mechanism
is
↑stretch
receptors
send
afferents
 to/through
vagus
to
respiratory
centers
(probably
pneumotaxic
 center)
‐>
↓inspiration
 o This
type
of
reflex
is
most
prominent
within
animals
and
infants,
not
 so
much
in
humans.
 ‐ There
are
a
bunch
of
other
cool
ones
like
shallow
and
deep
water
blackouts,
 dive
reflex…
but
he
didn’t
discuss
them
this
time
soooo
whatev.
 
 
 
 
 Go
Notes
48
 
 April
25,
2011
 Acid/base
regulation
 Buffers:
proteins,
phosphates,
HCO3‐,
NH3
 Henderson
Hasselbach
equation
 HCO3‐
vs
pH
plots
(davenport
plots)
 Renal
mechanism
(proximal
tubule
and
distal
nephron
 Respiratory
mechanism
for
pH
balance
 Acidosis
and
alkalosis
 
 Acid/Base
regulation!!!
 ‐ The
normal
pH
of
extra
cellular
fluid
is
tightly
regulated
within
a
finite
range
 ‐ pH
=
7.38‐742
(~7.40)
 o if
the
pH
is
<
7.35
=
acidosis
 o if
the
pH
is
>
7.45
=
alkalosis
 
 
 
 
 
 But
why
is
pH
so
important?
 ‐ We
all
remember
that
protein
structure
and
hence
protein
function
is
 dependant
upon
the
hydrogen
bonds
which
denote
2°
structure.

Hence,
all
of
 it
is
extremely
pH
sensitive.

All
aa’s
can
be
deprotonated
at
the
C‐term
and
 protonated
at
the
N‐terminus;
in
addition,
some
aa’s
have
specific
side
chains
 which
can
also
be
acidic
or
basic.

The
unique
pH
conditions,
enable
the
 formation
of
hydrogen
bounds
which
can
convey
all
2°
and
3°
structure.


 ‐ In
addition,
these
pH
sensitivities
are
magnified
when
considering
CNS
 function
or
more
specifically
neurophysiology.

Like
all
other
proteins,
the
V‐ gated
Na+
channels
of
neurons
are
extremely
pH
sensitive.

The
voltage
 sensor
is
an
alpha
helix
of
positive
aa’s
(lysines
and
arginines)
within
the
4th
 transmembrane
domain
of
the
channel.

Usually
when
a
depolarization
 occurs,
the
positive
charges
from
the
depol
cause
this
voltage
sensor
to
move
 toward
the
extracellular
region,
thus
opening
the
channel
and
allowing
 additional
Na+
to
influx.
 
 
 
 
 ++++++++ 
 +
 
 
 
 
 closed
 ++++
 
 Na+
 Go
Notes
49
 
 ‐ But
how
does
pH
affect
the
above
diagram?
 o Acidic
environments
=
will
result
in
an
excess
amount
of
protons
 coating
the
external
(top)
C
domain
of
the
channel.

If
there
are
a
lot
of
 positive
charges
by
protons,
the
voltage
sensor
is
repulsed
by
the
 external
positive
charges,
and
is
therefore
less
susceptible
to
open.

It
 takes
a
much
stronger
depolarization
to
elicit
an
activation
of
the
 voltage
sensor.
 This
is
essentially
CNS
depression
and
is
akin
to
hiring
the
 threshold
of
the
channel.


 Extreme
depression
can
and
will
lead
to
coma’s
or
death
 o Alkaline
environments
=
It’s
the
opposite
of
the
acidic
situation.

The
 channel
becomes
attracted
to
the
negative
C‐term
domain
and
is
 essentially
more
likely
to
open
and
fire
an
AP.


 This
is
CNS
hyperexcitability
and
is
just
as
deleterious.


 Can
lead
to
tetanus
of
muscle
tissue,
seizures,
etc.
 o Ca2+
ions
also
normally
shield
external
negative
aa’s.

So
if
Ca++
 decreases
=>
hyperexcitability
 
 o Hyperkalemia
(excess
K+)
=
can
also
lead
to
hyperexcitability
but
not
 by
affecting
these
channels.

Recall
that
the
K+
gradient
establishes
 the
negative
membrane
potential
Vrest
by
leaking
out
of
the
cell.

 Hyperkalemia
diminishes
this
effect
and
the
channels
therefore
 depolarize
if
the
gradient
is
reversed.

I
will
discuss
why
this
is
 important
a
little
bit
later.
 
 *Fig
20‐18
Acid
inputs/outputs
 ‐ The
acid/base
balance
is
primarily
determined
by
the
factors
which
increase
 acid
and
the
ways
in
which
acid
is
eliminated.
 ‐ H+
INPUT
=
diet
(aa’s
and
fatty
acids)
and
metabolism
(CO2,
lactic
acid,
and
 ketoacids)
 ‐ H+
OUTPUT
=
Ventilation
(CO2
expiration)
and
renal
excretion
(H+)
 
 Ventilation
is
a
major
means
of
decreasing
acid
(10,000
milli‐equivalents)

 ‐ recall
that
the
H+
can
recombine
with
HCO3‐
giving
us
CO2
to
be
expired
 ‐ this
mechanism
is
extremely
fast
because
the
chemoreceptors
sensitive
to
pH
 can
increase
ventilation
(therefore
CO2
expiration)
within
the
next
breath
 
 Renal
excretion
of
H+
via
the
kidneys
only
excretes
about
340
milli‐equivalents
and
 usually
takes
hours
to
days
to
adjust
pH
imbalances.
(TBD
more
later)
 
 There
are
multiple
buffer
systems
to
prevent
wide
fluctuations
of
pH
levels
 throughout
our
body.
 ‐ HCO3‐
which
is
the
main
extracellular
buffer
 ‐ The
main
intracellular
buffers
are
aa’s.

(like
Hb
or
phosphates).

This
is
 because
all
aa’s
can
be
protonated
or
deprotonated
based
on
pH
levels.
 Go
Notes
50
 ‐ In
urine,
the
buffers
include
phosphates
and
ammonia
(NH3
+
H+
⇔
NH4+).

 o Ammonium
ion
NH4+
is
the
main
excretion
of
protons
in
urine.
 
 Henderson‐Hasselbach
equation
(YAY
last
eq)
 
pH
=
pKa
+
log
[HCO3­]/(.03
x
PCO2)
 ‐ normal
pKa
of
carbonic
acid
is
6.1
 ‐ normal
HCO3‐
=
24mM
 ‐ normal
PCO2
=
40
 ‐ Therefore,
normal
pH
=
6.1
+
log
20
=
7.4
 
 What
controls
the
factors
of
the
HH
equation?
 ‐ the
lungs
primarily
adjust
the
pH
via
changing
the
PCO2
 ‐ whereas
the
kidners
adjust
the
pH
by
altering
the
HCO3‐
concentration
 ‐ However
the
time
course
for
the
two
organs
varies
 o Kidney
(hour‐hours)
response
 o Lungs
(sec)
respond
extremely
fast
due
to
peripheral
and
central
 chemoR
reflexes.
 
 
 Back
to
the
HH
real
quick:
 pH
=
pKa
+
log
[HCO3­]/(.03
x
PCO2)
 ‐ [HCO3‐]
=
24mmol

 ‐ [H2CO3]
=
PCO2
*
0.03mM/mmHg
=
40
*
0.03
=
1.2

 ‐ pH
=
6.1
+
log
(24/1.2)
=
6.1
+
1.3
=
7.4
 ‐ Notice
that
the
log
of
20
is
1.3
 o If
the
ratio
is
<20
=
than
the
log
is
<1.3
=
ACIDOSIS
 Can
be
caused
by
decreasing
HCO3‐
or
increasing
CO2
 o If
the
ratio
is
>20
=
than
the
log
is
>1.3
=
ALKALOSIS
 Can
be
caused
by
increasing
HCO3‐
or
decreasing
CO2
 ‐ You
don’t
actually
have
to
be
able
to
calculate
logs
without
a
calculator,
just
 plug
in
the
values
and
compare
your
ratios
to
20!
 
 
 April
27,
2011
 
 HCO3‐
vs
pH
plots
(davenport
plots)
 Renal
mechanism
(proximal
tubule
and
distal
nephron
 Respiratory
mechanism
for
pH
balance
 Acidosis
and
alkalosis
 Distal
nephron
 [HCO3‐]
vs
pH
plots
(Davenport
plots)
 acidosis
and
alkalosis
 Respiratory
and
Metabolic
compensations
 
 
 Go
Notes
51
 Renal
mechanisms

 ‐ Proximal
tubule
(PT)
*FIG
20‐21
 o This
is
where
salt
and
glucose
is
reabsorbed
 o Contains
luminal/apical
Na+/H+
antiport

 o Higher
concentration
of
Na+
in
the
filtrate
than
in
the
cell.

This
 generates
a
driving
force
for
the
movement
of
sodium
into
the
cell.
 Why
low
concentration
of
Na+
in
the
cell?
Massive
number
of
 Na+/K+
pumps
in
the
basolateral
membrane
(not
pictured)
 This
driving
force
allows
the
movement
of
H+
against
their
 concentration
gradient,
from
the
cell
into
the
lumen
of
the
 nephron

 o Large
amounts
of
carbonic
anhydrase
inside
the
cells
 Increase
in
H+
in
the
lumen
shifts
carbonic
anhydrase
reaction

 ‐>
CO2

 CO2
diffuses
back
into
the
cell
generating
additional
H+
&
 HCO3‐

 o How
do
we
get
HCO3‐
out?
Na+/HCO3‐
symport
on
the
basolateral
 membrane
 What
forces
allow
this
to
happen?

 Build
up
concentration
of
HCO3‐
inside
the
cell
generates
a
 concentration
gradient
across
the
membrane

 Why
does
Na+
want
to
leave
against
its
gradient?
 • 1
Na+
for
every
3
HCO3‐
(not
pictured…)
In
this
case,
 HCO3‐
gradient
is
the
driving
force
 o In
addition,
the
aa
glutamine
can
be
deaminated
in
order
to
form
 ammonium
(NH4+)
and
αKG
 NH4+
can
be
pumped
out
the
apical
side,
again
using
the
Na+
 gradient
as
the
driving
force
 αKG
can
be
broken
down
into
HCO3‐
which
will
be
reabsorbed
 basolaterally
using
the
same
3HCO3‐/1Na+
symport
 o NET
SECRETION
OF
H+
and
REABSORPTION
of
Na+
and
HCO3­
 SIDENOTE:
Acetazolamide
–
mild
diarrhetic
(increases
volume
of
urine)

 How
does
it
do
this?

 Inhibits
CA…
can’t
reabsorb
as
much
HCO3‐

 Lose
HCO3‐
and
Na+
in
the
urine

 Osmotic
gradient
causes
an
increase
of
water
excretion

 Can
be
used
to
treat
glaucoma,
high
altitude
sicknessetc.

 Why
does
it
help
high
altitude
sickness?
Inhibition
of
CA
will
cause
retention
of
 CO2
 increase
H+
and
decrease
pH
will
increase
ventilation
via
central
chemoreceptors
 
 H20
+
CO2
<‐>
H2CO3
<‐>
H+
+
HCO3‐
 ‐ Why
does
the
pH
change
so
much
with
CO2
changes
if
the
reaction
above
 creates
just
as
much
conjugate
base
HCO3‐
and
H+?
 o Well
simple
answer
is
that
pH
is
based
on
H+
(not
on
HCO3cause
that
 Go
Notes
52
 would
be
pHCO3)
 o But
also
because
when
H+
increases
it
changes
the
overall
relative
 concentration
10,000x
more
than
HCO3‐
(because
there
is
already
a
 shit‐ton
of
HCO3‐
to
begin
with.

Main
ECF
buffer
right?)
 Secondly
because
HCO3‐
is
a
weak
base
and
is
not
usually
 associated
with
the
H+
 
 Dr.
Fortes
then
went
on
about
how
to
calculate
acidosis/alkalosis
by
comparing
the
 log
ratio
to
log
20.

I
already
discussed
this
previously.
 
 Whenever
CO2
changes
=>
pH
changes
 ‐ this
imbalance
is
mostly
a
problem
with
the
lungs
(respiratory
in
nature)
 
 Whenever
H+
or
HCO3‐
changes
=>
there
will
also
be
pH
changes
 ‐ however
H+
and
HCO3‐
is
adjusted
by
the
kidneys
and
this
imbalance
is
more
 metabolic
in
nature
 
 Distal
nephron
=
intercalated
cells
 ‐ type
A
intercalated
cells
 o are
activated
via
acidic
conditions
(think
a‐A)
when
the
pH
is
<7.4
 o *Fig
20‐22a
 o Net
fxn
SECRETION
of
H+
and
REABSORPTION
of
HCO3‐
and
K+
 o Apical
transporters
 H+/K+
antiport,
H+
 ATPase
pump,
Cl‐
 leak
channel
 o Basolateral
transporters
 HCO3‐/Cl‐
antiport,
 K+
leak
channels
 
 HYPERKALEMIA
sidnote:
 ‐ notice
that
K+
“follows”
the
HCO3‐
movement
 ‐ Therefore
under
acidic
conditions
the
HCO3‐
reabsorption
also
causes
 reabsorption
of
K+
 ‐ This
can
lead
to
hyperkalemia,
which
is
bad
because….
 o Increasing
the
EC
[K+],
results
in
a
decreased
gradient
by
which
K+
 will
leak
out
of
neurons/excitable
tissue
 o If
the
gradient
is
completely
reversed,
K+
will
go
into
the
cell
rather
 than
out
of
it.

This
will
essentially
cause
a
depolarization
and
without
 a
normal
K+
gradient
the
cells
will
NOT
repolarize.
 o Mild
hyperkalemia
will
result
in
heart
arrythmias
or
palpitations.

 o BUT
extreme
hyperkalemia
(never
repolarizes)
can
stop
all
activity
as
 a
whole.

This
is
why
KCl
injection
is
the
third
drug
used
during
lethal
 injections
as
capital
punishment.

=>
stops
the
heart
completely.
 
 
 Go
Notes
53
 ‐ Type
B
intercalated
cells
 o Activated
during
alkalosis
(think
b
for
base)
 o Active
at
pH
>
7.4
 o *Fig
20‐22b
 o net
SECRETION
of
K+
 and
HCO3‐
and
 REABSORPTION
of
H+
 (again
K+
follows
 bicarb)
 o Apical
transporters
 HCO3‐/Cl‐
 antiport,
K+
leak
 channel
 H+/K+
antiport,
 H+
ATPase,
Cl‐
leak
 o Notice
the
transporters
are
just
opposite
of
the
type
A
cell.

If
 memorize
one
‐>
know
the
other
 
 How
do
all
these
mechanism
(lung
and
kidney)
work
together?
 ANSWER:
Davenport
plots.
Next
page!
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 Normal
pH
(7.40)
and
normal
HCO3‐
(24mM)
=
denoted
by
dark
black
circle.
 
 RESPIRATORY
pH
imbalances: 1. Respiratory
acidosis
 a. This
is
seen
primarily
by
an
increase
in
HCO3‐
and
a
decrease
in
pH
 due
to
increased
CO2
 b. Upper
left
quadrant
(green
arrow)
 Go
Notes
54
 c. Noticed
that
the
green
arrow
denotes
an
increase
in
PCO2
from
40
to
 60
 d. This
would
occur
via
anything
that
causes
hypoventilation
(why
it’s
 respiratory)
 e. So
COPD,
emphysema,
fibrosis,
and
extreme
alcohol
poisoning
 (alcohol
=
respiratory
depressant)
 f. Compensation
via
PT
and
type
A
cells,
will
increase
bicarbonate
 further,
but
will
somewhat
return
pH
closer
to
7.4
 2. Respiratory
alkalosis
 a. Seen
by
a
decrease
in
HCO3‐
and
an
increase
in
pH
due
to
decreased
 CO2
 b. Lower
right
quadrant
(yellow
arrow)
 c. Yellow
arrow
indicates
a
hyperventilation
which
decreases
CO2
from
 40
to
20mmHg
 d. Caused
via
hyperventilation

 e. Compensation
via
type
B
cells
which
decrease
HCO3‐
further
in
order
 to
approach
7.4
pH
 *
NOTICE:
these
respiratory
imbalances
have
no
respiratory
compensation
via
 hypo/hyper
ventilation.

Why?

Because
the
imbalances
are
themselves,
caused
by
 respiratory
issues;
therefore
a
problem
cannot
fix
itself.


We
must
rely
on
the
renal
 compensation
which
will
take
hours.
 
 
 
 
 April
29,
2011
 
 pH
Regulation
contd.
 acidosis
and
alkalosis
 Respiratory
and
Metabolic
compensations
 ‐‐‐‐‐‐‐‐‐O‐‐‐‐‐‐‐
 Digestive
system
 Overview
 Anatomy
+
Histology
 Motility:
peristasis,
segmentation,
haustrations,
mass
movements,
moving
motor
 complexes
 Phases
of
digestion
 
 Cephalic
 
 Oral
 
 Gastric
 
 Intestinal
(early
and
late)
 
 
 
 
 Go
Notes
55
 METABOLIC
pH
imbalances:
 1. Metabolic
acidosis
 a. Seen
via
decreased
HCO3‐
and
decreased
pH
 b. Lower
left
quadrant
(red
arrow)
 c. Red
arrow
just
denotes
a
decrease
in
HCO3‐
and
decrease
in
pH
 d. Notice
no
change
in
CO2
levels
(therefore
its
metabolic
in
nature)
 e. Caused
by
either
an
increase
in
acid
production
(diabetic
ketoacidosis,
 ketoacidosis
from
atkin’s
diet)
or
loss
of
HCO3‐
(diarrhea)
 i. Why
does
inc
H+
decrease
HCO3‐?
‐>
shifts
reaction
 eliminating
HCO3‐
 f. Compensation
=
hyperventilation
occurs
via
peripheral
chemoR
for
 pH
(occurs
within
seconds).

If
ventilation
is
not
sufficient
to
regain
 normal
pH
eventually
the
kidney
PT
and
type
A
cells
will
be
activated.
 2. Metabolic
alkalosis
 a. Seen
via
increased
HCO3‐
and
increased
pH
 b. Upper
right
quadrant
(blue
arrow)
 c. Blue
arrow
shows
increase
in
HCO3‐
and
pH
without
change
in
CO2
 d. Can
be
caused
via
increased
HCO3‐
(antacid
overdoes)
or
extreme
loss
 of
H+
(vomiting)
 e. Very
ineffective
compensation
(none
or
minimal).


 i. Why
wouldn’t
you
hypoventilate?
 1. Can’t
ever
hypoventilate
to
60mmHg
CO2
because
 central
chemoR’s
won’t
allow
it.

Recall
the
ventilatory
 CO2
curves.
 ii. What
about
type
B
cell
activation
 1. They
will
try,
but
it’s
very
ineffective
and
slow
 
 Figures
below
are
from
Ganong’s
review
of
medical
physiology.

Think
there
pretty
 self
explanatory
and
are
helpful
because
they
illustrate
chronic
and
acute
 imbalances
as
well
as
compensatory
views.

 Go
Notes
56
 
 Type
I
diabetes
 ‐ Characterized
byan
auto‐immune
(type
IV)
attack/destruction
of
beta
cells
 of
the
pancreas,
which
produce
insulin
 ‐ Insulin
is
necessary
for
the
absorption
of
glucose
from
the
circulatory
 system.
 ‐ In
order
to
produce
fuel
(without
glucose)
the
cells
will
undergo
beta‐ oxidation
(fat
metabolism)
that
produces
ketoacids:
β‐hydroxy
butyric
acid,
 aceto‐acetic
acid,
and
acetone.


 ‐ What’s
bad
is
that
hyperglycemia
can
cause
a
diabetic
coma,
but
 hypoglycemia
can
also
cause
a
coma
(brain
is
starving).


 o How
can
we
tell
the
difference
between
hyperglycemia
and
a
person
 who
might
have
skipped
a
meal
or
overdosed
on
insulin?
 o Who
do
we
give
insulin
to
and
who
needs
a
piece
of
candy?
 o If
we
give
insulin
to
the
hypoglycemic
one,
glucose
decreases
more
‐>
 death
 o Answer:
process
of
elimination.

If
the
coma
is
caused
by
 hyperglycemia
and
ketoacidosis
=>
fruity
breath
and
hyperventilation
 =
GIVE
insulin.

Otherwise,
candy
makes
him
dandy
 
 
 DIGESTION
 *Fig
21‐2
 4
MAJOR
PROCESSES:
 1. digestion
 2. secretion
 3. absorption
(no
regulation)
 4. motility
 Go
Notes
57
 
 Timing
of
the
secretions
and
motility
must
be
coordinated
in
order
to
ensure
 maximum
efficiency
for
digestion.

Therefore
they
are
highly
regulated,
whereas
the
 process
of
absorption
is
not.

The
body
will
absorb
as
much
as
it
possibly
can
 whenever
a
meal
is
eaten.

Natural
because
in
the
context
of
evolution,
many
 organisms
don’t
know
when
the
next
meal
will
come.
 
 *Fig
21‐
3
ANATOMY
 1. Mouth
 a. Salivary
glands
 i. Parotid
–
located
at
jaw
higne
 ii. Sublingual
–
inferior
to
tongue
 iii. Sub‐mandibular
–
inferior
to
jaw
bone
 b. Saliva
–
for
motility
(lubrication)
and
initiation
of
digestion
 i. Amylase
–
(carbs
and
starch)
 ii. Lysozyme
–
(bacterial
cell
walls)
 iii. Mucus/immunoglobulins/lipase
–
(initiation
of
fat
digestion
 but
is
minimal)
 c. mastication/chewing
–
via
skeletal
muscle
movement
of
jaw
 d. Deglutition/swallowing
–
tongue
pushes
back
‐>
stimulates
pharynx
‐ >
muscle
contraction
moves
esophagus
up
‐>
epiglottis
covers
trachea
 and
bolus
is
swallowed
into
esophagus
(if
cannot
be
swallowed
‐>
gag
 reflex)

 i. *FIG21‐24
 e. Sidenote:
typically
no
absorption
except
nitroglycerine,
some
pill
 prepared
B12,
etc
 f. Sidenote
#2:
advanced
Parkinson’s
patients
cannot
swallow
due
to
sk.
 Muscle
disruption
 2. Esophagus
 a. Upper
esophageal
sphincter
–
skeletal
muscle
which
guards
the
entry
 into
esophagus
and
prevents
food
from
returning
to
mouth
 b. Most
of
the
esophagus
is
smooth
muscle
–
movement
of
bolus
is
by
 peristalsis
(more
on
movement
later)
 c. Lower
esophageal
sphincter
–
smooth
muscle
–
normally
tonically
 contracted
preventing
acidic
chyme
(what
food
is
in
the
stomach)
 from
entering
the
esophagus,
only
relaxes
for
bolus
entry
into
the
 stomach
 i. Gastro‐Esophageal
Reflux
Disease
(GERD)
or
“heartburn”
 results
in
chyme
entering
the
esophagus
due
to
a
deficient
 lower
esophageal
sphincter
 d. NO
digestion/absorption
 3. Stomach
 a. 3
parts
(top
to
bottom)
 i. FUNDUS
–
storage
and
protection
 ii. BODY
–
secretion
and
mixing
 iii. ANTRUM
–
churning
and
mixing Go
Notes
58
 b. Surface
area
increased
by
folds
aka
ruggae
 c. From
in
(lumen)
to
out
 i. Mucosa
(epithelial
cells)
‐>
lamina
propria
(connective
tissue)
‐ >
muscularis
mucosal
(smooth
muscle,
movement
of
rugae
for
 churning)
‐>
submucosa
(connective
tissue
with
lymph/blood
 vessels
and
some
exocrine
glands)
‐>
Submucosal
plexus
 (network
for
secretions,
sends
signals
to
other
plexus
and
CNS)
 ‐>
muscularis
externa
first
oblique
muscle
and
circular
muscle
 to
decr.
Diameter,
(‐>
myenteric
plexus
network
receives
input
 from
submucosal
plexus
and
CNS
for
muscle
motility)
then
 longitudinal
muscle
to
decr.
Length
‐>
serosa
(CT
which
is
 continuous
with
peritoneal)
‐>
peritoneal
membrane
(CT
for
 entire
abdominal
cavity
which
contains
lymph/blood
vessels
 and
adipose
tissue)
 A. Peritoneum
–
can
be
used
as
a
dialysis
membrane
and
is
 subject
to
infection
or
peritonitis
 d. peristaltic
mixing
and
propulsion
 e. secretion
(more
on
this
soon)
 f. digests
fats
and
proteins
via
secretions
 g. minimal
absorption
except
for
alcohol
and
acetominophen
 h. pyloric
sphincter
–
food
leaves
through
this
sphincter
into
the
 duodenum,
rate
of
which
is
highly
regulated
(small
spurts
of
chyme)
 4. Small
Intestine
 a. Duodenum
–
receives
highly
acidic/proteolytic
chyme
from
stomach
 i. Short
–
20‐25cm
long
 ii. Receives
additional
secretions
from
pancreas,
liver,
and
gall
 bladder
via
the
SPHINCTER
OF
ODDI
 iii. Chemo,
osmo,
and
stretch
R’s
to
influence
the
secretions
and
 gastric
emptying
 b. Jejunum
–
additional
digestion
occurs,
main
area
for
absorption
of
 food/nutrients
(all)
 c. Ileum
–
longest
portion
–
same
fxn
as
above
 i. Ileocecal
sphincter
–
separates
end
of
SI
and
beginning
of
LI
 d. Plicae
–
folds
to
increase
SA
 e. Villi
–
protrusions
of
the
mucosa
into
lumen,
contains:
 i. Mucous
cells
–
secrete
mucus
 ii. Submucosa
layer
–
capillaries/lymph
vessels
 iii. Absorptive
cells
with
microvilli
for
SA
 iv. Endocrine
cells
–
(stem
cells)
found
in
intestinal
crypts
 A. Crypts
are
technically
just
adjacent
to
villi
and
increase
 SA
 f. same
layers
as
that
in
the
stomach
however
there
are
no
oblique
 muscles
and
the
mucosa
has
many
Peyer’s
patches
(mini
lymph
 nodes)
which
are
part
of
the
Gut
Associated
Lymphoid
Tissue
(GALT)
 g. movement
via
slow
waves,
peristalsis,
segemetation
and
MMC’s
 5. Large
Intestine/Colon
 Go
Notes
59
 a. Water
and
electrolyte
absorption
from
feces
 b. Ascending,
transverse,
descending
 i. Appendix
–
blind
sac
at
ascending
–
subject
to
infection
 (appendicitis)
 c. Rectum
–
terminal
end
of
LI
 d. Inner
anal
sphincter
–
smooth
muscle,
tonically
contracted
 e. Outer
anal
sphincter
–
skeletal
muscle
–
we
can
control
to
a
point
 f. Defecation
reflex
–
distension
of
the
rectal
wall
causes
inner
anal
 sphincter
to
relax
via
parasympathetic
input
‐>
POOP!
 
 
 May
2,
2011
 
 Digestive
system
 Anatomy
and
histology
 Motility:
Slow
waves,
peristalsis,
segmentation,
MMC’s,
haustration,
and
mass
 movements
 Enteric
nervous
system
 
 Submucosal
plexus,
myenteric
plexus
 Short
vs.
Long
reflexes
 Phases
of
digestion
 
 Cephalic,
Oral,
Gastric,
Intestinal
(early
and
late) 
 *Fig
21‐3b‐c
Anatomy
contd.
 ‐ See
last
lecture
for
my
entire
description
of
anatomy.

I
felt
it
was
better
to
 keep
all
of
it
together.
 
 *Fig
21‐3d‐e
Anatomy
and
location
of
submucosal
and
myenteric
plexus.
 
 REGULATION:
 1. CNS
(long
reflexes
to
the
enteric
NS)
 a. Parasympathetic
=
excitatory
“rest
and
digest”
(incr
motility
and
 secretions)
 i. ACh
‐>
muscarinic
AChR’s
 1. Inhibited
by
same
drugs
–
atropine,
belladonna
etc.
‐>
 decreased
motility
 b. Sympathetic
=
inhibitory
“fight
or
flight”
(decr
motility
and
 secretions)
 i. NE
‐>
α2
adrenergic
R’s
 c. Neurotransmitters
=
inhibitory
primarily
by
decreasing
motility
 i. Serotonin

 ii. Opiates
–
which
may
lead
to
constipation
(morphine,
 vicodin/norco)
 Go
Notes
60
 1. Immodium
activate
the
same
opiate
receptors
to
treat
 diarrhea
but
do
not
cross
the
blood
brain
barrier
so
no
 high.
 2. Enteric
Nervous
System
ENS
(aka
little
brain,
if
the
reflex
is
contained
only
 here
than
it’s
a
short
reflex)
 a. Occurs
within
the
GI
tract
(below
esophagus
starting
in
the
stomach)
 b. Integrates
sensory
information
from
mechanoR,
chemoR,
and
etc.
 c. Initiate
responses
via:
 i. Submucosal
plexus
–
neural
network
in
the
submucosa
 1. Controls
secretions
 2. Think
“S‐S”
submucosal‐secretions
 ii. Myenteric
plexus
–
neural
network
btw
the
circular
and
 longitudinal
muscle
layers
 1. Controls
motility
 2. Likewise
think
“M‐M”
myenteric‐motility
 3. Also
if
you
consider
the
myenteric
plexus’
location
it
 controls
the
adjacent
muscle
whereas
the
submucosal
 controls
the
adjacent
glandular/secretory
cells
 3. Endocrine
/
GI
peptides
(to
be
discussed
more
later)
 a. Endocrine

 i. CCK
–
increases
feeling
of
satiety
“fullness”
 ii. Ghrelin
–
hormone
which
increase
feeling
of
hunger
(inc
food
 intake)
 
 MOTILITY
(types
of
movement/mixing)
 1. Slow
waves
 a. *FIG
21‐4
 b. originate
from
auto‐rythmic
cells
–
interstitial
cells
of
Cajal,
 transmitted
via
gap
junctions
only
if
AP’s
are
suprathreshold,
increase
 freq
‐>
inc
strength.
 c. 3‐12
waves
per
minute
(highest
in
duodenum,
lowest
in
stomach)
 d. parasympathetic
input
is
excitatory
because
it
depolarizes
the
 membrane
potential,
intracellular
Ca2+
increases
‐>
contraction
 e. sympathetic
input
is
inhibitory
because
it
hyperpolarizes
cells
by
 opening
K+
channels
 2. Moving
Motor
Complexes
(MMC’s)
 a. Occur
every
90‐120
minutes
during
fasting
 b. Housekeeping
fxn
–
moves
bacteria/food
to
colon
making
room
for
 the
next
meal
 c. Originate
in
the
stomach
 d. Stimulated
by
hormone
Motilin
 3. Peristalsis
 a. *FIG
21‐5a
 b. Propulsive,
circular
contract,
longitudinal
contracts,
receiving
 segment
is
relaxes
 c. Affected
by
hormones,
paracrines,
and
autonomic
input
 Go
Notes
61
 
 
 4. Segmental
movement
 a. *FIG
21‐5b
 b. Segments
of
small
intestine
contract
in
alternating
manner
(circular
 contraction
only)
 c. No
net
movement
just
mixing,
thus
increasing
absorption
 5. Mass
movements
 a. Essentially
peristalsis/propulsion
of
entire
segments
of
the
Large
 Intestine
(empties
colon)
 6. Haustration

 a. Basically
segmentation
of
haustra
in
the
Large
Intestine
 May
4,
2011
 
 Cephalic
phase
 Oral
phase:mastication,
salivation,
deglutition
 Gastric
Phase
 
 Cells
and
secretions
of
the
gastric
mucosa
 
 Regulation
of
secretion
and
motility
 
 Digestion
 
 Peptic
ulcers
 Intestinal
Phase:
 
 Early:
secretions
by
pancreas,
liver,
gallbladder;
motility
+
digestion
 
 Late:
digestion
and
absorption
 
 *Fig
21‐23
Long
and
short
reflexes
of
the
GI
 This
figure
pertains
especially
to
the
Cephalic
phase
of
digestion
 
 Cephalic
phase:
“see,
smell,
or
think
food”
 i. Long
reflexes
begin
in
brain
‐>
parasymp
activation
via
vagus
‐>
ACh
on
 muscarinic
AChR’s
‐>
feed
forward
responses
resulting
in
increased
motility
 and
secretion
(of
both
salivary
and
gastric
cells)
in
anticipation
of
upcoming
 meal
 
 Oral
phase:
begins
when
food
enters
the
mouth
 i. food
‐>
mouth
‐>
saliva
secreted
‐>
chewing
(mastication)
‐>
bolus
is
 swallowed
(deglutition)
‐>
upper
esophageal
sphincter
‐>
esophagus
‐>
 lower
esophageal
sphincter
 a. mechanical
stimulation
initiates
salivary
glands
(taste,
especially
 through
sweet
R’s,
does
too)
 b. Saliva
 i. Hydrates
and
lubricates
 ii. Lisozyme
–
lyses
cell
walls
of
bacteria
 1. Why
licking
one’s
wounds
can
work
 iii. Salivary
amylase
–
Carb
and
starch
breakdown
 Go
Notes
62
 ii. iii. iv. Lipase
–
for
fat
breakdown
but
is
minimal
 c. Mastication
or
chewing
breaks
down
particles
increasing
SA
and
 mixing
in
saliva
 d. Deglutition
or
swallowing
–
*FIG
21‐24
 i. Tongue
pushes
bolus
to
back
of
pharynx
 ii. This
triggers
the
larynx
to
move
upwards
allowing
the
 epiglottis
to
cover
the
larynx
 iii. Contraction
of
muscle
pushes
the
bolus
into
the
 esophagus
while
the
upper
esophageal
sphincter
relaxes
 iv. Food
moves
down
the
esophagus
via
peristalsis
 most
breakdown
is
via
mechanical
mechanisms,
carb
digestion
begins
 by
amylase,
salivary
lipase
does
almost
nothing
 no
absorption
within
the
oral
phase

 a. except
by
some
special
sublingual
absorption
of
special
vitamin
 B12
treatments(to
be
discussed
later)
and
nitroglycerine
 (vasodilator)
 
 Peristaltic
motion
throughout
the
esophagus.

Already
discussed.
 
 Gastric
Phase:
begins
when
bolus
enters
the
stomach
via
the
lower
esophageal
 sphincter
 i. pH
of
the
stomach
during
fasting
is
from
1‐3.
 ii. multiple
cells
secrete
into
the
stomach

*Fig
21‐25
 
 Secretory
cells
 - Mucous
cells

(exocrine)
*FIG21‐27
 – Secrete
mucus
rich
bicarbonate
 – Lines
the
stomach
wall
to
provide
a
chemical
barrier
against
 the
acidic
pH
 - parietal
cells
within
the
middle
to
upper
part
of
the
gastric
pit
 (exocrine)
 – secrete
HCl
and
intrinsic
factor
 1. intrinsic
factor
is
a
protein
discovered
from
pernicious
 anemia
 2. essentially
intrinsic
factor
is
necessary
for
the
 absorption
of
vitamin
B12
 3. a
mandatory
component
of
RBC
synthesis
 4. lack
of
which
resulting
in
large,
but
few
RBC’s
 5. B12
is
sensitive
to
acid,
if
not
protected
from
the
gastric
 acid
(by
intrinsic
factor)
it
will
be
destroyed
prior
to
the
 intestinal
phase
 – *FIG
21‐6
(know
it)
–
for
my
test
I
had
to
draw
it
out
for
12
 easy
points
 1. Proton
comes
from
CA
rxn
not
from
water!!!!
 2. Proton‐Potassium
ATPase
pump
on
apical
 3. Cl‐
leak
channel
apical
 Go
Notes
63
 - - - 4. Bicarbonate‐Chloride
antiport
basolateral
 5. Net
secretion
of
HCl
causing
a
gastric
pH
of
2‐3
 – Regulation
of
parietals
 1. m3AChR’s
–
stimulatory
 2. H2
(histamine)
R’s
–
stimulatory
 a. Famous
H2
blockers
include
ranitidine,
 cimetidine
aka
“zantac”,
“tagamet”,
and
“pepcid


 i. Utilized
to
inhibit
acid
secretion
which
 cause
peptic
ulcers
 3. Gastrin
–
Stimulatory
via
G
cells
 4. Somatostatin
–
inhibitory
via
D‐cells
 Enterochromaffin‐like
cells
(ECL)
(paracrine)
 – Secrete
histamine
 1. Which
in
a
paracrine
manner
stimulate
the
parietal
cells
 Chief
cells
(exocrine)
 – Secrete
pepsinogen,
an
inactive
precursor
 – Which
is
activated
and
cleaved
into
pepsin
via
the
acid
 – Main
proteolytic
enzyme
in
the
gastric
phase
 – Optimum
pH
for
pepsin
is
3
 – ENDOPEPTIDASE
 – Chief’s
also
secrete
gastric
lipase
 G‐cells
(endocrine)
 – Secrete
a
hormone,
gastrin
 – Gastrin
stimulates
the
ECL
cells,
the
parietal
cells,
and
the
 smooth
muscle
cells
of
the
stomach
 – Which
will
increase
HCl
secretion
and
increase
motility
 D‐Cells
(endocrine)
 – Secrete
somatostatin,
main
inhibitory
hormone
 – Therefore
in
the
gastric
phase
it
inhibits

 Go
Notes
64
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 Ulcers
correlary:
 1. Excess
acid
treatment
of
ulcer
preventions
(overall
goal
inhibit
parietals)
 a. Proton
Pump
Inhibitors
(PPI’s)
 i. Block
H+/K+
pump
by
reacting
with
external
sulfhydryl
grp
 only
at
a
low
pH
 ii. Omeprazole
“prilosec”
now
OTC,

L‐omperazole
“nexium”,
and
 prevacid
 b. H2
blockers
–
block
histamine
R’s
responsible
for
much
acid
 secretion
 i. Cimetidine
(tagamet)
and
ranitidine
(zantac),
pepcid
 c. AChR
blockers
 i. Atropine
and
belladonna
 ii. In
rare
cases
they
would
perform
vagotomies
in
which
the
 vagus
nerve
was
cut
 2. Marshall
and
another
Australian
dude
Warren
–
discovered
bacteria
typical
 amongst
peptic
ulcers
 - they
discovered
Helicobactor
Pylori
“H
Pylori”
which
is
an
infection
by
 which
the
bacteria
infect
and
weaken
the
GI
lining
 - how
can
they
live
in
such
a
acidic
environment?
 Go
Notes
65
 – Secrete
Urease
 – Breaks
down
urea
(NH2)2C=O
<‐>
CO2
+
2NH3
 – NH3’s
generated
will
be
a
buffer
which
protects
the
H
Pylori
 - Diagnose
by
giving
radioactively
labeled
urea
–
CO2
or
NH3
generated
 in
the
stomach
is
a
positive
indication
of
H
Pylori
 - 90‐95%
of
peptic
ulcers
are
caused
by
H
Pylori
 - treat
with
antibiotics,
bismuth
(peptoBISMol),
and
PPI’s
 3. 
Iatrogenic
“caused
by
medicine”
 – 



Acetominophen
and
other
NSAID’s
 – 


Why?

They
themselves
are
strong
acids
pKa
of
3
 – 


But
more
importantly,
they
inhibit
the
formation
of
 prostaglandins,
because
they
are
COX‐1
inhibitors.

In
the
stomach,
 the
mucous
secreting
cells
are
stimulated
by
prostaglandins
 4. Zolinger‐Ellison
syndrome
–
tumorous
G
cells
which
excessively
secrete
 gastrin
 - Which
will
stim
ECL
and
parietal
cells
 5. Excess
stress
–
causes
increase
cortisol
secretion
 - Cortisol
is
the
main
stress
hormone
which
diminishes
the
capability
to
 fight
infection - Cortisol
also
inhibits
the
enzyme
that
converts
arachidonic
acid
to
 prostaglandins
(stimulus
for
mucus
secretion
remember)
 - This
is
similar
to
NSAIDs
 
 
 May
6,
2011
 
 Gastric
Phase
contd.
 
 Regulation
of
secretion
 
 Peptic
ulcers
 
 Digestion
and
motility
 Intestinal
phase
 
 Early
hormonal
and
exocrine
secretions
 
 
 Pancreas
and
liver
 
 Late
digestion
and
absorption
 
 
 Colon
–
absorption
(H2O
and
electrolytes)
 
 
 Secretion
 
 GI
reflexes
 
 *Fig
21‐26
integration
of
cephalic
and
gastric
phase
secretion.


 o Note
that
parasympathetic
activation
and
distension
of
the
stomach
 activates
G
cells
and
aa/protein
activation
of
G
cells
serve
to
increase
 HCl
secretion
directly
(parietals)
or
indirectly
(ECL
cells)
 o The
acid
in
the
lumen
of
the
stomach
stimulates
chief
cells
to
secrete
 pepsinogen
and
gastric
lipase
 Go
Notes
66
 o And
lastly
there
is
a
negative
feedback
loop
in
which
H+
activate
D
 cells,
which
inhibit
ECL,
G‐cells,
parietals
and
chief
cells
via
 somatostatin.
 
 Dr.
Fortes
then
went
on
to
reexamine
ulcer
causes
and
treatments,
but
I
have
 already
summarized
them
in
the
last
lecture
notes.


 
 Rest
of
the
gastric
phase:
 ‐ The
effect
of
gastric
lipase
digestion
of
fats
is
pretty
minimal
in
the
tummy.
 ‐ Motility
in
the
stomach
consists
mostly
of
peristaltic
motion.
 o If
the
pyloric
sphincter
is
closed
than
the
wave
will
cause
a
 “blowback”
of
the
chyme.

‐>
this
results
in
the
churning
function
of
 the
stomach.


 ‐ The
antrum
is
the
most
narrow
portion
of
the
stomach
and
serves
as
a
sieve
 in
order
to
eliminate
large
chunks
of
solid
material
that
still
needs
to
be
 broken
down.
 ‐ There
are
slow
waves
(initiated
by
interstitial
cells
of
Cajal)
in
the
stomach
 but
their
rate
is
slow
3/min.

(compared
to
12/min
in
the
duodenum.
 
 
 
 Early
intestinal
phase:
 ‐ The
duodenum
is
a
very
short
(12cm
or
so)
section,
which
receives
highly
 proteolytic
acidic
chyme
from
the
stomach.
 ‐ Because
of
that
fact
it
is
the
most
common
place
for
peptic
ulcers
to
occur
 o Protection
from
the
acidic
chyme
and
identification
of
the
chyme
 components
are
essential
 ‐ The
duodenum
is
armed
with
a
variety
of
sensory
mechanisms
designed
just
 for
those
purposes
 o Mechanoreceptors
–
stretch
activated
and
detects
chyme
entry
into
 the
duodenum
 o Osmoreceptors
–
detect
the
osmolarity
of
the
chyme
and
are
partially
 activated
by
stretch
(inc
osmolarity
‐>
inc
osmosis
‐>
inc
volume)
 o Chemoreceptors
for
 pH!!!
 Proteins/peptides/aa’s
 Lipids
 Carbs
 
 If
pH
decreases
in
the
duodenum
due
to
chyme
entry
this
will
stimulate
the
 secretion
of
Secretin,
a
hormone
made
by
the
duodenal
endothelium.
 ‐ Secretin
serves
two
purposes
 o Stimulates
the
pancreatic
duct
cells
to
secrete
bicarbonate
rich
juice
in
 order
to
neutralize
the
acid
 o Decreases
gastric
motility
and
gastric
emptying
 
 Go
Notes
67
 *Fig
21‐8
Bicarb
secretion
by
duct
cell
 ‐ Know
this
figure!
 ‐ CFTR
channel
is
a
Cl‐
leak
 channel
known
as
a
cystic
 fibrosis
transmembrane
 regulator
 o Gated
internally
by
 cAMP
 o If
cAMP
increases
 the
channel
is
open
 o Channel
is
 ubiquitous
in
sweat
 glands,
lungs,
 duodenum
and
 large
intestine
 o In
cystic
fibrosis
 these
channels
are
 nonfunctional
‐>
 resulting
in
less
 water
and
Na+
being
drawn
(paracellular
path)
by
osmosis.

As
a
 result
cystic
fibrosis
results
in
thick
immobile
mucus.

Increased
 susceptibility
to
infection
ensues.
 *Fig
21‐7
Pancreas
 ‐
pancreas
is
a
hybrid
organ
with
both
exocrine
and
endocrine
function.

For
the
 purposes
of
digestion
we
will
look
at
the
exocrine
portion
for
now.

Later
we
will
 examine
the
endocrine
portion
especially
as
it
pertains
to
metabolic
regulation
of
 glucose
via
insulin
and
glucagon.
 
 
 May
9,
2011
 
 SUPER
cool
lecture
by
the
infamous
Dr.
West.

I
don’t
know
yet
how
I
would
possibly
 test
upon
that
material.

So
at
the
very
least,
I
hope
that
you
enjoyed
it.


 
 
 May
11,
2011
 
 
 Digestion
and
motility
 Intestinal
phase
 
 Early
hormonal
and
exocrine
secretions
 
 
 Pancreas
and
liver
 
 Late
digestion
and
absorption
 
 
 Colon
–
absorption
(H2O
and
electrolytes)
 
 
 Secretion
 Go
Notes
68
 
 GI
reflexes
 
 Chemoreceptors
within
the
duodenum
also
recognize
the
presence
of
fats
and
 proteins.

This
will
result
in
the
secretion
of
cholecystokinin
(CCK)
dy
the
duodenul
 epithelium.
 ‐ CCK
has
a
variety
of
functions
 o Gall
bladder
contraction
‐>
bile
ejected
into
duodenum
through
 common
bile
duct
and
sphincter
of
Oddi
 o Relaxation
of
the
sphincter
of
Oddi
 o Increase
bile
secretion
by
the
liver
 o Decrease
gastric
emptying
and
motility
 o Stimulation
of
the
pancreatic
acinar
cells
to
secrete
their
zymogens
 o And
as
we
shall
see
inhibits
appetite
 
 The
components
of
bile
include:
 1. excess
cholesterol
 a. if
cholesterol
is
way
too
much,
they
can
crystallize
in
the
 gall
bladder
where
bile
is
concentrated
 b. the
resulting
gall
stones
will
cause
pain
and
can
result
in
 blockage
of
the
common
bile
duct
 2. bile
salts
(detergents
for
lipid
emulsification)
 a. cholate
and
deoxycholate
mainly
 3. Pigments
(Hb
breakdown
metabolism)
 a. Biliverdin
(green)
 b. Bilirubin
(red/orange)
 c. These
give
the
characteristic
color
of
feces.
 d. If
they
cannot
be
eliminated
in
the
feces
because
of
a
 blocked
common
bile
duct
‐>
they
deposit
in
the
skin
and
 eyes
and
myelin
sheaths
=
jaundice
 Again,
the
actions
of
CCK
are
 1. ↑
gall
bladder
contractability
 2. ↑
bile
secretion
by
liver
 3. relax
the
sphincter
of
Oddi
 4. ↓
gastric
emptying
and
motility
 5. ↑
pancreatic
acinar
cells
to
secrete
zymogens

 6. ↓
appetite
via
hypothalamic
centers
(CCK
is
also
secreted
in
the
hyp)
 
 Secretin
‐
↑
secretion
of
the
pancreatic
duct
cells
(HCO3‐
rich
juice)
 
 *Fig
21‐27
endocrine/exocrine
portions
of
pancreas
(again)
 
 Pancreatic
acinar
cells
secrete
inactive
digestive
enzymes
called
zymogens.
 ‐ George
Pallade
won
the
Nobel
prize
for
determining
the
exocytosis
 mechanism
through
these
cells
 Go
Notes
69
 ‐ These
zymogens
will
not
be
activated
until
they
are
cleaved
within
the
 duodenum.
 
 Chemoreceptors
within
the
duodenum
that
recognize
the
presence
of
carbs
or
 glucose
will
cause
the
secretion
of
GIP/GLP1.

Nicknamed
incretins.
 Glucose
insolinotropic
peptide
(GIP)
and
glucagon
like
peptide
(GLP1)
serve
 to
increase
insulin
secretion
by
the
β
cells
of
the
pancreas.


 ‐ This
is
a
feedforward
mechanism.

Insulin
is
necessary
for
cells
to
take
up
 and
utilize
glucose.

So
the
presence
of
carbs,
sets
in
motion
processes
for
 when
the
glucose
is
absorbed
in
the
bloodstream.
 
 
 
 
 
 
 
 
 
 
 Liver
&
Gallbladder

 Histology Go
Notes
70
 ‐ Hepatocyes have a variety of synthetic and metabolic functions ‐ Double circulation – systemic circulation from the hepatic artery and the hepatic portal vein which brings venous blood collected from the capillaries of the abdomen ‐ The liver gets first shot at almost everything absorbed in the abdomen (there are exceptions, discussed later) *Fig 21-10 ‐ Liver is mostly located in the right, upper abdomen ‐ Inferior is a small pouch which stores bile ‐ Bile ducts come out of the liver and pool into the common bile duct; a branch goes into the gallbladder. o The gallbladder has a very active transport epithelium which concentrates the bile by reabsorbing ions, water etc. ‐ When stimulated by CCK, the gallbladder contracts and pushes the bile towards the small intestine Liver Functions: - Receives…. o From the systemic circulation: bilirubin, metabolites of hormones/drugs, nutrients o From the hepatic portal vein: bile salts, nutrients, drugs, foreign substances - Functions… o Glucose and fat metabolism o Protein synthesis & Hormone metabolism Main protein: serum albumin (main protein responsible for osmotic pressure in the capillaries) o Urea production from the digestion of proteins o Detoxification, storage - Sends… o To the bile duct: Bile salts, bilirubin, water, ions, phospholipids o To the hepatic vein: A variety of things… (not all that important) Bile ‐ Bile Acids / Salts o Emulsify the lipids and allow the digestive enzymes to attack them (increases the surface area of the fats) o Without these, fat digestion is not possible and can cause steattorhea (loss of fat in the feces) ‐ Bile Pigments o Bilirubin – deep yellow Mostly insoluble in water The liver will convert some of the bilirubin into a more soluble form so that it can be excreted in the kidney o Biliverdin - green Go
Notes
71
 o Others (don’t worry about them) o These are the metabolic products of heme (hemoglobin, myoglobin, cytochromes) o If you centrifuge blood always looks yellow (because of bilirubin) o Urine – typically yellow, orange (depending on dilution factor) because of the bilirubin excreted ‐ Cholesterol o An important component of lipid membranes; also functions a precursor of bile salts o Excess cholesterol can be excreted via the bile o The gallbladder, when concentrating the bile, may crystallize the cholesterol gallstones (primarily composed of cholesterol, at later stages also includes calcium) o Contraction of the gallbladder with gallstones isometric contraction of the smooth muscle very painful (often misdiagnosed as appendicitis) o Gallstones can also get pushed into the bile duct where they may get stuck Bile will backup into the gallbladder and liver Liver will not be able to excrete bilirubin accumulation in the body jaundice (yellow pigmentation of the skin, white of the eyes, myelin of the brain, palms of hand, soles of the feet) Liver problems / obstruction of the bile duct… ‐ Jaundice ‐ Massive amount of pigments in the urine dark brown ‐ Also causes the feces to change color white/light gray ‐ Pools/droplets of fats in the feces steattorhea Excess beta-karatin (eating too many carrots..) ‐ Can give jaundice like symptoms ‐ Karatino-dermia 
 Other
liver
problems
(due
to
alcoholism)
 ‐ Chronic
alcoholism
will
cause
the
development
ofliver
cirrhosis.

Essentially
 cirrhosis
is
characterized
as
replacement
of
helthy
liver
tissue
with
fibrous
 scar
tissue.

The
scar
tissue
causes
fluid
to
build
up
within
the
liver
‐>
 increase
hydrostatic
P
=
increase
filtration.
 ‐ The
accumulation
of
fluid
within
the
peritoneal
cavity
is
called
ascites.
 
 
 May
13,
2011
 
 Intestinal
phase
contd.
 Digestion
and
absorption
 
 Carbs,
proteins,
lipids,
H2O,
ions,
vitamins
(either
lipid/H2O
soluble)
 Go
Notes
72
 Colon:
Absorption
and
secretion
of
ions
and
H2O
 GI
reflexes
 
 Ileo‐gastric,
gastro‐ileal
and
gastro‐colic
 
 *Fig
21‐13

Villi
w/
intestinal
crypt
 ‐ A
villus
is
composed
of
multiple
enterocytes
(absorptive
cells)
each
with
 microvilli
that
make
up
their
brush
border.
 ‐ Two
sets
of
circulation
 o Blood
circulation
via
a
capillary
bed
to
absorb
and
transport
absorbed
 material
 o Lacteals
–
open
ended
lymphatic
vessels
which
allow
are
immune
 system
to
protect
the
gut
from
deleterious
substances/organisms
and
 it
enables
the
absorption
and
transport
of
fat/cholesterol
in
the
form
 of
chylomicrons
 ‐ At
the
bases
of
the
crypts
are
stem
cells
which
constantly
regenerate
 enterocytes
 o FACT:
most
of
the
entire
endothelium
of
the
intestines
tends
to
be
 replaced
every
five
or
so
days.

A
significant
portion
of
feces
tends
to
 be
the
cellular
remains
of
the
old
cells,
which
simply
“slough”
off.

‐>
 that’s
why
even
as
infants,
solid
feces
occurs.
 
 
 
 *Fig
21‐29

Activation
of
zymogens

 ‐ Recall
that
the
pancreatic
acinar
cells
secrete
inactive
enzymes
in
order
to
 prevent
autodigestion
 ‐ The
major
one
is
trypsinogen,
which
is
activated
by
an
enteropeptidase
 located
within
the
brush
border
of
the
duodenum.

Active
form
is
Trypsin.
 o Trypsin
goes
on
to
activate
additional
trypsinogen
causing
a
cascade
 that
results
in
rapid
activation
 ‐ In
addition
trypsin
goes
on
to
activate
all
of
the
other
zymogens
by
cleaving
 off
the
regulatory
sequences
 o Chymotrypsinogen
to
chymotrypsin
(endopeptidase)
 o Procarboxypeptidase
and
proaminopeptidase
‐>
carboxy/amino
 petidase
(exopeptidase
which
release
free
aa’s
or
dipeptides
from
 either
the
amino
or
carboxy
termini).
 o Procolipase
‐>
colipase
(2FFA
and
a
monoglyceride)
 o Prophospholipase
‐>
phospholipase
(1FFA
and
a
diglyceride)
 o Nucleases
too
(not
shown)
 
 *Fig
21‐14
Carb
digestion
 ‐ Pancreatic
amylase
will
break
down
complex
carbs,
starches,
and
glycogen
 into
disaccharides
(still
too
big
for
absorption)
 ‐ Additional
enzymes
are
needed
to
breakdown
specific
disaccharides
into
 monosaccharides
 o Maltase
breaks
down
maltose
disaccharide
into
2
glucose
molecules
 Go
Notes
73
 o Sucrase
breaks
down
sucrose
disaccharide
into
1
glucose
and
1
 fructose
 Sucrose
=
table
sugar.

Fructose
is
the
most
potent
activator
of
 our
sweet
receptors
in
the
tongue.

Also
why
high
fructose
corn
 syrup
is
so
sweet.
 o Lactase
breaks
down
lactose
disaccharide
into
1
glucose
and
1
 galactose
 People
who
are
lactose
intolerant
typically
have
a
deficient
 lactase
enzyme.

As
a
result,
their
body
cannot
breakdown
the
 lactose
sugar.

However,
the
bacteria
that
occupy
the
gut
love
 it.

Their
increase
in
metabolism
can
cause
cramps,
nausea,
 irritation,
gas,
and
therefore
increase
motility.


 
 *Fig
21‐15
Carb
absorption
 − Once
the
carbs
have
been
broken
down
into
their
constituent
monosaccharides,
 absorption
can
occur
 a) On
the
apical
membrane
of
enterocytes
is
a
sodium
dependant
glucose
 symport.

SGLT
 i) Utilizes
the
sodium
gradient
to
bring
in
glucose
 b) Additionally
fructose
will
be
brought
in
via
a
GLUT5
transporter
 c) On
the
basolateral
membrane,
both
glucose
and
fructose
are
exported
out
via
 the
GLUT2
transporter
 
 GLUT
transporters
 TYPE
 AFFINITY
 LOCATION
 SPECIAL
PROPERTIES
 GLUT
1
 Intermediate
 Most
cells,
RBC’s
 
 GLUT
2
 Low
 Intestines,
 Simply
transports
down
 Proximal
tubule
 gradient
 of
nephron
 GLUT
3
 HIGH
 Neurons
 Functional
even
if
 [glucose]
is
low
 GLUT
4
 Intermediate
 Adipocytes
and
 Insulin
dependant
 skeletal
muscle
 deposition
of
transporters
 GLUT
5
 
 
 Fructose
transporter
 
 *Fig
21‐16

Protein
digestion
 − Note
that
there
is
a
difference
between
endopeptidases
and
exopeptidases.
 
 *Fig
21‐17

Protein
absorption
 − Apical
transporters
 a) Na+/H+
pump
antiport
 b) Di/tri
peptides
absorbed
via
a
H+
symport
 c) Single
aa’s
are
cotransported
using
a
Na+
symport
 − Basolateral
transporters
 a) Di/tripeptides
are
exported
using
a
H+
antiport
 Go
Notes
74
 b) Na+/K+
ATPase
 c) Na+/aa
antiport
 − Small
peptides
can
be
endocytosed
apically
and
exocytosed
basolaterally
(a
 process
known
as
transcytosis)
 a) Best
example
of
when
this
works
is
how
a
fetus
can
absorb
and
utilize
 maternal
antibodies
which
are
provided
through
lactation
 i) Rather
than
digesting
them
the
fetus
can
absorb
and
use
full
functional
 antibodies
(IgA
I
think?,
but
I
slept
through
immunology).

Part
of
the
 innate
immunity
that
enables
them
to
live
after
birth.
 
 *Fig
21‐18
triglyceride
breakdown
 − Lipase
=
TG
‐>
2FFA
and
monoglyceride
 − Colipase
=
phospholipid
‐>
1FFA
and
a
lysophospholipid
 − Phospholipase
‐>
1FFA
and
diglyceride
 
 *Fig
21‐19
 − FFA’s,
monoglycerides,
diglycerides,
phospholipids,
and
cholesterol
are
coated
 with
bile
salts
‐>
forming
micelles
 − Bile
salts
are
amphiphatic
with
a
polar
region
 ‐ Cholate
and
deoxycholate
 ‐ they
help
to
coat
the
nonpolar
products
above
in
order
to
increase
surface
 area
by
which
lipase
and
colipase
can
act
 
 *Fig
21‐20

Digestion
and
absorption
of
fats.
 − Fat
droplets
combine
with
bile
salts
(cholate/deoxycholate)
which
emulsify
 them
increasing
surface
area
for
digestion
 − The
enzymes
lipase/colipase
breakdown
triglycerides
into
FFA
and
 monoglyceride
 − Monoglycerides
and
FFA
diffuse
into
the
membrane
and
into
smooth
ER
 − Cholesterol
is
take
up
by
a
membrane
transporter
 − In
the
smooth
ER,
the
FFA
and
monoglycerides
are
recombined
into
triglycerides
 − The
TG’s,
cholesterol
and
protein
are
recombined
into
a
chylomicron
(cm)
 − The
cm
is
packaged
into
a
vesicle
by
the
golgi
and
is
exocytosed
basolaterally
 − The
chylomicron
is
too
big
to
enter
into
the
capillaries
so
instead
it
enters
into
 the
lacteal
(lymph)
vessel.

 a) Therefore
the
chylomicron
will
be
circulated
throughout
the
lymphatics
and
 will
not
enter
the
circulatory
system
until
the
lymph
vessels
empty
into
the
 subclavian
vein.

From
there
it
enter
the
superior
vena
cava
‐>
Right
atrium
 and
so
on.
 Vitamins:
 − Most
water
soluble
vitamins
(B
and
C)
are
taken
via
Na+
coupled
transport
 − Lipid
soluble
vitamins
–
are
absorbed
based
on
passive
diffusion
 a) But
if
there
is
some
problem
with
the
digestion
or
absorption
of
fat
(bile
duct
 blockage
or
no
bile
salts),
steatorrhea
will
occur
 b) Rather
than
diffusing
into
the
enterocytes,
the
fat
soluble
lipid
will
dissolve
in
 the
fat
that
is
in
the
feces
‐>
to
be
defecated

 Go
Notes
75
 c) Can
lead
to
vitamin
deficiencies
 
 Recall
the
other
symptoms
of
a
blocked
bile
duct
or
removal
of
the
terminal
ileum
 − Dark
urine
 − White
feces
 − Steatorrhea
 − Jaundice
 
 Olestra
drug
–
a
synthetic
lipid,
which
is
unabsorbable
because
cannot
be
 hydrolyzed
by
lipase
 ‐ can
result
in
ADEK
deficiency
 
 Alli
–
inhibition
of
pancreatic
lipase
 ‐ however
the
gut
flora
will
be
able
to
utilize
the
nutrients
resulting
in
 steatorrhea,
diarrhea,
gas,
and
ADEK
deficiency
 
 Ezetimibe
–
cholesterol
transporter
inhibitor
 ‐
no
clear
results
that
it
actually
decreases
cholesterol
 
 α‐glycosidase
–
amylase
inhibitors
 
 Gluten
stuff?
 ‐ So
you’ve
heard
of
gluten
free
bread
and
pasta…
 ‐ This
is
for
people
with
celiac
disease,
a
disease
in
which
the
immune
system
 mounts
an
unnecessary
response
to
gluten
 ‐ The
resulting
immune
response
due
to
those
antibodies
causes
chronic
 inflammation
of
the
absorptive
mucosa
 ‐ Typically
have
troubles
“keeping”
food
down,
and
what
little
food
does
enter
 into
the
intestines
will
be
subject
to
extremely
high
motility
 ‐ As
a
result,
these
people
have
a
real
inability
to
absorb
all
of
the
other
 nutrients
because
of
those
digestion
problems.
Look
like
they
have
 malnutrition.
 ‐ Celiac
disease
used
to
be
highly
misdiagnosed
as
an
eating
disorder
 (anorexia/bolemia)
and
therefore
were
treated
as
psychotic
patients
because
 they
wouldn’t
respond
to
normal
treatments
for
eating
disorders.

Even
 gastrointerologists
still
misdiagnose
them
today.
 
 I
mentioned
above
that
an
ileostomy
(removal
of
the
ileum)
can
cause
the
same
 symptoms
as
that
of
a
blocked
bile
duct.

But
why?
 − Bile
salts
are
reabsorbed
within
the
terminal
ileum.

Therefore
removal
of
the
 ileum
(as
in
cancer)
can
result
in
a
lack
of
bile
salts
‐>
all
symptoms
 − Usually
the
bile
salts
are
absorbed
there,
they
enter
the
entero‐hepatic

 circulation
to
the
liver,
the
liver
reacquires
them
and
recycles
them
into
newly
 secreted
bile.
 
 Go
Notes
76
 Also,
do
you
remember
that
the
parietals
secrete
intrinsic
factor
that
complexes
 with
vitamin
B12?
 ‐ Vitamin
B12
and
the
intrinsic
factor
are
also
absorbed
within
the
terminal
 ileum.

(pretty
much
everything
is)
 ‐ Therefore
ileostomy
will
result
in
both
steatorrhea
as
well
as
pernicious
 anemia!
 
 Iron
absorption!
 ‐ Only
Fe2+
(ferrous)
can
be
absorbed
 ‐ Ferric,
Fe3+
cannot
be
absorbed
 ‐ But
theacidic
nature
of
the
stomach
causes
all
ferric
Fe3+
to
be
reduced
to
 the
ferrous
Fe2+
 ‐ Ferrous
is
uber
essential
for
heme
production
 ‐ However,
like
all
other
heavy
metals
Fe
has
intrinsic
toxicity.
 o We
don’t
want
too
much
(toxicity),
but
we
can’t
have
too
little
 (anemia)
 o Therefore
this
needs
a
transporter
whose
expression
is
regulated
by
a
 liver
paracrine.
 o This
paracrine
is
only
secreted
when
we
need
iron!
Smart
huh?
 ‐ Ferritin
is
the
storage
protein
for
Fe2+
(to
prevent
toxicity)
 ‐ When
iron
transport
is
necessary
there
is
a
protein,
called
transferring,
 which
can
take
Fe2+
through
the
circulatory
system
 ‐ Some
of
the
iron
deficiency
anemia’s
are
due
to
nutritional
lack
of
Fe2+
as
 well
as
constant
hemorrhaging

 
 Calcium
absorption!
 ‐ transport
mediated
absorption
 ‐ once
absorbed
Ca++
is
bound
by
calbindin
 ‐ BOTH
transport
and
calbindin
is
mediated
by

 o the
parathyroid
hormone,
PTH
 o vitamin
D

 o and
calcitonin
(not
discussed)
 ‐ Vitamin
D
 o Can
be
obtained
in
the
diet
but
mostly
is
produced
by
the
skin
when
 exposed
to
sunlight
 o Lack
of
vitamin
D
results
in
a
lack
of
Ca++
absorption
 Rickets
in
children
or
osteomalacia
in
adults
 o This
is
why
post‐menopausal
women
who
are
susceptible
to
 osteoporosis
are
supplement
vitamin
D3
in
order
to
increase
Ca++
 absorption
 ‐ Ca++
is
transported
out
basolaterally
via
a
Ca++
ATPase
or
the
NCX
 (Na+/Ca++
exchanger)
that
transports
3Na+
in
for
1
Ca++
out.
 
 
 
 Go
Notes
77
 
 May
16,
2011
 
 Colon:
Absorption
of
ions
and
H2O
(colonocytes)
 
 Secretion
of
Na,
Cl,
H2O
(colonic
crypt
cells)
 
 Motility:
haustration,
mass
movements,
opiate
effect
 GI
reflexes
–
Gastro‐colic,
Gastro‐ileal,
Ileo‐gastric
 
 Defecation
 
 *Fig
21‐31

Anatomy
of
the
large
intestine
(colon)
 − By
the
time
chyme
gets
to
the
L.I.
its
mostly
just
dilute
feces.

Most
absorption
 will
be
of
ions
and
H2O
 − Ileocecal
valve,
ascending,
transverse,
descending,
sigmoin
colon,
and
rectum
 a) Noticed
the
blind
dead
end
sac
=
appendix
 b) Used
to
be
considered
a
vestigial
organ
but
recent
studies
show
that
it
does
 serve
some
functions
 c) Has
a
propensity
to
become
infected
and
inflamed
=
appendicitis
 d) Tx
=
immediate
removal
before
it
bursts
 i) If
it
does
burst
whole
abdominal
cavity
is
susceptible
to
infection
 e) Segments
are
distinguished
by
haustra
‐>
provides
excellent
structure
for
the
 purposes
of
haustration
(basically
segmentation
but
only
in
the
L.I.)
 i) If
the
purpose
of
the
colon
is
absorption
of
H2O
and
electrolytes,
the
 haustration
ensures
that
the
feces
are
mixed
appropriately
and
that
H2O
 is
absorbed
throughout
(not
just
at
the
surface)
 f) Note
the
tenia
coli
 g) Also
note
in
the
inlet,
there
are
significant
amount
of
lymphoid
nodules
called
 Peyer’s
patches.

They
are
part
of
the
gut
associated
lymphoid
tissue
to
 provide
base
by
which
the
immune
system
can
fight
disease
and
control
the
 bacterial
flora
of
the
gut
 
 Main
motility
in
the
L.I.
 ‐ haustration
(discussed
above)
 ‐ and
mass
movements
(peristalsis),
in
which
entire
segments
 ascending/transverse/descending/sigmoid
can
empty
the
feces
into
the
next
 segment
 
 Defecation
reflex
 − first
of
all
remember
that
there
are
two
anal
sphincters.
 a) 1.
The
internal
anal
sphincter
which
is
smooth
muscle
(involuntary)
 b) 2.
External
anal
sphincter
which
is
skeletal
muscle
(voluntary,
up
to
a
point)
 − When
feces
fills
the
rectum…
 a) Mechanoreceptors
sensitive
to
stretch
and
pressure
will
activate
 b) Signal
transmitted
through
sacral
nerve
of
the
spinal
cord
 c) Integrated
in
the
spinal
cord
 d) Afferent
input
which
causes
the
internal
anal
sphincter
to
relax
 Go
Notes
78
 − Potty
training

 a) If
potty
trained
we
can
voluntarily
overcome
this
urge
via
 control/contraction
of
the
external
anal
sphincter.
(CNS
input)
 b) Similar
reflex
and
set
of
sphincters
for
urinary
control
 − Spinal
chord
injury
 a) However
if
one
has
a
spinal
chord
injury
above
the
sacral
region
(which
are
 most
spinal
chord
injuries
(SCI’s),
one
loses
the
CNS
input
to
override
the
 reflex)
 b) Therefore
no
defecation
or
urinary
voluntary
control
=
sucks!
 c) Sidenote:

So
if
you
surveyed
SCI
patients,
which
function
do
you
think
they
 desire
the
most
(by
like
stem
cell
research
or
something)?

The
ability
to
 control
urination/defecation
or
the
abilty
to
walk?
 i) Answer:
Trick
question.

They’re
still
people,
so
actually
about
65%
 desire
the
ability
to
have
SEX
(mechanistically
or
sensually).

The
next
 35%
desire
urinary
and
defecation
control.

And
only
10%
really
want
to
 walk
again.
 
 Recall
that
the
colons
main
purpose
is
salt
and
H2O
absorption,
because
most
 nutrients
have
already
been
aborbed
in
the
S.I.
 *Fig
21‐21
(just
know
it)
 However
there
are
some
secretory
cells
within
the
colon.
 − Colonic
crypt
cells
secrete
salt
and
H2O
 − Know
*Fig
21‐9
 − But
if
the
purpose
of
the
colon
is
to
absorb
salt
and
H2O
why
do
these
cells
do
 the
opposite?
 a) Think
that
one
the
amount
of
secretion
is
much
less
than
that
of
absorption
 b) I
think
of
it
as
“lube”
for
the
surface
of
the
feces
so
that
it
can
still
move
 without
excess
friction
and
pain
during
mass
movements
 − Notice
that
these
cells
have
the
CFTR
channel.
 a) These
channels
are
cAMP
gated!
So
increase
cAMP
channels
open
more,
more
 Cl‐
secreted,
more
Na+
and
H2O
follow
by
electrogradient
and
osmosis
 (respectively)
 b) Secondly
remember
the
Gs
pathway
from
mamphys
one
 i) If
a
Gs
receptor
is
activated
‐>
GTP
is
bound
instead
of
GDP
‐>
Gαs
subunit
 dissociates
(active)
‐>
activates
adenylate
cyclase
(AC)
‐>
catalyzes
the
 reaction
converting
ATP
to
cAMP
‐>
cAMP
does
other
things
(in
this
case
 it
activates
CFTR
 ii) This
path
usually
turns
itself
off
because
the
Gαs
subunit
has
intrinsic
 GTPase
activity.

It
hydrolyzes
GTP
‐>
GDP
(the
Gα
and
Gβγ
reassociate
 yielding
the
inactive
form).
 c) If
there
is
a
cholera
toxin,
it
will
cause
ADP
ribosylation
of
the
Gαs
subunit
 thus
inhibiting
the
intrinsic
GTPase
activity.

Therefore
always
turned
on
‐>
 cAMP
is
constantly
made
‐>
channel
is
always
open

 Go
Notes
79
 i) Altogether
results
in
copious
amounts
of
salt
andH2O
loss
in
the
feces
=>
 diarrhea!

That’s
why
most
cholera
patients
die
of
dehydration.

Horrible
 disease
 
 *Fig
21‐1
Water
balance
 − note
the
inputs
of
9.0
liters
while
absorption
retains
8.9L.

Only
0.1L
lost
in
feces
 − pretty
efficient
 − However
diarrhea
results
from
unusually
high
motility
=
not
enough
time
for
 reabsorption.

If
chronic,
dehydration
can
ensue.
 − The
adverse
is
pretty
bad
too.

Well
at
least
really
uncomfortable.

If
motility
is
 too
slow,
too
much
reabsorption
occurs.

=>
stone
like
feces
which
is
hard
to
 move
(constipation)
and
can
cause
much
pain
and
discomfort.
 a) Opiate
medicines
like
morphine,
codeine,
vicodin,
and
norco
all
inhibit
 motility
via
opiate
receptors
within
the
GI
tract.

So
chronic
pain
relief
often
 results
in
chronic
constipation.
 
 Cholera
toxin
(which
I
just
covered
in
the
last
lecture
but
review
important
points)

 a) If
there
is
a
cholera
toxin,
it
will
cause
ADP
ribosylation
of
the
Gαs
subunit
 thus
inhibiting
the
intrinsic
GTPase
activity.

Therefore
always
turned
on
‐>
 cAMP
is
constantly
made
‐>
channel
is
always
open

 i) Altogether
results
in
copious
amounts
of
salt
and
H2O
loss
in
the
feces
=>
 diarrhea!

That’s
why
most
cholera
patients
die
of
dehydration.

Horrible
 disease
 
 The
same
CFTR
channel
in
*Fig
21‐9
is
ubiquitous
within
bronchioles
and
sweat
 glands
 − In
cystic
fibrosis
this
channel
is
non‐functional
 a) Sweat
glands
have
less
salt
reabsorption
‐>
salty
sweat
 b) In
lung
and
pancreas,
cystic
fibrosis
causes
very
thick
mucus
which
is
 immobile
because
of
viscosity.

That
results
in
susceptibility
to
infection.

 Macrophage
activation
in
response
to
the
infection
cause
cysts.
 − So
why
is
cystic
fibrosis,
a
genetic
disease,
still
propagated
through
evolution.

 Shouldn’t
natural
selection
eliminate
it?
 a) Heterozygous
individuals
for
cystic
fibrosis
have
a
phenotype
in
which
half
 the
CFTR
channels
are
nonfunctional
while
the
other
half
are
wild‐type
 b) Apparently
this
may
be
advantageous
because
if
infected
with
cholera
‐>
less
 severe
diarrhea.
 
 That
heterozygosity
advantage
is
similar
to
the
sickle
cell
anemia
advantage.
 ‐ sickle
cell
anemia
is
one
in
which
a
single
point
mutation
causes
valine
‐>
 glutamic
acid
in
hemoglobin
 ‐ hemoglobin
crystallizes
in
the
RBC
causing
the
misformed
RBC
with
a
sickle
 shape
 ‐ although
homozygous
sickle
cell
anemia
usually
results
in
death
in
6‐18
 months
after
birth
the
heterozygous
does
convey
some
“fitness”
 Go
Notes
80
 ‐ ‐ Malaria
(by
mosquitos)
typically
afflicts
RBC’s
causing
lysis,
but
they
don’t
 affect
sickled
RBC’s
as
much.


 Therefore
although
afflicted
with
a
semi‐functional
Hb,
they
are
more
 resistant
to
fighting
off
malaria.
 
 GI
reflexes
 1. Gastro‐Colic
 a. Distension
of
the
stomach
causes
a
feed‐forward
mechanism
that
 causes
mass
movements
within
the
colon
 i. It’s
essentially
making
room
in
colon
for
what
is
coming
 ii. Why
restaurants
are
required
to
have
bathrooms
 2. Gastro‐Ileal
 a. Distension
of
the
stomach
causes
a
feed‐forward
mechanism
causing
 increased
ileal
motility
and
relaxation
of
the
ileocecal
sphincter
 i. Again
it’s
making
room
 3. Ileo‐gastric
 a. Distension
of
the
ileum
cases
a
feed‐back
mechanism
which
decreases
 gastric
motility
and
secretion
 b. Slow
gastric
phase
down
so
that
there
is
enough
time
for
digestion
 and
absorption
within
the
small
intestine
 
 Opiate
Receptors
(covered
last
lecture!)
 ‐ basically
opiates
inhibit
motility
=>
constipation

 ‐ so
some
drug
companies
took
advantage
of
this
in
order
to
inhibit
motility.
 o They
synthesized
an
opiate
analog
which
does
not
cross
the
blood
 brain
barrier
=
no
high
or
pain
inhibition
or
dependency
issues
 o Called
immodium
=
Tx
for
diarrhea
 
 
 May
18,
2011
 
 Appetite
regulation
 
 Orexins
and
anorexins
 Metabolic
regulation
 Metabolic
pathways
 Hormonal
regulation
 
 Short
term:
insulin
and
glucagon
 
 Long‐term:
thyroid
hormone,
growth,
glucocorticoids
 
 Orexins
–
things
that
increase
appetite
 Anorexins
–
things
that
inhibit
appetite
 
 
 
 Go
Notes
81
 
 
 Appetite
and
metabolic
regulation
 
 Hypothalamus
has
two
regulatory
centers
for
appetite
 ‐ hunger
center
=
when
stimulated
‐>
increase
hunger
 ‐ satiety
center
=
when
stimulated
‐>
decrease
hunger/increase
satiety
 
 Distension
reflex
of
the
stomach
 ‐ distension
of
the
stomach
‐>
inhibits
hunger
 ‐ why
you
feel
“full”
 ‐ and
why
“tightening
our
belt”
came
from
 ‐ Bariatric
surgeons
take
advantage
of
this
to
combat
obesity
via
the
lap‐band
 o Essentially
decreases
the
volume
of
portion
of
the
stomach.

The
 stretch
receptors
activated
sooner
=>
less
hunger
 APPETITE
REGULATORS
 
 Increase
appetite:
 
 1.

Neuropeptide
Y
(central)
 − secreted
by
the
hypothalamus
and
acts
via
activation
of
the
hunger
center
 
 2.

Anandamide
(Opiate
Receptors)
(central)
 − for
endogenous
opiates
called
anandamide.
 − However
it
can
also
be
activate
via
exogenous
THC
 − THC
being
the
active
chemical
which
causes
the
“munchies”
from
smoking
bud,
 weed,
the
sticky
icky,
420,
“visiting/calling
Johnny”,
mary
jane,
MJ,
…
God
I
can
 go
on
and
on
 
 3.

Ghrelin
(peripheral)
 ‐ growth
hormone
releasing
hormone
 ‐ secreted
by
the
stomach
when
empty
 ‐ stimulates
hunger
and
release
of
GH
from
the
anterior
pituitary
 ‐ also
I
believe
this
is
the
one
that
causes
your
tummy
to
growl
 o get
it
growl
–
ghrelin;
whatever
don’t
judge
me
I’m
a
closet
nerd
 
 4. Agouti
Related
Peptide
(abnormal,
blocks
Melanocortin
receptors)
(central)
 ‐ MC4
receptors
usually
inhibit
appetite
via
αMSH
hormone
 ‐ Deficient
agouti
mice
create
this
agouti
related
peptide
which
blocks
MC4
 receptors
therefore
no
inhibition
 o Mice
are
obese
and
typically
have
no
pigment
deposition
in
the
skin
 o Why?
 The
protein
splicing
comes
from
neurons
in
the
hypothalamus
 call
POMC
(pro‐opio‐melano‐cortin)
neurons
 Go
Notes
82
 POMC
is
splice
resulting
in
opiate,
melanostimulating
hormone
 (MSH)
for
pigment
deposition,
and
adrenocorticotropic
 hormone
(ACTH)
for
cortisol
secretion
by
adrenal
cortex
 • Cortisol
the
stress
hormone
typically
results
in
loss
of
 appetite
too
(not
hungry
when
stressed)
 So
if
these
POMC
neurons
are
not
functioning
properly,
no
MSH
 (which
we
will
see)
that
inhibits
appetite
via
MC4
receptors,
 less
cortisol
that
inhibits
appetite,
and
no
MSH
for
pigment
 deposition
‐>
no
melanin
 • That’s
why
these
mice
are
fat
and
yellow
 
 Decrease
Appetite:
 
 Leptin
(peripheral)
 − 
Secreted
by
adipocytes
when
they
are
large
 − ie
if
there
are
increased
fat
stores
‐>
less
appetite
 − discovered
in
leptin
deficient
mice
that
are
extremely
obese
 − can
this
work
in
human
weight
loss
by
supplying
exogenous
leptin?
 a) not
really.

Most
obese
humans
have
normal
or
elevated
leptin
levels.


 i) Would’ve
been
nice
though
 ii) There
must
be
additional
mechanisms
that
are
still
to
be
determined
 
 CCK
(peripheral
and
central)
 − Secreted
by
duodenal
endothelium
but
also
by
hypothalamic
neurons
 − Activate
the
satiety
center
giving
fullness
 − Why
protein
boost
in
your
jamba
juice
helps
to
stave
off
your
hunger
 a) Well
any
protein
does
+
it
helps
to
slow
down
gastric
activity
 b) Why
if
you
eat
slowly
(chewing
thoroughly)
the
proteins
will
reach
the
 duodenum
and
cause
CCK
to
be
secreted
=>
feel
full
without
eating
a
bunch.
 c) If
you
scarf
down
your
food
there’s
not
enough
time
for
CCK
appetite
 regulation
to
take
effect
and
you
eat
much
more
than
you
would
normally
 need
 
 Insulin
(peripheral)
 − Secreted
by
the
beta
cells
of
the
pancreas
in
response
to
high
glucose
levels
 − Causes
uptake
of
glucose
and
fat
lipogenesis
 
 GLP‐1
(peripheral)
 − Because
it
increases
insulin
–
same
mechanism
as
above
 
 PYY3‐36
(central)
 − Short
peptide
segment
of
the
neuropeptide
Y
that
increases
appetite,
except
its
 only
the
segment
from
amino
acid
number
3‐36
 
 
 
 Go
Notes
83
 CRH
Corticotropin
Releasing
Hormone
(central)
 − Causes
secretion
of
cortisol
the
stress
hormone
 − Stress
inhibits
appetite
 
 CART
(cocaine
&
amphetamine
related
peptide)
(central)
 − Inhibits
appetite
 − Why
coke,
llelo,
white‐girl,
snow
and
addy
inhibit
appetite
 
 α‐MSH
(via
Melanocortin‐4

receptors:
MCR‐4)
(central)
 − MSH
the
hormone
that
cause
melanin
and
therefore
pigment
deposition
inhibits
 appetite
via
MC4
receptors
(already
discussed
the
precursor)
 
 Obestatin
(peripheral)
 − Inhibits
appetite
and
is
secreted
by
the
stomach
or
S.I.
I
think.
 − Same
precursor
peptide
as
in
Ghrelin,
but
it’s
secretion
is
due
to
the
stomach
 being
full
 − So
it’s
similar
to
how
PYY3‐36
opposes
that
of
NPY
 
 METABOLIC
REGULATION
 *Fig
22‐2
Let’s
tackle
this
figure
from
left
to
right
 1. Fats
(9kcal/g)
 a. Broken
down
into
FFA
and
glycerol
 b. FFA
pool
 i. If
high,
the
FFA
will
be
converted
into
fat
stores
in
adipocytes
 (known
as
lipogenesis)
 ii. Also
lipogenesis
can
be
stimulated
via
insulin
dependant
 mechanism
when
glucose
levels
are
high
 1. Why
insulin
makes
you
fat
(stimulates
anabolic
 processes)
 c. Lipolysis
(fat
breakdown)
can
occur
for
the
purposes
of
energy
usage
 (beta
oxidation)
 d. FFA
can
be
utilized
for
energy
via
beta‐oxidation
(also
forms
 ketoacids)
 i. 50%
of
muscle
metabolism
at
rest
uses
fat
rather
than
glucose
 ii. as
exercise
intensity
increases,
glucose
is
preferentially
use
 iii. that’s
why
moderate
exercise
like
walking
is
more
efficient
for
 weight
loss
rather
than
intense
exercise
 iv. beta‐oxidation
converts
acyl‐CoA
‐>
acetyl
CoA
‐>
KREBS
cycle
 to
create
ATP
via
oxidation
 2. Carbs
(4kcal/g)
 a. Falls
into
glucose
pool
 b. Glucose
highly
regulated
at
around
100mg/dl
of
blood
 i. Fasting
range
is
70‐110mg/dl
 ii. Fed
state
(after
a
meal)
is
140‐200mg/dl
 c. So
above
100mg/dl
the
hormone
insulin
dominates
causing
the
 stimulation
for
anabolic
processes
like
lypogenesis
and
glycogenesis
 Go
Notes
84
 
 
 i. Decreases
blood
glucose
levels
 d. Below
100mg/dl
the
hormone
glucagon
dominates
causing
catabolic
 processes
like
lipolysis
and
glycogenolysis
 i. Serves
to
increase
glucose
levels
 e. Glucose
is
used
by
most
cells
for
energy
purposes
(via
GLUT1
 transporters)
 f. Even
when
hypoglycemic
(50‐60mg/dl),
the
high
affinity
GLUT3
 transporters
of
neurons
can
still
grab
enough
glucose
for
sufficient
 neural
function
 i. However
if
the
blood
glucose
levels
decrease
further
to
 30mg/dl
the
neurons
become
starved
and
seizures,
loss
of
 consciousness
(LOC),
and
death
can
occur
 ii. In
addition
to
irritability,
nausea,
etc
etc.
 g. If
glucose
is
extremely
high
(hyperglycemic)
like
around
300mg/dl
 there
will
be
glucose
in
the
urine
(glucosurea)
because
it
exceeds
the
 renal
threshold
(ability
to
reabsorb
glucose
in
the
PT
of
nephron)
 i. Seen
in
diabetics,
expecially
type
2’s
 3. Proteins
(4kcal/g)
 a. aa
pool
 b. can
be
formed
into
protein
(translation)
and
protein
can
be
broken
 down
 c. aa’s
can
be
used
for
energy
by
conversion
into
glucose
via
 gluconeogenesis
(Cori
cycle
remember?)
 May
23,
2011
 
 Metabolic
regulation
 Metabolic
pathways
 Hormonal
regulation
 
 Short
term:
insulin
and
glucagon
 
 Long‐term:
thyroid
hormone,
growth,
glucocorticoids
 Regulation
of
metabolism
by
glucagon
and
insulin
 Fasted
state
vs
Fed
state
 Stimuli
for
secretion
and
actions
of
 
 Glucagon
 
 Insulin
 Diabetes
Mellitus

 
 Type
1
 
 Type
2
 Metabolic
syndrome
 Hypoglycemia
 
 *Fig
22‐5
Transport
and
Fate
of
dietary
fats
 − chylomicrons
eventually
enter
into
the
blood
at
the
subclavian
vein
 Go
Notes
85
 − in
the
circulatory
system
the
enzyme
lipoprotein
lipase
(lpl)
can
breakdown
the
 Cm
into

 a) FFA
and
glycerol

 i) Which
can
be
recombined
into
TG’s
for
storage
 ii) Or
can
be
used
via
beta‐oxidation
for
metabolism
 b) CM
remnants

 i) Which
are
reacquired
by
the
liver
to
be
used
again
 c) HDL‐C
(high
density
cholesterol)
 i) Good
cholesterol
 ii) Has
ApoA
(apo‐protein
A)
 iii) Endocytosed
by
the
liver
and
can
be
metabolized
into
bile
salts
or
can
be
 recombines
with
ApoB
to
create
LDL‐C
 d) LDL‐C
is
the
bad
cholesterol
 i) It’s
necessary
for
synthesis
of
membranes
as
well
as
steroidal
hormones
 ii) But
too
much
of
it
is
bad
 iii) Remember
it’s
low
density
 (1) So
a
lot
of
it
can
form
aggregates
with
each
other
forming
plaques
 (2) The
plaques
reduce
the
viscosity
of
blood
and
increase
overall
 resistance
by
decreasing
lumen
of
blood
vessels
 (3) Known
as
atherosclerosis
 
 Fasted State (low blood glucose) à increase secretion of glucagon Fed State (high blood glucose) à increase secretion of insulin Figure 22-8 Pancreas − Islet of Langerhans – small clusters of cell located in the pancreas − Alpha cells secrete glucagon − Beta cells secrete insulin i) Type I diabetics typically have non functional beta cells − D cells secrete somatostatin − The parasympathetic and sympathetic systems have neurons which terminate at the islets allowing nervous system influence of metabolism Figure 22-9 Insulin/Glucagon − These are not discrete states but rather balances between insulin/glucagon ratios − Both hormones are present in the blood most of the time. − The fed state is dominated by more insulin and less glucagon (1) The body is said to undergo “net anabolism” (2) Glucose is used for energy production (glycolysis, krebs cycle etc.) (3) An increase in glycogen synthesis (4) An increase in fat synthesis (5) An increases in protein synthesis − The fasted state is dominated by more glucagon, and less insulin (1) Causes an increase in glycogen breakdown (2) Increases gluconeogenesis (glucose from not glucose intermediates) (3) Increase ketogenesis (break down of fat) Go
Notes
86
 Figure 22-10 Glucose, glucagon and insulin levels - After absorbing nutrients from a meal, plasma glucose concentrations rise; this stimulates insulin release which allows glucose to enter the cells which removes the original stimuli for insulin - Plasma insulin levels and plasma glucose concentrations have direct relationships Note that glucagon levels are approximately constant throughout the day lending credence to the notion that the RATIO of glucagon/insulin is important, not the actual amount Fasted State Glucagon Stimuli − Decrease blood glucose (<100mg/dL) − Increase in amino acids (because of increased protein breakdown) − Increase sympathetic activity (increase epi and norepi) i) Epinephrine has similar effects to glucagon on the liver Glucagon Inhibitors − Insulin − Somatostatin − Increased fatty acids or ketoacids in the blood Glucagon Targets / Functions − Targets mostly the liver − Increase plasma glucose by glycogenolysis and gluconeogensis − Also during the fasted state: release of hormone sensitive lipase from adipocytes -> breaks triglycerides to free fatty acids -> beta oxidation in liver, muscle cells etc. or ketogenesis in the liver Glucagon Mechanism Gs -> increase adenlyl cyclase -> increase cAMP -> increase PKA -> activates glycogen phosphorylase kinase -> phosphorylates/activates glycogen phopshorylase -> stimulates reaction: Glycogen + ATP -> Glycogen -1 + Glucose-6-phosphate + ADP Fed State Insulin Stimuli − Increase blood glucose (>100mg/dL) − Increase in amino acids (from food, not protein breakdown) − Incretins (GLP-1, GIP) − Increase parasympathetic activity − Glucagon a) Why? Glucagon causes an increase in the blood glucose released from the Go
Notes
87
 liver, insulin is require for this blood glucose to be taken up by the cells How does blood glucose stimulate insulin secretion? − Increase in plasma glucose enters beta cells via GLUT 2 transporters glucose causes increase ATP synthesis ATP blocks K+ leak channels depolarizes the cell opens Ca2+ channels Ca2+ flows in and causes the exocytosis of insulin containing vesicles Insulin Inhibitors - Sympathetic nervous system - Decreased glucose Figure 22-11 Insulin Mechanism − Insulin binds receptor (with tyrosine kinase activity) phosphorylation cascade phosphorylates a variety of insulin receptor substrates (IRS proteins) (1) Two pathways to affect metabolic enzymes… (2) Growth/mitogenic pathway affects transcription factor (3) Metabolic pathway affects enzymes directly Insulin Targets / Functions Primary target are liver, adipose tissue and skeletal muscle − Main functions are to decrease blood glucose via increased glucose metabolism and regulation of GLUT transporters − Note: brain, kidney and intestine do not require insulin for glucose uptake GLUT 4 exocytosis − Figure 22-12 − Skeletal muscles and adipocytes require insulin for glucose uptake − Mechanism of insertion resembles that of the aquaporins in the collecting duct of the nephron − Insulin binds the receptor kinase signal transduction exocytosis of GLUT 4 receptors into the plasma membrane allows glucose to flow into the cell − Skeletal muscles can insert GLUT 4 receptors WITHOUT insulin (insuin independent pathway) i) Explains why exercise is so good for diabetics Liver − Figure 22-13 − The liver uses insulin indirectly to uptake glucose − The liver contains low affinity GLUT 2 transporters not GLUT 4 transporters, so why do they need insulin? − Insulin, via a signal cascasde, activates a hexokinase which causes the Go
Notes
88
 phosphorylation of glucose to glucose – 6 phosphate (1) Why is this important? Reduces the concentration of glucose intracellularly, mainting the concentration gradient, and glucose flows in − Insulin also stimulates glycogen synthase; this polymerazies glucose 6-P glycogen − In the absence of insulin (and in the presence of epi or glucagon), glycogen is broken down (glycogenolysis) into free glucose which causes a driving force for glucose out of the cell (essentially the exact opposite) Additional functions of insulin − Increases glycolysis − Increases glycogenesis, Inhibits glycogenolysis − Increase lipogenesis, Inhibits lipolysis − Increase protein synthesis, Inhibits protein breakdown Figure 22-17 Glucose Tolerance Test − For normal subjects, fasting glucose levels <110mg/100ml, >70mg/100ml (1) After administering 75g oral glucose; 30 minutes later < 150mg/100ml − Diabetic subjects will have fasting glucose levels above 115/120 mg/100ml (can be hundreds, if not thousands) (1) They will also have very large increases after ingesting the oral glucose and, more importantly, − blood glucose will take a much longer time to get back to fasting levels − Individuals in between these curves (normal fasting blood glucose levels, but delayed returns after ingestion of glucose) “Metabolic syndrome” characterized by a group of problems … (1) Obese (2) Hypertension (3) Increased blood triglycerides (4) These individuals, without intervention, become type 2 diabetics Diabetes − Two major groups of diabetes: diabetes inspidus, diabetes mellitus − Diabetes mellitus (latin - honeybees); urine tastes sweet (1) Caused by very high blood glucose exceeds renal threshold for reabsorption of glucose (proximal tubule only) glucose is excreted in the urine “glucosuria” (hence the sweetness) also increases the osmolarity, draws water into the tube − Diabetes insipidus (latin - no flavor); urine does not taste sweet (1) Caused by lack of ADH or poor response to ADH prevents insertion of aquaporins to reabsorpt water large volumes of urine − Both cause an insane amount of urine production 
 
 
 
 Go
Notes
89
 
 May
25,
2011
 
 Diabetes
 
 Type
1
 
 Type
2
 Role
of
adipocyte
hormones
 
 Adiponectin,
resistin,
etc
 Other
Hormones
 
 Cortisol,
GH,
thyroid
 
 Diabetes
Insipidus
 ‐ caused
due
to
a
lack
of
ADH
secreted
by
the
hypothalamus
(post
pit).
 ‐ This
results
in
a
lack
of
deposition
of
aquaporin
2
transporters
withing
the
 distal
nephron
and
collecting
duct.

‐>
less
H2O
is
reabsorbed
from
the
lumen
 resulting
in
large
amounts
of
dilute
uring
 ‐ “insipidus”
means
bland
or
without
flavor
 ‐ symptoms
caused
by
diabetes
insipidus
include
polydipsia
and
polyurea.
 
 Mellitus
 − “honey”
 − due
to
a
decrease
in
insulin
(either
secretion
or
sensitivity)
 − Polyurea
results
due
to
the
increase
in
osmolarity
of
the
filtrate
due
to
glucose
 in
the
urine
(glucosurea)
 − Glucosurea
occurs
because
of
hyperglycemia,
specifically
above
300mg/dl
of
 blood
which
is
the
renal
threshold
of
glucose
reabsorption
 − The
hyperglycemia
also
results
in
other
symptoms
 a) Occasionally
it
can
result
in
blindness,
because
the
increase
in
plasma
 osmolarity
will
draw
water
from
the
crystalline
lenses
of
our
eyes
 resulting
in
an
inability
to
focus.
 b) Also,
given
enough
time,
glucose
can
react
with
amino
acids
and
will
 glycosylate
amines
 i) Ie
Hb
can
be
glycosylated.

And
if
glycosylate
Hb
exceeds
6%
=>
it’s
a
 clinical
indication
of
diabetes
 − Over
a
more
prolonged
diabetes,
a
patient
can
develop
 a) Kidney
damage
 b) Nerve
damage
 c) Blindness
 d) Stroke
and
MI
(myocardial
infarctions)
 e) Atherosclerosis
 
 Type
1
diabetes
 ‐ Due
to
a
severe
lack
of
insulin
secretion
as
a
result
of
Beta
cell
destruction
by
 an
autoimmune
reaction
 ‐ Used
to
be
called
“juvenile”
diabetes
due
to
the
developing
immune
system’s
 Go
Notes
90
 inability
to
distinguish
between
self
and
an
infection
which
“triggers”
the
 immune
system
 ‐ Glucose
metabolism
is
extremely
impaired
resulting
in

 o ↑
gluconeogenesis
 o ↑
glycogenolysis
 o ↑
lipolysis
‐>
beta
oxidation
‐>
↑
ketoacids
 metabolic
acidosis
 o ↑
protein
breakdown
especially
of
skeletal
muscle
 “melting
body”
 ‐ Tx
=
exogenous
insulin
 
 *Fig
22‐16
Illustrates
the
effects
of
a
type
1
diabetic
 
 ‐ tissue
loss
 ‐ ketoacidosis
 ‐ hyperglycemia
 ‐ polyphagia
(satiety
center
requires
insulin
for
glucose
uptake)
 o these
specialized
neurons
are
therefore
designed
to
detect
glucose
 utilization
 o lack
of
which
is
interpreted
by
the
brain
as
starvation
 ‐ polyurea
(due
to
increased
osmolarity)
 ‐ dehydration
(due
to
polyurea)
 ‐ polydipsia
(increased
thirst
due
to
dehydration)
 ‐ loss
of
H2O
decreases
blood
volume
‐>
decreases
BP
‐>
can
result
in
circulatory
 failure
 ‐ hyperventilation
due
to
metabolic
ketoacidosis
 ‐ coma
and
death
 
 What
happens
if
a
type
1
diabetic
overdoses
on
insulin?
 ‐ Remember
that
the
main
Tx
for
type
1
diabetes
is
exogenous
insulin
 ‐ An
overdose
will
cause
a
severe
case
of
hypoglycemia
 ‐ “insulin
shock”
 o used
to
be
used
in
psychiatric
hospitals
as
an
alternate
(but
just
as
 horrible)
to
electroshock
therapy
 ‐ results
in
confusion,
seizures
(neurons
can’t
pick
glucose),
agitation,
 sympathetic
activation,
and
LOC
(loss
of
conciousness).
 ‐ Remember
how
to
tell
a
diabetic
coma
due
to
hypoglycemia
vs
 hyperglycemia
 o Hypoglycemia
–
pale,
clammy
skin,
sweat
 Tx
=
give
candy
or
anything
with
sugar
 o Hyperglycemia
–
ketoacidosis,
hyperventilation,
fruity
breath
 Tx
=
give
insulin
 
 
 
 But
what
about
type
2
diabetes?
 Go
Notes
91
 ‐ ‐ ‐ ‐ ‐ ‐ ‐ ‐ This
is
actually
an
accumulation
of
multiple
diseases
which
all
encompass
an
 increase
in
insulin
resistance
 Typically
many
of
these
individuals
have
normal
or
higher
insulin
levels
 o But
they
still
are
susceptible
to
hyperglycemia.
 o Insulin
resistance
is
a
delayed
response
after
ingestion
of
a
glucose
 containing
meal
 Recall
*Fig
22‐17
the
glucose
tolerance
test
 
 o Diabetics
[gluc]
>200mg/dL
after
two
hours
 o Whereas
a
normal
individual’s
[gluc]
drops
below
140mg/dL
after
 two
hours
 They’re
hyperglycemic
but
also
have
increased
glucagon
levels
too!
 o Why?
 o Pancreatic
alpga
cells
are
also
insulin
dependant.

So
when
alpha’s
 cannot
take
up
glucose
they
secrete
glucagon
which
increases
 gluconeogenesis
and
glycogenolysis
 Both
worsen
the
hyperglycemia
 o Ketogenesis
is
uncommon
in
type
2
diabetes
 Metabolism
is
somewhat
normal
but
diabetes
related
problems
will
occur
 due
to
abnormal
glucose
levels
and
metabolsism
 o Like
atherosclerosis,
neural
changes,
renal
failure,
blindness
 (retinopathy)
 Insulin
resistance
is
highly
associated
with
obesity
 o “thrifty”
genes
(genetic
influence)
in
which
individuals
have
a
very
 efficient
metabolism
therefore
they
utilize
less
and
store
more
 o People
with
visceral
fat
have
more
prominent
cases
of
type
2
 By
visceral
I
mean
the
“apple”
people

 • Fat
accumulation
of
the
stomach
area
who
also
have
 high
BP,
high
TG
levels,
atherosclerosis,
and
heart
 problems
like
MI’s
 As
oppose
to
the
“pear”
people
with
fat
in
the
legs,
buttocks,
or
 hips.
 o Tx
=
Exercise
and
weight
loss
 Most,
and
I
clarify
“most”
type
2
diabetes
can
be
cure
by
weight
 loss
which
decreases
insulin
resistance
 Mostly
because
exercise
can
result
in
a
noninsulin
dependant
 absorption
and
increased
utilization
of
glucose
 Back
to
visceral
fat
 o Adipocytes
secrete
a
hormone
called
“resistin”
 o Resistin
inhibits
insulin
effects
 o So
decrease
resistin
is
a
possible
Tx.

I’ll
talk
about
how
this
can
be
 done
later.
 o Adipocytes
also
secrete
“adiponectin”
which
serves
to
increase
 metabolism
thus
counteracting
resistin
 Other
drug
Tx.

(because
it’s
hard
to
make
patients
exercise)
 o Exogenous
insulin.

(more
of
a
type
1
Tx
but
should
theoretically
work
 here.

But,
it’s
easier
to
take
a
pill
which
increases
endogenous
insulin
 Go
Notes
92
 o o o o o o production
rather
than
injecting
exogenous
insulin)
 How?

“Sulfonylureas”
‐>
they
work
to
block
the
K/ATP
channels
of
 beta
cells
causing
a
depolarization
and
more
insulin
exocytosis)
 “Alpha
glucosidase
inhibitors”
(NOT
MENTIONED)
which
slow
 digestion/absorption
of
carbs.

 “Biguanides”
(SEMI
MENTIONED)
inhibit
hepatic
glycogenolysis
and
 gluconeogenesis
 “Metformin”
still
widely
used
(mechanism
not
well
known)
 But
the
other
biguanides,
“Phenformin”
and
“Buformin”
 worked
well
but
were
removed
from
the
market
due
to
 deleterious
interactions
with
the
heart
and
cause
acidosis
 “Glitazones”
which
are
PPAR‐γ
agonists
 activates
transcription
factors
which
increase
metabolism
 also
the
increase
adiponectin
and
decrease
resistin
 “Amylin”
(NOT
MENTIONED)
–
decrease
gastric
emptying,
suppresses
 glucagon,
and
increased
satiety
 “GIP/GLP1
agonists”
–
exogenous
incretins
which
increase
insulin
 release
 
 
 May
27,
2011
 
 Metabolic
regulation
continued
 Cortisol,
GH,
Thyroid
hormones
 ‐‐‐‐‐‐‐‐‐
 Temp
regulation
 heat
exchange
mechanisms
 thermoreceptors,
hyperthermia,
fever
 heat
exhaustion
and
heat
stroke
 
 Adrenal
gland
 ‐ the
cortex
has
three
histologically
distinct
areas
 ‐ specifically
the
adrenal
cortex ‐ the
zona
fasciculata
–
is
the
area
which
produces
the
glucocorticoids.
 o Sidenote:
the
zona
glomerulosa
=
aldosterone;
zona
reticulata
=
 androgens
 
 *FIG
23‐3
 The
HPA
pathway
 “Hypathalamo‐pituitary‐adrenal
axis”
 
 ‐ The
hypothalamus
will
secrete
CRH
(corticotropin
releasing
hormone)
 o secretion
of
which
follows
a
circadian
rhythm

 peaks
in
morning
but
decreases
at
night
 o but
additional
inputs
such
as
stress
can
alter
the
level
of
secretion
 Go
Notes
93
 ‐ ‐ CRH
acts
upon
the
anterior
pituitary
causing
a
release
of
ACTH
 ACTH
acts
upon
the
adrenal
cortex
to
secrete
cortisol
(a
glucocorticoid
highly
 associated
with
stress
 Notice
that
there
are
negative
feedback
loops
which
are
either
cortisol
or
ACTH
 based.
 
 Because
it
is
a
multiple
organ
pathway,
there
are
multiple
points
in
which
the
 regulation
can
be
disrupted
or
altered.
 ‐ If
the
problem
is
due
to
an
over
secretion
by
adrenal
gland
itself,
it
is
known
 as
a
1°
problem
 ‐ If
the
problem
is
the
anterior
pituitary’s
secretion
of
ACTH
then
its
2°
 ‐ And
if
in
the
hypothalamus
its
3°
 
 Effects
of
glucocorticoids
like
cortisol
 ‐ Although
cortisol
is
associated
with
stress,
it
is
essential
for
life!
 ‐ Protects
against
hypoglycemia
 o Needed
for
full
glucagon
and
catecholamine
activity
“permissiveness”
 o Overall
functions
are
catabolic
 ‐ ↑
gluconeogenesis
and
glycogenolysis
in
liver
 ‐ ↑
proteolysis

 o especially
of
skeletal
muscle
so
that
the
aa’s
are
substrates
for
 gluconeogenesis
 o why
stressed
people
are
skinny
 ‐ ↑
lipolysis
by
adipose
tissue
in
order
to
provide
energy
as
FFA’s
in
the
blood
 ‐ However,
it
↓
immune
activity
via
a
variety
of
pathways
 o Mostly
by
acting
as
an
anti‐inflammatory
agent
 o Specifically
by
preventing
cytokine
release,
antibody
production,
and
 leukocyte
mobility
 ‐ NOT
MENTIONED
 o Causes
a
negative
Ca++
balance,
decreases
intestinal
absorption
of
 Ca++,
and
increased
renal
excretion
of
Ca++
=>
catabolic
in
bone
 tissue
 o Excess/deficiency
in
cortisol
secretions
causes
mood
swings,
affects
 memory
and
learning
 ‐ Hypercortisolism
“Cushing’s
Syndrome”
 o Excess
gluconeogenesis,
hyperglycemia,
obese
legs,
cheeks,
mood
 elevation,
depression,
learning/memory
impairments
 o Caused
by
a
1°
adrenal
tumor,
or
pituitary
tumor
(↑ACTH)
2°,
or
 iatrogenic
–
too
much
cortisol
treatment
 ‐ Hypocortisolism
“Addison’s
diseases”
 o Hereditary
autoimmune–
hyposecretion
of
all
adrenal
steroids
due
to
 adrenal
cortex
damage
 *Fig
23‐4
Cortisol
fluctuation
 Growth
hormone
(GH)
 ‐ *Fig
23‐13
 Go
Notes
94
 ‐ ‐ ‐ ‐ ‐ ‐ ‐ ‐ ‐ Hypothalamus
secretes
GHRH
(GH
releasing
hormone)
or
somatostatin
 which
inhibits
GH
release
 The
anterior
pituitary
will
secrete
GH
 GH
acts
directly
on
many
tissues
 But
it
also
acts
indirectly
by
liver
 o Causing
the
secretiong
of
IGF’s
(Insulin
like
growth
factors)
 o IGF‐1
IGF‐2
 o Which
targets
R’s
which
are
receptor
tyrosine
kinases
 GH
secretion
is
also
secreted
via
a
circadian
rhythm
 o Peaks
during
sleep
 o However
other
things
can
affect
normal
rhythmic
secretion
 Arginine
increase
GH
 Whereas
glucose
inhibits
GH
release
 GH
causes
increased
growth
(duh!)
 o Also
increases
blood
glucose
 Regulation
of
secretion
is
of
course
a
negative
feedback
loop
 Lack
of
GH
during
childhood
development
‐>
pituitary
dwarfism
 If
the
anterior
pituitary
has
a
tumor
(1°)
which
increases
GH
secretion…
 o During
childhood
‐>
results
in
gigantism
 o However
after
puberty
(the
growth
plates
of
the
bones
especially
long
 bones
become
sealed)
‐>
now
the
GH
works
on
the
“thickness”
of
the
 bones
rather
than
the
length.
 Known
as
acromegaly
 *23‐14
acromegaly
progression
in
a
woman
 
 Thyroid
hormone
(T3/T4)
 ‐ *Fig
23‐8
 ‐ Thyroid
hormone
–
butterfly
shaped,
lies
across
the
trachea,
inferior
to
the
 larynx
 o C
cells
–
calitonin
(regulates
Ca++
levels)
 o Follicular
cells
which
secrete
the
thyroid
hormone
 o T3/T4
have
long
term
effects
on
metabolism
 ‐ Thyroid
gland
fxn
 o 1.

follicular
cells
make
enzymes
for
T3/T4
synthesis
and
glycoprotein
 =
thyroglobulin
 thyroglobulin
is
released
into
center
of
follicle
(colloid)
 o 2.

follicular
cells
can
absorb
I‐
(Na/I
symporter)
 o 3.

enzymes
combine
I‐
w/
tyrosine
on
thyroglobulin
 which
creates

 1)
triiodothyronine
T3
or





 2)
tetraiodothyronine
T4
(aka
thyroxine)
 o 4.

thyroglobulin‐T3/T4
complex
moves
back
into
follicle
by
 endocytosis
 o 5.

intracellular
enzymes
free
T3/T4
from
protein
 o 6.

T3/T4
diffuse
into
plasma
 Go
Notes
95
 ‐ ‐ ‐ ‐ ‐ o note:
synthesis
takes
place
in
colloid
 T3/T4
 o T3
is
3‐4
times
more
active
than
T4
 o T4
is
converted
to
T3
in
target
cell
by
deiodinase
 o T3/T4
initiate
transcription,
translation,
and
synthesis
of
proteins
 T3/T4
affect
quality
of
life
 o provides
substrates
for
oxidative
metabolism
 o increases
metabolism

 o thermogenic
 o inc
O2
consumption
in
most
tissues
 o changes
ion
xport
in
mitochondria
 uncoupling
of
oxidative
phosphorylation
 o modulates
protein,
carb,
and
fat
metabolism
 o in
children,
necessary
for
expression
of
GH
(normal
growth
and
CNS
 development)
 Hyperthyroidism
 o too
much
T3
or
T4
 o 4
major
effects
 1.

increases
O2
consumption
and
heat
production
 • warm
sweaty
skin
 • intolerance
to
heat
 2.

excess
T3/T4
increase
protein
catabolism
 • muscle
weakness
and
weight
loss
 3.

effect
on
NS
 • hyperexcitable
reflexes
 • irritability,
insomnia
or
psychosis
 4.

effects
beta
adrenergic
receptors
of
heart
 • elevated
HR
and
increase
force
(contraction)
by
up
 regulating
beta1
receptors
 Hypothyroidism
 o low
T3/T4
 o 4
effects
 1.

slows
metabolic
rate
and
O2
consumption
 • intolerance
of
cold
 2.

decreases
protein
synthesis
 • brittle
nails,
hair,
dry
thin
skin
 3.
NS
‐>
slowed
reflexes,
speech,
thought
and
fatigue
 4.
bradycardia
 Thyroid
pathway
 o thyrotropin
releasing
hormone
TRH,
is
produced
from
hypothalamus
 o TRH
goes
to
the
anterior
pituitary
which
releases
thyroid
stimulating
 hormone
(TSH)
 o TSH
stimulates
the
release
of
T3/T4
from
thyroid
gland
 o T3/T4
exhibit
negative
feedback
on
TSH/TRH
production
 o TSH
causes
the
growth
of
follicular
cells
 excessive
elevated
TSH
‐>
goiter
 Go
Notes
96
 
 
 o Primary
hyperthyroidism
 due
to
a
lack
of
I‐,
low
T3/T4
cause
an
increase
in
TSH
 • which
causes
the
hypertrophy/growth
of
thyroid
gland
 o hypersecretion
"grave's
disease"
 body
produces
antibodies
called
thyroid
stimulating
 immunoglobulins
TSI
 • these
act
like
TSH
 inc
T3/T4
negatively
feedsback
to
inhibit
TRH
and
TSH
 secretion,
however
TSI
remains
 • makes
patient
bug‐eyed
=
exophthalmos
 June
1,
2011
 
 Temp
regulation
 heat
exchange
mechanisms
 thermoreceptors,
hyperthermia,
fever
 heat
exhaustion
and
heat
stroke
 
 TEMPERATURE
REGULATION
 Why
is
it
important?
–
The
chemical
reactions
and
their
rates
are
greatly
affected
by
temperature
 Mediated by afferent input from both peripheral and central thermoreceptors (hot activated by capcaisin, cold by menthol) Normal
=
35.5
‐
37.7°C
 
 E
input
must
be
balance
with
E
output
 
 ‐
E
input
 
 
 hunger/appetite
 
 
 satiey
 
 
 social/psychological
factors
 
 
 environmental
 
 ‐
E
output
 
 
 Heat
50%
 
 
 Work
50%
 
 Heat
exchange
 1. Radiation
‐
no
molecular
contact
(needs
heat
gradient)
 2. Conduction
–
molecular
contact,
solids
(heat
gradient)
 3. Convection
–
molecular
contact,
air
(heat
gradient)
 4. Evaporation
–
cools
as
long
as
environment
allows
(humidity
gradient
needed)
 ‐If
the
environmental
temp
is
above
body
temp…
only
way
to
dissipate
heat
is
by
evaporation
 -If high environmental temp and high humidity… possibility of heat stroke because evaporation does ineffective 
 Internal
Heat
Production:
 1. Non‐shivering
Thermogenesis
 a. Increase
metabolism
 Go
Notes
97
 b. T3/T4,
NE/E,
cortisol
 c. Regulated
from
brown
fat
and
adipocytes,
sympathetic
input


 d. Uncouples
mitochondria
reactions.

There
are
proton
leak
channels
on
inner
 mitochondrial
membrane.

Electron
transport
chain
pumps
protons
out
like
normal,
but
 the
proton
gradient
never
is
made,
therefore
no
ATP
synthesis.

The
energy
is
released
 to
the
system
as
heat.
 2. Shivering
Thermogenesis
 a. Triggered
by
hypothalamic
thermoregulatory
center
 b. Rhythmic,
non
coordinated
movement
like
teeth
chattering,
shivering
 c. Via
ACh
release
unto
somatic
motor
neurons
‐>
skeletal
muscle
 
 Shell/Core:
 ‐

If
the
body
is
HOT
=
goal
is
to
dissipate
heat
by
decreasing
the
shell
and
increasing
the
core
 - heat
does
not
have
to
travel
far
to
be
released
to
external
environment,
like
no
 insulation
 - blood
vessels
dilate
to
skin/limbs
via
ACh
and
NO
onto
cholinergic
neurons
 (sympathetic
regulation)
 - increases
radiation
and
convection
to
external
environment
 - If
the
body
is
COLD
=
goal
is
to
conserve/generate
heat
by
increasing
the
shell
and
decreasing
the
 core
 - More
insulation
 - Blood
vessels
vasoconstrict
to
skin/limbs
via
NE
unto
alpha
1
adrenergic
receptors
 - Sympathetic
regulation
 - Increases
heat
conservation,
by
decreasing
loss
to
environment
 
 SET
POINT
PROBLEMS:
 1. Fever
(inc
in
hypothalamic
setpoint)
 a. Caused
by
toxins,
external
pyrogens
from
bacteria/antigens
‐>
immune
response
 b. Immune
cells
secrete
internal
pyrogens
(cytokines)
like
interleukins
(IL‐1
+
IL‐6)
plus
 TNFα
+
interferons
 c. Activates
COX
enzymes
which
turn
arachidonic
acid
into
prostaglandins.
‐>
increases
 inflammation,
increased
heat
generation
(metabolic
rate,
shivering,
vasoconstriction),
 which
result
in
higher
temps.
 d. In
addition
prostaglandins
reset
the
hypothalamic
set
point
higher
 e. Why?
At
high
temps
immune
cells
are
more
active
and
bacterial
proteins
are
vulnerable
 to
attack
 f. Greater
than
42
degrees
C
will
result
in
decreased
CNS
function
 g. NSAIDs
are
taken
to
prevent
the
inflammatory
reaction,
by
blocking
COX
enzyme
 2. Menopause
hot
flashes
 a. Due
to
lack
of
estrogen
 b. Lowers
the
setpoint
so
the
body
feels
too
hot
(sweating,
flushing)
 NON
SET
POINT
PROBLEMS
 1. Hyperthermia
 a. 38‐40°C,
body
generates
more
heat
then
its
able
to
dissipate
 b. body
starts
vasodilation
and
sweating
 c. can
lead
to
heat
stroke,
exhaustion,
low
BP
due
to
sweating
 i. heat
stroke
is
extremely
dangerous
because
the
low
BP
and
blood
volume
 further
impairs
ability
to
sweat;
so
don’t
exercise
in
heat
 d. Behavioral
responses
=
decr
appetite,
decr
activity,
seek
shade,
use
fans,
remove
 clothing
 Go
Notes
98
 2. Hypothermia
 a. Decreased
body
temp,
21‐24°C
 b. Can
cause
loss
of
consciousness
(LOC)
 c. Pacemaker
cells
of
heart
decrease
rhythm,
may
stop
altogether
 d. Thyroid
–
increases
T3/T4
production
to
upregulate
metabolism
and
uncouple
e‐
 transport
chain
 e. NE/E
released
on
adrenergic
receptors
to
increase
metabolic
rate
 f. Behavioral
responses
–
clothes,
shelter,
hot
drinks,
fetal
position
 
 Fever,
a
set
point
problem
is
due
to
the
presence
of
toxins
or
metabolites
from
 viruses
and
bacteria
 ‐ These
are
also
known
as
external
pyrogens

 ‐ The
external
pyrogens
will
be
targeted
by
your
immune
system
 ‐ As
part
of
the
inflammatory
response
to
the
external
pyrogens,
the
immune
 cells
produce
cytokines
to
ramp
up
immune
response
 o However,
those
cytokines
like
IL‐1,
IL‐6,
interferons,
and
TNF‐α
are
 internal
pyrogens
 ‐ In
the
hypothalamus,
the
cytokines
will
activate
the
COX
family
of
enzymes
 (1,
2,
and
3)
 o COX
enzymes
convert
arachidonic
acid
into
prostaglandins
 ‐ ↑
prostaglandins
will
raise
the
physiological
set
pt
 o the
body
thinks
its
too
cold,
and
will
initiate
all
of
the
hypothermic
 responses
for
temp
regulation
 less
heat
dissipation
(cutaneous
vasoconstriction
and
decrease
 sweating),
and
↑
heat
generation
(shivering
and
non‐shivering
 thermogenesis)
 BOTH
result
in
↑
HEAT
 
 Tx
of
fever:
 ‐ NSAID’s
(mainly
aspirin)
–
inhibit
all
COX
(1,
2,
and
3)
enzymes
thus
 preventing
the
set
pt
from
increasing
 ‐ Tylenol
(ibuprofen)
mostly
inhibits
pain
and
decreases
fever
by
inhibiting
 only
COX
3.

It’s
not
an
anti‐inflammatory
 ‐ If
prolonged
or
if
fever
is
too
high
–
COOL
down
individual

 
 If
fever
is
>42C
its
quite
dangerous…
 Because
of
seizures,
permanent
CNS
damage
(esp
in
children),
delerium
 (adults),
and
denaturation
of
certain
temp
sensitive
proteins.
 
 But
is
there
a
physiological
benefit
of
fever?
 1. The
increase
in
temperature
‐>
↑
immune
activity
‐>
resulting
in
a
more
 efficient
battle
against
the
bacteria/virus
 2. But
also,
many
bacteria/viruses
are
temp
sensitive.

So
the
↑heat
 decreases
their
viability
 
 NON‐SET
point
 Go
Notes
99
 ‐ ‐ ‐ 
 
 Hyperthermia
 o Imbalance
between
heat
acquisition/production
vs
dissipation
 o Most
common
cause
=
exercise
 o Heat
waves
too!

 Heat
exhaustion
 o Can
occur
when
one
exercises
in
hot
external
environment
(greater
 than
37C)
 o Increased
sweating
‐>
which
will
cause
dehydration
‐>
decreased
 blood
volume
‐>
increased
blood
osmolarity
‐>
decreased
BP
‐>
 increased
vasodilation
‐>
further
decreasing
BP
(because
V
increases)
 Heat
stroke

 o Can
develop
from
heat
exhaustion
 o High
mortality
rate
 o Same
symptoms
as
exhaustion
however
is
predicated
upon
 circulatory
shock
due
to
extremely
low
BP
and
BV
 o Disruption
of
normal
heat
disspation
causes
a
downward
“spiral”
 Spiral
=
the
body
tries
to
dissipate
heat
by
sweating,
but
the
 sweating
causes
dehydration.

The
dehydration
inhibits
 sweating
because
the
body
is
trying
to
conserve
fluid.

But
then
 no
ability
to
dissipate
heat.
‐>
heat
stroke
 June
3,
2011
 
 COPIED
AND
PASTED
FROM
A
PREVIOUS
 QUARTER

 
 MUSCLE
metabolism
 *
Fig
25‐1
 ‐ Sorry
I’m
not
going
to
summarize
this
big
old
large
figure
 ‐ Let’s
just
say
that
there
are
multiple
sources
and
avenues
by
which
E
 production
and
utility
can
occur
in
muscle
 ‐ Notice
that
resting
muscle
can
use
FFA
via
beta‐oxidation
 o Resting
muscle
preferentially
uses
fat
(60%)
compared
to
glucose
 (40%)
 o This
is
why
muscle
building
can
help
eliminate
fat
because
it
uses
 more
of
it
 ‐ Skeletal
muscle
and
cardiac
muscle
(striated)
 o Have
an
enzyme,
call
creatine
kinase
 o CK
converts
ATP
+
creatine
<‐>
phosphocreatine
and
ADP
 o This
enable
the
muscle
to
have
two
different
gas
tanks.


 o Why?
 Go
Notes
100
 There
is
a
thermodynamic
limit
to
the
amount
of
ATP
stores
 that
cells
can
have.
 Like
all
reactions
if
there
is
way
too
much
of
a
product
the
 reaction
favors
the
reverse
hydrolysis.

This
would
result
in
a
 lower
energy
from
the
ATP
 o So
by
converting
ATP
to
Creatine‐P,
it
enables
more
ADP
to
be
 converted
to
ATP
=
now
they
have
both
ATP
and
Creatine‐P
stores
 o If
CK
is
circulating
in
the
blood
stream
it’s
a
good
indication
of
muscle
 damage
 For
example
if
the
isoform
of
CK
in
the
heart
is
detected
in
the
 blood
after
an
MI,
it’s
level
is
an
indication
of
how
severe
the
 heart
attack
was.
 
 December
1,
2010
 
 Exercise
contd.
 Cardiovascular
response
 Respiratory
response
 ‐‐‐‐‐‐‐‐‐‐
 Reproductive
system
 Anatomy
 Sex
determination:
genotype,
phenotype,
etc
 Sex
devo
 Gametogenesis
 Hormonal
regulation
 Menstrual
cycle
 Sexual
response
 
 *Fig
25‐3
Substrate
metabolism
by
muscle
as
a
function
of
exercise
 ‐

During
rest
to
moderate
exercise
the
muscle’s
preferentially
utilize
fats
for
energy
 rather
than
glucose.

This
is
why
moderate
exercise
like
walking
is
probably
more
 effective
for
a
weight
loss
regiment
rather
than
intense
strenuous
exercise.

 However,
as
exercise
intensity
increases,
the
rate
of
beta
oxidation
is
simply
not
 sufficient
enough
for
energy,
and
glucose
utilization
occurs
because
glycolysis
and
 oxidative
phosphorylation
arefaster.
 
 *Fig
25‐4
O2
Consumption
 ‐

Notice
that
when
exercise
is
initiated,
the
rate
O2
does
not
immediately
reach
the
 peak
level
to
accommodate
the
exercise.

This
can
also
be
due
to
the
fuel
reserves
 which
take
time
to
demand
more
O2.

As
a
result
an
OXYGEN
DEBT
occurs.
 ‐

However,
right
after
exercise
ceases,
O2
consumption
takes
a
little
time
to
 decrease
back
to
basal
levels.

Why?

Because
the
O2
is
still
being
used
to
replenish
 the
energy
reserves
(Creatine‐P).

Remember
that
O2
debt
has
to
be
repayed.
 
 Cardiovascular
response
to
exercise
 Go
Notes
101
 ‐ ‐ ‐ ‐ ‐ ‐ ‐ ‐ sympathetic
is
activated
and
the
parasymp
is
inhibited
 ↑
HR,
↑
contractility,
↑
SV,
↑
BP
(systolic)
 Cardiac
Output
CO
=
driving
force/
resistance
 o A
derivation
of
Ohm’s

 o CO
is
also
equal
to
SV
x
freq
(if
you
forgot)
 *Fig
25‐8a
 o notice
that
the
peripheral
resistance
during
exercise
DECREASES
 o why?
‐>
because
of
epi/NE
upon
B2
adrenergic
receptors
of
 peripheral
arterioles
which
causes
vasodilation
 *Fig
25‐8b
 o ↑
MAP
and
obvious
↑
Sys
BP
 o but
diastolic
BP
increases
much
less
due
to
the
vasodilation
 *Fig
25‐7

 o distribution
of
blood
flow
during
rest
versus
exercise
 o perfusion
to
the
muscle
greatly
increases
from
~20%
of
5L/min
to
 88%
of
25L/min
(those
numbers
aren’t
exact
I’m
making
them
up
 from
memory
and
intuition)
 o perfusion
to
critical
organs
like
the
brain
stay
fairly
similar
9%
of
 5L/min
compare
to
3%
of
25L/min
 o whereas
blood
flow
to
the
stomach,
GI,
and
pancreas
decrease
 dramatically
 o blood
flow
to
the
skin
increases
to
accommodate
heat
dissipation
and
 sweating
mechanisms
 HR
increases
mostly
at
the
expense
of
the
diastolic
“filling”
phase
 o Therefore
there
is
a
point
in
which
the
HR
increase
will
not
increases
 the
cardiac
output
because
the
stroke
volume
will
decreases
 o This
is
the
point
of
diminishing
return
 Although
BP
does
increase
the
normal
baroreceptor
reflex
that
should
 decrease
HR
and
BP
does
not
occur
during
exercise
because
the
set
pt
is
 increased
to
a
higher
P
 
 
 
 Respiratory
response
to
exercise
 ‐ *Fig
25‐5
 ‐ Ventilation
increases
as
soon
as
exercise
increased
 ‐ And
ventilation
decreases
when
exercise
ceases
 ‐ What
causes
the
large
increases
in
ventilation
when
exercise
starts?
 o Low
O2?
NOPE!
High
CO2?
NOPE!
pH?
NOPE?
 o Haha
Dr.
Fortes
baits
students
into
that
one
every
quarter.
 o Yes
exercise
will
cause
decreased
O2,
increased
CO2,
and
decreased
 pH
in
the
VENOUS
side,
but
remember
all
chemoreceptors
are
on
the
 arterial
side
 o Remember
the
whole
thing
that
the
blood
equilibrates
with
the
 alveolar
air
in
only
0.25
sec.

Plus
the
hyperventilation
would
increase
 Go
Notes
102
 ‐ the
PAO2
and
decrease
the
PCO2.

So,
no
the
chemoreceptors
do
not
 increase
V
in
the
exercise
example.
 o Turns
out,
that
cortical
inputs
via
higher
brain
centers
(remember
 higher
brain
centers
can
affect
V
too,
just
like
emotion).

It’s
as
if
the
 motor
commands
by
your
cortex
to
move
your
muscles
also
increase
 V
via
respiratory
centers.
 o Butthat’s
not
all!
Proprioceptors
within
your
limbs
and
joints
that
 detect
relative
body
position
also
affect
ventilation.

Increased
 fluctuating
activity
by
these
proprioceptors
feedback
to
increase
 ventilation.


This
is
proven.

Don’t
believe
me?
Try
this…
Flap
your
 arms
around
like
a
bird
and
your
ventilation
will
increase.

If
you
 think
the
flapping
is
exercise
due
to
muscle
contraction,
then
have
 your
friend
flap
your
arms
for
you
and
you’ll
still
breath
faster.

If
you
 really
do
this
I
will
giggle
at
your
nerdiness.
 *Fig
25‐6

 o this
graph
shows
that
PaO2,
PaCO2,
and
pH
stay
pretty
much
the
same
 up
until
about
80‐85%
max
exercise
(CO2
even
decreases
but
pH
 decreases)
 o this
occurs
even
when
ventilation
is
increasing
dramatically!
 o Amazing
feat
of
homeostasis
 o Basically
ventilation
and
consumption
stay
perfectly
matched
up
to
 that
85%
intensity.
 o Why
does
it
change
at
85%?

Around
that
area
is
called
the
anaerobic
 threshold.

What’s
that?

That’s
point
in
which
aerobic
respiration
is
 not
fast
enough
to
provide
ATP
and
so
the
body
starts
anaerobic
 metabolism,
which
creates
lactic
acid.

(because
glycolysis
is
uber
fast
 compared
to
oxidative
phosphorylation).

Then
V
and
VO2
becomes
 mismatched.

The
lactic
acid
drives
ventilation
via
peripheral
chemoR
 ‐>
increases
ventilation
moreso
than
needed
‐>
why
CO2
decreases
 more
than
40mmHg.
 
 REPRODUCTIVE
SYSTEM
 
 *Fig
26‐2
chromosomal
sex.


 XY
=
male
 XX
=
female
 
 Do
I
really
have
to
explain
this?

I’m
not
lazy
I
just
don’t
think
I
can
really
help
that
 much.

Whatever.
 
 If
you
don’t
know,
 Phenotype:
♂ have
a
penis,
♀ have
a
vagina.
 Gonadal:
♂ have
testes,
♀ have
ovaries
 Sexual
Devo
(devo
is
short
for
development
or
the
verb
develops
btw)
 ‐ *
Fig
26‐8
male
anatomy
 Go
Notes
103
 ‐ o consists
of
testes,
internal
genitalia
(accessory
glands
and
ducts),
and
 external
genitalia
 o ext
genitalia
‐
penis
and
scrotum
 scrotum
‐
a
saclike
structure
that
contains
the
testes
 o urethra
‐
common
passageway
for
sperm
and
urine
 runs
through
ventral
aspect
of
shaft
of
penis
 surrounded
by
spongy
column
of
tissue
known
as
corpus
 spongiosum
 o corpus
spongiosum
+
2
columns
of
tissue
called
the
corpora
cavernosa
 are
the
erectile
tissue
of
penis
 o tip
of
penis
is
called
the
glans

 @
birth
it
is
covered
by
layer
of
skin
=
foreskin
aka
prepuce
 o scrotum
is
an
external
sac
that
the
testes
migrate
top
during
fetal
 devo
 b/c
proper
sperm
devo
must
be
2‐3
degrees
F
lower
than
core
 failure
of
testes
to
descend
is
known
as
cryptorchidism
 • can't
produce
gametes
but
androgens
synthesis
 continues
 o male
accessory
glands
and
ducts
include
 1.

prostate
gland
 2.
seminal
vesicles
 3.
bulbourethral
("Cowper's")
glands
 o bulbourethral
and
seminal
vesicles
empty
secretions
into
urethra
 through
ducts
 o prostate
glands
open
directly
into
urethral
lumen
 prostate
‐>
cancer
 benign
prostatic
hypertrophy
(enlargement)
 • causes
compression
of
urethra
 DHT
controls
fetal
devo
of
prostate
 o testes
 fibrous
capsule
enclosing
seminiferous
tubules
 btw
tubules,
interstitial
tissue
is
blood
vessels
and
Leydig
cells
 (testosterone)
 the
seminiferous
tubules
leave
testes
and
join
the
epididymis
 • single
duct
tightly
coiled
on
surface
of
testicular
capsule
 epididymis
becomes
the
vas
deferens
or
ductus
deferenes
 • travels
up
to
abdomen
where
it
empties
to
urethra
 *
Fig
26‐9
female
anatomy
 external
genitalia
=
vulva
or
pudendum
 • labia
majora
+
labia
minora
+
clitoris
(small
bud
of
 erectile
tissue)
 • urethra
is
btw
clitoris
and
vagina
 o vagina
partially
closed
by
hymen
if
V
card
still
 applies
 cervix
‐
neck
of
uterus
 • portrudes
from
the
upper
end
of
vagina
 Go
Notes
104
 cervical
canal
is
lined
w/
mucous
glands
which
secrete
a
 barrier
btw
vagina
and
uterus
 uterus
‐
hollow
muscular
organ
 • 3
layers
 o 1.

thin
outer
CT
 o 2.

thick
middle
layer
of
smooth
muscle
=
 myometrium
 o 3.

inner
layer
=
endometrium
 • endometrium
consists
of
epithelium
w/
glands
that
dip
 into
CT
layer
below
 o thickness
of
which
varies
during
menstrual
cycle
 o menstruation
is
the
sloughing
off
of
those
cells
 Fallopian
tube
 • smooth
muscle
(circular
+
longitudinal)
 • is
ciliated
 o moves
eggs
‐>
uterus
 • fertilization
occurs
here
 Fimbriae
 • flared
open
end
of
Fallopian
tube
 • associated/adjacent
to
ovary
 • finger
like
fimbriae
catches
egg
from
ovary
 Ovary
 • produces
eggs
and
hormones
 • outer
CT
layer
 • inner
CT
known
as
stroma
 • ovary
consists
of
thick
outer
cortex
filled
w/
ovarian
 follicles
in
various
stages
of
devo/decline
 • central
medulla
consists
of
nerve
and
blood
vessels
 • each
primary
oocyte
(tetraploid)
enclosed
in
a
primary
 follicle
w/
single
layer
of
granulosa
cells
‐>
basement
 membrane
‐>
outher
layer
of
cell
=
theca
 • 
 *Fig
26‐4
SRY
gene
directs
male
devo
 ‐ female
devo
is
the
default
path
of
devo
 ‐ is
SRY
present
(sex
determining
region
of
Y
chromosome)
‐>
causes
the
 transcription
of
multiple
proteins
to
differentiate
the
testes.
 ‐ Testes
two
types
of
cells
Leydig
and
Sertoli
 o Leydig
‐>
testosterone
secretion
‐>
Wolffian
duct
devos
into
accessory
 organs
and
DHT
causes
devo
of
male
external
genitalia
 o Sertoli
‐>
AMH
(anti
mullerian
hormone)
‐>
Mullerian
duct
(female
 precursor)
degenerates
 *Fig
26‐3a

Bipotential
gonad
at
6
wks
in
utero
 ‐ Has
a
bipotential
gonad,
and
both
a
mullerian
and
wolffian
duct
 ‐ Bipotential
gonad
has
a
cortex
and
a
medulla
 o Cortex
can
develop
into
an
ovary

 o Medulla
can
devo
into
a
testis
 Go
Notes
105
 ‐ If
no
SRY
‐>
no
testosterone
‐>
wolffian
degenerates
and
the
default
 mullerian
duct
will
devo
into
the
accessory
female
organs
 o Fallopian
tube,
uterus,
and
upper
vagina
 ‐ But
if
SRY
is
present,
medulla
‐>
testis
 o AMH
from
sertoli
causes
mullerian
duct
to
degenerate
(no
more
 default
female
accessory
organs)
 o Testosterone
from
Leydig’s
maintain
the
wolfiann
duct
which
will
 devo
into
the
seminal
vesicles,
vas
deferens,
epididymes,
and
prostate
 gland
 
 *Fig
26‐3b

Same
but
external
devo
 ‐ Remember
maleexternal
devo
requires
testosterone
by
Leydig’s
to
be
 converted
to
the
more
potent
DHT
by
enzyme
5α
reductase
 ‐ If
DHT
present,

 ‐ genital
tubercule
‐>
glans
penis
 ‐ urethral
folds
close
‐>
shaft
 ‐ labioscrotal
swelling
close
‐>
scrotum
and
shaft
 ‐ if
no
DHT,
female
devo
ensues
 o genital
tubercule
‐>
clitoris
 o urethral
folds
and
libioscrotal
swelling
‐>
labia
majora,
labia
 minora,
and
epithelium
 
 Cases
in
which
a
genotypical
male
(XY)
can
devo
female
external
genitalia
 ‐ basically
any
time
in
which
DHT
physiology
is
impaired
 ‐ 1.

Mutation
of
the
5‐alpha
reductase
enzyme
which
makes
DHT
 ‐ 2.

If
the
androgen
R
for
DHT
or
testosterone
are
mutated
 nonfunctionally
 o they
may
have
a
set
of
testes
(non‐dropped)
 o no
accessory
organs
male
or
female
(because
sertoli’s
still
 secrete
AMH)
 o but
female
external
genitalia
will
devo
 
 
 December
3,
2010
 
 Male
Gametogenesis
 @
birth
immature
germ
cells
 become
inactive
until
puberty
 at
puberty
cells
undergo
mitosis
 are
known
as
spermatagonia
 some
continue
mitosis
 others
meiosis
to
become
primary
spermatocytes
(tetraploid)
 after
first
meiotic
division,
2
secondary
spermatocytes
(diploid)
 in
second
meiotic
division
‐>
spermatids
 the
spermatids
devo
and
mature
into
sperm
 Go
Notes
106
 Female
gametogenesis
 germ
cells
(embryonic
stage)
are
oogonia
 completed
mitotic
replication
and
1st
stage
of
meiosis
by
5th
month
of
 fetal
devo
 mitosis
ceases
and
the
primary
oocytes
remain
(tetraploid)
 first
meiotic
division
occurs
at
puberty
 ‐>
1
large
egg
=
secondary
oocyte
(diploid)
and
1
polar
body
 that
disintegrates
 secondary
oocyte
begins
meiosis
 sister
chromatids
separate
but
cells
do
not
separate
unless
 fertilized
 ovulation
‐
release
of
mature
egg
 only
one
egg
per
primary
oocyte
 Gametogenesis
of
both
males
and
females
is
under
hormonal
control
 Brain
directs
reproduction
 hyp
and
ant
pit
control
gonadal
secretion
of
sex
hormones
 androgens,
estrogens,
and
progesterone
 both
male
and
females
make
androgens
and
estrogens
 aromatase
converts
testosterone
to
estradiol
 women's
ovaries
produce
estrogen
and
progesterone
 Hormonal
control
pathways
 hypothalamus
produces
gonadotropin‐releasing
hormone
GnRH
 GnRH
from
hyp
stimulates
the
ant
pit
to
release
gonadotropins
 Follicle‐stimulating
hormone
‐
FSH
 luteinizing
hormone
‐
LH
 FSH
+
steroid
sex
hormones
stimulate
gametogenesis
 LH
acts
on
endocrine
cells
stimulating
steroid
sex
hormone
 production
 ovary
and
testes
produce
hormones
that
act
on
ant
pit
 inhibins
‐
inhibit
FSH
 activins
‐
stimulate
FSH
 activins
also
promote
spermatogenesis,
oocyte
 maturation,
and
embryonic
NS
devo
 Hormone
feedback
 androgens/LOW
estrogen
inhibit
GnRH,
FSH,
and
LH
 FSH
and
LH
inhibit
GnRH
 if
high
estrogen
is
sustained
for
36hrs,
stimulates
gonadotropin
 release
(LH)
by
positive
feedback
 GnRh
is
pulsatile
 after
puberty
every
1‐3
hrs
(pulse
generator
in
hypothalamus)
 b/c
steady
high
[GnRH]
causes
down‐regulation
of
reseptores
 ie
prostate/breast
cancers
under
hormonal
sensitivity
can
be
 down
regulated
if
GnRH
is
constant
 Male
reproduction
 fig
26‐8
and
fig
26‐9
 consists
of
testes,
internal
genitalia
(accessory
glands
and
ducts),
and
 Go
Notes
107
 external
genitalia
 ext
genitalia
‐
penis
and
scrotum
 scrotum
‐
a
saclike
structure
that
contains
the
testes
 urethra
‐
common
passageway
for
sperm
and
urine
 runs
through
ventral
aspect
of
shaft
of
penis
 surrounded
by
spongy
column
of
tissue
known
as
corpus
 spongiosum
 corpus
spongiosum
+
2
columns
of
tissue
called
the
corpora
cavernosa
 are
the
erectile
tissue
of
penis
 tip
of
penis
is
called
the
glans

 @
birth
it
is
covered
by
layer
of
skin
=
foreskin
aka
prepuce
 scrotum
is
an
external
sac
that
the
testes
migrate
top
during
fetal
 devo
 b/c
proper
sperm
devo
must
be
2‐3
degrees
F
lower
than
core
 failure
of
testes
to
descend
is
known
as
cryptorchidism
 can't
produce
gametes
but
androgens
synthesis
 continues
 male
accessory
glands
and
ducts
include
 1.

prostate
gland
 2.
seminal
vesicles
 3.
bulbourethral
("Cowper's")
glands
 bulbourethral
and
seminal
vesicles
empty
secretions
into
urethra
 through
ducts
 prostate
glands
open
directly
into
urethral
lumen
 prostate
‐>
cancer
 benign
prostatic
hypertrophy
(enlargement)
 causes
compression
of
urethra
 DHT
controls
fetal
devo
of
prostate
 testes
 fibrous
capsule
enclosing
seminiferous
tubules
 btw
tubules,
interstitial
tissue
is
blood
vessels
and
Leydig
cells
 (testosterone)
 the
seminiferous
tubules
leave
testes
and
join
the
epididymis
 single
duct
tightly
coiled
on
surface
of
testicular
capsule
 epididymis
becomes
the
vas
deferens
or
ductus
deferenes
 travels
up
to
abdomen
where
it
empties
to
urethra
 Seminiferous
tubules
 2
types
of
cells
 1.

spermatogonia
in
various
stages
of
becoming
sperm
 2.

sertoli
cells
btw
columns
of
stacked
spermatogonia
 are
connected
to
other
sertoli
cell
by
tight
jxns
 blood‐testis
barrier
 compartments
of
seminiferous
tubule
maintain
different
 concentrations
of
solutes
 luminal
fluid
has
decr
[gluc]
and
inc
[K+]
and
high
steroid
 hormones
 Go
Notes
108
 Sperm
production
 spermatogonia
=
germ
cells
 clustered
as
basal
ends
of
sertoli
cells,
inside
basal
lamina
of
 seminiferous
tubules
 mitotic
division
to
inc
germ
cell
number
 others
enter
meiosis
to
become
primary
spermatocytes
 as
primary
spermatocytes
differentiate
into
sperm
they
move
towards
 lumen
 by
the
time
they
reach
luminal
ends
they
have
divided
twice
 and
are
spermatids
 embedded
spermtids
on
apical
membrane
of
Sertoli
cells
lose
 cytoplasm
and
develop
a
a
flagellated
tail
 chromatin
condenses
and
an
acrosome
(vesicle)
flattens
to
be
a
cap
 over
tip
of
nucleus
 acrosome
contains
enzymes
essential
for
fertilization
 mitochondria
are
conc
in
midpiece
of
body
 surround
microtubules
that
extend
into
tail
 sperm
released
into
lumen
of
sem.
tubule
w/
secreted
fluid
 migrate
out
of
testes
 fully
mature
sperm
in
12
days
in
epididymis
 Sertoli
cells
 regulate
sperm
devo
 provide
nourishment
for
sperm
 make
proteins,
hormones
(inhibin/activin),
growth
factors,
enzymes
 and
androgen‐binding
protein
(ABP)
 ABP
secreted
into
seminiferous
tubule
lumen
binds
to
testosterone
 thus
concentrating
testosterone
in
luminal
fluid
 Leydig
cells
 located
in
interstitial
tissuebtw
tubules
 secretes
testosterone
 become
inactive
after
birth
until
puberty
 note:
some
testosterone
‐>
estradiol
 Hormone
control
of
spermatogenesis
 hyp
secretes
GnRH
 stimulates
ant
pit
to
secrete
FSH
and
LH
 which
negatively
feedback
on
GnRH
 FSH
and
LH
stimulate
the
testes
 FSH
secretion
is
sensitive
to
GnRH,
but
is
also
influenced
by
inhibin
 and
activin
 FSH
stimulates
the
Sertoli
cells
 produce
paracrines
for
spermatogonia
which
promote
mitosis
 and
spermatogenesis
 also
stimulates
production
of
ABP
and
inhibin
 inhibin
has
neg
feedback
on
FSH
 LH
targets
leydig
cells
 they
begin
to
secrete
testosterone
 Go
Notes
109
 which
neg
feedback
on
LH
 testosterone
is
essential
for
spermatogenesis
 Male
accessory
glands
contribute
secretions
to
semen
 semen
‐
sperm‐fluid
mixture
 fluid
mix
includes

 mucus
(lube)
 buffers
(neutraliza
acid
in
vagina)
 nutrients
 seminal
vesicles
add
prostaglandins
that
increase
sperm
motility
and
 xport
 secretions
from
other
glands
are
immunoglobulins,
lysozyme,
and
 other
compounds
w/
antibacterial
action
 Androgen
sex
characteristics

 primary
 internal
sex
organs
and
external
genitalia
 secondary
 inverted
triangle,
broad
shoulders,
narrow
waist
 hair/beard
growth,
muscle
devo,
low
voice,
libido
 Female
production
 fig
26‐12
 anatomy
 external
genitalia
=
vulva
or
pudendum
 labia
majora
+
labia
minora
+
clitoris
(small
bud
of
 erectile
tissue)
 urethra
is
btw
clitoris
and
vagina
(receptacle
for
penis)
 partially
closed
by
hymen
 cervix
‐
neck
of
uterus
 portrudes
from
the
upper
end
of
vagina
 cervical
canal
is
lined
w/
mucous
glands
which
secrete
a
 barrier
btw
vagina
and
uterus
 uterus
‐
hollow
muscular
organ
 3
layers
 1.

thin
outer
CT
 2.

thick
middle
layer
of
smooth
muscle
=
 myometrium
 3.

inner
layer
=
endometrium
 endometrium
consists
of
epithelium
w/
glands
that
dip
 into
CT
layer
below
 thickness
of
which
varies
during
menstrual
cycle
 . menstruation
is
the
sloughing
off
of
those
 cells
 Fallopian
tube
 smooth
muscle
(circular
+
longitudinal)
 is
ciliated
 moves
eggs
‐>
uterus
 fertilization
occurs
here
 Go
Notes
110
 Fimbriae
 flared
open
end
of
Fallopian
tube
 associated/adjacent
to
ovary
 finger
like
fimbriae
catches
egg
from
ovary
 Ovary
 produces
eggs
and
hormones
 outer
CT
layer
 inner
CT
known
as
stroma
 ovary
consists
of
thick
outer
cortex
filled
w/
ovarian
 follicles
in
various
stages
of
devo/decline
 central
medulla
consists
of
nerve
and
blood
vessels
 each
primary
oocyte
(tetraploid)
enclosed
in
a
primary
 follicle
w/
single
layer
of
granulosa
cells
‐>
basement
 membrane
‐>
outher
layer
of
cell
=
theca
 Menstrual
cycle
 fig
26‐13
 monthly
gametogenesis
 menstruation
‐
bloody
uterine
discharge
 1.

ovarian
cycle
 2.

uterine
cycle
 Ovarian
cycle
 1.

Follicular
phase
 1st
part
 follicular
growth
in
ovary
 10
days
to
3
weeks
 2.

Ovulation
‐
ripened
follicle
release
oocyte
 3.

Luteal
phase

 post
ovulatory
 ruptured
follicle
turns
into
corpus
luteum
 secretes
hormones
that
prepare
for
pregnancy
 if
no
pregnancy
corpus
luteum
disintegrates
in
2
 weeks
 Uterine
cycle
 regulated
by
ovarian
cycle
 3
phases
 1.

Menses
‐
menstrual
bleeding
(same
time
as
 beginning
of
follicular
stage)
 2.

Proliferative
phase
‐
(latter
part
of
ovary
follicular
 stage)
 endometrium
growth
in
anticipation
of
 pregnancy
 3.

Secretory
phase
 corpus
luteum
hormones
convert
endometrium
 into
secretory
structures
 (corresponds
to
luteal
phase
of
ovarian
cycle)
 Hormonal
control
of
menstrual
cycle
 Go
Notes
111
 GnRH
from
hypothalamus
 FSH
and
LH
from
anterior
pituitary
 estrogen/progesterone/inhibin
are
secreted
from
ovary
 hormone
dominance
 follicular
phase
(estrogen)
 luteal
phase
(progesterone)
 although
estrogen
is
still
present
 Early
follicular
phase
 day
1
=
first
day
of
menstruation
 before
beginning
of
each
cycle
gonadotropin
(FSH
and
LH)
secretion
 from
ant
pit
increase
 under
influence
of
FSH
follicles
begin
to
mature
 as
follicles
grow,

 granulosa
cells
(under
FSH)
and
thecal
cells
(under
LH)
 produce
steroid
hormones
 thecal
cells
produce
androgens
which
are
converted
to
estrogens
(by
 aromatase)
in
granulosa
cells
 gradually
estrogen
levels
inc
 neg
feedback
of
FSH
and
LH
preventing
devo
of
other
follicles
 also
stimulates
more
estrogen
synthesis
by
granulosa
cells
 (pos
feedback)
 allows
continued
estrogen
synthesis
although
FSH
and
 LH
are
decreased
 as
follicles
enlarge,
granulosa
cells
secrete
fluid
into
central
cavity
=
 antrum
 contains
enzymes
and
hormones
for
ovulation
 only
dominant
follicle
(largest
antrum)
develops
 menstruation
ends
 estrogen
from
follicles
cause
endometrium
growth
 Late
follicular
phase
 estrogen
synthesis
peaks
 one
developing
follicle
left
 granulosa
cells
of
follicle
begin
to
secrete
inhibin,
progesterone,
and
 estrogen
 estrogen
changes
to
positive
feedback
on
GnRH
which
results
in
a
 LARGE
inc
in
LH
(LH
surge)
 FSH
inc
too
but
is
inhibited
by
inhibins
and
estrogen
 LH
surge
is
essential
to
ovulation
 1st
meiotic
division
occurs
 remember
high
[estrogen]
cause
endometrium
growth
 Ovulation
 16‐24
hrs
after
LH
peak,
ovulation
occurs
 mature
follicle
secretes
collagenase
 which
dissolves
CT
of
follicular
cell
 follicle
ruptures
‐
antral
fluid
and
egg
is
ejected
 egg
is
swept
to
Fallopian
tube
 Go
Notes
112
 
 LH
surge
also
causes
thecal
migration
to
antral
space
 becomes
luteal
cells
by
luteinization
 corpus
luteum
 begins
to
secrete
progesterone
(estrogen
diminishes)
 Early‐Mid
Luteal
phase
 corpus
luteum
produces
steadily
increasing
amounts
of
estrogens
and
 progesterones
 progesterone
is
dominant
in
luteal
phase
 estrogen
and
progesterone
exhibit
neg
feedback
on
hypothalamus
and
 anterior
pituitary
 FSH
and
LH
production
in
shut
down
 progesterone
continues
endometrial
preparation
for
pregnancy
 increased
blood
flow
 placental
devo
 progesterone
also
inc
basal
body
temp

 measured
in
morning
 Late
luteal
phase
and
menstruation
 corpus
luteum
lasts
for
12
days
if
no
pregnancy
occurs
(apoptosis)
 becomes
the
corpus
albicans
 as
luteal
cells
degenerate
progesterone
and
estrogen
decreases
 removal
of
negative
feedback
 initiates
FSH
and
LH
secretions
 w/out
progesterone
(b/c
corpus
luteum
dies)
blood
vessels
of
 endometrium
contract
 surface
cells
die
through
lack
of
nutrients
(menstruation)
 3‐7
days
 REPEAT
 Estrogen
effects
on
sex
characteristics
 female
genitalia
 breast
devo/fat
distribution
 note:
adrenal
androgens
‐>
libido/hair
growth ...
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This note was uploaded on 03/06/2012 for the course BIPN 102 taught by Professor Nefzi during the Fall '06 term at UCSD.

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