2a03 lectures1-33

Biology 2A03Lecture 1

Introduction to Physiology&

Homeostasis

Physiological determinates of animal performance1. Vertebrate muscle remodeling

3. Lifetime performance and muscle physiology

2. Regulation of lipid metabolism with environmental stress

4. Toxicogenomics

5. Interactions between oxygen delivery and fuel metabolism

Research in theMcClelland Lab

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

INSTRUCTIONAL ASSISTANT:

Ray Procwat, LSB-215, Ext 24399, [email protected]

LECTURES: Monday, Wednesday, Thursday 13:30 – 14:20, MDCL 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*******

Course Syllabus available on LearnLink

For the rest:Lab handouts will be available on LearnLink or by handout one week before the scheduled lab

Pick up Lab #1 handout in LSB 215

https://scidropadd.mcmaster.ca/dna

http://www.aw-bc.com/physiologyplace/

****All Quiz and exam questions taken from LECTURE and LAB material

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)

Course Syllabus available on LearnLink

What is Physiology?The goal of physiology is to explain the physical and chemical factors for the origin and progression of lifeORHow animals work!

Medical Physiology or Pathophysiology – abnormal physiology as the result of disease

Disciplines: Cellular Physiology, Developmental PhysiologyNeural, Renal, Muscle, Cardiovascular…… Physiology

Comparative, Animal or Integrative Physiology – how animal adapt to “abnormal” environments or life histories. Also environmental physiology, evolutionary physiology and physiological ecology

68 - 81ºC

2000-3000mHigh H2S

4000-5000m10% O2

0% O2!

When O2 removed happy produce ethanol

Hierarchical organization of the bodyCells

Tissues

Organs

Functional units

Organ Systems

Organism

Differentiated and specialized1) muscle, 2) nerve, 3) epithelial4) connective cells

Aggregate of specialized cells1) muscle, 2) nerve, 3) epithelial4) connective tissues

Subunits of an organs(e.g. multiple nephrons in a kidney)

Composed of the 4 tissue-types indifferent proportions and patterns

A collection of organs that functiontogethere.g. Circulatory System = heart,blood vessels, blood

Figure 1.2

Hierarchical organization of the body

Cells: in humans over 200 distinct kinds1) Muscle cells: specialized for contraction to produce movement

2) Nerve cells: generate and propagate electrical signals

3) Connective tissue cells: connect and support body structurese.g. bone, collagen, cartilage

4) Epithelial cells: secretion and absorption; protective rolee.g. skin

Subtypes can exist:– skeletal, movement of limbs and skin- cardiac, movement of heart- smooth, dilation of blood vessels, control of BP

Collection of organs that work together to accomplish a particular task

Simplified View of Overall Plan of Human Body

Fig 1.4

•Separates external from internal

•Keep constant internal envts.

•O2 in, CO2 out

The Internal Environment

Total Body Water = Intracellular H2O 28 L 2/3

Interstitial H2O 11 L

Plasma H2O 3 LECF 1/3

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

See Fig. 1-5

Proper cellular function depends on tight control of ECF components

Fig. 1-5

HomeostasisA Defining Feature of Physiology

Claude Bernard (1813-1878)

Walter Cannon (1871-1945)

Extended Bernard’s notion to the organizationof cells, tissues and organs. First to coin the term “homeostasis”

Noted that mammals are able to regulate their internal environment withina narrow range.

“The maintenance of static or constantconstant conditions in the internal environment”

Regulatedvariable

Integrating center

input output

Set point

Effectors

Sensors

Negative feedback

Compensatory response

Basic Negative Feedback Control

Examples: arterial blood pressure, body temperature, pH, PCO2

See Fig 1.7

•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

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

Regulatedvariable

Integrating center

receptors output

Set point

Effectors

Negative feedback

Compensatory response

Stimulus or error signal +/-

Afferent Pathway

Efferent Pathway

Afferent Pathway: going to

Efferent Pathway: going away

•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 Pathway

Set Point Efferent 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 proteinPeripheral

protein

-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

Tight Junctions

•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)

Intermembrane space: space btwn inner and out membrane

Folded structure w/in inner 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

mouse elephantO2 c

onsu

mp

tion /

Mb

Mit

och

ondri

al densi

ty /

g

mouse elephant

Hummingbirdflight muscle

Humanmuscle

…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


Protein activity&

Cell metabolism I

Membranes

Fig 2.15

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

Mitochondria

Fig 2.20

•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 molecules and ions including H+

•Contains respiratory

•O2 used in oxidative phosphorylation in mitochondria

• O2 comes from respiratory system, delivered by blood circulation

• Burness, Science (2002) diagram

• Respiratory system getting O2 to lungs

• 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:

1. Rates of synthesis and/or degradation

2. 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:

1. Allosteric modulation: - non-covalent binding of factors to other regulatory sites results in a change in

shape of the active site.

2. 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.

Fig 3-9, 3-10

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 PO4

2-

• Enzyme B: phosphatase removing PO4

2-

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)

Fig 3.4a

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

• Enzyme kinetics: studying rate of reactions

• S= substrate

• 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

S + E ES P +E Most important step

…cont’d

•As [S] ↑, VO

• Enzyme with higher affinity is able to catalyze the reaction at

a faster rate and will exhibit a higher degree of saturation

V0

[S]

½ Vmax

Km

Vmax 2x E

Change in affinity for Se.g. allosteric modulation

V0

[S]

1x E

Km

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]- Km can be determined from this plot- 1/ Km = affinity See Fig 3-7

Fig 3.8

Fig 3-7

•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)

Increasing ES complex

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

100% saturated.

BiologyLecture 4

Protein activity (cont..)

Transport I

Michaelis-Menten equation:

Relationship between [S] and reaction rateThe quantitative description of enzyme reaction rates to [S],

constants Vmax and Km occurs by the:

V0

[S]

½ Vmax

Km1

Vmax

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

Km = 1/affinity

Metabolic pathwaysA sequence of enzyme-mediated reactions leading to a

specific product

P feeds back to E2 (allosteric inhibition)

A B C D PE1 E2 E3 E4

Specific reaction steps may be regulated to control fluxthrough 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

ADP + Pi

ATP consumption

Body uses ATP in movement, processing,

molecular transport/synthesis, etc

ATP production

Body converts fatsAnd carbs to ATP

ATP can be produced by:

NOTE – body tries to keep ATP levels relatively

Constant (homeostatic)

a) Substrate level phosphorilation

(done in the absence of O2)

c) Oxidative phosphorilation (uses O2 in the mitochondrion)

b) Kreb’s cycle (TCA citric acid cycle)

[ATP]

Transport mechanismsTransport 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)

See Table 4-2

2. Mediated transport: facilitated diffusion, or usestrans-membrane protein channels to move molecules

Active transport

Primary (directly uses ATP to move molecules)

Secondary (doesn’t use ATP, uses an electropotential difference between areas)

Simple diffusionDiffusion: “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.

See Fig 4-2 Fig 4-4

Flux: movement from a compartment to another, per unit of time

Net flux = (F1-F2) flows towards the lower concentrationA gradient for diffusion is created, therefore downhill movement

Of the solute occurs.

F1 F2

The net flow is towards F2, butThere is flux both ways, unless

It is prevented by the cell membrane

F1 F2There is no net flow, as equilibriumHas been reached, however, there

Is still flux between the two areas

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

For example transport of oxygen to cells, CO2 from cells)

Single cells can use diffusion rather efficiently

Large animals generally require the use of a circulatory system

BUT- both these systems work in conjunction, eg O2 is circulatedCapillaries, and then diffuses into the cells from the capillaries.

1a) Flux across the lipid bilayer

F = Kp × A× (Co - Ci)

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

It is a function of: i) Temperature factors

ii) Solubility in the bilayer (eg. Polarityunpolar/uncharged molecules have a high Kpwhile polar/charged molecules have a low KP

iii) Size and shape of the molecule (moleculeswith less complicated shapes diffuse easier)

See Fig 4-1Fig 4-10

Box p113

Diffusion continued

Flux

Permeability constant

Area

Initial concentration difference between

inside/outside of area of diffusion

Metabolic pathways• A sequence of enzyme-mediated reactions leading to a

specific product:

A ↔ B ↔ C ↔ D ↔ P E1 E2 E3 E4

- Allosteric inhibition (end product inhibition)

• 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


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 ofselective transmembrane proteins channels

Both diffusion and electrical forces important for movement of ionsalso called electrochemical gradient.

Membrane potential involves the seperation of charges across aMembrane, creating an electrochemical gradient while allows for

Diffusion is required.

Fig 4.2

– Separation of charge = potential energy

Separation of Charge Across a Membrane

–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 • depends on the valence

of the ion being driven

ITC = neg charges ETC = pos charges

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, sothere is a net movement inwards

Fig 4-5

Ek= equilibrium potential whichreflects the driving force of the

movement.

Fig 4-13

Selective for type of ion -due to size and the charged

and polar surfaces of the protein subunits of the

channels

Channel Protein

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.

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

ECF = ~6mM ICF = ~1 mM

Glucose glucose

Glucose-6-phosphate

Fig 4-11Fig 4-12

Mediated transport can also become saturated and reach

maximal flux. Simple diffusion will increase, and cannot

become saturated.

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.

Bind substrates and undergoes conformational changes

2c) Primary active transport

Direct use of ATP to power movement of molecules against anelectrochemical 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 transporterAnd 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 mMInward movement of K+ is uphill (against the gradient)

And so requires the use of ATP to facilitate diffusion.

See Table 4.1

Intracellular K+ = extracellular K+ =

Inward movement of K+

Intracellular Na+ = 15 mM extracellular Na+

=145 mM

Outward movement of Na+

Fig 4-14

2c) Primary active transport

Note that an uneven distributionOf charge is created here.

Membranes are “leaky” to ions

Ion pumping to maintain proper Gradients, produces heat as a

by-product (up to 50% of cellularHeat 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 samesize 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 foruphill transport of another atom.

Usually Na+ whose binding changes the affinity of the transporterProteins for solute, via ALLOSTERIC MODULATION.

Primary active transport is needed to maintain the electrochemicalGradient which allows for secondary active transport.

This example is of cotransport/symport

- net binding increases the affinity ofthe protein for a second molecule.

Can also occur in opposite directions =

Countertransport/antitransport

High glucose

High H+


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 osmolebut 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])

Hypertonic:

Hypotonic:

Isotonic:

Fig 4-19

Cells are very permeable to water and impermeable to many solutes

Extracellular fluid has the same # of osmoles of nonpenetrating solute

Extracellular fluid has a greater # of osmoles of nonpenetrating solute

Extracellular fluid has the lower # of osmoles of nonpenetrating solute

Cell shrinks

Cell swells

No change in cell volume

300 mOsm

400 mOsm

200 mOsm

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 topenetrating solutes

isoosmotic But hypotonic

300 mOsm >300 mOsmnonpenetrate

penetrating

4 features of signal transduction pathways:

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

2) Amplification:

3) Desensitization / adaptation:

4) Integration:

The signal molecule fits in its receptorwhile others do not

Feedback shuts offreceptor or removes it

1 receptor binding can lead to 1,000,000 products

response- +

Outcome the result of integrationof both receptor inputs

1) Specificity:

Can also have messenger bind to multiple receptors with different affinities

ReceptorsThe 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

Fig 5-9Fig 5-10

Can become saturated with messenger

An increase in the # of receptorsincreases the % bound with messenger

Change in affinity for messenger

Can increase # of bound receptorsat the same [messenger]

Fig 5-10

Or…50% of the receptors are bound at a lower [messenger]

Receptors can be intracellular:

RM

R

See Fig 5-11

bind to lipophilic messengers

alters synthesis of a specific protein-act as transcription factors

Receptors can be located in the cytosol of in the nucleus

e.g. steriods = hormones

Receptors can be membrane bound:1) Channel-linked:

3 main types(e.g. binding opens ion channel)

Fig 5-12

Bind lipophobic messengers

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

2) Enzyme-linked:

Binding activates tyrosine kinase activity which phosphorylates a protein - on

tyrosine

Ligand-binding domain on extracellular surface andan enzyme active site on intracellular side

Fig 5-13

e.g. insulin receptor

3) G-protein-linked: (activate membrane proteins called G-proteins and begin a signaling cascade)G-proteins can be stimulatory (Gs) or

inhibitory (Gi)

2. Often activates an enzyme

Fig 5-14

1. Regulates a protein channel

e.g. Can open or close a“slow ” ion channel

- Channel does not act as receptor

e.g. adenylate cyclase to produce cAMP

α-subunit binds GTPto become active

Important 2nd messengers are:1) Ca2+

2) cAMP3) cGMP4) DAG

5) Eicosanoids6) IP3

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

Table 5-3Fig 5-16Fig 5-17Fig 5-18

Extracellular fluidMessenger

1 Receptor

GDP GTP

GDP GTP

2

Amplifierenzyme

Secondmessenger

Protein kinase

Activatesenzyme

Protein

ATP

+Protein – P

ADP+

3

4

5

6

Response in cellCytosol

Substrate

Adenylate cyclase

ATPcAMP

blood borne hormoneepinephrine

1x molecules

β-adrenergic receptor

G-proteinstimulatory 20x molecules

10x moleculesPKA

inactivePKA

active

-Example of a signal transduction pathway-Next slide

glycogen Glucose 1-P

inactivePhosphorylase b

Kinase

activePhosphorylase b

Kinase

inactiveGlycogen

phosphoryase b

activeGlycogen

phosphoryase a

(100x molecules)

(1000x molecules)

(10,000x molecules)

Amplificationof hormone signal

Adrenergic receptor can be desensitized by phosphorylation

Response of the cell (e.g. glycogen breakdown in liver cells)PKA

active10x molecules

PKAactive

Glycogen synthase (inactive)


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 drasticallyover large distances.

Diffusion is sufficient in a unicellular organism.

Multicellular organism’s require a circulatory system, as the distances

for diffusion are too large to be efficient.

High [waste] inside forcesWaste to flow to the outside.

Waste outNutrients in Nutrients in

Waste out

Circulatory SystemsA fast convection system = rapidly circulating fluids

between surfaces that equilibrate external milieu (environment) for cells deep inside an organism

1˚ role =

2ary role =

System consists of:

1) Fast chemical signalling

2) Dissipating heat

3) inflamatory/heat defences against micro-organisms

distribution of dissolved gasses and molecules from nutrition, growth, and repair.

1) A Convective medium = blood (communication system)

2) Plumbing = blood vessels (regulates blood pressure/distribution)

3) A Pump = heart (sensory and endocrine (hormonal) functions)

Fig 14-2

The Circulatory System1. Pulmonary circulation (lungs)

Low pressure system (20mmHg)

2. Systemic circulation

Delivers O2 to tissue and organs,NOT the lungs.

High pressure system (100mmHg)

Composed of 2 circuits

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!!!!

Picks up O2 from the lungs

Right ventricle lungs

Left atrium

Left ventricle Organs and tissues

Right atrium

Blood – plasma & cells (erythrocytes, leukocytes, platelets)

Composed of:

1) Plasma ~92%water

proteins ~7%

Electrolytes (ions)

gases

nutrients

wastes

Albumin, antibodies,

Major Cation (Na+ 145 mM)Major Anion (Cl- 100,140

mM) O2, CO2, N2

Glucose, lipids, amino acids

Urea, ammonia

See Table 16-1

-ISF and plasmavalues close to each

other-Except that

proteins > in the plasma

The capillary wall is very permeable to H2O and most plasma components,Except for proteins, based on their shape, size, and charge.

Hematocrit

ll

The fraction of blood composed of Red Blood Cells (RBC’s/erythrocytes)

Hematocrit =

lt

lt

l1

Can be measured after blood is centrifuged in a microhematocrit tube

Lightest

Most dense Total blood vol = ~5.5 L Plasma (54%) = ~3.0 L RBC’s (45%) = ~2.5 L

Plasma ~54%

Eryhtrocytes ~45%

Buffy coat (leukocytes and platelets) ~1%

2) Blood Cells – 1. Red blood cells (erythrocytes)

Most abundant cell in the blood stream-Major function to transport O2 from the lungs

CO2 from the tissues

-Contain large amounts of hemoglobin (85% of

protein content) for carrying O2

-In mammals do not contain nucleus/organellesand so cannot divide (transporter for the body)

-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, whichalso allows for easier diffusion.

280 x 106 Hb molecules per RBC

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.”

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

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 hormoneErythropoietin (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

Fig 16-4

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 O2Delivery, cycle is re-balanced

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 ofTesting times for athletes…resulted in stripping of medals.

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

Definitions

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

“Buffy coat”

Both of these types are cells are much less numerous in the blood than RBC’s


Circulation I

Q (or F) = ΔP

R

P1 P2

R

Q

The fundamental law of the circulation.

.

ΔP = pressure difference between 2 points in a circulation system.

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

P = force/area exerted by blood – generated by heart contractions.

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

R increases

Q decreases (flow slows)

Q (or F) = ΔP

R

The fundamental law of the circulation - Pressure.

ΔP = MAP – CVP

= 90 – 0 mmHg

= 1 Systolic P + 2 Diastolic P

3

MAP a weighted average of the time spent in each phase.

MAP is the overall pressure driving the blood into the tissues.

Fig 15-2

…where,

MAP = mean arterial pressureCVP = central venous pressure

Systemic vs Pulmonary PressuresΔP = MAP- CVP

Systemic = 90 mmHg Pulmonary = 15 mmHg

Recall: that Q = 5 L/minfor 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 foran even flow of blood through the system.

Low pressure low resistance circuit

1) Prevent fluid filtration in the lungs

3) Minimizes workload of the right ventricle.

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).

2) Prevents shunting of blood

Pulmonary Systemic

Fig 14-5

Right ventricle left ventricle

Shunting = the movement of blood in the body between

compartments, through thecirculatory system.

Poiseuille’s Law

π r4

8 η LR= -L of blood vessels is fairly constant. -Viscosity (η) is also fairly constant.

-Radius the most important factor in determining the resistance.

R α 1r4

e.g. Decreasing r by 2x Decreases flow by 16x

Q= π r4

8ηl

ΔP

What determines vascular resistance?

L

rQ

Polycythemia and decreased T˚C

Anemia and increased T˚C

constant

Since R=ΔP

Q

Polycynthemia = increase in # of RBC’s

Due to the constants, the resistance is dependant on

the radius.


Circulation III

Resistance vesselsCapable 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

In series

R1 R2 R3

RT = R1 + R2 + R3

Resistance greater thanany single R

R1 R2 R3

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

In parallelResistance is smaller

than any single R

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 thesame thing.

Fig 14-3

Capillary networks are small vessels arranged in parallel

Even though r is small per capillarytotal resistance of all capillaries

is relatively significant, due to the large number of capillaries in the

system.

Total Peripheral Resistance (TPR)

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 = cardiac output (CO)

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

Flow = ΔP /R

CO = MAP/TPR

Arteries ~12 mm

Arterioles~ 15

micrometresCapillaries~3

micrometresVenuoles ~10

micrometresVeins~5 mm

Low resistance, little pressure drop, acts as a pressure reservoir.

Major site of resistance, controls bloodflow patternshelps regulate arterial blood pressure.

Exchange site of nutrients and metabolic biproducts

Exchange of nutrients, O2, CO2 (but only a very small amount)

Low resistance, thin walled, distensible (stretchy),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)

mic

roci

rcu

lati

on

Inner radiusVascular system

See Fig 15-6

Varying degrees of elasticity and collagen fibre content.

Connective tissue

Smooth muscle

Endothelium(single layer of cells, which

allows for easy diffusion.

Fig 15-5

Capillaries contain a singlelayer of cells for easy diffusion

of blood.

Veins/arteries have valvesTo ensure a one-way flow

Of blood in the system.

ArteriesMuscular, highly elastic - High elastin to collagen ratio in

connective tissue

Compliance = ΔPΔV moderate compliance to smooth out

pressure fluctuations from the heart.

Large changes in pressure with small changes in volume make

arteriespressure reservoirs.

Large changes in volume with With small changes in pressure make veins volume reservoirs.

Fig 15-20

The higher the compliance the greater a vessel can be stretched,and therefore the higher the amount of elastin in the tissue.

Stores pressure which is then released between ventricle

contrations (diastole => relaxed)

Pressure stays in the walls when relaxed.

Arterial walls recoil during diastole, pushes blood

forwards and maintains blood flow at a constant

level.

Arteries as pressure reservoirs

Fig 15-7

Only 1/3 of the stroke volume(the volume the heart ejects per

contraction. Blood leaves the arteries at this time.

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 complianceof arteries – (low compliance = high PP)

e.g. hardening of arteries decreases ampherence(?) and PP

systolic

diastolic

PP

Arterioles are the major site of resistance in the circulatory system.


Circulation IV

Arteries as a pressure reservoir

Fig 15-7

•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

systolic

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

PP

Arterioles2 roles:

Control of vascular smooth muscle

Local (intrinsic)•Paracrine•E.g active hyperemic

Extrinsic1. SNS through NT norephinephrine (NorEpi)

2. PSNS (ParaSNS) not very important in controlling arterial radius

3. hormones

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

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)

See Fig 15-13

Fig 15-12

•Affects contraction of smooth muscle in vessel

wall

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

Fig 15-14

Increase in blood entering the tissue

Extrinsic controls

SNS

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

Table 15-2

•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

Fig 15-15

•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•Dominant effect usually vasoconstriction

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

See Table 15-1

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)

Fig 15-8

•Metarterioles act as bypass channels or shunts

from arteries to venuoles

•When resistance is low, blood may bypass capillary

bed

Capillaries

Important for:

•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

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

1) Continuous capillaries

Endothelial cell cleft

2) Fenestrated capillary

plasma

Fenestrations(pores)

Intercellulargap

See Figure 15.16a+bFigure 15.17

proteins

O2, CO2

O2, CO2

Na+, K+

proteins

• Most common type

• Small spaces (water-filled cleft) btwn endothelial cells

• Very permeable to lipid soluble molecules

• Less for water soluble solutes and proteins (passage restricted to water-

filled cleft)

• Proteins too large to pass through clefts• Also called sinusoidal capillaries

• Fenestrations can be large enough to allow large proteins or entire cell pass

(ex. WBC)

• High permeable capillaries

• Abundance in:

• Liver- plasma proteins synthesized (e.g albumin)

• Bone marrow- blood cell production

Bulk Flow

4 main forces determining direction of flow:

1) Capillary hydrostatic pressure (PCAP) filtration

2) ISF hydrostatic pressure (PISF) absorption

Two hydrostatic pressures due to fluids:

Two osmotic pressures (due to presence of non-permeating proteins – called oncotic pressure)

4) ISF oncotic pressure (ΠCAP) filtration

3) Capillary oncotic pressure (ΠCAP) absorption

Favours:

• 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

pre

ssure

Arterialend

Venousend

Bulk flow: net fluid flow across capillaries depends on the difference in filtration and absorption pressures

Net filtration pressure (NFP) =

PCAP= 38 mmHg PCAP= 16 mmHg

π ISF= 0 π ISF= 0PISF= 1 PISF= 1

π CAP= 25 mmHg π CAP= 25 mmHg

See Fig 15-18Table 15-3

(PCAP + (π CAP + π ISF) - PISF )

arterial venous

filtration

absorption

NFP = (38 + 0) – (25 + 1)

= + 12 mmHg

NFP = (16 + 0) – (25 + 1)

= - 10 mmHg

Because no proteins at ISF Blood Pressure

Osmotic Pressure

NFP -

NFP +


Circulation V

1) Continuous capillaries-More common type

-Small spaces (H20-filled cleft) between endothelial cells

-Very permeable to lipid soluble molecules

-Less for water soluble solutes & proteins (passage restricted to H20-filled cleft)Endothelial cell cleft

2) Fenestrated & sinusoidal capillaries

-Fenestrations can be large enough to allow large proteins or entire cells pass

(e.g. WBC)

-Highly permeable capillaries

-Liver – plasma proteins synthesized (e.g. albumin)

-Bone marrow – blood cell production

plasma

Fenestrations(pores)

Intracellulargap

O2, CO2

Na+, K+

proteins

proteins

-Proteins too large to pass through clefts

O2, CO2

See Figure 15.16a+bFigure 15.17

Bulk FlowCapillary membranes freely permeable to H2O and small solutes

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

1) Capillary hydrostatic pressure (PCAP) filtration

2) IF hydrostatic pressure (PIF) absorption

Two hydrostatic pressures due to fluids:

Two osmotic pressures (due to presence of non-permeating proteins – called oncotic pressure)

4) IF oncotic pressure (π IF)

absorption3) Capillary oncotic pressure (π CAP)

filtration

favours

Osmotic pressure

Blood pressure

pre

ssure

Arterialend

Venousend

Bulk flowNet fluid flow across capillaries depends on the differencein filtration pressure and absorption pressures

filtration absorption

Net filtration pressure (NFP) =(PCAP + π IF ) – (π CAP + PIF)

PCAP=38mmHg PCAP=16mmHg

π IF=0 π IF=0PIF=1 PIF=1

π CAP=25 π CAP=25

NFP +

NFP -

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

+12 mmHg -10 mmHg

See Fig 15-18Table 15-3

arterial venous

Filtration usually exceeds absorption with 3-4L entering

IF (= total plasma volume !)

This fluid is returned to the circulatory system by the

lymphatic systemLymph flow = ~4L/day

If not returned to circulation get edema

Extreme case failure of lymphaticsystem to clear fluid = elephantiasis

Due to low pressures there is normally no filtration in lung

capillariesFig 15-19

Filtration ~ 20L / dayAbsorption ~ 17L / day

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.)

Necessary force provided by ΔPbetween 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 return has a major effect of volume ejected by the heart= stroke volume

Thin-walled and highly compliant vessels to accommodate large volumes for small changes in pressure (“capacitance vessels”)

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

paracrine regulation of smooth muscle; respiratory & skeletal muscle pump

One-wayvalves

Skeletal muscle pump – muscle contraction increasesVenous pressure

Lower value closes and upper valve opens – reverse when muscle relaxes

Fig 15-22

The Heart

Composed of 3 layersOuter epicardium (connective tissue)

Myocardium (muscle)

Endothelium (extends throughout the CVS)

**Know functional anatomy and bloodflow patterns (see p421-422)

Mean arterial pressure (MAP) = CO x TPR Q x RΔP =

hr x SV

Cardiac muscleComposed of 3 cell types

1) 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

2) Pacemaker CellsDetermine the rate the heart beats

Located in 2 regions:

Two cell types display autorhythmicity: Spontaneously generate action potentials (AP’s)

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 toAV is blocked

AP - Membrane potential changes soinside of cell become (+) relative

to outside

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

(pacemaker)

Fastest depolarizing cells drive all other cells (they are linked together by gap junctions) =

pacemaker = sets pace for entire heart

Location Firing Rate at Rest SA Node 70-80 APs/min AV Node 40-60 APs/min Bundle of His 20-40 APs/min

Purkinje Fibers 20-40 APs/min

Autorhythmic Cells

Heart affected by changes in rates of AP generated by pacemaker

Regulation of heart rate (hr) (both rate & force are regulated)

Pacemakers get direct input by autonomic nervous system

SNS NE Acts on SA and AV nodes via β1 adrenergic receptors to increase hr

PSNS ACh Acts on SA and AV nodes via M2 muscarinic receptors to decrease hrVegus nerve

Cardiac nerve

(acetylcholine)Predominant factor in setting resting

heart rate of 70 bpm (rate without any inputs = 100bpm)

SNS and PSNS haveopposite effects

NOTE: SNS has more connections to myocardium

(more effects on forcethan PSNS)

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

Increases hr via same mechanisms as SNS

Temperature: directly alters the intrinsic rate of the SA nodeChanges hr by 15bpm / ˚C

e.g. 1 deg fever hr is ~85 bpm

Regulation of heart rate (hr)

Sequence of electrical events that triggers a heartbeat

1 AP initialed in SA node

AV node

Internodal & interatrialpathway

Spreads throughatrial muscle

2 Transmission slows down atthe AV node by ~0.15sec

3 AP transmitted through theAV node to the Bundle of HisDivides into the left and right

bundle branches

4 AP enters a network of branchesalong the ventricle muscle:

Purkinje FibersImpulse travels through ventricle

from apex towards valves

Fig 14-10

Ventricles have coordinated contractions

Separates atrial & ventriclestimulation

Biology 2A03

Lecture 12Circulation V

The Heart

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

**Know functional anatomy and bloodflow patterns (see p421-422)

Mean arterial pressure (MAP) = CO x TPR Q x RΔP =

hr x SV

Fig 14-1•All arteries don’t carry oxygenated blood

•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 muscleComposed of 3 cell types:-

1) 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

2) Pacemaker Cells• Determine the rate of heart beats

• Located in 2 regions:-

Two cell types display autorhythmicity: Spontaneously generate action potentials (AP’s)

i) 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

AP - Membrane potential changes soinside of cell become (+) relative

to outside

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

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

Autorhythmic Cells

•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

2

3

4

Fig 14-10AP initiated in SA

nodeSpreads

through atrial muscle

Internodal and interatrial pathway

AV node

Transmission slows down at the AV node by ~0-15s

Separator atrial & ventricle stimulation

AP transmitted through the AV node to the Bundle of His

Divides into L and R bundle branches

•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

SNS NE

PSNS AChVegus nerve

Cardiac nerve

(acetylcholine)

•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

•SA and AV nodes via M2 muscarinic receptor to

decrease hr

•Predominant factor in setting resting heart at

70bpm (rate without inputs = 100 bpm)

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 heart rate (hr):

Regulation of stroke volume•Volume ejected by ventricles with each heartbeat = stroke

volume (SV)•SV= end diastolic volume (EDV) – end systolic volume (ESV)

Ejection fraction =

p438

SVEDV

SV

EDV

ESV

EDV (ventricle filled) = 130mL

ESV (ventricle emptied) = 60mLSV (volume ejected) = 70mL

If EDV ↑ then SV ↑

If ESV ↑ then SV ↓

~67% at rest, increases during exercise

~33% of blood still left in heart


Circulation and Kidney I

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

Starling Law effects & *increased contractility (SNS, epi)

minor increase in MAP = CO*TPR

skeletal muscle dilation greater than constriction in other areas

Summary of cardiovascular changes during mild exercise

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.

Baroreceptor reflexes are the most important short term regulators of MAP (seconds to minutes)

The arterial baroreceptors continually monitor the systemic MAP and inform the cardiovascular control

centre in medulla of brain.

– Baroreceptors = stretch receptors

– Arterial baroreceptors • High pressure

baroreceptors• Sinoaortic

baroreceptors– Location

• Carotid sinusVia closso-pharyngeal nerves

(IX) (aka afferent branches)

• Aortic archVia vagus nerves (X) (aka

afferent branch)

X/IX refers to nerve designations, don’t need to

know them.

Fig. 15-26See Fig 15-27

Effect => stimulation of the autonomic nervous system.

The level of MAP is continually “coded” as A.P. frequency sent by the arterial baroreceptors.

Figure 15.25

A decrease in blood pressure (far right) gives less of a stretch, giving a decrease inThe rate of firing, opp holds true for middle (more stretch => increased RoF.

This is “reset” at a higher level in hypertension.

Baroreceptor (~30s reponse)

Note: remember this & previous slidefor tilt table experiment in next lab

– Following hemorrhage:

• Baroreceptor reflex • Increase in

sympathetic activity

• Decrease in parasympathetic

activity

– Result • Reflex

compensation

Figure 15.27

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 12.59Baroreceptorreflexes

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 MAPhappens at the kidney.

• 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

Kidney Function = Renal SystemChapter 19

Regulates:

kidney

Ureterundergoes wavelike

contractions of smooth

muscle.

Bladder smooth muscle with gap

junctions.

urethra

THE URINARY SYSTEM

Fig 19-1NOTE – all smooth muscles have gap junctions

Detrusor (smooth) muscle

ureters

Internal urethral sphincter

External urethral sphincter

THE URINARY BLADDER

Filling:•P.S.N.S = inactive

•S.N.S. = active•Somatic N.S. = active

involves co-operation of P.S.N.S , S.N.S. & Somatic N.SPeeing:

•P.S.N.S = active•S.N.S. = inactive

•Somatic N.S.= inactiveFig 19-21

PSNS control

SNS control (we control it consciously)

Skeletal Muscle under Somatic N.S control.

MICTURITIONREFLEX

Fig 19-22urination

Biology 2A03

Lecture 14

Kidney II

medulla cortex

ANATOMY OF A KIDNEY

Fig 19-2Read pages 579-584

Cortex

Medulla

t

t

t

t

pyramid

renalpelvis

Capsule (outertissue)

ureter NephronUses circulation

To filter waste

Lots of nephrons allows for easier/greater volume offiltration.

Nephron = basic unit of structure & function in the kidneyNephron = an individual kidney tubuleand 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.

Fig 19-3

Efferent Arteriole

Afferent Arteriole

Distal convoluted tubule

Common collecting

duct

Glomerulus inside of Bowman’s Capsule

Proximal convoluted tubule

Proximal tubule

Loop of Henle…loops into themedulla…important point, will be

covered later.

Afferentarteriole

Efferentarteriole

Fig 19-6

Glomerularfiltration

SNS input to both

To Renal Vein

GFR = GlomerularFiltration Rate

Peritubular CapillaryBed (reabsorbtion of

Stuff back into the blood)

Vasa Recta

This system uses Capillaries to help filter

stuff in and out

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.

• 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)

Nephron Components - Urine or Tubule side

The 3 Basic Exchange ProcessesPeritubular Capillaries

Afferent Arteriole

1. Glomerular Filtration passive due to Starling-Landis forces.

2. Tubular Reabsorption

3. Tubular SecretionMainly by active transport

Excretion

Efferent Arteriole

12 3

A Simplified Model of Nephron Function

(a) Many active transport processes for ions and nutrients.

(b) Passive diffusion (ions/nutrients) and osmosis (H20)

(c) Starling-Landis Forces.

Fig 19-7

Plasma may contain thingsthat cannot go through the

Bowman’s capsule therefore tubular secretion =>

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

• “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

1. Glomerular Filtration

Filtration fraction

Plasma flow = 625 mL GFR = 125 mL Filtration fraction = 125/625

= 20%

Afferentarteriole

Efferentarteriole

180 L filtered /day but only 1.5 L of urine excreted / day

Fig19-9

625 mL/min

~500 mL/min

125 mL/min

Fig 19-8

Bowman’s capsule

Basement membrane

Slit pore

podocyteFoot processes

Glomerulus membrane(filtration barrier)

Endothelial cell

Epithelial cell (podocyte)

fenestration

Fenestrations/slit poresAllow for movement of

Proteins under a certain Specified M.W. (68K Da)

Glomerular capillary

Bowman’s Capsule

Filtration Barrier at M.W ~ 68,000

• podocyte slit pores• basement membrane

matrix - negative charge repels proteins• endothelial fenestrae

Filtration Barrier

Lecture 15

Kidney III

Fig 19-8

podocyteFoot processes

fenestration

Glomerulus membrane(filtration barrier)

Endothelial cellBasement membraneEpithelial cell (podocyte)

Slit pore(between podocytes)

Renal corpuscle

Filtration slit

Glomerular capillary

Bowman’s Capsule

Filtration Barrier at M.W ~ 68,000

• podocyte slit pores• basement membrane

matrix - negative charge repels proteins• endothelial fenestrae

Filtration Barrier

1. Glomerular Filtration

NFP = (PGc + piBC) – (PBC + piGC)

= (60 mm Hg + 0 mm Hg) – (15 mm Hg + 29 mm Hg)

Starling -Landis Forcesinvolved in glomerular filtration

Fig 19-9Recall PCAP = 38 mm Hg for a systemic capillary

PGC

PBC

PiGC

PiBC

= + 16 mm Hg (net positive pressure outwards)

Constrict aff. arteriole? = increase aff. resistance =

decrease NFP = decrease GFP

Constrict eff. arteriole? = increase eff. resistance =

increase NFP = increase GFP

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

Afferentarteriole

Efferentarteriole

PGC

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.

Na+

Cl-

K+

Ca2+

HCO3-

H2OGlucose

Amino acidsVitamins

Ureacholine

H+

Na+

Cl-

K+

Mg2+

Ca2+

Na+

K+

Cl-

K+

Ca2+

H+

HCO3-

H2OUrea

K+

H+

NH4

H2O

H+

K+

Ca2+

Na+

Cl-

H2O

medullaryosmoticgradient

CCD

DCT

Some Patterns of Renal Handling

Filtered & additionallysecreted so totally

cleared from blood - e.g. PAH = Para-

amino hippuric acid

Filtered & largely but not completely

reabsorbed - e.g. H2O, ions, etc

Filtered & completely and reabsorbed, ie most

nutrients, such as glucose, amino acids

Reabsorption Barrier

Active transport of Na+ and glucose co-transport

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.

Reabsorption Barrier

Tight junctions between epithelial cells restrictparacellular 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

Filtered load

Excretion = Filtered (F) + Secreted (s) – Reabsorbed (R) = GFR*[x] + S – R [plasma content of object X being examined]

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)

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

• 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 contain 450 microg of PAH)

Excretion Rate

Conc in plasma

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 2A03Lecture 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

microgramAmount of plasma that would contain 450ug of

PAHp = plasma

u = urine

uFR = urine flow rate


• 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


• 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+ - vegetarians

Regulation of NaCl and H2O by the Kidney

- 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.

- Cl- follows Na+ passively therefore we will focus on Na+ reabsorption.

The Medullary Osmotic Gradient

aquaporins

1. Proximal tubule and cortex (leaky tight junctions)2. make descending limb permeable to H2O

3. Ascending limb but actively transport ions

H2O Reabsorption

Cortex

Medulla


Collecting Duct •Water is reabsorbed passively (osmosis),

generates a [ ] gradient

•Depends on O.P (1. Loop of Henle, 2. NaCl reabsorption)

•Counter-current multiplier system (loop of henle) serves to create high osmotic

pressure in ISF and blood vessels through which the CCD runs

•Tubular fluid is hypo-osmotic

•Water reabsorption is regulated by the permeability of DDT and CCD

100 mOsM

300 mOsM

1400 mOsM

O.P

onto bubble

H2O Reabsorption – DT/CCD Impermeable

100mOsm

100mOsm

100mOsm

100mOsm

100mOsm

300mOsm

1400mOsm

600mOsm

1000mOsm


•No water reabsorption (in this scenario)

•Urine has low osmolarity and high volume

100mOsm

300mOsm

1400mOsm

600mOsm

1000mOsm

H2O Reabsorption – DT/CCD Permeable


300mOsm

600mOsm

1000mOsm

1400mOsm

water

water

water

water

•water reabsorbed (in this scenario)

•Urine has high osmolarity and low volume

H2O Reabsorption – Regulation by ADH Regulation of NaCl and H2O by the

Kidney

•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.PADH

ADH receptorAquaporin 2

water

Aquaporin 3

cAMP/PKA pathway

waterwater

Lumen ISF Plasma

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


Ethanol (inhibits this)

Longterm Regulation of MAP

•Dehydration

•Brain shrinkage HANGOVER

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+]

Na+

K+

Na+

K+

K+Na+

receptor

aldosterone

Na+/K+ ATPase

(3 Na+ in/ 2 K+ out

[K+] [K+] [K+]Passive Active

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 KidneyInteractions 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 [NaCl]

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


Kidney cont… & Neuro I

Regulation of NaCl and H2O by the KidneyInteractions 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 [NaCl]

Low ADH / Low Aldosterone

High ADH / High Aldosterone

Low ADH / High Aldosterone

High ADH / Low Aldosterone

Highest Quite High

Lowest Quite Low

Quite High Lowest

Quite Low Highest

Two other hormones also control nephron function:

2. Angiotensin II - part of Renin-Angiotensin System (“RAS”)

1. 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.

Angiotensinogen is a large plasma protein, originally produced in the liver, and is ALWAYS present in large

amounts in the plasmaRenin 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:•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.

Fig. 20-15

See Fig 20-23 for overviewof response to hemorrhage

Changes in GFR can be used to regulate water loss

Control of GFR by constriction and vasodilation

NOTE: the patterns in change in flow is importantand most likely will be on the tests.

Controlled by hormone action

Neurophysiology I

Function of the Nervous system

- collects sensory information from specialized cells (sensory receptors).

- 2 cell types: neurons, glial cells

- processes sensory information (integration).

- transmits appropriate information (response) to effector organs (muscles, glands).

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)

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).

Function of PNS:

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

-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.

-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.

-Can be structurally and functionally classified.

Sensory/receptor

Effector organs

3 Functional classes of Neurons, Fig 8.4, pg 215

Structure of a Typical NeuronDendrites: numerous small 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.

Signal Direction

Two neurons communicating:

Synapse: neurotransmitter. Signal passed from presynaptic

neurons to post synaptic neurons

.

( Fig 8.2, pg 212)


Neurophysiology II

Sensory/receptor

Effector organs

1. Afferent neuron (input)

2.interneurons

3.Efferent neuron (output)

3 Functional classes of Neurons, Fig 8.4, pg 215

3 Structural Classes of Neurons, Fig 8.3, pg 214

2. Bipolar: 1 axon, 1 dendrite, generally

sensory neurons (olfaction = smell).

3. Pseudo-unipolar: subclass of bipolar, majority of sensory,

neurons, 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

Schwann Cells are the most numerous glial cells

in in the P.N.S.

Oligodendrocytes are the most numerous glial

cells of the C.N.S. Myelin sheath: multiple layers of

myelin lipid formed by plasma

membranes of glial cells wrapped

around axons like a jelly-roll. Functions

as insultation for the signal being

transmitted.Myelin sheath is regularly interrupted at

the Nodes of Ranvier (a.k.a. just Nodes)

Nodes

Schwann cell

Axon

oligodendrocyte

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.

Myelin Sheath

3 Basic Principles of Membrane Potentials

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.

Note: All cells have a “membrane potential” BUT we’ll focus on the membrane potential of neurons.

A difference in “electric charge” or voltage across the membrane of cells.

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

Inside Neuron

OutsideNeuron

3 Na+

2 K+

Electrogenic Na+/K+ -ATPases i) move more +’ve

charge outside the cell. ii) move K+ and Na+ against

the gradient to maintain an unequal distribution across

the membrane.

-70mV

RESULT: negative resting membrane potential.

Na+

K+

GK+ >> GNa+ :this means that more K+

leaves the cell than NA+ entering the cell. This

differential permeability of the membrane to

K+/Na+ leads to more +’ve charge leaving the

cell.

K+

K+

Na+

Cl-

Na+

A-

(Organic anions)

Electrical Potential

Equilibrium Potentials and Nernst Equation

(Chapter 4)

- 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.

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


- 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.**


Nernst Equilibrium Potential (EN) for K+:

EK+ = 61 log [K+]o [K+]i

= 61 log[4mM] [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

The Nernst Equation: (calculation of equilibrium potential)

EIon = - 61 log[Ion]outside [Ion]inside

Made from 4 constants (the -61)


- Na+ unequal distribution is a long way from equilibrium. Compare EM (-70 mV) with ENa

+ (+60 mV).

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).

- Therefore, greatest driving force for diffusion of Na+ (important for APs).

Note: by Nernst equation, -61 mV can sustain a 10-fold concentration difference because log 0.1 = -1.


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.

(EN) for Na+:= 61 log [145 mM] = +60 mV [15 mM]

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.

EM = -70 mV

Changes in Membrane Potential: Terminology

Resting Membrane Potential

K+ Equilibrium Potential

Na+ Equilibrium Potential

Fig 8-9, pg 223

Cl- Equilibrium Potential

Depolarization (membrane

becomes more positive)

Repolarization (return towards

resting spot)

Hyperpolarization (membrane

becomes more negative)

Changes in ion permeabilities (Gi)

Fig 8.9, pg 223

Na+ Equilibrium Potential

Resting Membrane Potential

Cl- Equilibrium Potential

K+ Equilibrium Potential

If GK+ increases, EM will move towards – 94 mV, causing a hyperpolarization or repolarization.

If GNa+ increases, EM will move towards +60 mV = depolarization

If GCl- increases, EM will move

towards -80 mV, causing

hyperpolarization.

NOTE: in some cells ECl- = EM: “passively distributed”. In this

case changing GCl-has no effect on EM.

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

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).

Axon Hillock

Fig 8.11, pg 226

Current Flow

Decrease in G.P. size with distance from origin is due to

decremental local current flow.

stimulus

Size of the arrows is proportional to the size of the GP’s in that area

Graded Potentials (GPs)

- 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).

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.

Fig 8.10, pg 225

Weak stimulus Strong stimulus

GP is “grade” in proportion to the strength of the stimulus.

Inhibitory, K+, Cl-Excitatory, Na+

Increased GK+, or GCl-

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

threshold threshold

At excitatory synapses, the neuro-transmitter generally opens both

Na+ & K+ channels ==> increased GNa+ & increased GK+==> net

depolarization“Excitatory Post-Synaptic Potential

“

At inhibitory synapses, the neuro-transmitter generally opens either K+ or Cl- channels ==> increased

GK+ or increased GCl-==> hyperpolarization

“Inhibitory Post-Synaptic Potential”

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 conducted instantaneously to “initial segment” (axon hillock) by

decremental local current flow.

At the initial segment, process of summation occurs - threshold potential may or may not be reached ==>

decision = integration of the signal .

The closer the origin of a PSP to the initial segment, the larger it still is when it arrives theres.

Temporal Summation – PSP’s in quick succession add up.

Spatial Summation - PSP’s from different synapses add up.

The threshold potential is lowest ==> easiest to reach at the initial segment.

Fig 9-8

Illustration of Integration

Integration normally occurs here

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 obey the “all or none rule” (unlike 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

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 questionsSame rooms as before – check LearnLink

80% new material, 20% from Lectures 1-11Bring: calculator, valid i.d.


Neurophysiology IV

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.

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

AP’s are a constantsize – obey an

“all ornothing rule”

AP’s are short-lasting relative to

GP’s

1. Resting potential- EM determined by leakage channels only: GK+ >> GNa+

1

1-2. EM increases due to G.P. & voltage-gated Na+ channels start to open. Na+

ions enter causing partial depolarization.22. At threshold potential, entry of Na+

ions exceeds exit of K+ ions= depolarization

Voltage-gated Na+ channels open explosively in a positive feedback loop:

GNa+ >> GK+ 3. So many voltage-gated Na+ channels

are open that EM surpasses 0 mV & enters overshoot phase. EM starts to

approach the equilibrium potential for Sodium (ENa+)

3

4. Before EM reaches ENa+, the voltage-gated Na+ channels automatically

close and voltage-gated K+ channels automatically open. GNa+ decreases and GK+ increases. K+ ions start to

exit. EM starts to return towards 0 mV (repolarization starts to occur)

4

GGNa+.

GK+

Direction of Na/K movement isNOT specified.

12

34

5-6. Exit of K+ ions greatly exceeds entry of Na+ ions resulting in

repolarization GK+ >> GNa+. EM decreases towards EK+

6-7. Hyperpolarization continues with EM close to EK+, because some

of the voltage-gated K+ channels remain open for some time.

(therefore a fairly high Potassium conductance for a while)

5

67

GGNa+.

GK+

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

GNa+.

Depolarization opens the activation

gate

~1 millisecond

Inactivation gate closes until EM returns to the

resting state.

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

Absolute Refractory Period (no second AP possible,

regardless of the stimulus) No 2nd AP possible regardless of stimulus

Relative RefractoryPeriod

Stronger than normal stimulus needed for

an AP

Refractory period plays an important role in information coding

at the initial segment, because the further above threshold is the G.P., the greater the frequency, until the

absolute refractory period is reached.

At sensory receptors, the greater the intensity of the

stimulus, the greater the G.P., and the greater the frequency,

until adaptation occurs.

Information is coded as the frequency of A.P.’s

Increased stimulus duration

Increased stimulus strengthcausing more/faster AP’s

Suprathreshold stimuli = above the threshold stimulus

Time between AP directlyrelated to amplitude of GP

Fig. 8-18

Gradient Potentials

Gradient Potentials

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.


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):

non-myelinated “slow” post-ganglionic fibres

of SNS & PSNS.

Myelinated “fast”fibres of somatic nervous

system.

Diameter: Myelination: ConductionVelocity:

~2 um 1-2 layers

~12-25 um ~100 layers

0.5-1.0 m/sec

75-100 m/s

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 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

Chemical Synapse

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 cellsNote: 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:

- auto receptors on pre-synaptic membrane may down-regulate subsequent n/t release.

- Multiple transmissions may temporarily exhaust synaptic vesicles of n/t.

- 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 synapsewith each other before synapsing with the

axon

Neuron content is differentAnd 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

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.

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

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 junctionsbecause summation of G.P.’s does not occur there.


Cell metabolism I and II

2. Cellular respiration:e.g. C6H12O6 +6 H2O+ 6O2 ===>

12H2O + 6CO2 + 38 ATP

1. Gas exchange:movement of O2 from environment to cell (mitochondria) & movement

of CO2 in opposite direction

Two meanings of “respiration” (both correct)

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

ADP + Pi

ATP consumption

MovementMembrane transportMolecular synthesis

ATP production

Metabolic pathwaysCarbohydrates

Lipids (fats)Proteins

ATP can be produced by:

Substrate–level phosphorylation:(can occur in the absence of O2)

c) Oxidative phosphorylation(by definition uses O2 in mitochondria)

a) Glycolysisb) Kreb’s Cycle (TCA or citric acid cycle)

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 3-18Fig 3-19

-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)

Chemiosmotic model

Fig 3.19O2 .O2

-

-Heat and Reactive Oxygen Species (ROS) are other byproducts

Acetyl-CoA

Aminoacids

Fattyacids

Glucose

pyruvate

CO2PDH

Kreb’sCycle

CO2

CO2

NADH & FADH2

(reduced e- carriers)

ETC2H+ + ½ O2

H2OADP + Pi ATP

e-

e-e-

e-

e-

e-

e-

e-

e-

Stage 1 -Acetyl-CoA production

glycolysis -Pyruvate is derived from glucosevia glycolysis – 2 NADH + H+ formed

-Oxidized to acetyl-CoA bypyruvate dehydrogenase complex

(PDH) – 2 NADH + H+ formed

Stage 2 -Acetyl-CoA oxidation

Stage 3 - Electron transfer and oxidative phosphorylation

See Fig 3-21Fig 3-23

lactate

-acetyl groups from pyruvatefatty acids and amino acids

enterthe Kreb’s cycle

- 3NADH + H+ and 1FADH2 formedfor each pyruvate

-Electrons transferred from reducing equivalents to ETC

ATP yields from fuel sourcesAnaerobic glycolysis: (O2 not used)

10 enzymatic steps

Fig 3-22

Harmful waste product

Substrate level phosphorylation

Reduction-oxidation balance maintained(cytosol redux)

Aerobic metabolisms of:

Carbohydrates:

Glucose

Glycolysis + oxidative phosphorylation

2 pyruvate 2 ATP & 2 NADH + H+2Pyruvate 2 acetyl-CoA 2 NADH + H+

2 acetyl-CoA Kreb’s Cycle 2 ATP, 6 NADH + H+ & 2 FADH2

3ATP / NADH + H+, 2ATP / FADH2

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

See Fig 3-21

ATP

2+66

2+18+4

38 ATP

CO2

0 4 2

6 CO2

ATP

ADP + Pi

Short-term regulation

Phosphocreatine (PCr)ATP storesGlycogen

work

Long-term regulation

Oxidation of:Glucose and Glycogen

FatsProteins

ATP supply ATP demand

Homeostasis of muscle ATP

MovementMembrane transportMolecular synthesis

PCr + ADP + H+ ATP + creatine

Glucose + 2Pi + 2ADP

2lactate + 2ATP + H2O

Glycolysis

ATP hydrolysis and Phosphocreatine buffering

0-10 seconds

4 to 120 seconds

Oxygen is not involved

CPK

Short-term regulation of [ATP]

Oxidative metabolism

Glucose +6O2 + 36ADP + 36Pi

6CO2 + 6H2O + 36ATP

Carbohydrate oxidation

Lipid oxidation

Trioleate (C57H104O6) + 80O2

57 CO2 + 52H2O + 104ATP

2-5 hours!

Oxygen required

Respiratory exchange ratio (RER)Also called respiratory quotient

(RQ)= CO2 produced/ O2 consumed

= 6 CO2 / 6 O2 = 1.0 for carbohydrates

RER = 57 CO2 / 80 O2 = 0.75 for fat

2. Cellular respiration:e.g. C6H12O6 +6 H2O+ 6O2 ===>

12H2O + 6CO2 + 38 ATP

1. Gas exchange:movement of O2 from environment to cell (mitochondria) & movement

of CO2 in opposite direction

Fig. 17-2

Conducting zone -no gas exchange

between air & blood here

Respiratory zone

Anatomy of the respiratory tract

Biology 2A03

Lecture 23Respiration I

Fig. 17-2

Conducting zone -no gas exchange

between air & blood here

Respiratory zone

Respiratory bronchioles

Anatomy of the respiratory tract

Larynx

trachea

PrimaryBronchi

SecondaryBronchiTertiarybronchi

Alveolar sacAlveoli

Reinforced with cartilage & smooth

muscle –Prevents gas exchange

with blood

Little cartilage or smooth muscle –

allows gas exchange with blood

Fig. 17-3

Anatomical features

Differences in wall thickness important for gas exchange

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 particles

Fig. 17-5

Respiratory Zone

Alveoli arranged in clusters

connected by pores whichallow equalization ofpressure in the lungs

Type I cells = epithelial layer

Type II cells = surfactant prod.

Macrophages= engulf foreign particles and pathogens

The Respiratory Membrane

T: Thickness A: Surface Area

K: Permeability Gas Constant

Diffusion rate = K x A x ΔPT

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

Respiratory Zone -site of O2 & CO2 exchange with blood

• Respiratory bronchioles• Alveolar ducts• Alveoli - 90%

10%

Lung Disease X

Alveolar surface is wet for gas exchange highSurface 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.

Chest Wall and Pleural Sac

760mmHg

756mmHgor -4mmHgrel to atm

Parietal pleura attached to thorax

Intrapleural fluidMuscus, negative

pressure

Visceral pleura attached to wall of

lungs

Fig 17-9

Pneumothorax - a rupture which connects the intrapleural space to the outside atmosphere

elimintates the negative pressure breathing becomes ineffective and the lung

may collapse.

The flexible, lubricated connection created by the negative intrapleural space ensures that when thorax changes size during breathing, the lungs

will follow

Inhalation - active phase during both rest & exercise

Breathing Cycle

•External intercostal muscles pull ribs out & up

•Diaphragm shortens and moves down

ThoracicVolume

==> LungVolume

==> Negative pressure in lungs (i.e below atm pressure)

==> Air flows in from atmosphere

“thoracic suction”

Exhalation - passive phase during rest - slow

•Internal intercostal muscles pull ribs

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

ThoracicVolume

==> LungVolume

==> Positive pressurein lungs (i.e above

atmospheric pressure)

==> Air flows out to atmosphere

Breathing Cycle

•Due to elastic recoil of thoracic & lung components

Exhalation - active phase during

**Prof Didn’t Cover This Slide. Maybe because it’s the same as the next slide**

•Internal intercostal muscles pull ribs in and down

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

upwards

Exhalation - passive phase during rest - slow

Exhalation - active phase during exercise - faster

•Due to elastic recoil of thoracic & lung components

Thoracic Volume

==> LungVolume

==>

Positive pressure in lungs (i.e above atm pressure)

==> Air flows out to atm

Thoracis pressure


Respiration II

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

Mon. March. 12, 2007

SpirometryTechnique used to measure air volume

Tidal Volume = amount of air breathed in and out on a single breath ~ 0.5 LInspir. 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 ~ 1LInsp. 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

Spirometer record

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 ?

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.

Not equivalent to each other

Anatomical Dead Space-New air always 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 (of dilution factor)

==> 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)

= (500ml x 12breaths) – (150ml x 12 breaths)

= 4200ml/min instead of 6000 without VD

150

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

Anatom. dead

space gets

pushed into

alveoli

Partial Pressure- a measure of the thermodynamic activity of gas molecules

diffuseGases 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 complicatedPartial 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

PO2 = 160 torr

Otherwise, to find the partialpressure, we need to apply Henry’s Law, & know both the concentration

& 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 torrPCO2 = 0.40 mL CO2/1000 mL water

1.32 mL CO2/1000 mL water/torr = 0.3 torr

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)

CO2 is about 30 x more soluble than O2 in water

The capacity of water to hold CO2 ( 0.40 mL/1000 mL water) is comparable to capacity of air to hold CO2 (0.39 mL/ 1000 mL air)

PO2 = 160 torr

PO2 = 160torr [O2] = 7 mL O2/ 1000 O2/1000 mL

[O2] = 210 mL O2/1000 mL Here, gases diffuse according to their partial pressures, not according to

their concentrations

Basic Components of gas transfer systems

1. Breathing movements

Continuous supplyto resp. surface

(convection)

2. Diffusion of O2 and CO2

across resp. epitheliumto blood.

3. Bulk transport

4. Diffusion of O2 and CO2

across capillary wallsto mitos in cells

Most of the total gas transport occurs by convection; diffusion is so slow that it is used only over very short distances - a

few um’s

PO2 drops with each step in O2 transport

PO2 at cell surface must be high enough for O2 diffusion to mitochondria.

The oxygen cascade

Biology 2A03

Lecture 25Respiration III

Alveolar partial pressures are very different from

outside air

PO2

160PCO2

0.3100

40

10040

10040

≥46≤40

All in mmHg(Torr)

4640

Partial pressures are the same in “venous” blood leaving the

systemic capillaries & entering the pulmonary capillary beds

4640

Memorize these key PO2 & PCO2

valuesSee Table 18-1

Systemic arteries

cells

Systemic veins

Alveolar air

Pulm veinsPulm arteryThe partial pressures are the same between compartments. Where the

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!!

These areas of diffusion have significantly different pressures

compared to the previous compartment

O2Transport in the Blood

1.5% - physically dissolved in plasma and RBC cytoplasm.

98.5% - chemically combined with hemoglobin (Hb)


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 thelevel of the single Hb molecule


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.

Fig 16-3

1 Hb = 4 globins + 4 hemes

Note: binding of O2 to Fe2+ is via an ionic bond, not an oxidation-reduction reaction

2 alphachains of141 aa’s

2 betachains of146 aa’s

All identical

A “functional” model of Hb

- - - - - - - - - - - - - - - -

Fe2+

Fe2+

Fe2+

Fe2+

-

-

-

-

- - - - - - - - - - - - - - - -

- - - - - - - - - - - - - - - -

- - - - - - - - - - - - - - - -X X X XX

X X X X X

X X X X X

X X X X X

Hemes GlobinsH+ H+ H+ H+ H+

H+ H+ H+ H+ H+

P P P P P

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.”

CO2

CO2

CO2

CO2

O2

O2

O2

O2


- - - - - - - - - - - - - - - -

Fe2+

Fe2+

Fe2+

Fe2+

- NH2

- NH2

- NH2

- NH2

-

-

-

-

- - - - - - - - - - - - - - - -

- - - - - - - - - - - - - - - -

- - - - - - - - - - - - - - - -X X X XX

X X X X X

X X X X X

X X X X X

O2

O2

O2

O2

Hemes Globins

CO2

CO2

CO2

CO2

H+ H+ H+ H+ H+

H+ H+ H+ H+ H+

P P P P P

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

Hb Hb(O2)4

High PO2 at the lungs promotes the formation of

exyhemoglobin

Low PO2 at the tissues promotes the formation of

deoxyhemoglobin

4x O2

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)

(driving force)Fig 18-8

PaO2PvO2

0

50

100

150

200

ml O

2 p

er

1000 m

l b

lood

Venousreserve

Fig 18-8

Loading point in pumonary capilaries

Unloading point inSystemic capilaries

Situation at rest

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 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.


- - - - - - - - - - - - - - - -

Fe2+

Fe2+

Fe2+

Fe2+

- NH2

- NH2

- NH2

- NH2

-

-

-

-

- - - - - - - - - - - - - - - -

- - - - - - - - - - - - - - - -

- - - - - - - - - - - - - - - -X X X XX

X X X X X

X X X X X

X X X X X

O2

O2

O2

O2

Hemes Globins

CO2

CO2

CO2

CO2

H+ H+ H+ H+ H+

H+ H+ H+ H+ H+

P P P P P

P P P P P



PCO2 = 55 TorrpH 7.6

pH 7.4

pH 7.2 Temp = 39ºC

P50

Loading point at restUnloading point at rest

Unloading point during exercise


pH 7.4

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

Loading pt.During exer.

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


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.

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.

Bohr Shift


- - - - - - - - - - - - - - - -

Fe2+

Fe2+

Fe2+

Fe2+

- NH2

- NH2

- NH2

- NH2

-

-

-

-

- - - - - - - - - - - - - - - -

- - - - - - - - - - - - - - - -

- - - - - - - - - - - - - - - -X X X XX

X X X X X

X X X X X

X X X X X

O2

O2

O2

O2

Hemes Globins

CO2

CO2

CO2

CO2

H+ H+ H+ H+ H+

H+ H+ H+ H+ H+

P P P P P

P P P P P



Increasing temp weakens the ionic bond between Iron and O2

PCO2 = 55 Torr

Temp = 39ºC

Unloading at rest Loading at rest

pH 7.4

pH 7.2

Unloading during exercise

P50, where 50% of O2 is bound to Hb

Loading point at restUnloading point at rest

Unloading point during exercise


pH 7.4

pH 7.2 Temp = 39ºC

Loading point

during exercise

During exercise, O2 unloading can be increased to 90% (i.e. venous reserve decreased to 10%) by combined effect of

Organic phosphate molecules are also important negative allosteric modifiers of O2 binding, but play

little role during exerciseMammals - 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 most 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

% Hb-O2

PO2 (torr)

Mucles (Mb)

Blood (Hb)


Respiration V

CO2 Transport in Blood

10 % - physically dissolved in plasma and RBC cytoplasm

30% - chemically combined with hemoglobin (Hb) as carbamino-CO2

There is a lot more CO2 than O2 in the blood

60% - as the HCO3- ion, mainly dissolved in the plasma

CO2 + H2O <====> H2CO3 <====> H+ + HCO3-

slow fast

carbonic anhydrase

XBuffered

by HbMoves into plasma in

exchange for Cl-

Carbonic anhydrase is the 2nd most abundant protein in RBC’s after Hb.

90% depends on presence of Hb & RBC’s

Both of these reactions tend to shift curve to the right, thereby helping to

unload O2.

“Band 3” Cl-/HCO3- exchange

= chloride shift

Fig 18-11

Most bicarbonate transported in

plasma

Driving pressureCells ==> capillary

Both of these reactions tend to shift curve to the

left, thereby helping to load O2 into the cells.

Fig 18-11

Driving pressure for CO2Driving pressure for CO2

Driving pressure for CO2 blood => alveoli

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

right in the systemic capillaries, .

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

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 the 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

Fig 18-15

Apneustic center

Pneumotaxic center

Respiratory control center

Rhythmicity center

I neurons E neurons

Spinal cord

Ventilatory muscles for inhalation(Diaphragm and intercostals)

x x

1) Regulation of inhilation/exhalation rhythm2) Regulation of rate and depth

Autorhythmicity and inhibit each other

Fires duringInhilation

Fires during exhalation

Always ON(not rhythmic)

Cyclically active(has a pacemaker)

Stimulates inhilation Terminates inhilation

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

Central Regulation of Ventilation

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

Figure 18.20

More sensitive and accurate than peripheral

chemoreceptorsMonitors PaCO2 through

changes in cerebral spinal fluid (CSF) and a resulting change in

pHCO2 can cross blood-brain barrier while H+ cannot easily

cross this barrier

Lots of carbonic anhydrase in the CSF

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

- connected to “respiratorycontrol centre” in pons & medulla

via glosso-pharyngeal nerves (IX)(afferent branches)

pons

medulla

via vagus nerves (X)(afferent branches)

Note: do not confuse with arterial baroreceptors, which

are a separate system.Fig 18-18

CarotidChemareceptors

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


Respiration VI

Peripheral (“Arterial”) Chemoreceptors

- connected to “respiratorycontrol centre” in pons & medulla

via glosso-pharyngeal nerves (IX)(afferent branches)

pons

medulla

via vagus nerves (X)(afferent branches)

Note: do not confuse with arterial baroreceptors, which

are a separate system.Fig 18-18

Carotid chemoreceptors

Aorticchemoreceptors

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)

mediated entirely via peripheral chemoreceptors

mediated almost entirely via

Peripheral chemoreceptors

(H+ does not easily cross blood brain barrier)

Fig 18-19

% sat drops

Hyperventilation decreased PCO2 and therefore H+

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

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

There are 2 major buffer systems in the blood that minimizechanges in free [H+] and [OH-]

1. Protein system (e.g. Hb, plasma proteins): H+ + Protein (neg) => H-Protein

OH- + H-Protein => H2O + Protein

2. CO2/HCO3- system:

H+ + HCO3- CO2 + H2OOH- + CO2 HCO3-

Depression of the nervous system

(coma)Normal pH

Over excitation of the nervous system – tetany of muscles

Minimizes but doesn’t reverse pH changes

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):

CO2 + H2O <====> H2CO3 <====> H+ + HCO3

-

carbonicanhydrase

Reaction does not go to equilibrium because HCO3- exported to the plasma by Chloride Shift

CO2 + H2O <====> H2CO3 <====> H+ + HCO3-

carbonicanhydrase

Respiratory Acidosis - If CO2 production exceeds excretion by ventilation==> net H+ and HCO3-

buildupRespiratory 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:

CO2 + H2O <====> H2CO3 <====> H+ + HCO3-

carbonicanhydrase

Respiratory disturbances -due to a disturbance of dissolved plasma [CO2] which is

regulated by breathing - fast (sec - min) :

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)

Constant

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

pH = pK + log [anion of acid]/[acid] = 4.0 + log[HCO3-]/[H2CO3]

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

c.a.

The Henderson-Hasselbalch Equation

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

-] Diss. [CO2] PaCO2 x aCO2

constant constant

Regulated by breathing ~ fast

constant

Regulated by metabolism & kidney ~slow

pHa = ~ 6.1 + log [HCO3-]

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+).

24 mmoles/L40.5 torr * 0.03 mmoles/L


PaCO2 x aCO2*

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

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

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

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

-Ventilation increases quickly to compensate, thereby lowering PaCO2.

-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


Respiration VII

Hormones I

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

pH = pK + log [anion of an acid] = 4.0 + log [HCO3-]

[acid] [H2CO3]

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

c.a.

======>The Henderson-Hasselbalch Equation

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

-] Diss. [CO2] PaCO2 x aCO2

~constantconstant

~constant

regulated by metabolism & kidney -slow

regulated by breathing -fast

pHa = ~ 6.1 + log [HCO3-]

PaCO2 x aCO2

pHa = ~6.1 + log 20 = 7.4


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+)

24 mmol/L

40.5 Torr x 0.03 mmol/Torr


PaCO2 x aCO2*

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

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

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

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

-Ventilation increases quickly to compensate, thereby lowering PaCO2.

-Ventilation decreases quickly to compensate, thereby raising PaCO2.

Fick Principle for O2 consumption:Tissue VO2 = Q x (CaO2 – CvO2)

=5L/min (200 ml O2/L – 150 ml O2) = 250 ml/min

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

During heavy exercise= 22 L/min (200 – 80 ml

O2)= 2800 ml/min

The ob gene encodes the hormone leptin

The ob / ob obesity mouse

Endocrinology

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.

- not completely separate from the .

(1) are often under nervous control.

- endocrine glands ==> secrete products .

(exocrine glands ==> secrete products to outside or via a duct leading to outside)

(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

Adipose tissuee.g. leptin

e.g. TH

e.g. Epicortisol

ANP

Renin, EPO

estrogen

testosterone

e.g. insulinsomatostatin

3 Classes of Hormones1. Amines (derived from a.a.

- Adrenomedullary hormones (catecholamines):

Dopamine - n/t & hypothalamic hormone which

Norepinephrine & epinephrine -

- Serotonin (5-hydroxytryptamine) -n/t & hormone derived from

tryptophan - involved in sleep, surpressing stress responses, &

moods. - Thyroid hormones (T4 = thyroxine, T3= triodo-thyronine) derived from tyrosine - regulate

metabolic rate, growth, brain development.

Other amines:

1

2

3

4

synth

Bio 2A03Lecture 30

Hormones I

The ob gene encodes the hormone leptin

The ob / ob obesity mouse

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.

- not completely separate from the nervous system.

(1) Endocrine glands are often under nervous control.

- endocrine glands ==> secrete products directly into ECF.

(exocrine glands ==> secrete products to outside or via a duct leading to outside)

(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.

(see Table 5-6 for comparison with NS)

e.g. GH, ADH

Adipose tissuee.g. leptin

e.g. TH

e.g. Epicortisol

ANP

Renin, EPO

estrogen

testosterone

e.g. insulinsomatostatin

1. Amines (derived from a.a. tyrosine, tryptophan):- Adrenomedullary hormones

(catecholamines): Dopamine - n/t & hypothalamic

hormone which inhibits prolactin secretion

Norepinephrine & epinephrine - n/t’s & adrenomedullary

hormones

- Serotonin (5-hydroxytryptamine) -n/t & hormone derived from

tryptophan - involved in sleep, surpressing stress responses, &

moods. - Thyroid hormones (T4 = thyroxine, T3= triodo-thyronine) derived from tyrosine - regulate

metabolic rate, growth, brain development.

Other amines:

1

2

3

4

synth

3 Classes of Hormones

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

Similar to Fig 5-5

Ring structure of cholesterol preserved so all have

lipophilic nature (can’t be stored in vesicles)

Table 5-5

Functionally, the 3 hormone classes based on chemical origin break down into two groups:

A. Peptides, Proteins , Serotonin & Catecholamines

B. Steroids & Thyroid HormonesA B

*(but endocytosis may occur)

*

Metabolic breakdown & rapid ( < 1 h) slow (hours - days)excretion

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 hormones3. 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”

Posterior Pituitary - neural tissue“neurohypophysis”

Hypothalamus - neural tissue

Axons terminate in the posterior pituitary

Release of neurohormones

PVN

Bio 2A03Lecture 31

Hormones II

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

PVN

Posterior Pituitary- neural tissue “neurohypophysis”

Axons terminate in the posterior pituitary

Hypothalamus- neural tissue

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

- 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.

- from giant neurons of supra-optic nucleus (5/6 with 1/6 from PVN.)

2. Oxytocin- from giant neurons of paraventricular nucleus

- reproductive functions – uterine contractions, milk ejection, orgasm (?)

Anterior Pituitary

Hypophysiotropic hormone

Anterior pituitary hormone

Tropic stimulates the release of another

hormone

Hypothalamus- pituitary portal system

Hypothalamic & Anterior Pituitary Hormones

At least 6 different (probably more) Hypophysiotropic

hormones = Releasing Hormones (factors) + Inhibiting Hormones (factors),

from 6 different giant neuron groups

5 different cell types release at least 6 different

anterior pituitary hormones which pass out

into general circulation

Very high local concentration (no dilution

with general circ.)

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.

* 2. Follicle Stimulating Hormone (FSH) – promotion of ovarian follicle development, sperm production, & sex hormone

production.

*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.

* All tropic hormones

Gonadotropins from same anterior pituitary cells

Fig 6-5

T3, T4

Neural Input from Higher CentersOther Hormones

+/-

e.g. stress+

-

+-

-

↑

Fig 6-6

Short loop –ve feedback

prevents the buildup of

excess anterior pituitary tropic

hormone

CRH

ACTH

CORTISOL

With long loop the target

hormone limits the secretion of

tropic hormones and therefore its

own release

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)

Neuromuscular junction

Mitochondria

SS – subsarcolemmal IM - intramyofibril

Multinucleated cells

Muscles made up of bundles (fascicles) of muscle fibers

Myofibrils

sarcomere

Each fiber (cell) controlled by only

1 motor neuron

The Sarcomere

-Sarcomeres are bordered by Z line which anchor thin filaments (actin) (blue)

-Thick filaments are joined at the M line (myosin) (red)

A band. Entire myosin bundle + overlapping regions of actin.

I band. Regions of actin filaments which do not overlap myosin. Bisected by Z line.

H zone. Area of sarcomere between opposing ends of actin filaments.

Classic features of sarcomeres

Thick Filament (Myosin)

100’s of myosins per thick filament arrange in a staggered fashion along the TF (think filament).

Each myosin is a dimer of 2 intertwined subunits

crossbridge

Tropomyosin partly covers the myosin

cross-bridge binding site

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.

Thin Filaments

Backbone composed of actin. G-actin (for globular protein) bind together to form F-actin (fibrous protein).

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

Excitation-contraction coupling

Voltage-sensitive receptor

(affected by depolarizatio

n of the membrane)

Coupled to SR Ca2+ channels

Muscles have excitable

membranes

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 = dihydropyridinereceptors.

Recruitment of motor units

1. Motor units

Motor unit: motor neuron and all the fibers

that it innervates5 fibers

7 fibers2. 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

1. Motor units differ in size

Motor unit: motor neuron and all the fibers it

innervates5 fibers

7 fibers2. 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

Larger than average cell bodies that are harder to depolarize. They also have

larger axon diameters

Greater the AP from the brainthe larger the motor units that

are recruited, and the larger thetension/force produced.

-When stimulated these different muscles take different times to reach peak tension

-They each contain different populations of muscle fibers

Extraocular myosinPrimarily Type II myosins

Primarily Type I myosin

- Contraction properties depend on proportions of fast and slow twitch fibers (proportions of fast and slow

myosins)

Some muscles generate moretension/force than others…this

graph is mis-leading.

Skeletal muscle fibre classificationMaximal shortening velocity – fast or slow fibres

In fast fibres cross-bridge shortening is approximately 4x faster than in slow fibres

ATP supply: oxidative or glycolyticOxidative 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.

Type I Type IIa Type IIbAlso named for Myosin

isoform (I, IIa and 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 trainedTo work over shorter distances…low mito cannot be trained for endurance as easily.

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.

Smooth Muscle

-Calmodulin the Ca2+ binding regulatory protein NOT troponin-tropomyosin

No regular alignment of myosin and actin as occurs in skeletal muscle

Dense bodies. Functionally equivalent to Z-lines in

skeletal muscle

-Ca-calmodulin complex binds to a myosin kinase which phosphorylates myosin. Only phosphorylated myosin can bind with actin. A Phosphatase will dephosphorylate for relaxation.

PSNS and / or PNS

Inputs influencing smooth muscle (SM) contraction1. 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)

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

muscle fibres).

Neurotransmitters in smooth muscle may have a stimulatory or inhibitory effect.Neurotransmitter is released, and diffuses over to the

muscle fibres to create the appropriate response. No direction junction.

2a03 lectures1-33

Documents

ob gene encodes

external urethral sphincter

lasting messages carried

master endocrine gland

displacing diaphragm upwards

surpressing stress responses

distal convoluted tubule

achieve independent nacl