Biology 2A03

Lecture 1

Introduction to Physiology
&
Homeostasis
Physiological determinates of animal performance
1. Vertebrate muscle remodeling 2. Regulation of lipid metabolism
with environmental stress

3. Lifetime performance and 4. Toxicogenomics

muscle physiology

5. Interactions between oxygen

delivery and fuel metabolism

Research in the
McClelland Lab
Course Syllabus available on LearnLink

INSTRUCTORS: Dr. G.B. McClelland – LSB 228

INSTRUCTIONAL Ray Procwat, LSB-215, Ext 24399,
ASSISTANT: procwat@mcmaster.ca
Monday, Wednesday, Thursday 13:30 – 14:20, MDCL
LECTURES:
1305
LABORATORIES: Monday-Friday – 2:30 - 5:20 pm or 8.30 – 11.20 am;
LS/104 or LS/105. Students must attend the lab section
to which they have been assigned. Those with conflicts
should visit https://scidropadd.mcmaster.ca/dna
Changes from assigned sections may be made for
reasons of academic conflict only. Documentation of
the conflict may be required.

*****Labs start next week – odd # sections 1st week*******

Pick up Lab #1 handout in LSB 215

For the rest:

Lab handouts will be available on LearnLink or by handout one week
before the scheduled lab
 http://www.aw-bc.com/physiologyplace/

****All Quiz and exam questions taken from LECTURE and LAB material
Course Syllabus available on LearnLink

MARKS: 32% 4 Quizzes (written during lecture slots 13:30 – 14:20)

Mon. Jan. 23,
Mon. Feb. 13,
Mon Mar. 13,
Mon Mar. 27;
Room assignments for quizzes will be announced in class

24% Laboratories (3 full lab reports @ 6% each; 2 short

questionnaires @ 3%
each)

44% Final Exam (2 hours)

 What is Physiology?
The goal of physiology is to explain the physical
and chemical factors for the origin and progression
of life OR
How animals work!
Disciplines: Cellular Physiology, Developmental Physiology
Neural, Renal, Muscle, Cardiovascular…… Physiology
Medical Physiology or Pathophysiology –
abnormal physiology as the result of disease

Comparative, Animal or Integrative Physiology –

how animal adapt to “abnormal” environments or
life histories.
Also environmental physiology, evolutionary physiology
and physiological ecology
 When O2 removed happy 
produce ethanol

0% O2!

4000-5000m 68 - 81ºC
10% O2 2000-3000m
High H2S
Hierarchical organization of the body
Cells Differentiated and specialized
2) muscle, 2) nerve, 3) epithelial
4) connective cells
Tissues Aggregate of specialized cells
2) muscle, 2) nerve, 3) epithelial
4) connective tissues
Functional units Subunits of an organs
(e.g. multiple nephrons in a kidney)

Organs Composed of the 4 tissue-types in

different proportions and patterns

Organ Systems A collection of organs that function

together
e.g. Circulatory System = heart,
Organism blood vessels, blood
Figure 1.2
 Hierarchical organization of the body
Cells: in humans over 200 distinct kinds
1) Muscle cells: specialized for contraction to produce movement
Subtypes can exist:
– skeletal, movement of limbs and skin
- cardiac, movement of heart
- smooth, dilation of blood vessels, control of BP

2) Nerve cells: generate and propagate electrical signals

3) Connective tissue cells: connect and support body structures

e.g. bone, collagen, cartilage

4) Epithelial cells: secretion and absorption; protective role

e.g. skin
Collection of organs that work together to accomplish
a particular task
Simplified View of Overall Plan of Human Body

•Separates external
from internal
•Keep constant
internal envts.
•O2 in, CO2 out

Fig 1.4
 The Internal Environment

Total Body Water = Intracellular H2O 28 L 2/3

Interstitial H2O 11 L
ECF 1/3
Plasma H 2O 3L

42 L or 60% body wt

Extracellular Fluid is rapidly transported by the circulation

and mixes between blood and tissues by diffusion through
capillary walls
Baths tissues and makes up the internal milieu of the body

Proper cellular function depends on tight control of ECF components

See Fig. 1-5
Fig. 1-5
 Homeostasis
A Defining Feature of Physiology

Noted that mammals are able to regulate

their internal environment within
a narrow range.

Claude Bernard (1813-1878)

Extended Bernard’s notion to the organization
of cells, tissues and organs. First to coin
the term “homeostasis”
“The maintenance of static or constant
constant conditions in the internal
environment”

Walter Cannon (1871-1945)

 Basic Negative Feedback Control
Set point

Sensors
Regulated Integrating center
variable
input output

Negative feedback

Effectors
Compensatory response
•Changes in the regulated variable is picked up by the sensors
•Reflex arcs = -ve feedback loop
•Set point compares input
•If s.p = input  nothing happens within body
•If s.p ≠ input  output causes a compensatory response using effectors, thus creating a –ve feedback
Examples: arterial blood pressure, body temperature, pH, PCO2
See Fig 1.7
 Lecture 2- Jan 5

• Reflexes: a key component of control systems

• Strictly defined as:

» Involuntary, unpremeditated, unlearned response to a stimulus

• Some are:
» Learned or required

• Most are:
» Attended by learning
 Homeostatic control systems- reflex arc
Afferent Pathway: going to
Efferent Pathway: going away Set point
Stimulus or
error signal +/-
Afferent Efferent
Pathway
Regulated Integrating center Pathway

variable
receptors output

Negative feedback

Effectors
Compensatory response

•Restoration of set point never complete or exact and a persistent error signal keeps
feedback loop in operation
•Hence the term “relatively” stable in definition of homeostasis
Afferent Set Point Efferent
Pathway Pathway

T-sensitive
nerve
endings

Compensatory
Response

Fig 1.9
 Intercellular communication

• Cell to cell communication is important for homeostasis

• Performed by intercellular chemical messengers
• 1) Hormones: Hormones secreting cells- target cells through
blood
– Slow acting
– Example: insulting and glucose homeostatsis
• 2) Neurotransmitter: Nerve- nerve; nerve- effector cell
– Fast acting
– Example: Acetylcholine and heart rate
• 3) Autocrine/Paracrine aagents: Local homeostatis responses
– Act locally on target cell by difffusion
– Examples includes ATP, nitric oxide (NO), fatty acid derivaties
(eicosanoids)
– Auto= same cell; para= neighbough cells
– See Fig 5.2
 Cells and compartments

• Review 1st year material on cell organelles:

– Nucleus, ER, Golgi, endosomes, lysosomes, peroxisomes,
mitochondria
• Membranes:
– 1) important as selective barrier to movements in and out of
cells and organelles
– 2) detect chemical messengers at the cell surface
 Membranes
•Integral proteins:
•Participate with chemical messengers
•On the surface of the phospholipids bilayer
•Transmembrane integral proteins:
•Inside the membrane
•Has a pore that selectively allows movement in and out of the cell
•Peripheral proteins:
•Attached to either inside or outside of the membrane

Integral proteins

Transmembrane integral
Peripheral protein
protein
 Tight Junctions
-Extracellular membranes of adjacent cells joined
-Transport pathway between cells (extracellular)
blocked
-Most substances must therefore go transecullarly
-Forms selective barriers
-E.g. most epithelial cells
•In tight junctions substances cannot
pass from one cell to the other due to
the close/tight proximity of the cells and
thus the substances must pass thru
transecullarly rather than thru
extracellular pathways.
Desmosomes
-Hold adjacent cells tightly together
-Found in areas of stretching (e.g. skin)
or highly mechanical stress (cardiac
cells)
 Gap Junction

- Protein channels (connexons) linking

cytosols of adjacent cells
- channels are very small (1.5nm
diameter) and limits what can pass
- connected in cardiac cells at
intercalated disks and important for
passage of electrical signals (Fig 14.8)
 Mitochondria- Powerhouse of the cell
• Main function is to provide cell with energy in the
form of ATP
• The site of cellular respiration (oxidative
phosphorlyation)

Folded structure w/in inner Intermembrane space:

membrane space btwn inner and out
membrane

Fluid in cristae
 Mitochondria

• Outer membrane: Freely permeable to small molecules

and ions
• Inner membrane:
- Impermeable to most small molecules and ions including H+
- Contains respiratory complexes (ETC)
- ATP synthase (F0F1)
• Matrix:
- Contains the citric acid cycle enzymes (Kreb’s, TCA)
- Fat oxidizing enzyme (B-oxidation)
- Pyruvate dehyrogenase (PDH)
Mitochondrial density is related to aerobic capacity

Mitochondrial density / g
O2 consumption / Mb

mouse elephant mouse elephant

Hummingbird Human
flight muscle muscle
 …cont’d
• Amount of mitochondria in cells can vary
between tissues and animals
• Oxygen consumption of mouse is > than
that of elephant
• And this mouse tissues have a lot more
mitochondria than elephant
• Mitochondria is important in metabolism
and ATP using O2
 Biology 2A03
Lecture 3

Protein activity
&
Cell metabolism I
Membranes

•Look at different types of proteins we already looked at….

Fig 2.15
Mitochondria
•Look at different structures
•Enzymes of Krebs cycle in matrix
•ETC on cristae of inner membrane
•“power house” of cell (generates ATP)
•ATP powers physiological processes

•Outer membrane: freely permeable to smell

molecules and ions
•Inner membrane: impermeable to small
Fig 2.20 molecules and ions including H+
•Contains respiratory
•O2 used in oxidative phosphorylation in
• Burness, Science (2002) diagram mitochondria
• Respiratory system  getting O2 to lungs • O2 comes from respiratory system,
delivered by blood circulation
• ATP is used for demand site, aids in:
– Muscle contraction
– Ion pumps (to transport)
– Protein synthesis
 Protein activity & cell metabolism
• Proteins and proteins functions are central to physiology
• Protein activity is controlled by:
– Rates of synthesis and/or degradation
– Changes in 3D conformation (shape)  determined by a.a composition,
important for ligand binding to active binding site

• The shape of proteins and therefore ligand binding modified by:

– Allosteric modulation: - non-covalent binding of factors to other
regulatory sites results in a change in shape
of the active site.
– Covalent modulation: - covalent binding of –ve PO42- to a.a side
chains by protein kinases
- changes in protein conformation and
distribution of –ve charges
- eg., serine, threonine, tyrosine

• Proteins kinases add PO42- from ATP to proteins

• PO42- can be removed by protein phosphates
• Kinases can be controlled allosterically demonstrating that the 2 systems
can interact
• Both allosteric and covalent modulation affect the binding affinity of enzyme
for substrate (ligand) or a binding site can be turned off or on.
 1. Allosteric modulation
• Blue protein with green
modulators
• The modulator binds to ligand
and changes the binding site
of the protein
• Eg. Substrate for fat
synthesis inhibits enzyme in
fat oxidation

2. Covalent modulation
• Phosphorylation and
dephosphorlyation rxn
• Red triangle (phosphate
groups) gets added to ligand
by enzyme
• Enzyme A: protein kinase 
adding PO42-
• Enzyme B: phosphatase 
removing PO42-
Fig 3-9, 3-10
 Enzymes
• Cell metabolism: sum of all chemical reactions that
occur in cells
1. Anabolism (synthesis)
2. Catabolism (breakdown)
• Virtually every chemical reaction in the body catalyzed
by enzymes
• Often read cofactors (trace metals such as Mg, Fe, Cu,
Zn)
• Or
• Coenzymes derived from vitamins (eg., NAD+, FAD,
and coenzyme A from B vitamins)
 WHY DO WE NEED ENZYMES?

•Uncatalyzed they occur at too slow rate (yrs in some cases) due to high
activation energy
•Enzymes decrease activation energy and increase reaction rates by a factor
of 105 to 1017

Fig 3.4a
• Enzyme kinetics: studying rate of reactions
S + E ES P +E
S= substrate Most important step
•
• E = enzyme (unused)
• Rates of enzymes reactions depend upon:
1. Substrate [S] or product [P] concentration (Law
of Mass Action) - ↑ in [S], rxn goes right; ↓ in [P]
rxn goes left
2. Enzyme concentration [E]
3. Enzyme activity (catalytic rate)
- Determines how quickly ligand binds to active
site and is removed
 …cont’d
Change in affinity for S
e.g. allosteric modulation
Vmax 2x E

1x E
V0 ½ Vmax V0

Km Km
[S] [S]

• Enzyme with higher affinity is

•As [S] ↑, VO
able to catalyze the reaction at
a faster rate and will exhibit a
higher degree of saturation
 Relationship btwn [S] & rxn rate
• The quantitative description of enzyme rxn reacts to
[S], constant Vmax and km occurs by the:
• Michaelis-Menten equation:
VO = [S] Vmax
Km +[S]
- Km = [S] at which VO = ½ max
- If affinity ↑, then # of ES complex ↑ at any given [S]
or the same # of [ES] at lower [S] (ie, Km
decreased)
- In other words, at high affinities ½ Vmax occurs at a
lower [S]
See Fig 3-7
- Km can be determined from this plot Fig 3.8
 Influence of substrate concentration on the
rate of an enzyme-catalyzed reaction

•At lower and moderate

concentrations, the rate of the rxn
increase as [S] increases
•At high concentrations, the curve
level offs; when [S] is very high,
the active site of every enzyme
molecule is occupied by substrate
100% of the time, and enzyme is
Fig 3-7 100% saturated.


Increasing ES complex

•Enzyme 100% saturated with S at Vmax

•A fixed concentration of enzyme is assumed for this plot of reaction rate
versus substrate concentration [S]. Binding of substrate to the enzyme
increases with increasing [S] until high substrate concentrations are reached,
in which case all enzyme molecules are bound (100% saturation)
 Biology
Lecture 4
Protein activity (cont..)
Transport I
Relationship between [S] and reaction rate
The quantitative description of enzyme reaction rates to [S],
constants Vmax and Km occurs by the:
Michaelis-Menten equation:

Km = [S] at which the reaction rate Vo is equal to 1/2Vmax

If affinity increases then the #ES complexes increases, at any
given [S], or at the same #ES, the Km occurs @ lower [S]

Vo = ([S]*Vmax)/(Km + [S])
Vmax

V0 ½ Vmax
Km = 1/affinity

Km1 [S]
 Metabolic pathways
A sequence of enzyme-mediated reactions leading to a
specific product

P feeds back to E2 (allosteric inhibition)

E1 E2 E3 E4
A B C D P

Specific reaction steps may be regulated to control flux

through an entire pathway.
Classically these are called rate limiting steps, but now we use
“modern control theory”, which looks at the relative control
At each specific enzymatic step.
 Metabolic Pathways – ATP Synthesis
One of the major roles of metabolic pathways is to convert
potential energy into food (eg creates ATP for use in cellular
functions.
ATP production ATP ATP consumption

[ATP] Body uses ATP in movement,

Body converts fats
processing, molecular
And carbs to ATP ADP + Pi transport/synthesis, etc

ATP can be produced by: a) Substrate level phosphorilation

(done in the absence of O2)

NOTE – body tries to keep

b) Kreb’s cycle (TCA citric acid
ATP levels relatively cycle)
Constant (homeostatic) c) Oxidative phosphorilation (uses
O2 in the mitochondrion)
Transport mechanisms
Transport across membranes
Membrane provide a selective barrier between the ICF and ECF
(inter/extra cellular fluid)
*See Table 4.1 for differences between ICF and ECF
Transport mechanisms include:
1. Diffusion: simple movement across the lipid bilayer,
does not directly consume energy (ATP)

2. Mediated transport: facilitated diffusion, or uses

trans-membrane protein channels to move molecules

Primary (directly uses ATP to move

Active transport molecules)
Secondary (doesn’t use ATP, uses an
electropotential difference between areas)
See Table 4-2
 See Fig 4-2
Simple diffusion Fig 4-4
Diffusion: “the movement of molecules from one location to
another due to random thermal motion
Movement is from a region of higher concentration to an area
of lower concentration, until equilibrium is reached.
Flux: movement from a compartment to another, per unit of time
Net flux = (F1-F2) flows towards the lower concentration
A gradient for diffusion is created, therefore downhill movement
Of the solute occurs.

F1 F2
F1 F2
There is no net flow, as equilibrium
The net flow is towards F2, but
Has been reached, however, there
There is flux both ways, unless
Is still flux between the two areas
It is prevented by the cell membrane
Net flux depends upon: 1) Temperature ( ^^ Temp => ^^Flux)
2) Permeability (how porous is the membrane?)
3) Mass of molecule (larger masses are harder)
4) Surface area of regions ( ^^ SA => ^^ Flux)
Diffusion:
- times (t) are proportional to the distance travelled (i.e. x^2)

- therefore is only efficient over short distances

Single cells can use diffusion rather efficiently

Large animals generally require the use of a circulatory system
For example transport of oxygen to cells, CO2 from cells)

BUT- both these systems work in conjunction, eg O2 is circulated

Capillaries, and then diffuses into the cells from the capillaries.
 See Fig 4-1
Diffusion continued Fig 4-10
1a) Flux across the lipid bilayer Box p113

F = Kp × A × (Co - Ci)
Initial concentration
Flux Area difference between
inside/outside of area of
Permeability constant diffusion

Kp: is a measure of the ease of passage across a mebrane

It is a function of: i) Temperature factors

ii) Solubility in the bilayer (eg. Polarity
unpolar/uncharged molecules have a high Kp
while polar/charged molecules have a low KP
i) Size and shape of the molecule (molecules
with less complicated shapes diffuse easier)
 Metabolic pathways
• A sequence of enzyme-mediated reactions leading to a
specific product:
- Allosteric inhibition (end
product inhibition)

E1 E2 E3 E4
A ↔ B ↔ C ↔ D ↔ P

• Specific reaction steps may be regulated to control flux

through entire pathway
• Classically these are called “rate binding” steps but
modern critical theory does not use this term
– Critical theory: looks at the relative control each
enzymatic step
 Biology 2A03
Lecture 5
Transport Mechanisms II
2a) Diffusion through transmembrane protein channels
Important for the movement of charged ions which normally
do not diffuse across lipid bilayers

Na+, K+, Cl- and Ca2+ pass through the membrane with the aid of
selective transmembrane proteins channels

Both diffusion and electrical forces important for movement of ions

also called electrochemical gradient.

Membrane potential involves the seperation of charges across a

Membrane, creating an electrochemical gradient while allows for
Diffusion is required.
 Separation of Charge Across a Membrane
– Separation of charge =
potential energy
–Electrical forces
• act similar to diffusion,
movement towards lowest
concentration
–Membrane potential is
negative (always relative to
inside)
• + goes INTO the cell
• - goes OUT of the cell (due
to the electrochem gradient

–Magnitude of electrical
driving force
ITC = neg charges ETC = pos charges
• depends on the valence of
the ion being driven

Fig 4.2
Electrochemical Driving Forces
Direction of ion movement depends
on balance between electrical and
Chemical forces
If these are equal the
electrochemical force is ZERO
For this example:
(TOP) Chem > Elec Forces, therefore
there is a net movement outwards

(BOTTOM) Elec > Chem forces, so

there is a net movement inwards

Ek= equilibrium potential which

reflects the driving force of the
movement.
Fig 4-5
Channel Protein

Selective for type of ion

-due to size and the charged and
polar surfaces of the protein
subunits of the channels

Electrically repel/attract certain

ions, through a Channel Protein,
which consist of polypeptides
around a central core, which creates
the channel to transport the ions.

Opening of the pore can be regulated,

often through conformational changes of
the protein, eg phosphorilation, etc.

Fig 4-13
2b) Facilitated Diffusion (actually a mediated transport)

Net flux of molecules across membranes is from a high

Concentration to a low concentration (downhill movement).

Not coupled with ATP hydrolysis to move molecules uphill.

Flux 1 >> Flux 2

Glucose glucose
ECF = ~6mM ICF = ~1 mM

Glucose-6-phosphate
 Differs from simple diffusion in
that it involves selective membrane
transporters for large or polar
molecules.
The substrate bonds, causing a
conformational change in the
protein.
Mediated transport can also
become saturated and reach
Bind substrates and undergoesmaximal flux. Simple diffusion will
conformational changes increase, and cannot become
saturated.

Fig 4-11
Fig 4-12
2c) Primary active transport

Direct use of ATP to power movement of molecules against an

electrochemical gradient or uphill
Covalent modulation of transporter (by phosphorilation through ATP)
Increases the affinity of the binding site, and so the efficiency of the
Protein.
Dephosphorylation occurs by conformational change of the transporter
And decreases the affinity of the binding site.
Examples include: Na+ / K+ -ATPase, Ca2+ -ATPase, H+ -ATPase
H+/K+ -ATPase

Intracellular K+ = 15 mM, extracellular K+ = 4 mM

Inward movement of K+ is uphill (against the gradient)
And so requires the use of ATP to facilitate diffusion.

See Table 4.1

2c) Primary active transport
Intracellular Na+ = 15 mM
extracellular Na+ =145 mM

Outward movement of Na+

Intracellular K+ =
extracellular K+ =

Inward movement of K+
Note that an uneven distribution
Of charge is created here.

Fig 4-14
 Membranes are “leaky” to ions
Ion pumping to maintain proper
Gradients, produces heat as a
by-product (up to 50% of cellular
Heat production is done this way).

Endotherms have leakier membranes than ectotherms (i.e. allow for

ionic exchange much easier)
This results in a metabolic rate that is often 10 times that of the same
size ectotherms.
2b) Secondary active transport
Uses [ion] gradient across membrane as a source of energy

As ion moves down its concentration gradient it provides energy for

uphill transport of another atom.

Usually Na+ whose binding changes the affinity of the transporter

Proteins for solute, via ALLOSTERIC MODULATION.

Primary active transport is needed to maintain the electrochemical

Gradient which allows for secondary active transport.
 This example is of cotransport/symport
- net binding increases the affinity of
High glucose the protein for a second molecule.

High H+ Can also occur in opposite directions =

Countertransport/antitransport
Biology 2A03
Lecture 6
Signal transduction
Osmosis

Water diffusion: although water is polar it has high permeability

in membranes due to its small size

Flux can be increased by the presence of aquaporins = protein channels

H2O concentration depends on the # of dissolved particles

Total [solute] in solution determines osmolarity (colligative properties)
1 mole of dissolved particles = 1 osmolar solution
e.g. 1M of glucose in solution = 1 osmole
but 1M of NaCl = 2 osmoles since it ionizes in solution to Na+ and Cl-
The higher the osmolarity of a solution the lower the H2O concentration

Osmosis in the direction of higher osmolarity (or lower [H2O])

Cells are very permeable to water and impermeable to many solutes

Isotonic: Extracellular fluid has the same # of osmoles of

nonpenetrating solute
No change in cell volume

300 mOsm
Hypertonic: Extracellular fluid has a greater # of osmoles of
nonpenetrating solute
Cell shrinks

400 mOsm
Hypotonic: Extracellular fluid has the lower # of osmoles of
nonpenetrating solute
Cell swells

200 mOsm Fig 4-19

Compare to osmolarity
Relates the osmolarity of a solution relative to normal extracellular
fluid without regard to penetrating or nonpenetrating nature of
solutes

A solution can be isoosmotic at 300 mOsm but hypotonic due to

penetrating solutes

300 mOsm >300 mOsm

nonpenetrate
penetrating

isoosmotic But hypotonic

Signal Transduction Pathways detect intercellular messengers and
convert them into a biologically meaningful response

4 features of signal transduction pathways:

1) Specificity: The signal molecule fits in its receptor
while others do not
Can also have messenger bind to multiple
receptors with different affinities

2) Amplification: 1 receptor binding can lead to 1,000,000 products

3) Desensitization / adaptation: Feedback shuts off

receptor or removes it

4) Integration: Outcome the result of integration

of both receptor inputs
- +
response
 Fig 5-9
Receptors Fig 5-10
The magnitude of a cell’s response depends on:
1) the messenger’s concentration
2) the # of receptors present
3) affinity of receptor for messenger

Show characteristics very similar

to enzymes

Can become saturated with

messenger
 An increase in the # of receptors
increases the % bound with messenger

Change in affinity for messenger

Can increase # of bound receptors

at the same [messenger]

Or…50% of the receptors are

bound at a lower [messenger]

Fig 5-10
Receptors can be intracellular: bind to lipophilic messengers
alters synthesis of a specific protein
-act as transcription factors

M R

Receptors can be located in the cytosol of in the nucleus

e.g. steriods = hormones

See Fig 5-11

 Bind lipophobic messengers
Receptors can be membrane bound: 3 main types
1) Channel-linked: (e.g. binding opens ion channel)

Called ligand-gated channels

This is an example of a
“fast” channel
Channel also acts as the
receptor
Allows channel to open quickly
and briefly

Fig 5-12
2) Enzyme-linked:Ligand-binding domain on extracellular surface and
an enzyme active site on intracellular side
Binding activates tyrosine kinase activity
which phosphorylates a protein - on tyrosine

e.g. insulin receptor

Fig 5-13
3) G-protein-linked: (activate membrane proteins called
G-proteins and begin a signaling cascade)
G-proteins can be stimulatory (Gs) or
inhibitory (Gi)
1. Regulates a protein channel
e.g. Can open or close a
“slow ” ion channel
- Channel does not act as
receptor
2. Often activates an enzyme
e.g. adenylate cyclase to
α-subunit binds GTP
to become active produce cAMP

Fig 5-14
Second messengers
Intercellular chemical messenger which reaches the cell surface
is called the first messenger
The intracellular messenger produced by the binding of the first
messenger is called the second messenger
Act as chemical relays from the plasma membrane to the
biochemical machinery inside the cell

Important 2nd messengers are:

• Ca2+
• cAMP
• cGMP
• DAG
• Eicosanoids
Table 5-3
• IP3 Fig 5-16
Fig 5-17
Fig 5-18
Messenger blood borne hormone Extracellular fluid 1x molecules
epinephrine
1
Receptor β-adrenergic receptor

2
Adenylate cyclase
β GDP GTP
γ α α
GDP GTP
Amplifier
G-protein Substrate 3 enzyme
stimulatory 20x molecules
ATP Second
messenger
cAMP
Activates 4
enzyme

Protein kinase
10x molecules
5
PKA Protein Protein – P PKA
inactive + + active
ATP ADP
6
Cytosol Response in cell
Next slide
-Example of a signal transduction pathway-
Response of the cell (e.g. glycogen breakdown in liver cells)
PKA
10x molecules
active
inactive active
Phosphorylase b Phosphorylase b (100x molecules)
Kinase Kinase Amplification
of hormone signal
inactive active
Glycogen Glycogen
phosphoryase b phosphoryase a(1000x molecules)

glycogen Glucose 1-P(10,000x molecules)

Glycogen synthase (inactive)

PKA
active

Adrenergic receptor can be desensitized by phosphorylation

Biology 2A03
Lecture 7
Circulation I
Circulation
Why have a circulatory system?
Diffusion times (t) are proportional
to the distance covered
Diffusion gradients for nutrients or wastes can decrease drastically
over large distances.
High [waste] inside forces
Waste to flow to the outside.
Waste out
Waste out
Nutrients in
Nutrients in

Diffusion is sufficient in Multicellular organism’s require a

a unicellular organism. circulatory system, as the distances for
diffusion are too large to be efficient.
Circulatory Systems
A fast convection system = rapidly circulating fluids
between surfaces that equilibrate external milieu
(environment) for cells deep inside an organism
1˚ role = distribution of dissolved gasses and molecules from
nutrition, growth, and repair.

2ary role = 1) Fast chemical signalling

2) Dissipating heat
3) inflamatory/heat defences against micro-organisms
System consists of:
1) A Convective medium = blood (communication system)
2) Plumbing = blood vessels (regulates blood pressure/distribution)
3) A Pump = heart (sensory and endocrine (hormonal) functions)
The Circulatory System Composed of 2 circuits
1. Pulmonary circulation (lungs)
Picks up O2 from the lungs
Low pressure system (20mmHg)

Right ventricle lungs

Left atrium

2. Systemic circulation
Delivers O2 to tissue and organs,
NOT the lungs.
High pressure system (100mmHg)
Left ventricle Organs and tissues
Right atrium
Both have an arterial components
(blood FROM the heart) and a venous
component (blood TO the heart).
*flow through each of these circuits is
EQUAL!!!!
Fig 14-2
 Blood – plasma & cells (erythrocytes, leukocytes, platelets)
1) Plasma water ~92%
Composed of:
proteins ~7% Albumin, antibodies,

Electrolytes (ions) Major Cation (Na+ 145 mM)

Major Anion (Cl- 100,140 mM)
-ISF and plasma
values close to each gases O2, CO2, N2
other
-Except that
proteins > in the nutrients Glucose, lipids, amino acids
plasma

wastes Urea, ammonia

The capillary wall is very permeable to H2O and most plasma components,
Except for proteins, based on their shape, size, and charge.
See Table 16-1
 Hematocrit
The fraction of blood composed of Red Blood Cells (RBC’s/erythrocytes)
Can be measured after blood is centrifuged in a microhematocrit tube

Lightest l1
Hematocrit =
lt
Plasma ~54%

lt

Buffy coat (leukocytes and platelets) ~1%

ll
Eryhtrocytes ~45%

Most dense Total blood vol = ~5.5 L

Plasma (54%) = ~3.0 L
RBC’s (45%) = ~2.5 L
2) Blood Cells –
1. Red blood cells (erythrocytes)
Most abundant cell in the blood stream
-Major function to transport O2 fro
CO2 from t
-In mammals do not contain nucleus/organelles
and so cannot divide (transporter for the body)
-Contain large amounts of hemoglobin (85% of
protein content) for carrying O2

-and the enzyme carbonic anhydrase important

for CO2 transport

-Shape of cells important for O2/CO2 diffusion

-Biconcave disk – thicker at the edges, gives a high SA/Vol ratio,
which provides easier diffusion, and greater flexibility, which
also allows for easier diffusion.
 280 x 106 Hb molecules per RBC

Hb is a tetramer (M.W. ~ 68,000), composed of 4 sub-units

Each unit consists of a “heme” ring structure, & a polypeptide
chain (globin) which binds CO2, H+, phosphates, etc, which
change the affinity of hemoglobin for O2
Hb exhibits the property of allosteric modulation = “binding
at one site on a molecule affects binding at a second site,
usually by changing the shape of the molecule.”
Regulation of erythrocyte production
Blood components are under tight reflex (homeostatic) control

Red blood cell production occurs in bone marrow

Have relatively short (120 days) life span (compared to other

vertebrates)
Approximately 1% per day
breakdown occurs in spleen and liver
Product= bilirubin (yellow colour)
Production (erythropoiesis) is primarily regulated by the hormone
Erythropoietin (EPO), which is secreted by specialized cells in
the kidney.
Increased release triggered by a decrease in O2 delivery to the
kidney.
Fig 16-4
 Regulation of erythrocyte
production

O2 delivered to the kidney

EPO secreted by the kidney

Plasma EPO

Production of RBC’s in
Bone marrow

Blood hemoglobin (HB)

Blood O2 carry capacity

Restoration of typical O2
Delivery, cycle is re-balanced
Fig 16-4
Ways to increase red blood cells

High altitude: low levels of O2 stimulates production of RBC’s

Blood doping: previously stored RBC’s are injected into people.

Epo: requires ~3 wks to clear system, allows for window of

Testing times for athletes…resulted in stripping of medals.

Definitions
Polycythemia: RBC’s (hematocrit) levels are too high. An
increase in viscousity makes circulation difficult.

Anemia: Low ability for

1) Carrying RBC’s 2) Low HB per RBC , or 3) both
“Buffy coat”
2. Leukocytes- eosinophils, basophils, neutrophils, moncytes,
lyphocytes

-Produced in bone marrow and lymphoid tissue

-Defense and cleanup functions
3. Blood platelets – important for hemostasis

-Formed by the breakdown of WBC’s

-Involved in blood clotting

-Form a platelet plug to stop the bleeding

Both of these types are cells are much less numerous in the
blood than RBC’s
Biology 2A03
Lecture 8
Circulation I
 The fundamental law of the circulation
. ΔP
Q (or F) =
R
ΔP = pressure difference between 2 points in a circulation system.
P = force/area exerted by blood – generated by heart contractions.

R = friction that impedes flow (not measured directly, but is calculated)

Internal friction (viscousity) External friction (friction with vessel wall)

P1 P2
.
Q
R

Q decreases (flow slows)

R increases
The fundamental law of the circulation - Pressure
. ΔP
Q (or F) = …where,
R

ΔP = MAP – CVP
= 90 – 0 mmHg
= 1 Systolic P + 2 Diastolic P

MAP a weighted average of the

time spent in each phase.

MAP is the overall pressure driving the blood into the

tissues.
MAP = mean arterial pressure
CVP = central venous pressure Fig 15-2
Systemic vs Pulmonary Pressures
ΔP = MAP- CVP

Systemic = 90 mmHg
Pulmonary = 15 mmHg

Recall: that Q = 5 L/min

for each circuit.

And: Q = deltaP/R

Therefore: R must be lower

in pulmonary curcuit.

Fig 15-3 Also NOTE: Q pulmonary is equal to the Q systemic, allowing for
an even flow of blood through the system.
 Pulmonary
Low pressure low resistance circuit
1) Prevent fluid filtration in the lungs
2) Prevents shunting of blood
3) Minimizes workload of the
right ventricle.
Shunting = the movement
of blood in the body between
compartments, through the
circulatory system.
Right ventricle
Systemic
High pressure & resistance circuit
1) Ensure good fluid filtration
in the systemic capillaries to
ensure nutrient distribution.
2) Rapid shunting of blood
3) Left ventricle has a high
workload as a result of 1) and 2).
left ventricle
Fig 14-5
 Poiseuille’s Law
L
Q= ΔP π r 4
Q r
8ηl
ΔP
What determines vascular resistance?Since R=
constant
Q

8 η L -L of blood vessels is fairly constant.

R=
π r4 -Viscosity (η) is also fairly constant.
Polycynthemia = increase in # of RBC’s
Polycythemia and decreased T˚C
Due to the constants, the
resistance is dependant on Anemia and increased T˚C
the radius.
Rα 1 -Radius the most important factor in
determining the resistance.
r4
e.g. Decreasing r by 2x
Decreases flow by 16x
Biology 2A03
Lecture 9
Circulation III
Resistance vessels
Capable of active and passive changes in radius
Active (smooth muscle contractions)
Passive (stretch in the capillary)
arterioles & pre-capillary sphincters have smooth muscle
for active changes in radius.
Addition of R’s R1 R2 R3
In series Resistance greater than
any single R
RT = R1 + R2 + R3

Resistance is smaller
In parallel R1 R2 R3
than any single R

1/RT = 1/R1 + 1/R2 + 1/R3

RT= 1/ (1/R1 + 1/R2 + 1/R3)

 Most major resistances are
arranged in parallel.

Portal circulation an example of

resistance in series (i.e. all capillaries
are working together to do the
same thing.

Capillary networks are small vessels

arranged in parallel
Even though r is small per capillary
total resistance of all capillaries
is relatively significant, due to the
large number of capillaries in the
system.
Fig 14-3
 Total Peripheral Resistance (TP

Combined resistance of all blood vessels within the

systemic circuit

Resistance across a network of blood vessels

depends on the resistance of all vessels.

Flow through network varies with resistance.

Vasoconstriction in network  increase

resistance  decreases the flow
Vasodilation in network  decrease resistance
 increases the flow.
Relating Pressure Gradients and Resistance in the
Systemic Circulation

Flow = ΔP /R

– Flow = cardiac output (CO)

– ΔP = Mean Arterial Pressure (MAP)
– R = Total Peripheral resistance (TPR)

CO = MAP/TPR
 Vascular system
Inner radius
Arteries ~12 mm Low resistance, little pressure drop, acts as a
pressure reservoir.
microcirculation

ArteriolesMajor site of resistance, controls bloodflow patterns

~ 15 micrometres helps regulate arterial blood pressure.
Capillaries
~3 micrometres Exchange site of nutrients and metabolic biproducts
Venuoles Exchange of nutrients, O2, CO2 (but only a very
~10 micrometres small amount)
Veins Low resistance, thin walled, distensible (stretchy),
~5 mm adjusts blood return to heart, and acts as a blood
reservoir (can/does hold ~60% of the blood volume)
All parts of the circulatory system have endothelium (inner layer), all but
capillaries have smooth muschle and connective tissue (outer layer)
Connective tissue Varying degrees of elasticity and
Smooth muscle collagen fibre content.

Endothelium
(single layer of cells, which
See Fig 15-6
allows for easy diffusion.
 Capillaries contain a single
layer of cells for easy diffusion
of blood.

Veins/arteries have valves

To ensure a one-way flow
Of blood in the system.

Fig 15-5
Arteries
Muscular, highly elastic - High elastin to collagen ratio in connective
tissue
Compliance = ΔV moderate compliance to smooth out
ΔP pressure fluctuations from the heart.

Large changes in pressure with

small changes in volume make arteries
pressure reservoirs.

Large changes in volume with

With small changes in pressure make
veins volume reservoirs.

The higher the compliance the greater a vessel can be stretched,

and therefore the higher the amount of elastin in the tissue.
Fig 15-20
Arteries as pressure reservoirs

Stores pressure which is then

released between ventricle
contrations (diastole => relaxed)
Pressure stays in the walls when
relaxed.
Only 1/3 of the stroke volume
(the volume the heart ejects per
contraction. Blood leaves the
arteries at this time.
Arterial walls recoil during
diastole, pushes blood
forwards and maintains blood
flow at a constant level.

Fig 15-7
 systolic
PP
diastolic
Arterioles are the major site of
resistance in the circulatory system.

Pressure peaks during ventricular ejection (systole) =

Systolic Pressure (SP), lowest is Diastolic Pressure (DP)
between contractions.
SP-DP = Pulse Pressure (PP)
Depends on speed of ejection, stroke volume and compliance
of arteries – (low compliance = high PP)
e.g. hardening of arteries decreases ampherence(?) and PP
Biology 2A03
Lecture 10
Circulation IV
Arteries as a pressure reservoir

•Stores pressure which is then

released between ventricle
contractions (diastole), great
increase in P with a small
increase in V

•Only 1/3 of the stroke volume

leaves the arteries at this time

•Arterial walls recoil during

diastole (heart relaxed) and this
maintains bloodflow constant

Fig 15-7
 systolic

PP
diastolic

•Shows pressure fluctuation during systole and diastole

•Pressure peaks during ventricular ejection (systole) = systolic pressure (SP),
lowest is diastole pressure (DP) between contractions
•SP-DP = pulse pressure (PP)
•PP depends on stroke volume, speed of ejection and compliance of arteries –
(low compliance high PP) e.g. hardening of arteries, decreases compliance and
increases PP
•Huge drop in pressure, because this is the major site of restriction in the
circulatory system
Arterioles
2 roles:
1. Determines relative bloodflow to tissues
• E.g rest to exercise muscle bloodflow 1L/min to 20L/min
2. Helps regulate Mean Arterial Pressure (MAP)

• Major site of resistance in cardiovascular system, Largest ∆P

• Adjust resistance of vessels going to tissues by adjusting radii both passively

(stretch) and actively (nerves, hormones, etc)

• Are well innervated (nerve terminal exists here) and contain smooth muscle
that contracts (vasoconstriction) or relaxes (vasodilation)

• Always some intrinsic tone (basal tone) plus tonic constriction due to basal
firing of Sympathetic Nervous System, e.g when standing
Control of vascular smooth muscle

Local (intrinsic) Extrinsic

•Paracrine 2. SNS through NT norephinephrine (NorEpi)
•E.g active 3. PSNS (ParaSNS) not very important in
hyperemic controlling arterial radius
4. hormones
 See Fig 15-13
Active hyperemia
•Local chemical change causes bloodflow to increase in proportion to metabolic
activity of that organ
•Way organs are able to match their metabolic activity with the delivery of
nutrients and exiting of wastes
•↓ oxygen, ↑ carbon dioxide, ↓pH, ↑ adenosine, etc.
•Products of metabolism act on blood vessels and cause vasodilation and
increases bloodflow  act on –ve feedback
•Occurs in heart and skeletal muscle since it has large variation in metabolic rate
•Other intrinsic factors : Endothelim-1 (vasoconstriction), NO (nitric oxide,
vasodilation)

•Affects contraction of
smooth muscle in vessel wall

Fig 15-12
 Reactive hyperemic
•Triggers are same but trigger reasons are different
•Decrease in bloodflow causes metabolites to changes and trigger
an increase in bloodflow

Myogenic response
•Change in vascular resistance in response to stretch of blood
vessels in absence of any external factors
•Regulate bloodflow to be constant in tissues in phase of
stretching the vessel

Increase in blood
entering the tissue

Fig 15-14
 Table 15-2
Extrinsic controls

SNS
•Arterioles highly innervated and have α-adrenergic receptors (post-
synaptic) which trigger vasoconstriction through NorEpis
•Changes above or below tonic constriction (nerves always active)
•Important role in controlling whole body arterial blood pressure

PSNS: Not a big role in vascular smooth muscle regulation

Hormones: Epinephrine from adrenal medulla causes vasoconstriction

via α-adrenergic receptors, vasodilation via B2- adrenergic
•Skeletal muscle have alpha and B2- adrenergic receptors

•In most vascular beds, alpha outnumber B2 (except in skeletal

muscle)
•Epinephrine has greater affinity for B2 receptors
 •Distribution of bloodflow at rest
•During exercise, huge increase in bloodflow to skeletal muscles
•High [Epi] – binds alpha and B2 receptors
•Vasodilation in skeletal and cardiac muscle vascular beds
•Decrease TPR
•Vasoconstriction in most vascular beds
•A way of maintaining TPR  maintain blood pressure
Fig 15-15
•Dominant effect usually vasoconstriction
 See Table 15-1
Other vasoconstrictor hormones

•Angiotensis II – renin – ANG system

•Vasopressin – posterior pituitary
•Endothelin-1 (mostly acts as peptide paracrine against release by
endothelial cells)

Vasodilator hormones

•Atrial natriuretic hormone – secreted by the heart

 Metarterioles & Precapillary sphincters
•Passive and active changes in radius and R
•Both contain rings of smooth muscle, no innervation, only affected
by local factors (intrinsic control)

•Metarterioles act as bypass

channels or shunts from
arteries to venuoles
•When resistance is low,
blood may bypass capillary
bed

Fig 15-8
Capillaries
•Thin walled tube of endothelial cells
•Permeate most tissues and cells (any cell in body) generally within
1mm from a capillary
•Small in radius but networks have large surface area ~ 10-40 billion
capillaries for a combined surface area of 6000m2
Important for:
1. Exchange of materials between
blood and cells.
2. Normal distribution of ECF
(composed of plasma & ISF)

• Increased SA leads to lower

blood velocity, important to
maximize time for exchanging
nutrients and wastes
 O2, CO2 1) Continuous capillaries
• Most common type
plasma
• Small spaces (water-filled cleft) btwn
proteins endothelial cells
• Very permeable to lipid soluble molecules
• Less for water soluble solutes and proteins
Endothelial cell cleft (passage restricted to water-filled cleft)
• Proteins too large to pass through clefts
2) Fenestrated capillary
Na+, K+ • Also called sinusoidal capillaries
O2, CO2 • Fenestrations can be large enough to allow
large proteins or entire cell pass (ex. WBC)
proteins
• High permeable capillaries
• Abundance in:
Intercellular
gap • Liver- plasma proteins synthesized (e.g
albumin)
Fenestrations
(pores) • Bone marrow- blood cell production
See Figure 15.16a+b
Figure 15.17
 Bulk Flow
• Very important homeostatic mechanism
• Capillary membranes freely permeable to water and small solutes
• Net flow of fluid from plasma to ISF= filtration
ISF to plasma= absorption
• Role is to maintain fluid balance btwn plasma and ISF = ECF
4 main forces determining direction of flow:
Two hydrostatic pressures due to fluids: Favours:
1) Capillary hydrostatic pressure (PCAP) filtration
2) ISF hydrostatic pressure (PISF) absorption
Two osmotic pressures (due to presence of non-permeating proteins
– called oncotic pressure)
3) Capillary oncotic pressure (ΠCAP) absorption
4) ISF oncotic pressure (ΠCAP) filtration
 Bulk flow: net fluid flow across capillaries depends on the
difference in filtration and absorption pressures
Net filtration pressure (NFP) = (PCAP + π ISF) - (π CAP + PISF )

arterial
PCAP= 38 mmHg PCAP= 16 mmHg
venous
π CAP= 25 mmHg π CAP= 25 mmHg

filtration NFP = (16 + 0) – (25 + 1)

NFP = (38 + 0) – (25 + 1)
= - 10 mmHg
PISF= 1
= + 12 mmHg absorptionPISF= 1
π ISF =0 π =0
ISF
Because no
proteins at ISF Blood Pressure
pressure

NFP +
Osmotic Pressure
NFP -

Arterial Venous
See Fig 15-18
end end
Table 15-3
Biology 2A03
Lecture 11
Circulation V
 O2, CO2 1) Continuous capillaries
-More common type
plasma
-Small spaces (H20-filled cleft) between
proteins endothelial cells
-Very permeable to lipid soluble molecules
-Less for water soluble solutes & proteins
cleft
Endothelial cell (passage restricted to H20-filled cleft)
-Proteins too large to pass through clefts
Na+, K+ 2) Fenestrated & sinusoidal capillaries
O2, CO2 -Fenestrations can be large enough to
allow large proteins or entire cells pass
proteins (e.g. WBC)
-Highly permeable capillaries
Intracellular -Liver – plasma proteins synthesized
gap
(e.g. albumin)
Fenestrations -Bone marrow – blood cell production
(pores)
See Figure 15.16a+b
Figure 15.17
Bulk Flow
Capillary membranes freely permeable to H2O and small solutes

Net flow of fluid from plasma to interstitial fluid (IF) = filtration

interstitial fluid to plasma = absorption
The role of bulk flow is to maintain fluid balance between plasma
and IF = ECF
4 main forces determining direction of flow (Starling-Landis forces)

Two hydrostatic pressures due to fluids: favours

1) Capillary hydrostatic pressure (PCAP) filtration
2) IF hydrostatic pressure (PIF) absorption
Two osmotic pressures (due to presence of non-permeating proteins
– called oncotic pressure)
3) Capillary oncotic pressure (π CAP) absorption
4) IF oncotic pressure (π IF) filtration
 Bulk flow Net fluid flow across capillaries depends on the difference
in filtration pressure and absorption pressures
Net filtration pressure (NFP) = (PCAP + π IF ) – (π CAP + PIF)

PCAP=38mmHg PCAP=16mmHg venous

arterial π CAP=25 π CAP=25

NFP=(38 + 0) – (25+1) NFP=(16 + 0) – (25+1)

PIF=1 PIF=1
+12 mmHg π IF=0 filtration -10 mmHg
absorption π IF=0

Blood pressure
pressure

NFP +
Osmotic pressure

NFP -

Arterial Venous
See Fig 15-18
end end
Table 15-3
 Filtration ~ 20L / day
Absorption ~ 17L / day
Filtration usually exceeds
absorption with 3-4L entering IF
(= total plasma volume !)
This fluid is returned to the
circulatory system by the
lymphatic system
Lymph flow = ~4L/day

If not returned to circulation get

edema
Extreme case failure of lymphatic
system to clear fluid = elephantiasis
Due to low pressures there is
normally no filtration in lung
Fig 15-19 capillaries
Venuoles and veins
Return blood back to the heart (via vena cava) and act as a
volume reservoir (50-80% of blood volume – vasoconstr. or dil.)

Thin-walled and highly compliant vessels to accommodate large volumes

for small changes in pressure (“capacitance vessels”)

Necessary force provided by ΔP between peripheral veins (10-15mmHg)

and right atrium (~0mmHg). Adequate because of low R of veins

Veins also have one-way valves that ensure movement towards the heart

Venous pressure depends on volume of blood; nerve, hormonal and

paracrine regulation of smooth muscle; respiratory & skeletal muscle
pump

Venous return has a major effect of volume ejected by the heart

= stroke volume
One-way Skeletal muscle pump – muscle contraction increases
valves Venous pressure
Lower value closes and upper valve opens – reverse
when muscle relaxes
Fig 15-22
Mean arterial pressure (MAP) = CO x TPR ΔP = Q x R
The Heart hr x SV
**Know functional anatomy and bloodflow patterns (see p421-422)
Composed of 3 layers Outer epicardium (connective tissue)
Myocardium (muscle)
Endothelium (extends throughout the CVS)
Cardiac muscle
Composed of 3 cell types
• Contractile cells: majority of cells (99%)- have properties of skeletal
(striated – actin and myosin) and smooth muscle (gap junctions)
All cardiac cells interconnected (as a syncytium) through Gap junctions –
protein channels linking cytosols – small in diameter
Concentrated at intercalated disks which contain connections that hold
the cells tightly together and resists mechanical stress (desmosomes)

Fig 14-8
 Two cell types display autorhythmicity: Spontaneously generate
action potentials (AP’s)

AP - Membrane potential changes so

inside of cell become (+) relative
to outside

2) Pacemaker Cells
Determine the rate the heart beats
Located in 2 regions:
i) Sinoatrial node (SA) ii) Atrioventricular node (AV)
SA has a higher intrinsic rate (70 impulses/min) than the AV node
(50 impulses/min).
Can take over if SA fails or transmission to
AV is blocked
Fig 14-11
3) Conduction fibers (Bundle of His & Perkinje fibers)
Rapidly conduct (4m/s) AP generated by the pacemaker cells
Cell-cell rate through gap junctions is 0.4m/s
The heart consists of 2 syncytiums (atriums and ventricles)
connected by conduction fibers
Fig 14-9
Autorhythmic Cells

Location Firing Rate at Rest

SA Node 70-80 APs/min
(pacemaker)
AV Node 40-60 APs/min
Bundle of His 20-40 APs/min
Purkinje Fibers 20-40 APs/min

Fastest depolarizing cells drive all other cells

(they are linked together by gap junctions) =
pacemaker = sets pace for entire heart
Regulation of heart rate (hr) (both rate & force are regulated)
Heart affected by changes in rates of AP generated by pacemaker

Pacemakers get direct input

by autonomic nervous system
SNS and PSNS have
opposite effects

NOTE: SNS has more

connections to myocardium
(more effects on force
than PSNS)

SNS NE Acts on SA and AV nodes via β1

Cardiac nerve
adrenergic receptors to increase hr
PSNS ACh Acts on SA and AV nodes via M2
Vegus nerve muscarinic receptors to decrease hr
Predominant factor in setting resting
(acetylcholine) heart rate of 70 bpm (rate without any
inputs = 100bpm)
Regulation of heart rate (hr)

Hormones (e.g. epinephrine) can affect heart rate

Increases hr via same mechanisms as SNS

Temperature: directly alters the intrinsic rate of the SA node

Changes hr by 15bpm / ˚C
e.g. 1 deg fever hr is ~85 bpm
 Sequence of electrical events that triggers a heartbeat
1 AP initialed in SA node Fig 14-10

Spreads through Internodal & interatrial

atrial muscle pathway
AV node
2 Transmission slows down at
the AV node by ~0.15sec
Separates atrial & ventricle
stimulation
3 AP transmitted through the
AV node to the Bundle of His
Divides into the left and right
bundle branches

4 AP enters a network of branches

along the ventricle muscle:
Purkinje Fibers
Impulse travels through ventricle
from apex towards valves
Ventricles have coordinated contractions
Biology 2A03

Lecture 12
Circulation V
Mean arterial pressure (MAP) = CO x TPR ΔP = Q x R
The Heart hr x SV
**Know functional anatomy and bloodflow patterns (see p421-422)
Composed of 3 layers • Outer epicardium (connective tissue)
• Myocardium (muscle)
• Endothelium (extends throughout the CVS)

Divided into 4 chambers separated by valves (ensure unidirectional

flow)

•Walls thickness depends on work performance

•Atria only pump to the ventricles
•Right ventricle only pumps to pulmonary circuit
•Left ventricle thickest wall because it performs most work pumping
to rest of the body
 •All arteries don’t carry oxygenated blood Fig 14-1
•Valves ensure that bloodflow is in only one direction
Functional anatomy and bloodflow patterns (see p421-422)
• Heart has four valves that keep blood flowing in
the proper direction
• Atrioventricular valves (AV valves)
– Separate atrium and the ventricle
– Permits blood to flow from the atrium to the ventricle
– When atrial pressure is higher than ventricular
pressure, the valves open
– When ventricular pressure becomes higher than atrial
pressure, the valves close
• Bicuspid valves (BV) or mitral valve
– AV valve on the left has two flaps or cusps of
connective tissue and thus called BV
• Tricuspid valve (TV)
– AV valve on the right has three cusps and called TV

Fig 14-6
• Semilunar valves
– Located between the ventricles and arteries
– Aortic semilunar valve is located between
the left ventricle and the aorta
– Pulmonary semilunar valve is located
between the right ventricle and the pulmonary
trunk
– Function similar to AV- make blood flow in
one direction and prevent it from flowing in
opposite direction

Fig 14-7
Cardiac muscle
Composed of 3 cell types:-
• Contractile cells: majority of cells (99%) have properties of skeletal
(straited-actin and myosin) and smooth muscle (gap junctions)
• All cardiac cell are interconnected (as a syncytium) through Gap Junctions-
protein channels linking cytosols-small in diameter (electric current)
• Concentrated at intercalated disk which contain connections that hold the
cells tightly together and resist mechanical stress (desmosomes)
• Sarcomeres are units of myosin and actin

Fig 14-8
Two cell types display autorhythmicity: Spontaneously generate
action potentials (AP’s)

AP - Membrane potential changes so

inside of cell become (+) relative
to outside

2) Pacemaker Cells
• Determine the rate of heart beats
• Located in 2 regions:-

• Sinoatrial node (SA) ii) Atrioventricular node (AV)

• SA has a higher intrinsic rate (70 impulses/min) than the AV
node (50 impulses/min)
• AV can take over if SA fails or transmission to AV is blocked

Fig 14-11
 3) Conduction fibers (Bundle of His & Purkinje fibers)
•Rapidly conduct (4m/s) AP generated by the pacemaker cells
•Cell-cell rate through gap junctions in only 0.4m/s
•The heart consists of 2 syncytiums (atrium and ventricles)
connected by conduction fibers

Fig 14-9
Autorhythmic Cells

Location Firing Rate at Rest

SA Node (pacemaker) 70-80 APs/min
AV Node 40-60 APs/min
Bundle of His 20-40 APs/min
Purkinje Fibers 20-40 APs/min

•Fastest depolarizing cells drive all other cells

•Pacemaker = sets pace for entire heart

•Heart contraction called myogenic (trigger within)

•Contrast to neurogenic for skeletal muscle (trigger from nerve)
 Sequence of electrical events that triggers a heartbeat
1 Fig 14-10
AP initiated in SA node

Spreads through Internodal and interatrial

atrial muscle pathway
AV node
2
Transmission slows down at the
AV node by ~0-15s
Separator atrial & ventricle
stimulation
3
AP transmitted through the AV
node to the Bundle of His

Divides into L and R bundle branches

4
•AP enters a network of branches along the ventricle
muscle: Parkinje Fibers
•Impulse travels through ventricle from apex
towards valves
•Ventricles have coordinated contractions
 Regulation of heart rate (hr) – both rate and flow are regulated
•Heart rate affected by changes in rates of AP generated by pacemakers

•Pacemakers get direct input

by autonomic nervous system
•SNS & PSNS have opposite
effects
•Note: SNS has more
connector & myocardium
(more force effects then
PSNS)
•Acts on SA and AV nodes via
B-adrenergic receptor to
increase hr
SNS NE •SA and AV nodes via M2
Cardiac nerve muscarinic receptor to
decrease hr
PSNS ACh
•Predominant factor in
Vegus nerve
setting resting heart at
(acetylcholine) 70bpm (rate without inputs =
100 bpm)
Regulation of heart rate (hr):

Hormones (e.g. epinephrine) can affect heart rate

•Increase hr via same mechanism as SNS

Temperature:
•directly alters the intrinsic rate of the SA node, changes hr by
156 bpm/oC
•e.g. 1 degree fever hr is ~85bpm
 Regulation of stroke volume
•Volume ejected by ventricles with each heartbeat = stroke volume (SV)
•SV= end diastolic volume (EDV) – end systolic volume (ESV)

EDV (ventricle filled) = 130mL

ESV (ventricle emptied) = 60mL

SV (volume ejected) = 70mL

If EDV ↑ then SV ↑
EDV
If ESV ↑ then SV ↓

SV
Ejection fraction = SV
EDV ESV
~67% at rest, increases during exercise
p438
~33% of blood still left in heart
 Biology 2A03
Lecture 13
Circulation and Kidney I
 Summary of cardiovascular
changes during mild exercise
due to increased CO & large
decrease in skeletal muscle Resist.
- active hyperemic Beta2-
vasodilation
due to large increase in Heart Rate

& small increase in Stroke Vol.

due to increased SNS, Epi,
Temp, and decreased PSNS
skeletal muscle dilation greater
than constriction in other areas

Starling Law effects & *increased

contractility (SNS, epi)
minor increase in MAP = CO*TPR
increased pressure pulsatility
mainly due to increased SV
 Despite all these complex changes, the MAP did not
change very much -this reflects the homeostatic role
of the baroreceptor reflexes.

The role of the baroreceptors (sensory receptor

neuron) is to keep systematic MAP as close to
100mm of Hg as possible.

The arterial baroreceptors continually monitor the

systemic MAP and inform the cardiovascular control
centre in medulla of brain.

Baroreceptor reflexes are the most important short

term regulators of MAP (seconds to minutes)
 – Baroreceptors = stretch
receptors
– Arterial baroreceptors
• High pressure
baroreceptors
• Sinoaortic
baroreceptors
– Location
• Carotid sinus
Via closso-pharyngeal nerves (IX)
(aka afferent branches)
• Aortic arch
Via vagus nerves (X) (aka afferent
branch)

X/IX refers to nerve designations,

don’t need to know them.

Effect => stimulation of the autonomic nervous system.

Fig. 15-26
See Fig 15-27
 A decrease in blood pressure (far right) gives less of a stretch, giving a decrease in
The rate of firing, opp holds true for middle (more stretch => increased RoF.

The level of MAP is continually “coded” as A.P. frequency sent

by the arterial baroreceptors.
This is “reset” at a higher level in hypertension. Figure 15.25
Baroreceptor (~30s reponse)

– Following
hemorrhage:
• Baroreceptor reflex
• Increase in
sympathetic
activity
• Decrease in
parasympathetic
activity
– Result
• Reflex
compensation

Note: remember this & previous slide

for tilt table experiment in next lab
Efferent pathways of the
Baroreceptor Reflex

Sympathetic nerve goes to

pacemaker cells to increase
heart rate, and to heart
muscles to increase the
rate of contraction.

Figure 15.27
 Figure 12.59
Baroreceptor
reflexes

Baroreceptor reflexes
also facilitate a short term
partial restoration of
blood plasma volume by
reabsorbtion of fluid from
interstitial space and
lymph

Long-term reg. of MAP

happens at the kidney.
 Kidney Function = Renal System
Chapter 19
Regulates:
• Blood plasma volume
• All ions (e.g Na+, Cl-, HCO3-, K+, Ca2+, Mg2+,SO4=)
• Acid-base status (pH of the body fluids)
• Excretion of all metabolic wastes – urea, uric
acid, ammonia, etc.
• Excretion of all foreign substances
• Retention of all valuable substances
• Red blood cell levels - via EPO
• Production of the renal hormones
• Gluconeogenesis from amino acids during fasting
 THE URINARY SYSTEM

kidney

Ureter
undergoes wavelike
contractions of smooth
muscle.

Bladder
smooth muscle with gap
junctions.

urethra
NOTE – all smooth muscles have gap junctions Fig 19-1
 THE URINARY BLADDER

ureters

Detrusor (smooth) muscle

PSNS control

Internal urethral sphincter

SNS control (we control it consciously)

External urethral sphincter

Skeletal Muscle under Somatic N.S control.
involves co-operation of P.S.N.S , S.N.S. & Somatic N.S
Filling: Peeing:
•P.S.N.S = inactive •P.S.N.S = active
•S.N.S. = active •S.N.S. = inactive
Fig 19-21 •Somatic N.S. = active •Somatic N.S.= inactive
MICTURITION
REFLEX

Fig 19-22
urination
Biology 2A03

Lecture 14
Kidney II
 ANATOMY OF A KIDNEY
Cortex

Medulla
pyramid
t

renal
t
pelvis
t medulla cortex

t
ureter Nephron
Capsule (outer Uses circulation
tissue) To filter waste

Lots of nephrons allows for easier/greater volume of

Read pages 579-584 Fig 19-2
filtration.
 Nephron = basic unit of structure & function in the
kidney
Nephron = an individual kidney tubule
and its associated blood supply
• Each renal pyramid contains 100,000-200,000 nephrons
• 8-15 pyramids per kidney, each with separate branches of
renal artery and renal vein
• 1.0 -1.5 million nephrons per kidney x 2 => 2-3 million
nephrons total in your waste filtration system…lots of
filtration, similar to arteries…small, but large surface area
when combined with others
• by the time the urine leaves nephron, it is fully formed
(processed so that it only contains wastes, nutrients have
been removed and sent for processing)
• we can understand urine formation by understanding the
fuction of a single nephron.
 Glomerulus inside of
Bowman’s Capsule
Efferent Arteriole
Afferent Arteriole Proximal convoluted tubule

Distal convoluted
tubule Proximal tubule

Common
collecting Loop of Henle…loops into the
duct medulla…important point, will be
covered later.

Fig 19-3
 Glomerular
GFR = Glomerular filtration Efferent
Filtration Rate arteriole

Peritubular Capillary Afferent

Bed (reabsorbtion of arteriole
Stuff back into the blood)

SNS input to both

Vasa Recta

To Renal Vein
This system uses
Capillaries to help filter
stuff in and out

Fig 19-6
Nephron Components - Blood side

- essentially two capillary beds in series,

joined by an arteriole = “portal system”
• Afferent Arteriole = 1st important site of vasular
resistance control

• Glomerulus = 1st capillary bed, site of formation of primary urine

by filtration (bulk flow of protein free plasma)
• Efferent Arteriole = 2nd important site of vascular resistance control

• Peritubular Capillary Bed & Vasa Recta = 2nd capillary bed, site of
reabsorbtion (selective transport from tubule to IF, recovery) &
secretion (selective transport back to tubule, waste disposal)

• Filtration, reabsorbtion, and secretion are the 3 basic processes by

which the urine is formed
 Nephron Components - Urine or Tubule side
- tubule is essentially a single winding tube along
which the urine flows & gets progressively
modified
• Bowman’s Capsule = receives the primary urine by filtration
from the glomerulus
• Proximal Convoluted Tubule = largest part, quantitatively
the most important for reabsorption and secretion.
- 65% of Na+, Cl-, H20 reabsorption occur here (fixed value)
- 95-99% of everything else is reabsorbed here (fixed value)
- > 90% of secretion occurs here for most substances
• Loop of Henle = critical part of the counter-current system
for concentrating urine & conserving
H20.
- 20 % of Na+, Cl-, and H20 reabsorption occur here (fixed
value)
- *Fixed value = can’t be modified by actions of hormones.
 Nephron Components - Urine or Tubule side

• Distal Convoluted Tubule (DCT) - 2nd largest part of nephron

• Common Collecting Duct (CCD) - drains many nephrons into
the renal pelvis & is the other critical part of the
countercurrent system
- together, the DCT & CCD account for ~15% of Na+, Cl-, and
H20 reabsorption (variable value => responsive to hormones)
- variability occurs because these are sites of hormone action,
controlling reabsorption (& also secretion)
- key hormones are aldosterone & ADH (antidiuretic hormone =
vasopressin), also atrial natriuretic hormone & angiotensin
II
- the DCT & CCD are the major sites of K+ secretion ( if
potassium levels are high, heart may experience trouble
functioning properly)
 A Simplified Model of Nephron Function
The 3 Basic Exchange Processes
Efferent Peritubular
Arteriole Capillaries

2 3
1 Excretion
• Glomerular Filtration
passive due to Starling-Landis forces.
2. Tubular Reabsorption
Afferent (a) Many active transport processes for
Arteriole ions and nutrients.
(b) Passive diffusion (ions/nutrients)
Plasma may contain things and osmosis (H20)
that cannot go through the (c) Starling-Landis Forces.
Bowman’s capsule therefore
3. Tubular Secretion
Fig 19-7 tubular secretion =>
Mainly by active transport
 1. Glomerular Filtration
• A volume equivalent to 20% of the plasma flowing
through the glomerular capillaries is filtered, forming
the primary urine collected into Bowman’s capsule.
• This “filtrate” contains a representative sample of
everything in the plasma except proteins (& protein-
bound substances)
- M.W cutoff ~ 68,000; smallest plasma protein = albumen
~ 69,000 (albumen is too large to be filtered/secreted)
• Glomerular Filtration Rate = GFR = 180 Litres/day

• Entire plasma volume of the body is converted to

primary urine every 25 minutes!
• > 99% of the filtrate is subsequently reabsorbed in the
tubule
1. Glomerular Filtration

• “A shotgun strategy” for excretion (process

everything initially, then recover useful contents)
• a fraction (20%) of everything in plasma is filtered
- valuable substances are selectively reabsorbed
- wastes, foreign substances are not reabsorbed
• Therefore the kidney can excrete virtually any waste
or foreign substance
 Filtration fraction
~500 mL/min

Efferent
arteriole 125 mL/min

Plasma flow = 625 mL

GFR = 125 mL
Afferent
arteriole Filtration fraction = 125/625
= 20%

625 mL/min 180 L filtered /day but only 1.5 L of

urine excreted /
Fig19-9
 Bowman’s capsule

podocyte
Foot processes

Fenestrations/slit pores
Allow for movement of
Proteins under a certain
Specified M.W. (68K Da)
fenestration
Endothelial cell
Glomerulus membrane Basement membrane
(filtration barrier)
Epithelial cell (podocyte)
Fig 19-8 Slit pore
Filtration Barrier
Bowman’s Capsule

Filtration Barrier at
M.W ~ 68,000
• podocyte slit pores
• basement membrane
matrix - negative
charge repels proteins
• endothelial fenestrae

Glomerular capillary
Lecture 15

Kidney III
 Renal corpuscle
podocyte
Foot processes
Filtration slit

fenestration
Endothelial cell
Basement membrane
Glomerulus membrane
(filtration barrier) Epithelial cell (podocyte)

Fig 19-8
Slit pore
(between podocytes)
Filtration Barrier
Bowman’s Capsule

Filtration Barrier at
M.W ~ 68,000
• podocyte slit pores
• basement membrane
matrix - negative
charge repels proteins
• endothelial fenestrae

Glomerular capillary
 1. Glomerular Filtration
Starling -Landis Forces
involved in glomerular filtration

PBC
PGC

PiGC
PiBC

NFP = (PGc + piBC) – (PBC + piGC)

= (60 mm Hg + 0 mm Hg) – (15 mm Hg + 29 mm Hg)
= + 16 mm Hg (net positive pressure outwards)

Recall PCAP = 38 mm Hg for a systemic capillary

Fig 19-9
Efferent
arteriole Constrict aff. arteriole? =
increase aff. resistance =
decrease NFP
PGC
= decrease GFP

Constrict eff. arteriole? =

increase eff. resistance =
increase NFP
= increase GFP
Afferent
arteriole
Balance of aff. and eff. resistance is very important in
controlling a proper equilibrium of flow and filtration,
and balancing the GFR.

Level of MAP is also very important in controlling GFR

3. Tubular Secretion
• A relatively few substances (~20) which are often present
in great excess are actively transported into the urine from
the blood
• e.g. H+, K+, urea, ammonia, uric acid, antibiotics, PAH
• occurs mainly in proximal convoluted tubule, except for K+
2. Tubular Reabsorption
• All “valuable” substances (a very large number) are
reabsorbed from the urine into the blood by a combination
of active and passive mechanisms.
• e.g. ions, H20, amino acids, fatty acids, vitamins, hormones.
• occurs mainly in proximal tubule, but variable reabsorption
of H20, Na+, Cl-, and urea in DCT & CCD determines final
urine volume and composition
• because of this active transport work, kidneys can account
for 20% of BMR of the whole body.
 Ca2+
Na+ Na+
Cl- Cl-
H2O K+
Ca2+
HCO3-
Na+ H+ H 2O
K+ H+
K+ Glucose
Cl- Amino acids
K+ Vitamins
Ca2+ Urea
Na+
H+ choline
Cl- H2O
HCO3-
K+
H 2O Mg2+ DCT
Urea Ca2+ medullary
K+ osmotic
H+ gradient
NH4

CCD
 Some Patterns of Renal Handling

Filtered & additionally Filtered & largely but Filtered & completely
secreted so totally not completely and reabsorbed, ie most
cleared from blood - reabsorbed nutrients, such as
e.g. PAH = Para- - e.g. H2O, ions, etc glucose, amino acids
amino hippuric acid
 Reabsorption Barrier

Active transport of Na+

and glucose co-transport
 Reabsorption Barrier
Plasma membrane only a barrier for macromolecules

Tubule epithelia the 1º barrier for reabsorption

proximal tubules have more microvilli
than either the DCT or CCD.
Tight junctions between epithelial cells restrict
paracellular transport (i.e. forces diffusion THROUGH the
cells. Proximal tubules have leaky tight junctions, tighter
junctions found in DCT and CCD, ie Proximal tubules have more
SA and looser tight junctions => ^^ transport (selective).

Proximal tubules also have higher mitochondrial content

due to many active transport processes

The same barriers must be crossed for secretion

See Fig 19-17
Excretion Rates

Excretion = Filtered (F) + Secreted (s) – Reabsorbed (R)

= GFR*[x] + S – R [plasma content of object X being examined]
Filtered load
 Analysis of Renal Function
• Excretion Rate = Ex = [X]u * UFR
• Clearance Rate = Cx= the rate (ml/min) at which
plasma is “totally cleared” of a substance by the
kidney (eg all K+ is removed)
Excretion Rate

Cx = ([X]u * UFR / [X]p) Conc in plasma

• If X is a substance which is totally cleared from

the plasma (e.g. PAH) – then clearance rate
is total, Renal Plasma Flow Rate
• e.g.
CPAH=(450 microg/mL + 2 mL/min)/1microg/mL
= 900 mL/min (amount of plasma which would
 Analysis of Renal Function
• If X is a substance which is freely filtered at the
glomerulus (like virtually everything else in plasma),
but neither secreted nor reabsorbed, then its
clearance rate is the glomerular filtration rate (GFR) -
e.g. inulin
Cinulin = GFR=

• GFR is 20% of renal plasma flow (20% of 900ml/min is

180ml/min)
• Filtration rate of x =
Biol 2A03
Lecture 16
Renal IV
 Analysis of Renal Function
• Excretion Rate: Ex = [x]u x uFR
• Clearance Rate: Cx= the rate (mL/min) at which plasma is “totally
cleared” of a substance by the kidney

Cx = [x]u x uFR Excretion Rate

[x]p Conc. in plasma

• If x is a substance which is totally cleared from the plasma (e.g.

PAH) then the clearance rate is total renal plasma flow rate

CPAH= 450 ug/mL x 2mL/min = 900 mL/min

1 ug/mL

Amount of plasma that

microgram
would contain 450ug of
p = plasma PAH
u = urine
uFR = urine flow rate
 Analysis of Renal Function
• If X is a substance which is freely filtered at the
glomerulus (like virtually everything else in plasma), but
neither secreted nor absorbed, then its clearance rate is
the glomerular filtration rate (GFR) e.g. insulin

• Cinulin = GFR= 90 ug/mL x 2 mL/min = 180 mL/min

1 ug/mL

• GFR is 20% of renal plasma flow (20% of 900 mL/min is

180 mL/min)

• Filtration rate of x = [x]p x GFR

 Analysis of Renal Function
• CRx= clearance rate of x

• CRx= = clearance rate of x = Cx .

GFR Cinulin

• CRx= excretion rate of x = [x]u x uFR

filtration rate of x [x]P x GFR
 CRx tells you quantitatively how a
substance is handled by the kidney
• CRx = 1.0 - substance is neither secreted nor reabsorbed on a
net basis

• CRx > 1.0 – substance is net secreted e.g. PAH

• CRx < 1.0 – substance is net reabsorbed e.g most ions and
nutrients
Typical values:
• water - CRH2O = 0.01 99% reabsorbed
• sodium CRNa+ = 0.005 99.5 % reabsorbed, only 0.5%
excreted
• Urea CRurea = 0.56 44% reabsorbed
• potassium CRK+ = 0.01 – 2.0 – varies from strong reabsorption
in K+ - depleted individuals to strong secretion in K+ -
 Regulation of NaCl and H2O by the Kidney
- Cl- follows Na+ passively therefore we will focus on
Na+ reabsorption.

- 65-70% of Na+ and H2O reabsorbed by Proximal

tubule (PT), No hormonal regulation.

- ~15% of Na+ and H2O reabsorbed by Distal

Convoluted Tubule (DT) and Common Collecting Duct
(CCD), Varied by hormonal regulation.

- DT and CCD have 2 cell types: 1) Principle cells are

the site of Hormonal regulation of Na+ and H2O
reabsorption. 2) Intercalated cells are involved in
acid-base balance.
 The Medullary Osmotic Gradient

aquaporins

• Proximal tubule and cortex (leaky tight junctions)

• make descending limb permeable to H2O
• Ascending limb but actively transport ions
 Regulation of NaCl and H2O by the Kidney
H2O Reabsorption
Collecting Duct
•Water is reabsorbed passively (osmosis),
generates a [ ] gradient
100 mOsM
•Depends on O.P (1. Loop of Henle, 2. NaCl
300 mOsM Cortex reabsorption)
•Counter-current multiplier system (loop of
O.P Medulla henle) serves to create high osmotic
pressure in ISF and blood vessels through
which the CCD runs
•Tubular fluid is hypo-osmotic
1400 mOsM
•Water reabsorption is regulated by the
onto bubble permeability of DDT and CCD
Regulation of NaCl and H2O by the Kidney

H2O Reabsorption – DT/CCD Impermeable

100mOsm
•No water reabsorption (in this
300mOsm 100mOsm scenario)

600mOsm •Urine has low osmolarity and high

100mOsm
volume
1000mOsm 100mOsm

1400mOsm 100mOsm
Regulation of NaCl and H2O by the Kidney

H2O Reabsorption – DT/CCD Permeable

100mOsm
•water reabsorbed (in this
water
scenario)
300mOsm 300mOsm
water •Urine has high osmolarity and low
600mOsm 600mOsm volume
water
1000mOsm 1000mOsm
water
1400mOsm 1400mOsm
 Regulation of NaCl and H2O by the Kidney
H2O Reabsorption – Regulation by ADH
•Ant diuretic hormone (ADH), a small peptide also known as vasopressin,
released from the posterior pituitary gland by neurosecretory cells that originate
in the hypothalamus
Low O.P High O.P
ADH

Aquaporin 2 ADH receptor

water
cAMP/PKA pathway
water
water
Aquaporin 3

Lumen ISF Plasma

 Regulation of NaCl and H2O by the Kidney
H2O Reabsorption – Summary of ADH Action

1. ADH binds receptor on basolateral membrane of

principal cells.

2. Receptor activates cyclic adenosine 3’, 5’

monophosphate / Protein Kinase A (cAMP / PKA)
pathway.
3. PKA stimulates production of Aquaporin 2 and
insertion of Aquaporin 2 into the apical membrane of
principal cells.
Result: increased permeability of DDT/CCD to water
leads to increased reabsorption of water
Longterm Regulation of
MAP

Ethanol
(inhibits this)

•Dehydration
•Brain shrinkage
HANGOVER
 Regulation of NaCl and H2O by the Kidney
Na+ Reabsorption and its Regulation by Aldosterone
-Na+ reabsorption is coupled to K+ secretion
-Aldosterone is a steroid hormone released from the
adrenal cortex in response to low NaCl in ECF
[Na+] [Na+] [Na+]
receptor
Na+ aldosterone

K+
Na+
Na+ K+

Na+/K+
K+ ATPase

[K+] [K+] (3 Na+ in/ 2

Passive [K+] Active K+ out
Regulation of NaCl and H2O by the Kidney
Na+ Reabsorption – Summary of Aldosterone Action

1. Aldosterone diffuses across basolateral membrane

and binds to a cytoplasmic receptor in principal cells.

2. Receptor activation leads to: a) openning of Na+

and K+ channels in apical membrane. b) synthesis of
more Na+ and K+ channels for insertion into apical
membrane. c) synthesis of more Na+/K+ATPases for
insertion into basolateral membrane.
Result: increased permeability of DDT/CCD to Na+,
increased NaCl reabsorption and K+ secretion
 Regulation of NaCl and H2O by the Kidney
Interactions between ADH and Aldosterone
-Since H2O and Na+ control systems are at least
partially separated, humans can achieve independent
NaCl and H2O balance over a wide range of intakes.
(0.5 to 25L/day H2O and 0.05 to 25g/day NaCl)
Plasma Hormone Levels Urine Flow Rate Urine [N

Low ADH / Low Aldosterone Highest Quite high

High ADH / High Aldosterone Lowest Quite low

Low ADH / High Aldosterone Quite high Lowest

High ADH / Low Aldosterone Quite low Highest

 Biology 2A03
Lecture 17
Kidney cont… & Neuro I
 Regulation of NaCl and H2O by the Kidney
Interactions between ADH and Aldosterone
-Since H2O and Na+ control systems are at least partially
separated, humans can achieve independent NaCl and H2O
balance over a wide range of intakes. (0.5 to 25L/day H2O
and 0.05 to 25g/day NaCl)
Plasma Hormone Levels Urine Flow Rate Urine [N

Low ADH / Low Aldosterone Highest Quite High

High ADH / High Aldosterone Lowest Quite Low

Low ADH / High Aldosterone Quite High Lowest

High ADH / Low Aldosterone Quite Low Highest

Two other hormones also control nephron function:
• Atrial Natriuretic Hormone (“ANH, ANF, ANP”) - released
by walls of atria in response to high venous filling pressure
(usually indicative of high blood volume associated with high
NaCl content in body)
ANH increases NaCl and H2O excretion by raising GFR &
inhibiting active Na+ readsoption.
2. Angiotensin II - part of Renin-Angiotensin System (“RAS”)
Angiotensinogen is a large plasma protein, originally produced
in the liver, and is ALWAYS present in large amounts in th
plasm
Renin is an enzyme released by juxtaglomerular (see Fig 19-
5) of the kidney in response to low NaCl content in body.
Renin cleaves angiotensinogen to angiotensin I.
Angiotensin Converting Enzyme (“ACE”) is located in capillary
endothelia, especially in lungs, & cleaves angiotensin I to
angiotensin II.
Fig 19-5
 Low Body NaCl

Angiotensin II - Multiple Effects: Fig. 20-15

•Stimulates aldosterone from adrenal cortex, thereby
increases Na+ reabsorption.
•Directly stimulates Na+ reabsoption itself
• Constricts most systemic arterioles, thereby raises MAP
•Yet it reduces GFR (afferent R increases)
•Consequences: increases NaCl & H2O retention, increased
blood volume & increased MAP.
See Fig 20-23 for overview
of response to hemorrhage
Changes in GFR can be used to regulate water loss

NOTE: the patterns in change in flow is important

and most likely will be on the tests.
Controlled by hormone action

Control of GFR by constriction and vasodilation

Neurophysiology I
 Function of the Nervous system

- collects sensory information from specialized cells

(sensory receptors).

- processes sensory information (integration).

- transmits appropriate information (response) to

effector organs (muscles, glands).

- 2 cell types: neurons, glial cells

 Organization of the Nervous System
-2 Parts:
1) Central Nervous System (CNS): spinal cord and
brain, area where integration occurs = decision making
2) Peripheral Nervous System (PNS): everything
outside the spinal cord and brain (except enteric
nervous system – gastrointestinal tract)

Function of PNS:
Conducts information from external and internal
sensors to the CNS (afferent division) AND from the
CNS to effector organs that are usually muscles and
glands (efferent division).
 Efferent division of PNS
-2 Parts:
1) somatic nervous system: motor neurons that
regulate skeletal muscle contractions. Only Excitory
information which causes voluntary action.
2) autonomic nervous system: neutons that
regulate internal organs and structures ( smooth
muscle, cardiac muscle, glands, etc)
Both excitatory and inhibitory information. Involuntary
activity.

Divided into sympathetic (SNS) and parasympathetic

(PSNS) nervous systems which usually have opposite
effects on effector organs.
Organization of the Nervous System
Figure 8.1, page 211.
 2 Cell Types: (neurons and glial)
A) Neurons
-Basic functional unit.
- Excitable cells: can produce rapid electrical signals
“Action Potentials” (APs) = waves of electrochemical energy
that pass along the length of the neuron. Use AP’s to
transmit information rapidly over long distances.
-Many different types and anatomies (ie: afferent sensory
neurons, interneurons, efferent motor neurons), in humans
they can be 1millimetre to 1 metre in length.

-Make up 10% of cells of the nervous system.

-Can be structurally and functionally classified.

3 Functional classes of Neurons, Fig 8.4, pg 215

Sensory/receptor

Effector organs
 Structure of a Typical Neuron
Dendrites: numerous small
Signal Direction branches, receive most of
incoming information from other
neurons via synapses. Results in
Graded Potentials (GP’s).
Cell body or soma: contains most
organelles, metabolic functions.
.
Axon hillock: trigger zone, fires
APs as a result of summation of
GPs. Site of most integration
Axon: thick process, rapidly .
conducts outgoing information
coded as AP’s
Terminals: make synapses with
other neurons or effector cells.
 Two neurons communicating:

Synapse: neurotransmitter. Signal

passed from presynaptic neurons
to post synaptic neurons

( Fig 8.2, pg 212)

Biology 2A03
Lecture 18
Neurophysiology II
 3 Functional classes of Neurons, Fig 8.4, pg 215

2.interneurons

Sensory/receptor
1. Afferent neuron (input)

3.Efferent neuron (output)

Effector organs
3 Structural Classes of Neurons, Fig 8.3, pg 214
2. Bipolar: 1 axon, 1 3. Pseudo-unipolar: subclass of
dendrite, generally sensory bipolar, majority of sensory, neurons,
neurons (olfaction = smell). dendritic processes (through the
peripheral axon) transmits action
potentials.

1. Multipolar: most
common neuron, multiple
projections (1 axon, the
rest are dendrites).
 2 Cell Types:
B) Glial Cells
- supportive, nutritive, & protective cells of the nervous
system, but NOT directly involved in signal transduction.

- represent 90% of the nervous system.

- provide nutrients and remove wastes to/from neurons

- provide electrical insulation (“myelin sheath”) which

prevents cross-talk & greatly increased A.P. velocity

- provide protection against toxins etc. - contribute to

“blood-brain barrier”

- provide homeostatic regulation of ECF around axons

& synapses- e.g. remove excess K+ and neurotransmitters
 Myelin Sheath
Oligodendrocytes are the Schwann Cells are the most
most numerous glial cells numerous glial cells in in the
of the C.N.S. P.N.S.
Myelin sheath:
multiple layers of
Nodes
myelin lipid formed
by plasma membranes
Schwann cell of glial cells wrapped
around axons like a
Axon jelly-roll. Functions
as insultation for the
signal being
oligodendrocyte transmitted.
Myelin sheath is regularly interrupted at
the Nodes of Ranvier (a.k.a. just Nodes)
 Myelin Sheath

Oligodendrocytes and Schwann Cells insulate against “cross

talk”, but their most important function is to facilitate a
high conduction velocity for AP’s.

These cells insulate > 99% of the distance along the axon.
Nodes of Ranvier occupy < 1% of the total distance.
Kyelin sheath insultates the diffusion of ions, reducing
interference in the signal being sent.
APs are rather slow events involving diffusion of ions.
However, APs can leap at the speed of electricity (~
instantaneous) from one Nodes ot the next Node by saltatory
propagation.
AP conduction velocity may be accelerated up to 1000x by
saltatory propagation.
 3 Basic Principles of Membrane Potentials

A difference in “electric charge” or voltage across the

membrane of cells.

Note: All cells have a “membrane potential” BUT we’ll

focus on the membrane potential of neurons.

1. At a “macro” level, there are equal numbers of + and –

charges in biological solutions (electrical neutrality), though
this does NOT mean that there is no transfer of ions…it is
simply balanced by an equal transfer of +/-.
2. At a “micro” level, membrane potentials result from
minutes charge imbalances across membranes e.g. in AP < 1
out of every 100,000 Na+ and K+ ions actually moves.
 3 Basic Principles of Membrane Potentials
3. Most membrane potentials are associated with 3
factors:
(i) Unequal distribution of ions across membranes.

(ii) An active transport mechanism which maintains/restores

this unequal distribution - e.g. Na+/K+/ATPase pumps.

(iii) Differential permeability of the membrane to different

ions

Note: for ions, the electrical analogue of permeability is

Conductance (G) which is essentially the inverse of
Resistance (i.e. how much flows, not how the flow is
impeded).
 The Resting Membrane Potential
Electrogenic Na+/K+ -ATPases Electrical Potential
i) move more +’ve charge
outside the cell. ii) move K+ -70mV
and Na+ against the gradient
to maintain an unequal
distribution across the 2 K+
membrane. 3 Na+
GK+ >> GNa+ :this means that K+ K+
more K+ leaves the cell than
NA+ entering the cell. This
K+
differential permeability of Na+ Na+
the membrane to K+/Na+
leads to more +’ve charge
leaving the cell. A- Na+ Cl-
(Organic
anions)
RESULT: negative resting Inside Outside
membrane potential. Neuron Neuron
 Equilibrium Potentials and Nernst Equation
(Chapter 4)

- The Nernst Equation looks at only one ion at a time.

- predicts the membrane potential (EM) if the unequal ion

concentrations are fixed & the membrane is permeable only
to the ion being considered.
- predicts the membrane potential (EM) necessary to
sustain the unequal distribution of that ion at equilibrium
- i.e. the point of balance between the electrical and
concentrational forces on that ion.
 Equilibrium Potentials and Nernst Equation

- Most importantly, the difference between Nernst

Equilibrium Potential (EN) and the actual Membrane
potential (EM) represents the net driving force on the
ion in question. So the further away that EN is from
the EM, the greater the driving force for the diffusion
of that ion.

**Note: The actual membrane potential (EM) is determined

by simultaneous permeability to several ions. So, Nernst
Equation cannot calculate the actual membrane
potential.**
 Equilibrium Potentials and Nernst Equation
The Nernst Equation: (calculation of equilibrium potential)
Made from 4 constants (the -61) EIon = - 61 log[Ion]outside
[Ion]inside
Nernst Equilibrium Potential (EN) for K+:

EK+ = 61 log [K+]o = 61 log[4mM]

[K+]i [140 mM] = -94 mV

Nernst Equilibrium Potential (EN) for Na+:

= 61 log[145mM]
[15 mM] = -60mV
Nernst Equilibrium Potential (EN) for Cl-:
= - 61 log[110mM]
[5mM] = - 80 mV
 Equilibrium Potentials and Nernst Equation
Note: by Nernst equation, -61 mV can sustain a 10-fold
concentration difference because log 0.1 = -1.

Driving Forces for Diffusion of ions:

- K+ and Cl- unequal distribution across membrane are
close to equilibrium.
Compare: EM (-70 mV) with EK+ (-94 mV) and Ecl- (-80
mV).
- Na+ unequal distribution is a long way from
equilibrium. Compare EM (-70 mV) with ENa+ (+60 mV).

- Therefore, greatest driving force for diffusion of

Na+ (important for APs).
Biology 2A03
Lecture 19
Neurophysiology III
 Recall:

Equilibrium potential (EN) via the Nernst Equation

EN = “A hypothetical value for the membrane potential at
which the electrical driving force is equal and opposite to
the chemical driving force producing an electrochemical
driving force of zero.”
If EN = EM for an ion then no electrochemical driving force
acting on it to move in or out of the cell.

If EN ≠ EM there will be a driving force for that ion in or out

of the cell depending on the direction and size of the force.
For example Na requires large positive outward directed
electrical force (that is far from EM) to counteract a large
inward concentration gradient. So Na has a large driving force
for inward movement.
(EN) for Na+: = 61 log [145 mM] = +60 mV
[15 mM] EM = -70 mV
 Changes in Membrane Potential: Terminology

Depolarization
(membrane Na+ Equilibrium Potential
becomes more
positive)

Repolarization
(return towards
resting spot)

Resting Membrane Potential

Hyperpolarization Cl- Equilibrium Potential
(membrane
K+ Equilibrium Potential
becomes more
negative)

Fig 8-9, pg 223

 Changes in ion permeabilities (Gi)

Na+ Equilibrium Potential

If GNa+ increases, EM will move towards +60 mV = depolarization
NOTE: in some cells ECl- = EM:
“passively distributed”. In this
If GCl- increases, case changing GCl-has no effect
on EM.
EM will move
towards -80 mV, Resting Membrane Potential
causing Cl- Equilibrium Potential
hyperpolarization.
K+ Equilibrium Potential
If GK+ increases, EM will move towards – 94 mV,
causing a hyperpolarization or repolarization.

Increasing the permeability of a membrane for an ion will naturally cause an

increased movement of that ion, causing a change in the membrane potential
Fig 8.9, pg 223
 Graded Potentials (GPs)
Relatively small changes in membrane potential caused by
changes in GK+, GNA+ & GCl-that are due to opening (or
closing) of specific K+, Na+, Cl- channels in the cell
membrane.
The changes in GK+, GNa+, & GCl- , that cause GPs are usually
at synapses (neurotransmitter release) or
at the peripheral ending of an afferent neuron in response
to stimulation of a sensory receptor.
GPs are therefore usually small (few mV or less) and are .
conducted away from the site of origin by local flow of
electrical current.
Local current flow is decremental: small change in
membrane potential (GPs) becomes even smaller as it moves
away from the site of origin (different from AP’s, which
are constant regardless of distance).
 Fig 8.11, pg 226
Current Flow
Axon Hillock
stimulus

Size of the arrows is

proportional to the size
of the GP’s in that area

Decrease in G.P. size with

distance from origin is due to
decremental local current flow.
 Graded Potentials (GPs)

Why are they “Graded”:

Because the size of GPs depends on the size of the
stimulus

So, a weak stimulus produces a small GP , a stronger

stimulus produces a larger GP.
- opening of K+ or Cl- channels causes
of membrane potential (inhibitory graded potential).
- opening of Na+ channels causes depolarization of
membrane potential (excitatory graded potential).
Fig 8.10, pg 225

Weak stimulus Strong stimulus

GP is “grade” in proportion to the

strength of the stimulus.

Excitatory, Na+
Inhibitory, K+, Cl-

Increased GK+, or GCl-

 G.P’s at synapses on dendrites or soma are Post-Synaptic Potentials.

threshold threshold

At excitatory synapses, the neuro- At inhibitory synapses, the neuro

transmitter generally opens both Na+ transmitter generally opens either K
& K+ channels ==> increased GNa+ & or Cl- channels ==> increased GK+ o
increased GK+==> net depolarization increased GCl-==> hyperpolarizatio
“Excitatory Post-Synaptic Potential “ “Inhibitory Post-Synaptic Potentia
 Single EPSP’s (e.g. +0.5 mV) are too small to raise EM to the
threshold needed to intiate an Action Potential.
IPSP’s (e.g. -0.5 mV) move EM further away from the threshold.
EPSP’s & IPSP’s on dendrites & soma are conducte
instantaneously to “initial segment” (axon hillock) by decrement
local current flo
The threshold potential is lowest ==> easiest to reach  at
the initial segment.
The closer the origin of a PSP to the initial segment, the
larger it still is when it arrives theres.
At the initial segment, process of summation occurs - threshol
potential may or may not be reached ==> decision = integration o
the signal
Temporal Summation – PSP’s in quick succession add up.
Spatial Summation - PSP’s from different synapses add up.
 Illustration of Integration

Integration normally occurs here

Fig 9-8
GPs versus APs
 Action Potentials (A.P.’s) result from large local changes of
GNa+ & GK+ (GCl- does not usually change) which occur once the
threshold potential is passed by summation of G.P.’s.
A.P’s only occur in cells where there are “excitable membranes”
==> membranes possessing voltage gated Na+ & K+ channels ==>
in addition to the regular leakage Na+ & K+ channels

A.P.’s obey the “all or none rule” (unlike G.P.’s)

Unlike G.P’s, A.P’s are short lasting (e.g. 1-3
millisecs) ==> as long as summated G.P. stays
above threshold potential, A.P.’s will keep
firing, each separated by a “refractory period”

A.P.’s are large (eg 100-120 mV), and are

propogated long distances from the site
of origin without changes in size ==>
“decremental conduction”
 Fig. 6-19,
p.170

Long-lasting summated G.P’s may hold membrane potential

above threshold for a very long time - e.g. 100 msec ==>
 Quiz # 2 – Monday March 5th
35 multiple choice questions
Same rooms as before – check LearnLink
80% new material, 20% from Lectures 1-11
Bring: calculator, valid i.d.
Biology 2A03
Lecture 20
Neurophysiology IV
 AP’s are short-
AP’s are a constant lasting relative to
size – obey an GP’s
“all or
nothing rule”

Sub-threashold GP’s AP “fires” as soon as summated GP passes the threshold

Long-lasting summated G.P’s may hold membrane potential

above threshold for a very long time - e.g. 100 millisec ==>
A.P.’s will keep firing repetitively, separated by a Refractory
Period.
 4 • Resting potential- EM determined by
3 leakage channels only: GK+ >> GNa+
1-2. EM increases due to G.P. & voltage-
gated Na+ channels start to open. Na+ ions
2 enter causing partial depolarization.
1 2. At threshold potential, entry of Na+
ions exceeds exit of K+ ions= depolarization

Voltage-gated Na+ channels open explosively

G 3. So many voltage-gated
in a positive Na+loop:
feedback channels
GNa+ >> are
GK+
GNa+. open that EM surpasses 0 mV & enters
overshoot phase. EM starts to approach the
equilibrium potential for Sodium (ENa+)
GK+ • Before EM reaches ENa+, the voltage-
gated Na+ channels automatically close
and voltage-gated K+ channels
automatically open. GNa+ decreases and GK+
Direction of Na/K movement is increases. K+ ions start to exit. EM starts
NOT specified.
to return towards 0 mV (repolarization
 4
3
5-6. Exit of K+ ions greatly exceeds
5 entry of Na+ ions resulting in
repolarization GK+ >> GNa+. EM decreases
2
1 7 towards EK+
6

6-7. Hyperpolarization continues with

GNa+. EM close to EK+, because some of the
G voltage-gated K+ channels remain open
for some time. (therefore a fairly high
GK+ Potassium conductance for a while)
 Absolute Refractory Period (0.5 - 3 msec) - axon cannot
carry another A.P. This corresponds to a period when the
voltage-gates Na+ channels are inactivated and are closed to
the passage of Na+ & thereafter remain closed for a
definite period==> “Na+ inactivation period”.
Relative Refractory Period (2-15 msec) - axon can carry
another A.P. but requires a greater than normal stimulus (e.g.
G.P). This corresponds to a period when voltage-gated Na+
channels can be re-opened but some K+ channels remain
OPEN. .
The Refractory Period limits the frequency at which axons can
carry A.P.’s. - e.g. if Absolute Ref. Period was 2 msec, the
maximum AP frequency would be about 500 AP’s/second.

Note: Na+,K+-ATPase continues to operate at a steady rate,

correcting the very minor ionic imbalances that result from
A.P.’s
 Voltage gated Na+ channels
Depolarization
opens the activation
gate

GNa+.

~1 millisecond

Inactivation gate closes

until EM returns to the
resting state.
Absolute Refractory Period
(no second AP possible,
regardless of the stimulus) No 2nd AP possible
regardless of stimulus

Relative Refractory Stronger than normal

Period stimulus needed for
an AP

In absolute refractory period most of the Na+

channels are open then inactivated and most of the K+
channels start to open
In relative refractory more and more Na+ channels are
able to be activated and many of the K+ channels start
to slowly close
 Information is coded as the frequency of A.P.’s
Refractory period plays an important
role in information coding at the initial
segment, because the further above
Gradient Potentials threshold is the G.P., the greater the
frequency, until the absolute
refractory period is reached.
Increased stimulus duration

Fig. 8-18 At sensory receptors, the greater

the intensity of the stimulus, the
greater the G.P., and the greater
the frequency, until adaptation
occurs.
Gradient Potentials Suprathreshold stimuli = above the
threshold stimulus
Increased stimulus strength Time between AP directly
causing more/faster AP’s related to amplitude of GP
Adaptation - a property of all sensory receptors

==> for any constantly applied stimulus, the frequency of A.P.s,

and therefore the perception of intensity, gradually declines
with time.
==> Very complex - explained by electrochemical (e.g.
channel closing), mechanical (e.g. gradual deformation of
receptor structure), and sometimes synaptic events.

Tonic receptors - adapt very slowly - generally associated with

life-critical sensation - e.g. pain receptors, blood gas
chemoreceptors.

Phasic Receptors - adapt very quickly -generally associated

with detecting changes in the environment - e.g. touch
receptors, sound receptors. (are you wearing clothes??)
Propagation of A.P. - in a non-myelinated axon

Local current flow

(decremental) occurs at the
interface region, and brings
the EM of the neighbouring
excitable membrane to
threshold ==> this region now
fires an A.P. ==> A.P. moves
along.
 Local current flow also
occurs at the other
interface, but the
neighbouring region is in
Absolute Ref. Period, &
cannot fire an A.P. ==> A.P
cannot move backwards.

The larger the axon

diameter, the faster the
propagation - e.g. squid
“giant axon” - Hodgkin &
Huxley - Nobel Prize.
Biology 2A03
Lecture 21
Neurophysiology V
Propagation of A.P. - in a myelinated axon
- same mechanism, but
decremental local current
flow is effective over longer
distances because of the
insulation (current is not
dissipated in the membrane).

- Nodes of Ranvier are

strategically placed so that
there is enough current
remaining to bring the next
Node to threshold potential.

- A.P. occurs only at Nodes, &

“leaps” to next Node by
saltatory propagation ==> up
to 1000-fold greater velocity.
 Only the vertebrates have myelinated axons and there
are many advantages:
1. Much higher conduction velocity.
2. Saves space - axons can be much thinner, and more
of them can be accommodated in the same space.
3. Metabolically much cheaper - because A.P.’s occur only at
Nodes, most of the voltage-gated Na+ & K+ channels, and
most of the Na+,K+ATPase molecules have been lost in the
inter-nodal regions.
Contrast (vertebrates): Diameter: Myelination: Conduction
Velocity:
non-myelinated “slow” ~2 um 1-2 layers 0.5-1.0 m/sec
post-ganglionic fibres of
SNS & PSNS.

Myelinated “fast”fibres ~12-25 um ~100 layers 75-100 m/s

of somatic nervous
system.
 A.P travels down an axon until it reaches the terminal knob(s)
where it activates a synaptic transmission.
Two types of synapses:
(1). Electrical Synapses - direct cytoplasmic connections (gap
junctions) between pre-synaptic and post-synaptic cells.
A.P. passes directly from one cell to the next by local current flow.
Common in cardiac & smooth muscle, but rare in nervous system
(< 1%) - defensive reactions only.
Advantages: speed, low energetic cost (one way directionality)
Disadvantages: non-rectifying, no capacity for integration
(current can flow in both directions)
(2) Chemical synapses - arrival of A.P. causes release of neuro-
transmitter (n/t) from the pre-synaptic membrane
n/t diffuses across synaptic cleft, reacts with receptors on post-
synaptic cell, which creates a G.P.
Common in nervous system (> 99%).
Advantages: rectifying (one way directionality), facilitates integration
Disadvantages: slow speed, high cost, can have delay of 0.2-2 millisec)
 1-2. Arrival of A.P. opens voltage-gated
Chemical Synapse Ca2+ channels  Ca2+ enters

[Ca2+] = 10-3M
[Ca2+] = 10-8M

3. Ca2+ activates docking of synaptic vesicles &

release of n/t into synaptic cleft by exocytosis
( > 90% of synaptic delay). This involves
contractile SNARE proteins.
4. n/t diffuses across synaptic cleft (10-20 nm -
< 10% of synaptic delay)
5. n/t reacts with post-synaptic proteins receptor
proteins, resulting in changes in GK+, GNa+ or GCl-  GP
Termination mechanisms for synaptic transmission

6. n/t may be broken down by enzymes interspersed between

receptor proteins - e.g. acetyl cholinesterase (green blob)
.
7. n/t may be actively transported back into the pre-synaptic
membrane for re-packaging into vesicles.
8. n/t may simply diffuse away from the synaptic cleft.
9. n/t may be actively taken up & metabolized by nearby glial cells
Note: Mechanisms 7, 8, & 9 will all decrease n/t concentration in
cleft, so n/t will dissociate from receptor proteins, thereby
stopping the post-synaptic stimulation.
 The “traditional view” was that n/t release followed the all or
none low- that one A.P. always released the same amount of n/t,
and thereby created the same size GP at the post-synaptic
membrane
We now know this is over-simplistic ==> many exceptions:
- Multiple transmissions may temporarily exhaust synaptic
vesicles of n/t.
- auto receptors on pre-synaptic membrane may down-regulate
subsequent n/t release.

- Desensitization or loss of post-synaptic receptor proteins may

occur in response to multiple transmissions.

- upregulation of n/t release and/or post-synaptic receptor

density may occur in frequently used or rarely used (!) pathways.

- Presynaptic inhibition or facilitation of n/t release may occur via

axo-axonic synapses.
===> frequency code is greatly modified at chemical synapses
 Transmissions at axo-axonic synapses may modify n/t release

Presynaptic
inhibition

Where two pre-synaptic neurons synapse

with each other before synapsing with the
axon

Neuron content is different

And so the neurotransmitters
May cause some kinda of
Destructive interference.
 The “traditional view” that synapses followed the All-or-None
Law arose because all the early research on synapses was done on
one of the largest synapses - the neuromuscular junction - where
this is true (Fatt, Katz, & Miledi - Nobel Prize).
Chemical synapse
between somatic motor
neuron & skeletal muscle
cell.

Many terminal processes

embedded in grooves in
post-synaptic membrane.
Contact area, amount of
n/t released, & receptor
numbers are all much
greater than in neuron-
neuron synapses.

Creates a GP large enough to produce an AP

The G.P on post-synaptic membrane (motor end plate) is called an
End Plate Potential (E.P.P.).

So much acetylcholine (n/t) is released by one A.P in pre-synaptic

neuron that one E.P.P. is +50 mV ===> suprathreshold & fires A.P. in
muscle cell.

One A.P in somatic motor neuron always normally elicits one

A.P. in the skeletal muscle cell.

There is no capacity for integration at neuro-muscular junctions

because summation of G.P.’s does not occur there.
 Biology 2A03
Lecture 22
Cell metabolism I and II
Two meanings of “respiration” (both correct)
1. Gas exchange:
movement of O2 from environment to
cell (mitochondria) & movement of CO2
in opposite direction

2. Cellular respiration:
e.g. C6H12O6 +6 H2O+ 6O2 ===> 12H2O +
6CO2 + 38 ATP
 Metabolic Pathways – ATP Synthesis
One of the major roles of metabolic pathways is to convert the
energy in food (stored as fuel) to ATP to power cellular functions

ATP production ATP ATP consumption

Metabolic pathways Movement
Carbohydrates Membrane transport
Lipids (fats) ADP + Pi Molecular synthesis
Proteins

ATP can be produced by: a) Glycolysis

b) Kreb’s Cycle (TCA or citric acid cycle)
Substrate–level phosphorylation:
(can occur in the absence of O2)
c) Oxidative phosphorylation
(by definition uses O2 in mitochondria)
 Oxidative Phosphorylation
Most important mechanisms of ATP production in mammals

Involves the reduction of O2 to H2O with electrons donated from

reducing equivalents (NADH + H+, and FADH2)

ATP production the result of:

1) Flow of e- through membrane-bound carriers

2) e- flow coupled with H+ transport from matrix to
intermembrane space
3) Energy for ATP synthesis provided by H+ travelling
back into the matrix via ATP-ase (F0F1)

See Fig 3-18

Fig 3-19
 Chemiosmotic model

O2 .
Fig 3.19 O 2-

-Electron transport chain – inner mitochondrial membrane

-Electrons from NADH +H+ and FADH2 pass along chain to
lower E states until combined with O2
-Accompanied by proton transport to intermembrane space
-Protons reenter via ATPase and energy used to produce ATP
(3 ATP / NADH and 2 ATP / FADH2)
-Heat and Reactive Oxygen Species (ROS) are other byproducts
Amino Fatty Glucose Stage 1 -Acetyl-CoA production
acids acids -Pyruvate is derived from glucose
e- glycolysis
via glycolysis – 2 NADH + H+ formed
pyruvate lactate -Oxidized to acetyl-CoA by
e- e-
PDH CO2 pyruvate dehydrogenase complex
e- (PDH) – 2 NADH + H+ formed
Acetyl-CoA
Stage 2 -Acetyl-CoA oxidation
-acetyl groups from pyruvate
e- fatty acids and amino acids enter
Kreb’s the Kreb’s cycle
e-
Cycle
e- CO2 - 3NADH + H+ and 1FADH2 formed
e- for each pyruvate
CO2

NADH & FADH2

Stage 3 - Electron transfer and
(reduced e- carriers)
oxidative phosphorylation
e-
2H+ + ½ O2 -Electrons transferred from
ETC reducing equivalents to ETC
H2O
ADP + Pi ATP See Fig 3-21
Fig 3-23
ATP yields from fuel sources
Anaerobic glycolysis: (O2 not used)

10 enzymatic steps

Substrate level phosphorylation

Reduction-oxidation balance maintained

(cytosol redux)

Harmful waste product

Fig 3-22
Aerobic metabolisms of:
ATP CO2
Carbohydrates: Glycolysis + oxidative phosphorylation
Glucose 2 pyruvate 2 ATP & 2 NADH + H+ 2+6
2Pyruvate 2 acetyl-CoA 2 NADH + H+ 6 0
2+18+4 4
2 acetyl-CoA Kreb’s Cycle 2 ATP, 6 NADH + H+
2
& 2 FADH2
3ATP / NADH + H+, 2ATP / FADH2 38 ATP

Fats: β-oxidation produces acetyl-CoA for Kreb’s Cycle 6 CO2

See Fig 3-21

Homeostasis of muscle ATP

ATP supply ATP demand

Short-term regulation
ATP
Phosphocreatine (PCr)
ATP stores work
Glycogen ADP + Pi Movement
Membrane transport
Long-term regulation Molecular synthesis

Oxidation of:
Glucose and Glycogen
Fats
Proteins
Short-term regulation of [ATP]
0-10 seconds
ATP hydrolysis and Phosphocreatine
buffering
PCr + ADP + H+ ATP + creatine
CPK

4 to 120 seconds
Glycolysis
Glucose + 2Pi + 2ADP
2lactate + 2ATP + H2O

Oxygen is not involved

 Oxidative metabolism
Carbohydrate oxidation
Glucose +6O2 + 36ADP + 36Pi
6CO2 + 6H2O + 36ATP
Respiratory exchange ratio (RER)
Also called respiratory quotient (RQ)
= CO2 produced/ O2 consumed
= 6 CO2 / 6 O2 = 1.0 for carbohydrates

2-5 hours! Lipid oxidation

Trioleate (C57H104O6) + 80O2

57 CO2 + 52H2O + 104ATP

RER = 57 CO2 / 80 O2 = 0.75 for fat

Oxygen required
 1. Gas exchange:
movement of O2 from environment to
cell (mitochondria) & movement of CO2
in opposite direction

2. Cellular respiration:
e.g. C6H12O6 +6 H2O+ 6O2 ===> 12H2O +
6CO2 + 38 ATP
 Anatomy of the respiratory tract

Conducting zone -
no gas exchange
between air & blood
here

Respiratory zone

Fig. 17-2
Biology 2A03

Lecture 23
Respiration I
 Anatomy of the respiratory tract

Larynx

trachea
Conducting zone -
Primary no gas exchange
Bronchi between air & blood
Secondary here
Bronchi
Tertiary
bronchi
Respiratory zone

Alveolar sac
Respiratory
Alveoli
bronchioles
Fig. 17-2
Anatomical features

Reinforced with cartilage

& smooth muscle –
Prevents gas exchange
with blood

Differences in wall thickness

important for gas exchange

Little cartilage or
smooth muscle – allows
gas exchange with blood

Fig. 17-3 30Mil alveoli – 100m2 Surface Area

 Important Conducting Zone Functions
• Larynx - phonation, guards entrance to trachea
• Cartilage & smooth muscle provide great strength
• Smooth muscle can constrict/relax, varying
resistance to air flow (bronchioles)
SNS  NE  β2-adrenergic recepters -
bronchodilation
PSNS ACH  muscarnic receptors -
bronchoconstriction
• Warms air to 37OC
• Humidifies air to 100% R.H
• Cleanses air by removing particles - mucus & cilia
provide the “mucus escalator”, macrophages ingest
Respiratory Zone

Alveoli arranged in clusters

connected by pores which
allow equalization of
pressure in the lungs

Type I cells = epithelial layer

Type II cells = surfactant prod.
Macrophages= engulf foreign
particles and pathogens
Fig. 17-5
The Respiratory Membrane

Diffusion rate = K x A x ΔP
T

T: Thickness
A: Surface Area
K: Permeability Gas Constant

If K for O2 = 1, K for CO2 is 20

Respiratory Zone -site of O2 & CO2
exchange with blood
• Respiratory bronchioles
10%
• Alveolar ducts
X
• Alveoli - 90% Lung Disease

Alveolar surface is wet for gas exchange  high

Surface tension at air-water interface

Small size of alveoli (radius ~ 0. 1mm) makes them

unstable

Alveoli have an innate tendency to collapse

 Factors preventing alveolar collapse
• Alveolar pores equalize pressures between alveoli
• Alveolar “Type II Cells” secrete surfactant (a
protein + phospholipid = detergent-like substance)
which reduces surface tension by up to 90%
Note: “Respiratory Distress Syndrome” (RDS) in pre-mature
babies is due to inadequate surfactant.
• Negative pressure outside the alveoli (-4 mm Hg, i.e
below atmospheric pressure) in the intrapleural
space helps to hold the alveoli open
• The other function of the intrapleural space is to
serve as flexible, lubricated connection between
the lungs and the thoracic wall.
 756mmHg
Chest Wall and Pleural Sac
or -4mmHg
rel to atm
760mmHg

Intrapleural fluid
Muscus, negative pressure
Parietal pleura
attached to thorax
Visceral pleura
attached to wall of lungs
The flexible, lubricated connection created by the negative intrapleural space
ensures that when thorax changes size during breathing, the lungs will follow

Pneumothorax - a rupture which connects the

intrapleural space to the outside atmosphere 
elimintates the negative pressure  breathing
becomes ineffective and the lung may collapse.

Fig 17-9
 Breathing Cycle
Inhalation - active phase during both rest & exercise
•External intercostal muscles pull ribs out & up
•Diaphragm shortens and moves down

Thoracic ==> Lung ==> Negative pressure in lungs (i.e below

Volume Volume atm pressure)

==> Air flows in from

“thoracic suction”
atmosphere
**Prof Didn’t Cover This Slide. Maybe because it’s the same as the next slide**
Breathing Cycle
Exhalation - passive phase during rest - slow

•Due to elastic recoil of thoracic & lung components

Thoracic ==> Lung ==> Positive pressure

Volume Volume in lungs (i.e above atmospheric
pressure)
==> Air flows out to
atmosphere

Exhalation - active phase during

•Internal intercostal muscles pull ribs

•Abdominal muscles push “guts” in, thereby displacing diaphragm upwards

 Exhalation - passive phase during Exhalation - active phase during
rest - slow exercise - faster

•Due to elastic recoil of thoracic & •Internal intercostal muscles pull ribs
lung components in and down

Thoracis pressure

Thoracic==> Lung ==>

Volume Volume
Positive pressure •Abdominal muscles push “guts” in,
in lungs (i.e above==> Air flows out
thereby displacing diaphragm upwards

atm pressure) to atm

 Mon. March. 12, 2007

** Next quiz 3 will cover primarily on “Respiratory System”

Biology 2A03
Lecture 24
Respiration II
Technique used to measure air volume

Spirometry
 Spirometer record

Tidal Volume = amount of air breathed in and out on a single breath ~ 0.5 L
Inspir. Res. = max. amount that can be inhaled above normal inhalation ~ 3 L
Expir. Res. = max. amount that can be exhaled beyond normal exhalation~1.5L
Resid. Vol. = amount left inside, cannot be exhaled even with max. effort ~ 1L
Insp. Capacity = tidal volume + insp. reserve ~3.5 L
Functional Residual Capacity = exp. reserve + residual volume ~2.5 L
Vital Capacity = exhale maximally, then quantify max inhalation ~ 5.0 L
Total Lung Capacity = measured after maximal inhalation , ~ 6.0 L
 Minute Ventilation = total air flow into (and out of) the respiratory system per minute

Minute Ventilation = Tidal Volume * Breathing Rate

e.g. 6750 ml/min = 450 mL * 15/min.

Minute Ventilation = Alveolar Ventilation ?

Not equivalent to each other

This difference is because of Anatomic Dead Space which is

air “stuck” in the conducting zone (always contain air and cannot be completely
emptied)
Alveolor Ventilation (VA):

VA = [Tidal Volume – Anat. Dead Space] * Breathing Rate

4500 ml/min = [450 mL – 150 mL] * 15/min.

-New air always Anatomical Dead Space
get diluted by
old air
- Old air has
less 02 & more
CO2 than atm
in air

Fresh air comes in

Dead air gets

pushed into
alveoli (stuck
in anatomical
dead space)
 300 mL of “new” air is entering the 2500
mL functional residual capacity
which contains “old” air

Dilution Factor = (300 mL new + 2500mL old)/ 300 mL new = 9.3 times (
dilution facto

==> Only ~10% replacement of alveolar air per breath at rest

==> Very constant O2 & CO2 levels in alveolar air at rest

==> Alveolar O2 is much lower , & alveolar CO2 is much higher , than in outside air

==> Alveolar O2 & CO2 values become closer to those in outside air during exercise
when tidal volume increases & anatomic dead space remains unchanged
 Minute alveolar ventilation = f x (VT – VD)
Anatom.
dead
space
gets
= (500ml x 12breaths) – (150ml x 12 breaths)
pushed
into
150
alveoli
= 4200ml/min instead of 6000 without VD

2 x f = 8,400 mL/min.
2 x VT = 10,200 mL/min.

Better to increase tidal volume (Vt) than to increase beating

frequency (f)

Table 17-1
Partial Pressure- a measure of the thermodynamic
activity of gas molecules
diffuse
Gases dissolve according to their partial pressures, not
react necessarily according to their concentrations
.
Dalton’s Law:
Total pressure = sum of partial pressure
Room air: Total Pressure = PN2 + PO2 + PCO2 + PH2O

~ 760 mm Hg (torr) [barometric pressure] = 599 torr + 160 torr +

0.3 torr + (0 – 47 torr) [depending on relative humidity]

“torr” = in honour of Torricelli, inventor of barometer

 In an air phase, Dalton’s Law can be applied directly
Partial Pressure = Total pressure * Volume (mole) Fraction

[Remember: equal moles of gases occupy equal volumes]

[1 mole of any gas occupies about 22.4 L @ STP (standard temperature &
pressure]

Dry Room Air:

PO2 = 760 torr * 210 mL O2/1000 mL air (21%)
= 160 torr

PCO2 = 760 torr * 0.39 mL CO2/1000 mL air (0.04%)

= 0.3 torr

Note: the same principles apply to N2 (mole fraction = 79%), we generally pay little
attention to N2 as it is an inert gas
 In a fluid phase, situation is more compl
Partial pressure of a gas in a fluid is equal to the partial
pressure of that gas in the air phase with which the fluid is in equilibrium (real or
theoretical equilibrium)

PO2 = 160 torr Otherwise, to find the partial

pressure, we need to apply Henry’s
Law, & know both the concentration
PO2 = 160 torr & the solubility of the gas in the
particular liquid

Henry’s Law = concentration of a dissolved gas is proportional to the partial pressure &
to the solubility coefficient

Concentration = Partial Pressure * Solubility coefficient Partial Pressure

* =
Concentration
Solubility Coefficient

* constant for a particular gas in a particular fluid under

defined conditions
 Water equilibrated with Room Air

PO2 = 7 mL O2/ 1000 mL water

0.044 mL O2/1000 mL water/torr
= 160 torr
PCO2 = 0.40 mL CO2/1000 mL water
1.32 mL CO2/1000 mL water/torr
= 0.3 torr
CO2 is about 30 x more soluble than O2 in water

The capacity of water to hold O2 ( 7 mL/ 1000 mL water) is much lower than the
capacity of air to hold O2 ( 210 mL/1000 mL air)

The capacity of water to hold CO2 ( 0.40 mL/1000 mL water) is comparable

capacity of air to hold CO2 (0.39 mL/ 1000 mL ai
[O2] = 210 mL O2/1000 mL Here, gases diffuse according to their
PO2 = 160 torr partial pressures, not according to
their concentrations
PO2 = 160torr
[O2] = 7 mL O2/ 1000 O2/1000 mL
 Basic Components of gas transfer systems

1. Breathing movements 3. Bulk transport

Continuous supply Most of the total gas transport occurs by
to resp. surface convection; diffusion is so slow that it is
(convection) used only over very short distances - a
few um’s

2. Diffusion of O2 and CO2 4. Diffusion of O2 and CO2

across resp. epithelium across capillary walls
to blood. to mitos in cells
The oxygen cascade

PO2 drops with each step in O2 transport

PO2 at cell surface must be high enough for O2

diffusion to mitochondria.
Biology 2A03

Lecture 25
Respiration III
 PO2
Alveolar partial pressures are
All in 160 PCO2 Alveolar air very different from outside
mmHg 0.3
(Torr)
air
100
40
Pulm artery Pulm veins
The partial pressures are the same
100 between compartments. Where the
40 46 40
changes occur are @ the alveoli and at
the capillaries, where diffusion can
cause a change in the gas content of
the blood. NEED TO KNOW THESE
PARTIAL PRESSURES!!
Systemic veins
These areas of diffusion have
100 significantly different pressures
40 46 Systemic arteries 40 compared to the previous compartment

cells Partial pressures are the same in

Memorize ≤40 ≥46 “venous” blood leaving the systemic
these key PO2 capillaries & entering the pulmonary
capillary beds
& PCO2 values See Table 18-1
 O2Transport in the Blood
1.5% - physically dissolved in plasma and RBC cytoplasm.

98.5% - chemically combined with hemoglobin (Hb)

280 x 106 Hb molecules per RBC

4 O2 molecules bound per Hb molecules
~ 109 O2 molecules per RBC
~ 5 x 109 RBC’s per mL of blood
~ 5500 ml blood per person
~ 3 x 1022 O2 molecules in the body (at 100% saturation)

Fortunately, we can understand the whole process at the

level of the single Hb molecule
 280 x 106 Hb molecules per RBC
1 Hb = 4 globins + 4 hemes

2 alpha 2 beta All identical

chains of chains of
141 aa’s 146 aa’s

Fig 16-3

Hb is a tetramer (M.W. ~ 68,000), composed of 4 similar units

Each unit consists of a “heme” ring structure, which binds

& a polypeptide chain (globin) which binds CO2, H+,

phosphates etc.
Note: binding of O2 to Fe2+ is via an ionic bond, not an
oxidation-reduction reaction
 A “functional” model of Hb

Hemes Globins
P P + P P P
X H+ X H X H+ X H+ X H+
O2 Fe 2+ - - - - - - - - - - - - - --- - CO2

O2 Fe2+ - - X- - - X- - X- - - -X - -X - - - - CO2

O2 Fe2+ - - - - - - - - - - - - - --- - CO2

X X X X X
O2 Fe2+ - - - - - X- - - - - - - - --- - CO2
X H+ H+ X H+ X H+ X H+
P P P P P

Hb exhibits the property of allosteric modulation =

“binding at one site on a molecule affects binding at a
second site, usually by changing the shape of the
molecule.”
 A “functional” model of Hb

Hemes Globins
P P + P P P
O2 - X H+ X H X H+ X H+ X H+
Fe 2+
- - - - - - - - - - - - --- - - NH2 CO
2
O2 Fe2+ - - X- - - X- - X- - - -X - -X - - - - - NH2 CO
2

O2 Fe2+ - - - - - - - - - - - - - --- - - NH2 CO

2
X X X X X
O2 Fe2+ - - - - - X- - - - - - - - --- - - NH2CO
2
X H+ H X
+
H X
+
H X
+
H +
P P P P P
H+, CO2, & phosphate are negative allosteric modulators of O2 binding
O2 is a negative allosteric modulator of H+, CO2, & phosphate binding

O2 is a positive allosteric modulator for for further O2 binding

- 1st O2 helps the 2nd, & the 2nd helps the 3rd; 4th is not helped
 4x O2

Hb Hb(O2)4

High PO2 at the lungs

promotes the formation of
exyhemoglobin

Low PO2 at the tissues

promotes the formation of
deoxyhemoglobin
 This allosteric co-operativity is the reason for the sigmoidal
(S-shaped) “O2 dissociation (association?) curve” of the blood

This is simply a plot of the extent of a chemical reaction -

the driving force (PO2) versus the amount of product (%Hb-O2)

(Product =
% Hb-O2)

Fig 18-8
(driving force)
 Loading point in pumonary capilaries

200

ml O2 per 1000 ml blood

Unloading point in
Systemic capilaries

150

100
Venous
reserve
50

PvO2 PaO2
0

Fig 18-8
Situation at rest
Important “design features” of the sigmoidal curve:
• Flat region at top provides an important safety margin
for O2 loading during:
-high altitude exposure
- respiratory diseases
- shift in blood curve to right during exercise
2. Knee and steep part is strategically located to facilitate
a greater O2 unloading during exercise with only a
relatively small decrease in systemic tissue PO2 and
therefore in PvO2
@ 40 torr ==> ~75% Hb-O2
@ 20 torr ==> ~35% Hb-O2
So a small decrease in PvO2 creates a large increase in O2
unloading during exercise .
PvO2 decreases because of increased consumption
(increased metabolic rate) in the systemic tissues.
This is helped by 3 additional factors during exercise:

1. An increase in PvCO2 shifts the curve to the right

PvCO2 increases because of increased CO2
production in the systemic tissues.
2. A decrease in pHv shifts the curve to the right
pHv decreases because of increased [H+] from
lactic acid and CO2
production in the systemic tissues: CO2 + H2O
====> H2CO3 ====> H+ + HCO3-
3. An increase in blood temperature shifts the curve
to the right.
Blood temperature rises due to greater heat
production in the systemic tissues.
 A “functional” model of Hb

Hemes Globins
P P + P P P
O2 - X H+ X H X H+ X H+ X H+
Fe 2+
- - - - - - - - - - - - --- - - NH2 CO
2
O2 Fe2+ - - X- - - X- - X- - - -X - -X - - - - - NH2 CO
2

O2 Fe2+ - - - - - - - - - - - - - --- - - NH2 CO

2
X X X X X
O2 Fe2+ - - - - - X- - - - - - - - --- - - NH2CO
2
X H+ H X
+
H X
+
H X
+
H +
P P P P P
H+, CO2, & phosphate are negative allosteric modulators of O2 binding
O2 is a negative allosteric modulator of H+, CO2, & phosphate binding
 Loading point at rest
Unloading point at rest

pH 7.6
pH 7.4 PCO2 = 55 Torr

pH 7.2 Temp = 39ºC

P50

Unloading point during exercise

 Unloading pt. during rest. Loading pt. during rest.

Loading pt.
During exer.
pH 7.6
pH 7.4 PCO2 = 55 Torr

pH 7.2 Temp = 39ºC

During exercise, O2 unloading can

be increased to 90% (ie venous
reserve decreased to 10%) by
combined effect of PvO2,
PvCO2, pHv and temp.

Unloading pt. during exercise

Biology 2A03
Lecture 26
Respiration IV
 O2 bound to Hb, does not directly
Contribute to PO2 => only dissolved
O2 does.

O2 bound to Hb does not directly

Contribute to the total amount of
O2 that will diffuse.
Important “design features” of the sigmoidal curve:
1. Flat region at top provides an important safety margin
for O2 loading during:
-high altitude exposure
- respiratory diseases
- shift in blood curve to right during exercise
2. Knee and steep part is strategically located to facilitate
a greater O2 unloading during exercise with only a
relatively small decrease in systemic tissue PO2, and
therefore in PvO2.
@ 40 torr ==> ~75% Hb-O2
@ 20 torr ==> ~35 % Hb-O2
So a small decrease in PvO2 creates a large increase in O2
unloading during exercise.
PvO2 decreases because of increased O2 consumption
(increased metabolic rate) in the systemic tissues.
 This is helped by 3 additional factors during exercise:

1. An increase in PVCO2 shifts the curve to right.

PvCO2 increases because of increased CO2 production
in the systemic tissues.
Bohr Shift 2. A decrease in pHv shifts the curve to the right.
pHv decreases because of increased [H+] from lactic
acid & CO2 production in the systemic tissues:

3. An increase in blood temperature shifts the curve

to the right .
Blood temperature rises due to greater heat
production in the systemic tissues.
 A “functional” model of Hb

Hemes Globins
P P + P P P
O2 - X H+ X H X H+ X H+ X H+
Fe 2+
- - - - - - - - - - - - --- - - NH2 CO
2
O2 Fe2+ - - X- - - X- - X- - - -X - -X - - - - - NH2 CO
2

O2 Fe2+ - - - - - - - - - - - - - --- - - NH2 CO

2
X X X X X
O2 Fe2+ - - - - - X- - - - - - - - --- - - NH2CO
2
X H+ H X
+
H X
+
H X
+
H +
P P P P P
H+, CO2, & phosphate are negative allosteric modulators of O2 binding
O2 is a negative allosteric modulator of H+, CO2, & phosphate binding
Increasing temp weakens the ionic bond between Iron and O2
 Unloading at rest Loading at rest

pH 7.4
PCO2 = 55 Torr
pH 7.2 Temp = 39ºC

P50, where 50% of O2 is bound to Hb

Unloading during exercise

 Unloading point at rest Loading point at rest

Loading
point during
exercise
pH 7.6
pH 7.4 PCO2 = 55 Torr

pH 7.2 Temp = 39ºC

During exercise, O2 unloading can

be increased to 90% (i.e. venous
reserve decreased to 10%) by
combined effect of

Unloading point during exercise

 Organic phosphate molecules are also important negative
allosteric modifiers of O2 binding, but play little role during
exercise
Mammals - 2,3 diphosphoglycerate (2,3 DPG)
Birds – inositol pentaphosphate (IP’s)
Fish & amphibians – ATP and GTP

Increase in RBC [phosphate] shifts curve to the right in mos

mammals during anemia, high altitude and respiratory diseases.
This helps improve O2 unloading to the systemic tissues

However some mammalian species which are native to high

altitude have very low levels of RBC [2,3-DPG], therefore a
left shifted curve => an adaptation to improve O2 loading?

The situation is parallel in fish during chronic hypoxia

(decrease in oxygen)
 Mammalian fetus has a different Hb ==> Hb-f in which
2 gamma chains (different a.a. sequence) replace 2 beta chains
Hb-f is very insensitive to 2,3 DPG, so fetal curve is to
the left of the maternal curve => facilitates O2 transfer
across the placenta.
Muscle Mb curve is to left of blood Hb curve ===> facilitates
O2 transfer from blood to the muscles
Mucles (Mb)

% Hb-O2 Blood (Hb)

PO2 (torr)
Biology 2A03
Lecture 27
Respiration V
 CO2 Transport in Blood
There is a lot more CO2 than O2 in the blood
10 % - physically dissolved in plasma and RBC cytoplasm
30% - chemically combined with hemoglobin (Hb) as
carbamino-CO2
60% - as the HCO3- ion, mainly dissolved in the plasma
carbonic
anhydrase
CO2 + H2O <====> H2CO3 <====> H+ + HCO3-
X
slow fast
Buffered Moves into plasma in
by Hb exchange for Cl-

Carbonic anhydrase is the 2nd most abundant protein in

RBC’s after Hb.
90% depends on presence of Hb & RBC’s
 Driving pressure
Cells ==> capillary

Both of these reactions

tend to shift curve to the
right, thereby helping to
unload O2.

“Band 3” Cl-/HCO3- exchange

= chloride shift
Most bicarbonate
transported in plasma
Fig 18-11
 Driving pressure for CO2 blood => alveoli
Driving pressure for CO2

Both of these reactions

tend to shift curve to the
left, thereby helping to
load O2 into the cells.

Fig 18-11
 So the Bohr Effects (and temperature effects) are not
just restricted to exercise.

Even at rest, small H+ & CO2 Bohr effects and temp. effects
shift the O2 dissociation curve slightly to the right in the
systemic capillaries, .

The reverse happens at pulmonary capillaries, the O2

dissociation curve is shifted slightly to the left, thereby
helping O2 .
 The Haldane Effect - the Mirror Image of th
Bohr Effect (again a negative allosteric effect
The addition of O2 to the Hb
helps to unload CO2 at the
pulmonary capillaries

The removal of O2 from the Hb

helps to load at the systemic
capillaries

While these effects are small

at rest, they become much
more important during
exercise
 Central Regulation of Ventilation
1) Regulation of inhilation/exhalation rhythm
2) Regulation of rate and depth

Respiratory control center

Always ON Cyclically active
(not rhythmic) (has a pacemaker)

Apneustic Pneumotaxic
center center
Stimulates inhilation Terminates inhilatio

Rhythmicity center
Autorhythmicity and inhibit each other
I neurons x x E neurons
Fires during Fires during
Inhilation exhalation
Spinal cord
Ventilatory muscles for inhalation
Fig 18-15 (Diaphragm and intercostals)
 Central Regulation of Ventilation
Apneustic and pneumotaxic centers: in pons sets pattern
and depth of breathing
I and E neurons of the rhythmicity center: in medulla set
the rate of breathing
Activity of the whole “respiratory control center” is
affected by:
-Movement and position receptors in limbs (joint-tendon receptors)
-Stretch receptors in windpipe
-Plasma hormones (e.g. epinephrine increases ventilation)
-Plasma K+, lactate
Peripheral chemoreceptors: monitor PaO2, pH, PaCO2
Central chemoreceptors: monitor PaCO2 (arterial)
 Central Chemoreceptors

More sensitive and accurate

than peripheral chemoreceptors

Monitors PaCO2 through changes

in cerebral spinal fluid (CSF) and
a resulting change in pH
CO2 can cross blood-brain
barrier while H+ cannot easily
cross this barrier
Lots of carbonic anhydrase in
the CSF

Figure
 Central Chemoreceptors
Central chemoreceptors are the most important controls
of breathing
Located in the medulla near the rhythmicity centre and
monitors PCO2 only
Actually monitors the pH of the ECF (CSF) and reflects
the PCO2 of the CSF
Even slight increase from a setpoint of PaCO2= 40.5
Torr will cause CSF pH to decrease and stimulate
ventilation (and vice versa)
Every breath is triggered by a slight increase in PaCO2
Peripheral (“Arterial”) Chemoreceptors

pons - connected to “respiratory

control centre” in pons & medulla
medulla
via glosso-pharyngeal nerves (IX)
(afferent branches)

Carotid
Chemareceptors

via vagus nerves (X)

(afferent branches)

Note: do not confuse with

arterial baroreceptors, which
Fig 18-18 are a separate system.
 Peripheral (“Arterial”) Chemoreceptors
- monitor PaO2 (setpoint ~ 100 torr) ===> stimulate ventilation
in response to decreases PaCO2 (not very sensitive to small
changes) though small decreases sensitize the responsiveness
to increased PaCO2
- monitor pHa (set point ~ 7.4) ===> stimulate ventilation in
response to decreased pHa (increased [H+]), & vice versa.
- monitor PaCO2 ( set point ~ ) ===> stimulate
ventilation in response to increased , & vice versa
(direct & indirect responses?), backing up central receptors
- mainly a fine-tuning, back-up and safety system which
becomes more important during special circumstances:
- new-born infants
- Drug and alcohol narcosis
- High altitude – low PaO2
- Severe exercise – decreased pHa due to lactic acid
Biology 2A03
Lecture 28
Respiration VI
 Peripheral (“Arterial”) Chemoreceptors

pons - connected to “respiratory

control centre” in pons & medulla
medulla
via glosso-pharyngeal nerves (IX)
(afferent branches)
Carotid
chemoreceptors

via vagus nerves (X)

Aortic (afferent branches)
chemoreceptors
Note: do not confuse with
arterial baroreceptors, which
Fig 18-18 are a separate system.
 Peripheral (“Arterial”) Chemoreceptors
- monitor PaO2 (setpoint ~ 100 torr) ===> stimulate ventilation
in response to decreases in PaO2 (not very sensitive to small
changes) though small decreases sensitize the responsiveness
to increased PaCO2
- monitor pHa (set point ~ 7.40) ===> stimulate ventilation in
response to decreased pHa (increased [H+]), & vice versa.
- monitor PaCO2 (set point ~40.5 torr) ===> stimulate
ventilation in response to increased PaCO2, & vice versa (direct
& indirect responses?), backing up central receptors
- mainly a fine-tuning, back-up and safety system which
becomes more important during special circumstances:
- New born infants
- Drug or alcohol narcosis
- High altitude (low PaO2)
- Severe exercise (decrease pHa due to lactic acid)
 Fig 18-19

% sat drops mediated entirely via

peripheral chemoreceptors

pH change not due to PCO2 (eg lactate during exercise)

mediated almost entirely via

Peripheral chemoreceptors
(H+ does not easily cross
blood brain barrier)
Hyperventilation decreased PCO2
and therefore H+
 Fig 18-19

Mediated via the central chemoreceptors

Respiratory and circulatory systems create a

balanced pH (acid/base content) of the body
 Acid-Base Balance- the control of ECF and ICF pH
Chapter 18, pp 568-571 & Chapter 20, pp. 632- 641
We focus on ECF pH ==> normal arterial blood plasma pHa ~7.4
ICF (cytoplasmic pH ~7.0) depends critically on ECF pH 7.4

7.00 <======7.20 <==7.40 ==> 7.60 ======> 7.80

Depression of the Over excitation of the nervous
system – tetany of muscles
nervous system Normal pH
(coma)

There are 2 major buffer systems in the blood that minimize

changes in free [H+] and [OH-]
1. Protein system (e.g. Hb, plasma proteins):
H+ + Protein (neg) => H-Protein
Minimizes but doesn’t reverse
OH- + H-Protein => H2O + Protein pH changes

2. CO2/HCO3- system:
H+ + HCO3-  CO2 + H2O
OH- + CO2  HCO3-
The protein and CO2 buffer systems are in equilibrium with
each other, & with all other less important buffer systems
(e.g. phosphate, ammonia) - by the isohydric principle.

Only the CO2/HCO3- buffer system is subject to active

physiological regulation – the others follow passively
.
The major principles of acid-base regulation can be
understood by following the CO2/HCO3- system.

If CO2 is excreted as fast as it is produced in metabolism,

there is no net acid-base effect (i.e. equilibrium):
carbonic
anhydrase
CO2 + H2O <====> H2CO3 <====> H+ + HCO3-
Reaction does not go to equilibrium because HCO3- exported to
the plasma by Chloride Shift
 carbonic
anhydrase
CO2 + H2O <====> H2CO3 <====> H+ + HCO3-
Respiratory Acidosis - If CO2 production exceeds
excretion by ventilation==> net H+ and HCO3- buildup
Respiratory Alkalosis - If CO2 excretion by ventilation
exceeds production ==> net H+ and HCO3- loss
Metabolic Acidosis - If an acid (H+) other than CO2 is added
to the blood (e.g. lactic acid) , reaction is driven to the left,
and a HCO3- is lost
-If a HCO3- is lost directly (e.g. diarrhea), reaction is
pulled to the right, and an H+ ion is added to the blood.
Metabolic Alkalosis - If a base (OH-, HCO3- ) is added to
the blood, it forms or adds HCO3-, reaction is driven to the
left, and an H+ oin is lost
- If an H+ is lost directly (e.g. vomiting) , reaction is pulled
to the right, and a HCO3- is added to the blood.
For these “Metabolic” disturbances:
net H+ loss = net HCO3- gain

net H+ gain = net HCO3- loss

For “Respiratory” disturbances, H+ and HCO3- are net gained
or net lost in equal amounts as CO2 is gained or lost:
carbonic
anhydrase
CO2 + H2O <====> H2CO3 <====> H+ + HCO3-
Respiratory disturbances -due to a disturbance of dissolved
plasma [CO2] which is regulated by
breathing - fast (sec - min) :
Constant

Dissolved [CO2] = PaCO2 x Sol. Coefficient (aCO2)

Metabolic disturbances - due to a disturbance of plasma
[HCO3-] which is regulated by metabolism & kidney
function - slow (hours - days)
 pH = pK + log [anion of acid]/[acid] = 4.0 + log[HCO3-]/[H2CO3]

c.a.
However: [H2CO3] <===> Dissolved [CO2] = PaCO2 x aCO2

The Henderson-Hasselbalch Equation

(H. Smith (1954) - “a most useful monument to human laziness”)

Regulated by metabolism & kidney ~slow

pHa = pK’ + log [HCO3-] = ~ 6.1 + log [HCO3-]

Diss. [CO2] PaCO2 x aCO2

constant constant
constant
Regulated by breathing ~ fast
 pHa = ~ 6.1 + log [HCO3-] 24 mmoles/L
40.5 torr * 0.03 mmoles/L
PaCO2 x aCO2
The log stuff is approx 20 normally)
pHa = 7.4

*
pHa is regulated at 7.4 by keeping [HCO3-] at 20
PaCO2 x aCO2
Respiratory acidosis - PaCO2 is too high (therefore pHa too
low) due to hypo-ventilation.
-If it’s a chronic effect, kidney slowly compensates by
accumulation of HCO3- (excreting H+).

Respiratory alkalosis - PaCO2 is too low (therefore pHa too

high) due to hyper-ventilation.
-If it’s a chronic effect, kidney slowly compensates
by excreting HCO3- (accumulation of H+).
* pHa is regulated at 7.4 by keeping [HCO3-] at 20
PaCO2 x aCO2

Metabolic acidosis - [HCO3-] is too low (therefore pHa too

low) - e.g due to addition of lactic acid to blood.

-Ventilation increases quickly to compensate, thereby

lowering PaCO2.

Metabolic alkalosis - [HCO3-]is too high (therefore pHa too

low) - e.g due to metabolism of some foods.

-Ventilation decreases quickly to compensate, thereby

raising PaCO2.
 Quiz 3 March 26th in lecture time slot.

35 multiple choice questions

75% on new material (including Labs)

25% on material from Quiz 1 and 2

Same room assignments

Bring calculator and i.d.

Course evaluation at end of lecture this Friday

Biology 2A03
Lecture 29
Respiration VII
Hormones I
 pH = pK + log [anion of an acid] = 4.0 + log [HCO3-]
[acid] [H2CO3]
c.a.
However: [H2CO3] <===> Dissolved [CO2] = PaCO2 x aCO2

======>
The Henderson-Hasselbalch Equation
(H. Smith (1954) - “a most useful monument to human laziness”)
regulated by metabolism & kidney -slow

pHa = pK’ + log [HCO3-] = ~ 6.1 + log [HCO3-]

Diss. [CO2] PaCO2 x aCO2

~constant ~constant
constant
regulated by breathing -fast
 pHa = ~ 6.1 + log [HCO3-] 24 mmol/L

PaCO2 x aCO2 40.5 Torr x 0.03 mmol/Torr

pHa = ~6.1 + log 20 = 7.4

*
pHa is regulated at 7.4 by keeping [HCO3-] at 20
PaCO2 x aCO2
Respiratory acidosis - PaCO2 is too high (therefore pHa too
low) due to hypo-ventilation.
-If it’s a chronic effect, kidney slowly compensates by
accumulating HCO3- (excreting H+)

Respiratory alkalosis - PaCO2 is too low (therefore pHa too

high) due to hyper-ventilation
-If it’s a chronic effect, kidney slowly compensates
by excreting HCO3- (accumulating H+)
* pHa is regulated at 7.4 by keeping [HCO3-] at 20
PaCO2 x aCO2

Metabolic acidosis - [HCO3-] is too low (therefore pHa too

low) - e.g due to addition of lactic acid to blood.

-Ventilation increases quickly to compensate, thereby

lowering PaCO2.

Metabolic alkalosis - [HCO3-]is too high (therefore pHa too

high) - e.g due to metabolism of some foods.

-Ventilation decreases quickly to compensate, thereby

raising PaCO2.
 Alveolar O2 transport:
VAO2 = (VT – VD) x f
=(500 ml/breath – 150 ml/breath)
x 12 breaths /min
= 4200 ml/min x 0.21 = 882 ml/min O2.
Blood O2 Transport:
TO2 = Q x CaO2
Where: CaO2 = O2dissolved + O2.Hb
=3ml O2 L-1 +(1.34 ml O2 g-1 Hb)(150g Hb L-1)
= 200 ml O2 / L
= 5 L/min x 200 ml 02/L
= 1000 ml/min O2
Fick Principle for O2 consumption:
Tissue VO2 = Q x (CaO2 – CvO2)
=5L/min (200 ml O2/L – 150 ml O2)
= 250 ml/min
During heavy exercise
= 22 L/min (200 – 80 ml O2)
= 2800 ml/min
Endocrinology

The ob / ob obesity mouse

The ob gene encodes the hormone leptin

 The Endocrine System
(Chapter 5 (140-143, 157-158) – Ch 6)
- the other long-distance communication system in the body.
- slow, long-lasting messages carried in the blood-stream, with
long-lasting effects.
- endocrine glands ==> secrete products .
(exocrine glands ==> secrete products to outside or via a duct
leading to outside)
- not completely separate from the .
(1) are often under nervous control.
(2) Many hormones are released as .
(3) Many substances which act as hormones in the general
circulation serve .
(4) The hypothalamus-pituitary complex is the
.
e.g. GH, ADH

e.g. TH

e.g. Epi ANP

cortisol
e.g. insulin Renin, EPO
somatostatin

estrogen
Adipose tissue
e.g. leptin
testosterone
 3 Classes of Hormones
1. Amines (derived from a.a.
synth - Adrenomedullary hormones
(catecholamines):
Dopamine - n/t & hypothalamic
1 hormone which

Norepinephrine & epinephrine -

2
Other amines:
- Serotonin (5-hydroxytryptamine) -n/t
3 & hormone derived from tryptophan -
involved in sleep, surpressing stress
responses, & moods.
4 - Thyroid hormones (T4 = thyroxine,
T3= triodo-thyronine) derived from
tyrosine - regulate metabolic rate,
growth, brain development.
 Bio 2A03
Lecture 30
Hormones I
The ob / ob obesity mouse

The ob gene encodes the hormone leptin

 The Endocrine System
(Chapter 5 (140-143, 157-158) – Ch 6)
- the other long-distance communication system in the body.
(see Table 5-6 for comparison with NS)
- slow, long-lasting messages carried in the blood-stream, with
long-lasting effects.
- endocrine glands ==> secrete products directly into ECF.
(exocrine glands ==> secrete products to outside or via a duct
leading to outside)
- not completely separate from the nervous system.
(1) Endocrine glands are often under nervous control.
(2) Many hormones are released as n/t’s from neurons.
(3) Many substances which act as hormones in the general
circulation serve as n/t’s in the brain.
(4) The hypothalamus-pituitary complex is the
neuro-endocrine interface.
e.g. GH, ADH

e.g. TH

e.g. Epi ANP

cortisol
e.g. insulin Renin, EPO
somatostatin

estrogen
Adipose tissue
e.g. leptin
testosterone
 3 Classes of Hormones
1. Amines (derived from a.a. tyrosine, tryptophan):
synth - Adrenomedullary hormones
(catecholamines):
Dopamine - n/t & hypothalamic
1 hormone which inhibits prolactin
secretion
Norepinephrine & epinephrine -
n/t’s & adrenomedullary hormones
2
Other amines:
- Serotonin (5-hydroxytryptamine) -n/t
3 & hormone derived from tryptophan -
involved in sleep, surpressing stress
responses, & moods.
4 - Thyroid hormones (T4 = thyroxine,
T3= triodo-thyronine) derived from
tyrosine - regulate metabolic rate,
growth, brain development.
Need to know enzymes and order
 2. Protein & Polypeptide Hormones
- the major class of hormones.
- synthesized by proteolytic cleavage of pre-prohormones on E.R.,
& resulting prohormones are then often further cleaved to
hormones during packaging into vesicles by Golgi apparaatus.
- hormones (& pro-hormones, & “pro-fragments”) are released
by Ca2+-initiated exocytosis.

Similar to Fig 5-4

3. Steroid Hormones -derived from cholesterol
- the second major class of hormones.
- produced by gonads (sex hormones), placenta (female sex
hormones), and adrenal cortex (mineralocorticoids, glucocorticoids,
& sex hormones).

glucocorticoid mineralocorticoid Sex hormones

Ring structure of cholesterol

preserved so all have lipophilic
nature (can’t be stored in Similar to Fig 5-5
vesicles)
 Functionally, the 3 hormone classes based on chemical
origin break down into two groups:

A. Peptides, Proteins , Serotonin & Catecholamines

B. Steroids & Thyroid Hormones
A B

*(but endocytosis may occur)

Metabolic breakdown & rapid ( < 1 h) slow (hours - days)
excretion
Table 5-5
Effects on Target Cells:
1. Direct - activate or inhibit some function of the cell.
2. Indirect = “permissive effects” - alter the sensitivity of
the target cell to other hormones by up-regulating or down-
regulating their receptors
Controls on Hormone Secretion:
1. Changes in plasma [nutrients] or [ions] - e.g. [glucose]
on insulin & glucagon; [Ca2+] on calcitonin & parathyroid
hormone

2. Another hormone (or self-inhibition) - e.g. hypothalamic

releasing/ inhibiting hormones on anterior pituitary hormones

3. Neural controls - direct from CNS (hypothalamic hormones)

or via the autonomic nervous system
 Direct CNS Control Via Autonomic N.S.

Portal system
 Hypothalamus -Pituitary Complex:
- “master endocrine gland(s)”
- “neuro-endocrine interface”
PVN

Hypothalamus - neural tissue

Axons terminate in the posterior

pituitary

Posterior Pituitary - neural tissue

“neurohypophysis”

Release of neurohormones
 Bio 2A03
Lecture 31
Hormones II
 Hypothalamus -Pituitary Complex:
- “master endocrine gland(s)”
- “neuro-endocrine interface”
PVN

Hypothalamus- neural tissue

Axons terminate in the posterior

pituitary

Posterior Pituitary- neural tissue

“neurohypophysis”

Release of neurohormones
 Posterior Pituitary Hormones
-”octapeptides” (8 a.a.’s peptides) synthesized in soma of giant
neurons of the hypothalamus.
-slowly transported down the giant axons by axonal transport &
stored like neurotransmitter in synaptic vesicles in terminal
knobs on blood vessels in post. pituitary.
- released by A.P’s coming down giant axons
1. Antidiuretic Hormone = ADH = Vasopressin
- from giant neurons of supra-optic nucleus (5/6 with 1/6 from PVN.)
- released as a response to low blood volume, low blood pressure,
high ECF osmotic pressure (hypothylamic osmoreceptors).
- promotes water retention at kindey and raises blood pressure by
vasocontricting systemic arterioles.
2. Oxytocin
- from giant neurons of paraventricular nucleus
- reproductive functions – uterine contractions, milk ejection,
orgasm (?)
Anterior Pituitary

Tropic stimulates the

release of another hormone

Hypophysiotropic hormone

Hypothalamus- pituitary
portal system

Anterior pituitary
hormone
 Hypothalamic & Anterior Pituitary Hormones
At least 6 different (probably
more) Hypophysiotropic hormones
= Releasing Hormones (factors) +
Inhibiting Hormones (factors),
from 6 different giant neuron
groups

Very high local concentration

(no dilution with general circ.)

5 different cell types

release at least 6 different
anterior pituitary hormones
which pass out into general
circulation
 Hypophysiotropic hormones - released like NT’s by A.P.’s
- All are short polypeptides (3-44 A.A.’s) except dopamine
1. Gonadotropin Releasing Hormone (GnRH) – stimulates both
LH & FSH release.
2. Growth Hormone Releasing Hormone (GHRH) – stimulates GH
release.

3. Somatostatin (SS) = Growth Hormones Inhibiting Hormones

(GHIH)- inhibits GH release.

4. Thyrotropin Releasing Hormone (TRH) – stimulates TSH release.

5. Dopamine = Prolacting Inhibiting Hormones (PIH)- inhibits

prolactin release.

6. Corticotropin Releasing Hormone (CRH) – stimulates ACTH

release
Anterior Pituitary Hormones - all long polypeptides or proteins
* 1. Luteinizing Hormone (LH) – promotion of ovulation, formation
of corpus luteum, & sex hormone production.
* All tropic hormones
* 2. Follicle Stimulating Hormone (FSH) – promotion of ovarian
follicle development, sperm production, & sex hormone production.
Gonadotropins from same anterior pituitary cells

*3. Growth Hormone (GH) – general actions on most tissues:

promotes IGF-1 release (which promotes growth); protein
synthesis, alters carbohydrates and lipid metabolism
* 4. Thyroid Stimulating Hormone (TSH) – stimulates thyroid
growth, T3 & T4 production.
5. Prolactin (PL) - general reproductive functions, promotion of
breast development & milk production; suppresses ovulation
during breast-feeding; ionoregulation effects (?)
6. Adrenocorticotrophic Hormone (ACTH) - promotes
glucocorticoid production by the adrenal cortex  chronic
stress coping responses mainly mediated by cortisol.
Neural Input from Higher Centers
Other Hormones
+/-
e.g. stress Fig 6-5
+

-
-

-
+

T3, T4 ↑
 Short loop –ve
CRH feedback
prevents the
buildup of excess
anterior pituitary
tropic hormone

ACTH

With long loop the

target hormone
limits the
secretion of
CORTISOL
tropic hormones
and therefore its
own release

Fig 6-6
Biol 2A03

Lecture 32
Muscle 1
 Skeletal Muscle
- Connected to at least 2
bones
- Some exceptions: some facial
muscles, larynx, external
urethral sphincter

Smooth Muscle
- No striations
- Found in blood vessels, GI
tract, uterus

Cardiac Muscle
- Show characteristics of
both skeletal & smooth
muscles
Comparison of skeletal, smooth and cardiac muscle
 Structure of a skeletal muscle fiber (cell)
Muscles made up of bundles (fascicles) of muscle fibers
Neuromuscular junction
Each fiber (cell)
controlled by only 1
motor neuron
Multinucleated cells

Myofibrils
Mitochondria
SS – subsarcolemmal
IM - intramyofibril
sarcomere
The Sarcomere A band. Entire myosin bundle + overlapping
regions of actin.
I band. Regions of actin filaments which do not
Classic features overlap myosin. Bisected by Z line.
of sarcomeres
H zone. Area of sarcomere between opposing
ends of actin filaments.

-Sarcomeres are bordered by Z line which anchor thin

filaments (actin) (blue)
-Thick filaments are joined at the M line (myosin) (red)
Thick Filament (Myosin) crossbridge

Each myosin is a dimer of 2 intertwined subunits

100’s of myosins per thick filament arrange in a staggered

fashion along the TF (think filament).
Thin Filaments Tropomyosin partly covers
the myosin cross-bridge
binding site

Backbone composed of actin. G-actin (for globular protein) bind

together to form F-actin (fibrous protein).

Ca2+ binding to troponin causes

change in shape of molecule.

Troponin bound to tropomyosin.

Therefore conformational change to
troponin drags tropomyosin away
from cross-bridge binding site.
Sliding-Filament Theory of muscle contraction

Actin and myosin

do not shorten but
rather the thick
and thin filaments
slide past each
other.
The crossbridge cycle

Ca2+ essential for

crossbridge
attachment
 Muscles have
excitable membranes
Voltage-
sensitive
receptor
(affected by
depolarization
of the
membrane)

Coupled to SR
Ca2+ channels

Excitation-contraction coupling
 1. Action potential targets
charged amino acid residues
in DHP.

2. DHP conformation change

which, via foot proteins,
opens ryanodine channel.

3. Ca2+ released from

sarcoplasmic reticulum into
cytosol.

DHP = dihydropyridine
receptors.
Recruitment of motor units
Motor unit: motor neuron
5 fibers
and all the fibers that it
innervates

1. Motor units

7 fibers
2. A muscle can have
hundreds of motor units.
The size principle units are
recruited for small muscle
forces. units are
used for larger forces

Larger than average that are

harder to . They also have larger
Biology 2A03

Lecture 33
Muscle II
The Last One!
Recruitment of motor units
Motor unit: motor neuron
5 fibers
and all the fibers it
innervates

1. Motor units differ in size

7 fibers
2. A muscle can have
hundreds of motor units.
Muscle tension can be
varied greatly
The size principle Small motor units are
recruited for small muscle
forces. Larger motor units are
used for larger forces

Greater the AP from the brain

the larger the motor units that
are recruited, and the larger the
tension/force produced.

Larger than average cell bodies that are

harder to depolarize. They also have larger
axon diameters
 Extraocular myosin
Primarily Type II myosins
Primarily Type I myosin

Some muscles generate more

tension/force than others…this
graph is mis-leading.

-When stimulated these different muscles take different

times to reach peak tension
-They each contain different populations of muscle fibers
- Contraction properties depend on proportions of fast
and slow twitch fibers (proportions of fast and slow
myosins)
Skeletal muscle fibre classification
Maximal shortening velocity – fast or slow fibres
In fast fibres cross-bridge shortening is
approximately 4x faster than in slow fibres
ATP supply: oxidative or glycolytic
Oxidative fibres.
-Mitochondria rich.
-ATP derived from oxidative phosphorylation.
-Highly vascularised.
-Contain large amounts of oxygen transporting
myoglobin. --Often called red muscle.
Glycolytic fibres.
-Few mitochondria.
-ATP derived from glycolysis.
-Rich in glycolytic enzymes.
-Poorly vascularised.
-Small amounts of myoglobin. = White muscle.
 Also named for Myosin
isoform (I, IIa and IIb) Type I Type IIa Type IIb

Muscles with low mitochondria are well suited for short bursts of energy use
Eg. In sprinters. Muscles with high mito levels are well suited for long-term endurance
Eg. In marathon runners. The two cannot be converted…but high mito can be trained
To work over shorter distances…low mito cannot be trained for endurance as easily
Smooth Muscle

 Lack the striations of skeletal muscle.

 Controlled by autonomic nerves = involuntary control.
 Mononucleate (skeletal = multinucleate)
 Smooth Muscle can divide throughout life of an individual
(skeletal = unable to divide once differentiated).
 Smooth muscle division can be stimulated by paracrine
agents.
No regular alignment of myosin and actin as occurs
in skeletal muscle

Dense bodies. Functionally

equivalent to Z-lines in
skeletal muscle
-Calmodulin the Ca2+ binding regulatory protein NOT
troponin-tropomyosin
-Ca-calmodulin complex binds to a myosin kinase which
phosphorylates myosin. Only phosphorylated myosin can bind with
actin. A Phosphatase will dephosphorylate for relaxation.
 Inputs influencing smooth muscle (SM) contraction
1. Spontaneous AP in plasma membrane of SM cell (e.g.
pacemaker cells in intestinal tract)
2. Autonomic NS neurotransmitter release (SNS + PSNS)
3. Hormones (e.g. epinephrine)
4. Local chemical changes (e.g. active and reactive hyperemia)
5. Stretch (myogenic response)

PSNS and / or PNS

Smooth muscle fibres do not have motor
end-plate (unlike skeletal muscle fibres).

Neurotransmitters in smooth muscle may have a stimulatory or

inhibitory
Neurotransmitter is released, and effect.
diffuses over to the
muscle fibres to create the appropriate response. No
direction junction.