Week 1

Single cell organisms are in direct contact with the environment.

Metabolism happens via the cell membrane which is very important.
Survival of such cells depends entirely on the extracellular space.

In multicellular organisms, individual cells are not in contact with the

environment.
Extracellular fluid in such organisms remove waste and provide nutrients.

Nervous and Humoral (hormones) systems helps maintain the normal

conditions in the cells.

Lungs: Gas exchange

Kidneys: Urine removal
GI Tract: Providing nutrients

Capillary beds take away waste from individual cells and provide nutrients.
Diffusion is usually used but only work over short distances.

Fluctuations in organisms internal environment should be minimized via

homeostatic mechanisms.

Homeostasis - The processes which maintains nearly constant internal

conditions.
Looks after body temperature, blood pH, blood sugar level, Na+, K+, Ca2+,
Cl- concentration

Nutrients come from: GI tract, Respiratory system, Liver

Removal of waste from: Respiratory system, Kidney, GI tract

Feed forward control systems:

Anticipates the disturbances coming so the body prepares for the
changes

Feedback control systems:

The disturbance occurs and acts on the body causing a change.
Feedback system acts against the disturbance.
Open loop control system:
Uses effectors to get the desired response.

Closed loop control system:

Uses measured parameters to compare actual output to desired output.

Guidance vs Control

Guidance:
Feed forward
No feedback
Not sure exactly what happens
Stable
No acting back

Control:
Feedback
Knows exactly what happens
A bit unstable
Acting back

In a control circuit:
- Controlled parameter
- Sensor
- Controlling center
- Effector system
- back to controlled parameter

Set Point - The optimal value of something.

The controlling center checks this reference range against the sensed
value and if required, the effector system carries out changes.

Control circuits can be Neuronal or Humoral

Neuronal: Fast, Well Localized, Shorter acting time

Humoral: Slower, More diffused, Greater acting time.

effectors in the neuronal controlling circuit involves: glands, smooth and

skeletal muscles
Humoral controlling circuit has hormones and blood.

Excess thyroid hormone prevents its own production. This is negative

feedback control.

Humoral Controlling Circuit:

Hypothalamus
Ant. Pituitary Gland
Target Gland
Hormone

The hormone can inhibit the production at the hypothalamus and ant.
pituitary gland.

Humoral circuit contains: paracrine, autocrine and endocrine systems.

Neuronal + Humoral = Mixed control circuit

Example of Mixed Control Circuit is the oxytocin reflex.

Works before or during feed to make milk flow.
Neuronal afferentation & Humoral efferentation.

A feed forward acts only forward, not controlled by errors. (Eg: saliva
secretion)
Negative feedback is very common. Keeps variable around reference
range.
Positiove feedback is rare. Eg: Blood clotting or childbirth

eg of positive feedback:
- Baby pushes against cervix, stretches it
- Streching causes nerve impulses sent to brain
- Brain stimulates pituitary gland to release oxytocin
- Oxytocin causes uterus to contract causing baby to push

eg of negative feedback:
- Gastrin hormone produced
- Gastric acid in stomach produced
- More Somatostatin produced which directly inhibits gastrin production.
To make the control range wider: effector mechanisms + Behavioural
mechanisms.

After an error or disturbance, there is a delay after which there is a

correction to bring the variable value back to the set point.
There is usually some residual error.

Higher the gain, better the correction mechanisms.

In a normal case:
disturbing signal pushes the system out of balance and then control
system gets activated

In servo mechanisms:
Reference range changes and then control system gets activated.

Biomembrane functions:
- Transport (regulates intracellular & intercellular transport processes)
- Compartmentalization (closed room for chemical reactions)
- Signal sending & transduction (senses and transducts signals
extracellular signal to intracellular area)
- Interceullular interactions
- Biomechanical activity (with membrane bound enzymes)
- Energy production (mitochondrial ATP synthesis)
- Cell - Cell recognition (distinguishing between foreign & own
cells/particles.

Fluid Mosaic model:

Continous fluid, 2D lipid double layer with embedded proteins which forms
a mosaic (spots in the membrane)
Thickness is 7 nm

Phospholipid molecule is the basic element of the biomembrane.

Has a polar, hydrophilic head (phosphate group)
and a hydrophobic, apolar tail/chain (fatty acid chain)
Since both hydrophilic and hydrophobic parts both exist, it is
amphipathic.

2 rows of phospholipid molecules make up the biomembrane.

Van der Waals forces stabilizes the membrane structures.
Phosphyrlation is a strong cellular signal.

Glycolipids are carbohydrate units bound ontop of the head group of

lipids.
Functions:
- Cell recognition (Glycolipids bind to lectines)
- Receptors of pathogens (Eg: Cholera toxin, HIV)
- Membrane protection (forms a protective layer
- Blood types (There are different glycolipids patterns depending on blood
type)
- Inhibit RBC aggregation (via negatively charged surfaces)

Lipid Polimorphism:
Lipid bilayers are bent. They can have different 3D structures.
Lamellar 3D structure or Hexagonal 3D structure (there are 2 of them)

Length of fatty acid chains are not always the same.

Lipid interdigitation: Phosphlipid molecules with different fatty acid length
arepositioned accordingly.

The biomembrane is a fluid structure. Phospholipid molecules can move

throughout the membrane. The movement is spontaneous.
- rotation: Rotates around its own longitudinal axis
- flexion: Fatty acid chains flex, bend sideways.
- Lateral diffusion: Movement of whole phospholipid molecule from one
place in membrane to another. Few micrometer per second.
- Flip flop: Phospholipid molecule of one row flips and goes the the other
row. Uses the enzyme flippase. This happens once a month.

At high temperatures:
Cholesterol decreases membrane fluidity. Solidifies it (Immobilizes fatty
acid chains)

At low temperature:
Cholesterol increases membrane fluidity (inhibits fatty acid interactions)

Cholesterol can also:

- inhibit lateral diffusion (make it more rigid, stable membrane)
- Decrease membrane permeability (fill gapds between phospholipids)
- Temperature adaptation (inhibits phase transition)

Too much LDL cholesterol eventually causes foam cells to form which leads
to fatty streask -------------> Atherosclerosis.

Lipid rafts:
Part of phospholipid bilayer where the components of of the bilayer is
different compared to the rest of the bilayer.
Lipid rafts condensate necessary molecules and proteins on one area of
the membrane (molecular accumulation)

At the lipid raft, there is more cholesterol and longer, saturated fatty acids
chains, stronger Van der Waal's forces which causes easier integration of
membrane proteins. Thus the membrane is thicker and more stable.

Caveola: Has different phospholipid proteins. Has caveolin protein.

For sensing environmental factors and mechanical stress.

Transmembrane proteins have intramembrane, cytoplasmic and

extracellular domains. They are amphipathic and span the whole thickness
of the membrane.
There are also membrane proteins that are:
In the inner layer only
In the outer layer only.

Glycocalyx:
Carbohydrate shield on the outer membrane surface. Glycolipids connect
with each other to form it.

Membrane Protein molecules can also move in the membrane.

It is better to have the proteins condensated at one site where they are
required.

Membrane Proteins can:

- Aggregate
- Connect to extracellular molecules
- Connect to intracellular molecules (cytoskeleton)
Diffusion: Movement of a particle from a region of higher concentration to
a region of lower concentration down a concentration gradient.

Osmosis: Movement of water molecules from a region of high water/slovent

potential to a region of low water/solvent potential through a semi
permeable membrane

Osmolarity = Amt of solute (mol) / Volume of solvent (l)

Use osmolarity for highly diluted solutions

Osmolality - Amt of solute (mol) / Mass of solvent (kg)

Use osmolality for highly concentrated solutions.

Osmotic pressure = conc x gas constant x absolute temperature

The smaller and more apolar a molecule is, the quicker it can pass
through a biomembrane.
Water cannot diffuse fast enough through a membrane due to its high
concentration. Relies on aquaporines.

Faciliated diffusion relies on intramembrane proteins that can undergo

conformational changes. Molecules bind to these proteins which then
change in shape and release the molecules in the area of lesser
concentration.
There is a maximal transporter speed.
Faciliated diffusion is faster than simple diffusion.
Ping pong mechanism: Irrevesrsible conformational change.
Eg: Glucose transporter in RBC membrane.
Inhiibtion of tranposrter can be competitive, non competitive or
uncompetitve.

Active transport: Movement of molecules from a region of low

concentration to a region of high concentration against the concentration
gradient with the help of carrier molecules. Energy is required.
Energy can be provided by:
ATP Hydrolysis (primary active transport)
Energy of light (primary active transport)
Ionic gradients (secondary active transport)
Secondary Active Transport:
The active transport of molecules is driven by energy of an already
existing electrochemical gradient of another molecule.
Usually sodium gradient is used.
Secondary active transport can be symport or antiport

Sodium Potassium pump (aka ATPase):

3 sodium ions bind to the pump.
ATP molecule binds and loses a phosphate group. BEcome ADP
This dephophyrlation releases energy and causes a conformational
change causing the sodium ions to be released extracellular and 2
potassium ions joining from the outside.
Release of ADP causes the pump to return to its original shape and
potassium is transported inwards.

Due to this sodium potassium pump, intracellular space is negatively

charged relative to extracellular space.
1/3 of total cellular energy is spent on the sodium potassium pump.

Calcium pump:
Transport of calcium is driven by sodium gradients.
With the use of ATP phosphorylation, Ca2+ ions are pumped out of the cell.
These pumps are present in the sarcoplasmic membrane in muscle cells
and in cell membranes.
Due to the change in intracellular Ca2+ concentrations:
Protein activation
Muscular contraction
Neuronal transmission
Apoptosis.

Intracellular Ca2+ should be very low. Usually 10^-7 M

ABC transporters
ATP
Binding
Casette sequence

Has a double nucleotide binding domains

Funtions:
Bile secretaions of hepatocytes
Drug elimination
Drug and toxin transport

Transmembrane ion channels are proteins that transport ions along the
electrochemical graidient towards the space with lower concentration.
Allow passive diffusion.
Such ion channels can be:
Ligand gated
Phosjyrylation gated
Voltage gated
Strech or pressure gated

Ion channels are selective.

They can be super selective/specific and let through only one ion or they
can be less specific and let through one group of ions.

Electrochemical gradient influences the direction of ion transport.

Phagocytosis - the cell eats other cells or particles with endocytosis

(inavagination of the cell membrane and then budding off)

Vesicular transport is common within the cell in which molecules are

transported within small vesicles made up of phospholipids.
Very important in neural communication:
1) Neurotransmitters go into vesicles in the cell
2) Vesicles dock at and join plasma membrane and releases
neurotransmitters via exocytosis (triggered by influx of Ca2+) into
extracellular matrix.
3) Empty vesicle disjoins from the plasma membrane and goes back into
the cell

Regular ranges of:

Blood pH: 7.38-7.42
Blood glucose level: Less than 6mMol/L
Body temp: Around 37 degrees celsius
Homeostasis uses humoral and neuronal systems

Extracellular fluid is made up of blood plasma and interstital fluid.

60% of total body weight is is water.

From this 60%,
40% is intracellular
20% is extracellular. From this 20%,
15% is interstitial fluid
4-5%is blood plasma
1% is transcellular fluid

Neuronal control uses reflex arc.

afferent efferent
branch branch
Receptor ------------> CNS -----------------> Effector

Effector branches can be motor neurons and autonomic nerves

Effectors are skeletal muscles and glands

The receptor checks the actual value against controlled parameters.

The CNS sets the set point of the controlled parameter.

Humoral regulation:
Hypothalamus ----------> Hypophysis ----------> Target gland
eg:
TRH ---------------------------> TSH ---------------------> (At thyroid) T3,T4
T3,T4 hormones give feedback to the hypothalamus.

Insulin comes form beta cells of Langerhans islets of pancreas.

Insulin is released when blood glucose levels rise because insulin reduces
blood glucose concentration by encouraging the uptake of glucose and
its conversion to glycogen.

Prolactin: Milk production

Oxytocin: Milk ejection

Ferguson reflex is an example of mixed control system.

Baby sucking on mothers nipples has both humoral and neural systems
involved.

Blood clotting cascade and childbirth are positive feedback mechanisms.

Guidance system: Process when there is no feedback. Only feed forward.

Claude Bernard recognized the importance of internal environment.

Walter Cannon coined the term homeostasis.

Biomembranes are phospholipid bilayers with embedded proteins.

Phospholipids have hydrophilic phosphate head and 2 hydrophobic fatty
acid chains.
Thickness of membrane is 6-7 nm.

Integral proteins are present in the membrane.

Hydrophilic and large particles cant diffuse through the phospholipid
bilayer. Must use integral proteins.

Primary and secondary active transport use energy.

Primary active transport uses energy from ATP hydrolyzation.
Secondary active transport uses energy from NA graident made by Na/K
pump.

Diffusion, Osmosis and facilitated diffusion don't use energy.

Endocytosis and exocytosis are vesicular transport.

Neurotransmitters produced in neurons are transported to the synaptic

cleft by exocytosis.
Week 2
Ligand: A molecule that binds to cell receptors.
Ligand binding is super specific.
Eg of ligands: Amines, Steroids, Nucleotides.

Receptors: Specifically recognize and bind to ligands with high affinity.

Gap junction: Cells are very close to one another. Ions and small molecules
can be transported freely via passive transport. Local communication
method

Neurocrin: Communication method between nerve and glial cells. Local

communication method, communicating cells are very close to one
another.

Paracrin: One cell releases a communicating molecule which reaches cells

in the neighbourhood. Similar to endocrine but distance is very low.
Communiacting molecule is eliminated by enzymes.

Endocrine: Hormones. Travel large distances. in bloodstream.

Juxtacrine: Small distances. Physical contact between cells. Local

communication.
Receptors in the cell membrane undergo conformational change upon
ligand binding thus signal is relayed across the membrane to the receptor
cytoplasmic domain.

Receptor can be in the cytoplasm as well (eg IP3)

The downstream effect of ligands depends on the intracellular machinery.

There is always a terminating downstream mechanism.

Agonism: Supporting the receptor function

Antagonism: Inhibition of receptor function

Partial agonist: Synthetic ligand cannot achieve full biological effect.

Competitive antagonist: Competes for ligand binding site
Non competitive antagonist: Allosteric binding site.

Kinases and phosphatases are responsible for phosphorylation.

Specificity of kinases and phosphatases is super high.

Kinases binds phosphate molecules.

Phosphatases remove phosphate molecules.

GPCR - G protein coupled receptors.

G proteins have guanine nucleotides - GDP and GTP.

Alpha subunits converts GDP (inactive) to GTP (active).

There is also effector activation.

GPCR response termination is by desensitization.

Arrestin binding (competitive inhibition)

First messenger is a ligand that causes intracellular changes. Cant go

through the membrane.

Second messengers (cAMP) moves intracellularly.

cAMP - soluble 2nd messengers.

Activates many ceullar activities

Phospholipase C causes diacylglycerol (DAG) and IP3 to be released.

DAG is membrane bound.
IP3 is a soluble second messenger. Causes opening of Ca2+ channels.

Glucose is stored as glycogen.

Signal amplification is very powerful and fast.

Receptor Protein Tyrosin Kinases (RTKs). Membrane-bound receptors

Are found as monomers.
Due to ligand binding, 2 RTKs bind together and thus signalling complexes
bind are started

Insulin receptors are present as stable dimers.

Due to insulin binding, three is conformational change again.
(Transautophosphyrlation)

In type 2 diabetes, due to overstimulation of insulin, insulin receptors

become desensitized and stop responding.

Ca2+ ion as an intracellular messenger - muscle contraction, synaptic

communication, immune response.
Ca2+ signalling can be global or local.

Nitrogen Monoxide is an intercellular messenger. Activates cGMP which

relaxes smooth muscle cells.
Argininine gives Nitrogen Monoxide.

Receptors can be present on the nuclear membrane itself. Steroid

hormones bind to such receptors.

Transmembrane potential can be changed by:

the types of pumps present.
Ongoing cellular processes
Which ion channels are open.

Transmembrane potential is present in almost every cell.

Cell tries to keep this potential stable.

Howerve, in the pacemaker of the heart, this transmembrane potential
oscillates.

Ion Extracellular Intracellular (mmol/L)

Na+ 150 15
Cl- 100 5
K+ 4.5 150
Ca2+ 1.8 0.0001

Steady state: Point at which diffusion force and electrical force is the same
at a given potential level. There is equilibrium between the 2 forces.
This potential level is the Nerst potential.'
Nerst potentials are characteristic for each ion.

Nerst equation: Determines equilibrium potential of a given ion having

different extracellular and intracellular concentrations.

Eion = RT/ZF x ln (ECF conc/ ICF conc)

Z = valence of ion
R = gas constant
F = Faraday Constant.

Nerst Potentials:
Na = +60mV
Ca = +130mV
K = -90mV
Cl = -80mV

The entire membrane potential is influenced by many ions, ion pumps,

Donnan Effect (immobile charged macromolecules ka effect in intracellular
effect)

Goldman-Hodgkin-Katz (GHK equation) determines the whole resting

membrane potential.

Permeability in resting membrane potential:

K+ : Na+ : Cl-
1 : 0.04 : 0.45

Resting membrane potential = -70mV

Whenever membrane potential becomes more positive, it is depolarisation.

Whenever membrane potential becomes more negative, it is
hyperpolarization.

Na-K pump is electrogenic.

3 Na+ go into extracellular fluid. 2 K+ come into intracellular fluid due to its
action.

Plasma membrane can act as a capacitor. Build up charge.

Natural changes of membrane potential:

- Post synaptic potentials (Na+ ion channels open, Na+ ion flood into cell)
- Receptor potentials
- Pacemaker potentials

In graded membrane potentials:

There are graded changes. This means proportional changes to the
external stimulus on the cell. Doesnt cross threshold.

Action potential is an all or nothing signal.

Not a proportional response.
Fast and sharp
Rapid change of membrane potential
Distributtion is fast.

Myelin sheaths decrease axonal capacitance and increases axonal

membrane resistance.
There are no leaky channels in myelin sheaths. Thus impulses get sped up
due to myelin sheaths.

Ion channels can be voltage gated or non voltage gated.

At depolarization (-40 mV), ion channels are opened.

Na+ and K+ channels are both voltage dependent.

As depolarisation occurs, Na+ channels show inward current (Na+ ions go
into the cell).

For Na+:
-70mV is the resting membrane potential.
-40mV is when depolarisation begins and takes place. (Na+ ions come into
the cell)
+40mV is the maximal membrane potential. (This is the reversal potential
for Na+. Here, Na ions are driven outta the cell)

For K+:
-70mV = Resting potential
At +40mV there is repulsion which drives K+ outta the cell.
-90mVmV is the reversal potential for K+. At this membrane potential, ions
come into the cell.

At resting potential, Na+ concentration is greater outside the cell and K+

concentration is greater inside the cell.

Amplitude and width of action potential is always the same in one cell
type.
Different cell types show different action potential widths.

For an action potential, membrane potential must reach the certain

threshold (-40mV). All or none principle.

Depolarization (From -70mV to +40mV)

Peak (+40mV)
Repolarization (From +40mV to -70mV)
Hyperpolarization (From -70mV to -90mV)

Volatage gated K+ channels open with a delay.

Action potentials are generated in the axon initial segment.

Axon potentials jump from Node of Ranvier to Node of Ranvier in
myelinated neurons.

Na+ channels can be inactivated which stops ions from going through.

Refractory period - When Na+ channel is inactivated.

There is absolute and relative refractory period.

Absolute: Is the period of time during which a second action potential

ABSOLUTELY cannot be initiated, no matter how large the applied
stimulus is. Relative: Is the interval immediately following the Absolute
Refractory Period during which initiation of a second action potential is
INHIBITED, but not impossible.

Axons can be I, II, III, IV

I is the thickest and has highest conducting velocity. IV lowest for both.

Membranes have a lipid bilayer. Proteins are next to phospholipids within

it.
Receptors mediate the effect within the cell.

Water soluble molecules only pass through via transporters or channel

proteins.
Channel proteins are a hole.
Substances do not bind to the channel proteins. However, these channel
proteins are specific.

Water channels and ion channels can be opened and closed by:
membrane potential changes
Chemical substances
Mechanical effect

Carrier proteins have a maximum capacity. They can be saturated

If one substance can be carried by a carrier protein - uniport.

If 2 substances are transported by a carrier protein in the same direction -
symport
If 2 substances are transported by a carrier protein in opposite directions
- antiport.

Passive transport is always down the concentration gradient.

All active transport and facilitated diffusion uses carrier proteins.

Because these processes are done by carrier proteins, there is
saturationamd competitive inhibition present.
Primary active transport = Energy is provided by ATP. ATP is split at the site
of transport.
Secondary active transport: No ATP is split. Energy is provided by ionic
(usually Na) gradient.

Voltage gated - due to change in membrane potential

Ligand gated - Due to ligand binding
Strech and movement gating - Due to stretch
Phosphorylation gated - Due to addition or removal of phosphate group.

The above 4 open or close ion channels.

In osmosis, water flows to the more concentrated area (place of higher

osmolarity)

Na/K pump moves both the ions against their concentration gradient. Can
be saturated.

Indirectly, ionic gradients do use ATP.

Receptors can be:

- Containing ion channels
- G protein coupled receptors
GTP binding proteins - Forms GDP + Phosphate group
Such receptors look like a snake and have extracellular cytoplasmic
domain.
G proteins Activate 2nd messenger systems (cAMP, Ca2+)
G proteins activate phospholipase C which gives rise to IP3 and DAG.

IP3 releases Ca2+ from sarcoplasmic reticulum.

- Tyrosine Kinase Receptors do phosphorylation. (Activate/Inhibit enzymes)

In a neuron, depolarization will be conducted in a neuron.

Opening a sodium ion channel opens the neighbouring Na+ channels.
This is how action potential is propogated.

Resting Na+ permeability is low.

Resting K+ permeability is high.
Absoluete Refractory period - Cant evoke an action potential at all
Relative Refractory period - A second action potential can be activated but
initiation will require a greater stimulus than before.

Depolarization opens the Na+ channels immediately.

Depolarization also deactivates the Na+ channels with a delay.

Myelinated axons conduct impulses faster than unmyelinated ones.

Impules jump from one Node of Ranvier to the next Node of Ranvier.

Endocytosis and exocytosis are vesicular transport. Seperate from

membrane transport.

For neurotransmitter release, intracellular Ca2+ concentration must be

high.

Depolarisation occurs at the end of the presynaptic neuron.

Ca2+ ion channels open and Ca2+ ions flood into the cell.
Ca2+ causes vesicles containing neurotransmitters to dock at the plasma
membrane.
Neurotransmitters are then released into the synapse.

Endocytosis is receptor mediated.

Non polar, Non charged substances can go straight through the lipid
bilayer (Gases like O2, CO2 and steroid hormones)

Ion channels can be called leaky channels

Ion Extracellular Intracellula

Na 145 15
K 4.5 150

Electrochemical gradient drives the movement of ions.

Ficks Diffusion Law:

Speed of diffusion = -D x Delta C x A/d

-D is a coefficient
Delta c is change in concentration
A is surface area of diffusion
d = thickness of membrane

Facilitated diffusion has a maximal velocity as it can be saturated. This is

due to the presence of carrier proteins.
Passive diffusion does not have a maximal velocity.

GLUT 1 present on RBC membranes

GLUT 2 in the islets of Langerhans. Glucose sensor
GLUT 4 in insulin dependent cells like adipocytes.

Nephron is the functional and morphological unit of kidney

Na+ - Glucose transporter is present in nephrons. This reabsorbs Na+ and
glucose.

If there is a hyphen between 2 things: Co transporter (Na+ - Glucose)

If there is a slash between 2 things: Anti transporter (Cl-/HCO3)

Osmotic pressure: the pressure value at which osmosis stops.

Osmotic pressure of plasma: 660 kPa (4950 mmHg)

In osmosis, solvent moves to the more concentrated area. Doesnt always

have to be water.

Na/K pump is important in restoring membrane potential.

Makes intracellular more -ve and makes extracellular more +ve.

Digitoxin/ouabanine blocked the Na/K pump and induces muscle

contraction.
Resting membrane potential is the potential difference between the 2 sides
of the membrane when there is no depolarization or hyperpolarization.
It is characteristic to each cell type
For skeletal muscle cells: -90mV
For nerve cells: -70mV
For smooth muscle cell: -50mV

K+ has higher membrane permeability.

Na+ has very low membrane permeability.

GHK equation =
RT/F x log (P Na [Na+ o] + P K [K+ o] + P Cl [Cl- i]) / (P Na [Na+ i] + P K [K+ i] +
P Cl [Cl- o])

R = Gas Constant (8.31)

F = Faraday Constant (96485)
T = temperature in Kelvin

P Na [Na+ o] means:
permeability of Na+ x Concentration of Na+ intracellularly.

Equilibrium potential is a potential value in which the 2 driving forces

(created due to concentration difference and volatge difference) are the
same

Equilibrium potential for a single ion: Use NErst equation

E Na = RT/ZF x log (Na+ o/ Na+ i)

Z = charge of ion

Equilibrium potential for Na+ = +60mV

Equilibrium potential for K+ = -90 mV

Whether an ion channel is open or closed can influence permeability of

the cell membrane for ions.

Local potential changes wont spread on the plasma membrane.

Eg:
Receptor potential (Local potential of receptor cells. Eg: Sensory neurons)
Pacemaker potential (at pacemaker cells in heart)
Electrotonic potential
Post synaptic potential.

If the membrane potential becomes more and more positive:

Depolarization
If the membrane potential becomes more and more negative:
Hyperpolarization.

If depolarization crosses the threshold then this causes action potential.

Synapse is where 2 cells can communicate with each other.

Chemical synapse has neurotransmitters and receptors.
Electrical synapses are gap junctions.

If a post synaptic potential caused depolarisation - Excitory post synaptic

potential
If a post synaptic potential causes hyperpolarization - Inhibitory post
synaptic potential.

EPSP neurotransmitters:
Noradrenaline, Glutamate, Acetylcholine

IPSP neurotransmitters: GABA, Glycine

GABA and glycine cause opening of chloride channels.

Week 3
Axons dont form a continous network..

Places where neurons communicate with each other are called synapses.

Chemical synapses use neurotransmitters and receptors.

Electrical synapses have gap junctions between 2 neurons.

Connection types:

1) Axodendriticc synapse (between an axon and the dendrite of another

neuron)
2) Axosomatic synapse (between an axon and other neuronal cell body)
3) Axoaxonal synapse )between 2 axons of different neurons)
4) Axomyelininc synapse (Between an axon and a myelin sheath)
Myelin sheaths are made by oligodendritic cells.

Transmitter types:

1) Excitaory transmitters. (Gray I)

Eg: Glutamate. Such transmitters are stored in round vesicles in the
presynaptic neuron. Excitory synapses are asymmetric.
2) Inhibitory transmitters (Gray II)
Eg: GABA. Such transmitters are stored within oval vesicles in the
presynaptic neuron..
Inhibitory synapses are symmetrical
3) Modulatory transmitters
Uses monoamines as neurotransmitters. (eg: Serotonin, Dopamine)
Such neurotransmitters are stored within small, dense core vesicles. (Have
a black spot in the center)
4) Peptide transmitters
Stored in large, dense vesicles. (Black spot in the center)
Post synaptic Density is the dark part on the post synaptic membrane.
Post synaptic density contains proteins.

Electrical synapses

USes gap junctions

No need for neurotransmitters.
There are tunnels/channels (Connexon pores) which connect the
membranes..
6 connexions form a connexon pore.
Connexon pores allow ions, ATP, cAMP, amino acids to move from one
membrane to another, in either direction. Peptides and large proteins
cannot move through a connexon pore.
Direction of transport depends on concentration.
This is a relatively fast process.
No synaptic delay.
Bidirectional transport.

Chemical Synapses

There are no pore/tunnels between 2 membranes

Needs neurotransmitters and receptors
Relatively slow
Synaptic Delay (Time you need to transfer info from one neuron to another
via a chemical synapse)
One way transport. From presynaptic to post synaptic neuron.

A synapse is made up of a tetrapartite

Tetrapartite:
Presynaptic terminal + Post synaptic membrane + Astrogilal cells +
Microglial cells

1) Transmitters are stored in vesicles in the presynaptic terminal

2) Action potential arrives at the presynaptic terminal
3) Opening of voltage gated calcium channels
4) Calcium ion inflow into presynaptic terminal.
5) Calcium induces vesicle fusion with presynaptic membrane
6) Transmitter released into synaptic cleft
7) Transmitter moves across synapse and binds to post synatic receptors
8) Opening of post synaptic ion channels
9) Generation of Excitory or Inhibitory Post Synaptic Potential
10) Transmitter elimination (Glial uptake, Presynaptic reuptake, Enzymatic
degradation)
11) Vesicle retrieval from pre synaptic membrane.

Synaptic Vesicle Fusion:

1) Vesicle docking
This happens in the active zone of the presynaptic membrane.

4 important proteins are involved in synaptic vesicle fusion and docking.

In the vesicle membrane: Synaptobrevin & Synaptotagmin
In pre synaptic membrane: SNAP-25, Syntaxin.

2) SNARE Complex formation

This forms between proteins. At this stage, there are no pores between
vesicles and membranes.

3) Calcium Synaptotagmin binding

4) Membrane fusion, pore formation, Neurotransmitter release.

Neurotransmitter content of 1 vesicle = 1 quantum.

Calcium Calmodulin dependent protein Kinase II is used for bringing

vesicles towards the presynaptic membrane.

EPSP - Excitatory Post Synaptic Potential

Excitatory transmitter - Glutamate.
After binding to post synaptic receptors, excitatory neurotransmitters
cause an inflow of Ca2+ ions into the post synaptic neuron.
This causes local and graded depolarisation of the post synaptic
membrane

IPSP - Inhibitory Post Synaptic Potential

Inhibitory transmitter - GABA/Glycine
After binding to a post synaptic receptors, inhibitory neurotransmitters
cause an inflow of Cl- ions via chloride channels into the post synaptic
neuron. They can also cause an outflow of K+ ions.
This causes hyperpolarization in the post synaptic neuron.

Multiple EPSPs and multiple IPSPs can be summed up together

Spatial Summation:
EPSPs and IPSPs from different dendrites are received at the same time
and simultaneously send to the cell body and are summed at the axon
hillock.

Temporal Summation:
EPSPs and IPSPs do not appear at the same time. There is some delay and
once all gathered together, they are added up at the axon hillock.

Summation allows the threshold to be crossed.

Neurotransmitters rarely work alone. They often use co transmitters.

Co transmitters: Peptides released after high frequency stimulations. They

prolong the EPSPs and IPSPs

Neurotransmitter - Co Transmitter
Acetylcholine - Vasoactive Intestinal Polypeptide (VIP)
Norepinephrine - Neuropeptide (WPY)
Glutamate - Substance P (SP) / Calcitonin Gene Related Peptide (GRP)

Classification of neurotransmitters:

1) Acetylcholine
2) Amino Acids (GABA, Glycine, Glutamate)
3) Biogenic Amines (Dopamine, Serotonin, Adrenaline)
4) Peptides (Endorphins)
5) Gases (NO, CO)
6) Purines (ADP, ATP, Adenosine)
7) Lipids (prostaglandins)
7 is synthesized from plasma membranes.

Acetylcholine, Amino Acids and Biogenic amines are typical

neurotransmitters.

Neurotransmitter receptors can be:

Ionotropic (ligand gated) ion channels
Metabotropic (G protein coupled receptors)

Acetylcholine is the key of the autonomic nervous system.

Ionotropic receptorss: Nicotinic
Metabotropic receptors: Muscarinic
Present in sympathetic preganglionic and parasympathetic pre and post
ganglioinic. Also in motor endplates
Used for attention, memory, autonomic neurons.

Glutamate present in neocortex pyramidal cells.

Ionotropic receptors: NMDA, AMPA
Metabotropic receptors: mGlu R1-R8
Is a general excitatory transmitter. Used in learning.

GABA (gamma amino butryic acid)

Present in Purkinje cells, neocortex interneurons.
Ionotropic receptors: GABA-A/C
Metabotropic receptors: GABA B
Is a general inhibitory transmitter. Used in anxiety.

Glycine.
Present in the spinal cord and in the brainstem.
Ionotropic receptor: GlyR
No metabotropic receptor.
Is an inhibitory transmitter.

Serotonin, Dopamine and Norepinephrine come from the brainstem and

go to the basal ganglia (movement control), Limbic system (Memory,
Emotion), Prefrontal cortex (cognitive function
Axomyelitic synapse is in between an axon and a myelin sheath.
Myeline sheaths are made by oligodendrite cells

Synapsis between neurons and astrocytes (and other glial cells) do exist.

Retrograde neurotransmission:
Goes from post synaptic neuron to pre synaptic neuron.

1) Endocannabinoid
2) NGF (nerve Growth Factor): Travels in the presynaptic neuron in vesicles.
3) NO (Nitrogen monoxide)

Volume transmission:
Neurotransmitters diffuse to distant targets outside the synapse. Act on
extrasynaptic receptors.

Autonomic nervous system.

Sympathetic - Uses energy
Parasympathetic - Saves energy.

Pathway is:
Preganglionic neuron
Autonomic ganglion
Postganglionic neuron

In the autonomic nervous system:

Cranial and Sacral divisions are parasympathetic. (uses acetylcholine)
Thoracolumbar division is sympathetic. Uses acetylcholine in
preganglionic neurons only. At target organs, sympathetic system uses
norepinephrine and epinephrine as neurotransmitters instead.
Sympathetic nervous system transmitter are norepinephrine and
epinephrine.
Released in post ganglionic terminus
Eliminated via: Presynaptic reuptake, Diffusion into metabolism, Break
down by MAO.

Tyrosine ---> Dopamine ----> Epinephrine -----> Norepinephrine

Adregenic receptors:
Can be Alpha or Beta
Alpha 1 receptors: Linked to IP3/DAG. Peripheral vasoconstriction.
Alpha 2 receptors: Binds an inhibitory protein. Inhibits overactivity.
Reduces cAMP levels.
All 3 Beta receptors increase cAMP which activates protein kinase A
Beta 1: Receptor for heart
Beta 2: Receptor for blood vessels. Prefers epinephrine.
Beta 3: Present in adipose tissues.

Adrenal medulla is in the sympathetic nervous system.

Chromaffin cells in the adrenal medulla synthesize and release
epinephrine.

Parasympathetic neurotransmitters are Acetylcholine throughout.

Receptor for acetylcholine is Nicotonic acetylcholine receptors in
ganglion. It has a central channel and is surrounded by 2 alpha and 3
beta subunits in a circle shape.
In target organs, acetylcholine bind to a muscarinic receptor.
Inhibitor of parasympathetic nervous system - Atropine.

Acetyl CoA + Choline -----------------> Acetylcholine

Enzyme used is choline-acetyl transferase

In the synaptic cleft, acetylcholinesterase degrades Acetylcholine to

acetate and choline
There is choline reuptake.
Parasympathetic cotransmitters:
VIP (peptide) - Vasodilation
NO (gas) - smooth muscle relaxation
ATP (purine) - Smooth muscle contraction

Between the preganglionic neuron and ganglionic neuron, there are 3

receptors involved:
- Peptide receptors (uses IP3/DAG)
- Metabotropic receptor (Gives late EPSP)
- Ionotropic receptor (Early EPSP)

Varicosities are bulbous enlargments of postganglionic fibres. They

contain vesicles.
Varicosities + Schwann Cells makes up vegetative network.

Sympathetic Cholinergic Innervation:

In some places, sympathetic fibres use acetylcholine (Those that innercate
sweat glands and their vessels)

Non Adregenic non Cholinergic Transmission

There is synaptic activity in autonomic nervous system independent of
acetylcholine and catecholamines.
Instead they use independent cotransmitters like VIP, NO, ATP

Sensory neurin present in the dorsal root ganglion. Propogation from

periphery to CNS (relays sensory neruon)
In autonomic and somatic motor neuron, propagation is from CNs to
periphery.

Somatic motor neuron targets skeletal muscles. Voluntary movement

Autonomic: Involuntary. Heart, Smooth muscles, Endocrine glands.

In an autonomic ganglia, 1st and 2nd motor neurons meet.

Synaptic Delay value - 1.5 millisecond.

Classical neurotransmitters are:
Acetylcholine
Epinephrine, Norepinephrine, Histamine, Dopamine, Serotonin.

These classical neurotransmitters:

- stored in vesicles
- Have specific post synaptic receptors
- Eliminated from synaptic cleft.

NO cant be stored in vesicles cuz it'll diffuse out. NO doesn't need post
synaptic receptors because it'll just diffuse to its target.

In sympathetic system, Acetylcholien is used only in preganglionic

neurons.
In parasympathetic system, Acetylcholine is used in preganglionic and
postganglionic neurons and in motor end plates (skeletal muscle)

Elimination of acetylcholine is by acetylcholinesterase.

There is choline reuptake.
Botulinum toxin blocks the release of Acetylcholine

Ca2+ channels are voltage gated.

Voltage comes from action potential.

Tyrosine -----> Dopamine ----> Norepinephrine -----> Epinephrine

Norepinephrine receptors are G protein coupled receptors.

How to remove neurotransmitters from synaptic cleft:

- Diffusion into bloodstream
- Neuronal reuptake
- Enzyme activity.

MAO is responsible for neuronal degradation of norepinephrine.

Degradation happens pre synaptically.

Cotransmitters are released at the same time as neurotransmitters.

Cotransmitters have their own vesicles and receptors.
On their own, they can mediate some effects.
Acetylcholine receptors:
1) Ionotropic - Nicotinic receptor. Present at skeletal muscle and autonomic
ganglia.
2) Metabotropic receptor - GPCR

G proteins type S -----> Adenyl Cyclase ------------> cAMP

Inhibitory type G protein reduces cAMP.

Ca2+ Intracellular - 10^-4 millimole

Ca2+ Extracellular 1 millimole

Ionotropic receptors can be AMPA, NMDA, Kainate

Chloride ion inflow causes hyperoplarization in the cell

Higher the action potential, more the neurotransmitters released .

Electrical synapses (gap junctions) have connexions.

Connexons are made from 6 connexions with a hole in between.
Electrical synapses are the pathway for fast transmission.

Chemical synapses
Presynaptic terminus is always a neuron.
Postsynaptic Cell can be dendrite, axon, soma, glial cell.

Neurotransmitters:
- Acetylcholine
- Amines (Dopamine, Serotonin, Noradrenaline, Adrenaline)
- Gases (NO, CO)
- Peptides (VIP)
- Amino Acids: Glycine, Glutamate, GABA.

Action potential reaches the end of the axon.

Ca2+ channels open.
Ca2+ ions flow in and bind to calmoduline.
Calmoduline + Ca2+ activates the calmoduline-calcium dependent kinase.

Synaptotagmine is a docking molecule.

After vesilce docks at presyanptic membrane, neurotransmitters are
released into synaptic cleft.

The receptors that neurotransmitters bind to van be ionotropic or

metabotrpoic.

Metabotropic receptors have 5 transmembrane domains.

eg: Muscarinic receptor for acetylcholine.
After a ligand binds to a metabotropic receptor, secondary messenger
system is activated.

G protein is a heterotrimer. (Has 3 different subunits)

Alpha subunits binds the GDP - Resting phase.
After binding of ligand, GDP----------------> GTP
GTP activates 2nd messenger systems (IP3/DAG)

3 types of G proteins:
Gq, Gs, Gi
All 3 types have the alpha, beta, gamma subunit.

Gq ka alpha subunit will activate phospholipase C.

Phospholipase C hydrolases the phospholipid membrane to give IP3 and
DAG 2nd messengers.

IP3 goes to sarcoplasmic reticulum of cell.

Due to IP3 binding to receptors, Ca2+ is released into cytosol.
Ca2+ also acts as a second messenger.

DAG (diacylglycerol) activates enzymes/ion channels in cell membrane.

Gs ka alpha subunit activates adenyl cyclase which makes cAMP from ATP.
cAMP activates protein kinase A.

Gi inhibits adenyl cyclase and prevents cAMP production.

Action potential is formed in neurons when actual cell potential crosses

the threshold.
Action potential shape is characteristic for each cell type.
Synaptic transmission is entirely dependent on action potential.

Nerve cell resting potential = -70mV.

After threshold is reached, depolarization occurs. (Na+ flows into cell
because voltage gated Na+ channel open)
After opening, Na+ channels become inactive.

In repolariation, voltage gated K+ channel opens and K+ come into the cell.
Membrane potential becomes more and more negative. Goes till -90.

Na+/K+ pump restores resting membrane potential.

ANS always has 2 neurons in its pathway.

CNS --------(Preganglionic fiber)----------(Ganglia)-----------(postganglionic

fiber)------------- Target Organ.

In the CNS, preganglionic fibers come from spinal cord ka lateral horn.
Preganglionic fibers form the spinal and cranial nerves.

Varicosities are bulbous. Contain synaptic vesicles.

Symapthetic pathway: preganglionic fiber is short. Postganglionic fiber is

long.
Parasympathetic pathway: Preganglionic fiber is long. Post ganglionic fiber
is short.

In preganglionic fibers (sympathetic and parasympathetic), the

neurotransmitter used is acetylcholine.
In postganglionic fibers: Sympathetic - Noradrenaline
Parasympathetic - Acetylcholine

Sweat glands are an exception.

They are innervated y sympathetic cholinergic nerves. Have acetylcholine
instead of noradrenaline.

In adrenal medulla, chromaffin cells release adrenaline into circulation.

Sympathetic and parasympathetic usually have antagonistic pathways.

The exception is the salivary gland where they both produce saliva.
Sympathetic nerves produce mucous rich saliva.
Parasympathetic nerves produce serous saliva rich in enzymes.

Adrenal gland, Arterioles, Pilloerector muscles have only sympathetic

innervation.
Lacrimal gland have only parasympathetic innervation.

Sympathetic innervation increases heart rate and contraction force.

Parasympathetic innervation decreases heart rate only. Heart ventricles
don't have parasympathetic innervation.

Nerve fibers are:

Aalpha, Abeta, Agamma, Adelta, B, C

B is myelinated
C is unmyelinated.

Limbic system is for memory and learning.

Hypothalamus is for food intake, thirst and temperature regulation.
Medulla for cardiovascular and respiratory function.

PNMT transfers noradrenaline to adrenaline. PNMT is present in the

adrenal medulla.

Tyrosine----->Dopamine----------->Noradrenaline.
MAO oxidizes noradrenaline.
COMT - methylates noradrenaline.

Acetylcholien is stored in light, small vesicles.

It is produced by acetyl coenzyme A + choline
Acetylcholinesterase breaks down acetylcholine to acettae+choline.
Cotransmitters of acetylcholine: NO and VIP.
NO can diffuse through the lipid bilayer directly.
NO is made from arginie via the enzyme NOS (NO synthase)
NO synthase activated by calmodulin-calcium complex

Nerst equation is for 1 ion only.

GHK equation for multiple ions.
Na+ equilibrium potential is +60mV
K+ equilibrium potential is -110mV

K+ is the most permeable ion to the lipid due to the many K+ leaky
channels.

In depolarisation Na+ channels open

In hyperpolarization Cl- channels open.

After crossing the threshold, very sharp increases in slope due to voltage
gated channel.
Over threshold, all voltage gated channels channels remain open at the
same time leading to sharp, massive influx of Na+. Increases permeability
of Na+.

Theoretically maximum voltage is +60mV but practically it is +30mV.

These voltage gated channels can be open or inactive.

In relative refractory period, a higher stimulus could elicit an action

potential.

Tetraethyl ammonium (TEA) blocks voltage gated K+ channel.

TTX blocks voltage gated Na+ channels.

Electrotonic Potential is the potential before an action potential.

It is the potential in depolarisation uptil threshold value.
Electrotonic potential is due to ligand gated leaky channels.
Week 4
Skeletal muscles have cross striations and voluntary control.
Muscle contraction can be induced by motor nervous stimulations
Muscles contract and relax to cause movement and transport (heart,
peristaltic movement)

Muscle fibers are 10-20 cm in length.

10-100 micrometer in diameter.

Myofilaments are arranged parallel.

Z lines.
Area between 2 Z lines is one sarcomere.
Sarcomere is the contracting unit of muscle fibers.

There are membrane invaginations on the muscle fibers.

These membrane invaginations carries action potential to deep part of
muscle fiber and the middle myofibrils.
Such membrane invaginations are called transversal tubules.

Endoplasmic reticulum in muscles is called sarcoplasmic reticulum.

Sarcoplasmic reticulum has terminal cistems.
Sarcoplasmic Reticulum stores Ca2+
Sarcoplasmic Reticulum, Transversal Tubule, Sarcoplasmic Reticulum: Triad

Thick filament (middle of sarcomere) has myosin.

Thin filament (lateral areas of sarcomere) has actin
Myosin and Actin are contractile proteins.

Tropomyosin and Troponin are regulatory proteins for sarcomere

contraction.

Aktinin and Titin are structural proteins involved.

Thick filament is made up of 200-300 myosin molecules.

Myosin structures have tail (heavy chains) and head (light chains)
structures..
Myosin has 2 heavy and 4 light chains.
Myosin head binds and splits ATP for its energy requirements.
Myosin head could form cross bridges with actin filaments.

Actin has binding sites for myosin, tropomyosin and troponin.

Troponin complex is at the end of the tropoyosin band.
Troponin I (TnI): Holds tropomyosin over the myosin binding sites on actin.

In relaxed muscles:
Troponin Complex makes sure myosin binding sites on actin are blocked.

Ca2+ binds to troponin and changes the complex. Sets the myosin binding
sites on actin free from tropomyosin and able to bond.

When muscles contract, sarcomere lengths shortens but A band length

does not.
This is cuz thin filament is pulled inwards.

Cell body of motor neurons are found in the spinal cord in the ventral
horn.

Axons of motor neurons are thick with myelin sheaths. Saltatoric

Conduction.
Surface of muscle membrane communicates with motor neurone terminal
junction. Area of contact between the 2 is large.

Nicotinic Receptors of Ach are ionotropic. Non selective for cations.

End plate potential is an electronic potential. (Potential is below action
potential)

Botulinum Toxin - Blocks Ach release

Curare - Blockes binding of Ach to its receptor
Nerve Gas, Neostigmine inhibis acetylcholinesterase.

Excitation-Contraction Coupling:
- Action potential depolarizes muscle fibers. Both the deeper parts and the
surface fibers. Deeper fibres depolarized due to T tubules
- T tubules contain Dihydropyridine Receptors (DHPR)
- Once depolarisation reaches DHPR, it changes conformation.
- This causes RyR (Ryanodine Receptor) to change it shape as well.
- RyR is a Ca2+ channel. Due to its change in shape, Ca2+ channel opens
and Ca2+ ions flow in

Myosin binds to and splits ATP.

Release of energy changes the conformation of myosin neck.
Ca2+ binds to Troponin C and lets tropomyosin slide away from myosin
binding site on actin.
Now myosin head can bind to actin.
At this stage, myosin head is bound to actin and has ADP+Pi attached as
well.
1st power stroke: Pi leaves and actin is pulled by 6-8nanometer
2nd power stroke: ADP leaves myosin head and actin is further pulled 2-4
nanometer.

Thus the thin filament is pulled towards the middle and sarcomere gets
shorter and shorter.

If Ca2+ concentration reduces, Ca2+ leave troponin complex. Tropomyosin

is pulled back onto myosin binding sites on actin and the muscle relaxes.

5 cross bridges formed per cycle.

Creatin Phosphate provides phosphate group to ADP to form ATP.

Free fatty acid, glucose, glycogen breakdown are all sources of energy for
skeletal muscle contraction.

Muscle Fibres.
Tupe I: Slow Oxidative
Type IIa: Fast Oxidative
Type IIb: Fast glycolytic

Type I (slow oxidative) muscle fibres permanently produce ATP. Type I

muscle fibres need oxygen. Slow but long lasting contraction
Type I muscle fibres are red.
Type IIa (fast oxidative) muscle fibres produce fast and strong contraction
of muscle. Doesnt need oxygen.

Efficacy of muscle contraction is 20-30%

Muscle contraction force reduces if not enough ATP is generated because

ATP is needed for cross bridge formation and function.

Activity of muscle enzymes are negatively affected by lower pH which

comes from the buildup of LActic Acid (due to anaerobic respiration)

Depletion of Acetylcholine also leads to muscle fatigue

Rigor Mortis - Stiffness after death due to lack of ATP

ATP binds to myosin head during cross bridge formation.

Ca2+ - ATPase binds Ca2+ back into the sarcoplasmic reticulum.

Lactic Acid buildup and filament breakdown leads to muscle fatigue

Androgens and growth hormones do influence muscle mass.

Muscle fiber shortening is induced by muscle fiber action potential.

There is a significant gap between muscle fiber action potential and

muscle fiber contraction because the intracelluar steps take time.
Thus there is summation of contractions.
Multiple unfuse tetanus make up a fused, complete tetanus.

Size principle: Smallest motor units are used first and then if required,
larger motor units are recruited.

The force of muscle contraction increases if:

Frequency of action potentials increase
Number of motor units increase.

Muscle contraction leads to shortening of muscle fiber and generation of

force.
In isotonic contraction:
Muscle tensions stays the same but the muscle got shorter.
In isometric contraction:
Muscle length stays the same but muscle tension changes and force is
generated.
Most contractions in humans are auxotonic.
Both length and tensions changes due to muscle activity

The best muscle contraction is when the sarcomere length is 2.2

micrometer. This length is where thick and thin filaments fit perfectly into
each other.
Anything shorter or longer will give a lower percentage of maximum force
due to imperfect fitting.

In the smooth muscle cells, there are no cross striations.

Myosin and Actin filaments positions are not strictly regulated.
Smooth muscles contain minisarcomeres which are longer than
sarcomeres and fastened to outer cell membrane.
When a smooth muscle contracts, all muscle dimensions get shorter in all
directions due to fastening.
Thin filament runs freely unidirectionally and thus myosin head has more
space to contract in.

Smooth muscle cells have no troponin and contracts to 30% of its initial
length.
Skeletal muscles contract up to 60% of its initial length and thus smooth
muscle cells can contract more than skeletal muscles.

In smooth muscle, myosin head has a regulatory function on one of its

light chains.

Ca2+ enetrs smooth muscle cell.

Ca2+ - Calmodulin complex forms and this complex activates MLCK.
MLCK phosphorylates the light chain of the myosin head
After phosphorylation, myosin head can bind to actin and ATP.
Further process is the same.

MLCP removes phosphate group from myosin light chain and myosin head
relaxes
Source of Ca2+ in skeletal muscles is the sarcoplasmic reticulum.
In smooth muscles, ligand and voltage gated Ca2+ channels open and and
provide Ca2+ from extracellular sources along with sarcoplasmic reticulum.

IP3 (secondary messenger) can open IP3 channels of the sarcoplasmic

reticulum to release Ca2+ into the cytoplasm.

In smooth muscle cells, there is Ca2+ induced Ca2+ release.

Ca2+ acts on RyR on the sarcoplasmic reticulum membrane.

MLCP - Myosin Light Chain Phosphatase

MLCK - Myosin Light Chain Kinase

To increase the contractility of smooth muscle cells:

MLCK increase and MLCP decrease.
To decrease the contractility of smooth muscle cells:
MLCK decrease and MLCP increase.
This is because MLCK activates myosin head and cross bridge formation.
MLCP relaxes muscle as it prevents cross bridge formation.

Smooth muscles can be multi units or single units.

Smooth muscles have lower energy requirements for contraction
There is long, sustained contraction with little energy expenditure.
Force generated however is not very high.
This is because in smooth muscles, cross bridge takes longer to form and
stay for longer

When skeletal muscles contract, 2 bones are pulled towards each other.

Epimysium surrounds the whole muscle.

Perimysium surrounds the fasicle.
Endomysium surrounds surrounds the muscle fibres.

Skeletal muscles are striated and voluntary.

Myofibrils are surrounded by sarcoplasmic reticulum.
The membrane of the muscle fiber is called sarcolemma.

Myosin head has ATP activity.

Ca2+ comes from sarcoplasmic reticulum.

Action potential activates DHPR.

DHPR are on the transverse tubule membranes .
Rianodine Receptors are activated by DHPR.
Rianodine Receptor allows Ca2+ to flow out of the sarcoplasmic reticulum
(via terminal cisternae) into the sarcoplasm.

Troponin has 3 parts.

Troponin I: Inhibition
Troponin T: Acts as a glue for Tropomyosin
Troponin C: Able to bind free Ca2+

When Ca2+ binds to the troponin complex,

Troponin I pulls tropomyosin away and the myosin binding sites on the
actin are free and available.

A motor unit is made up of a single motor neuron + muscle fibres that it

innervates.

Neuromuscular junction is just the synapsis

Nicotinic receptors are ionotropic receptors of Acetylcholine.

Acetylcholine can have ionotropic (Nicotinic) or Metabotropic (Muscarnic)

receptors.

Curare inhibits all voluntary muscles (skeletal muscleS).

Curare binds to acetylcholine receptors and prevents acetylcholine from
binding

Choline acetyl transferase generates acetylcholine by joining Acetyl

Coenzyme A group and Choline group.

Muscle fibres consume glucose.

Glucose forms ATP in mitochondria
ATP is used to shorten muscles.
Fatty Acids are an alternate source of energy for muscle fibres as is Lactic
Acid fermentation.

White muscles have a short twitch duration.

Red muscles have long, slow contraction.

More the cross bridges formed, stronger is the force generated.

2.2 micrometers is the length at which maximum number of cross bridges
form in a sarcomere.

As frequency of stimuli increases, contractions are summated.

Isometric contraction - Same length, change in muscle tension.

Isotonic contraction - Same muscle tension, change in muscle length.

Smooth muscles have random arrangement of filaments and no troponin.

Smooth muscles are connected by gap junctions.
Smooth muscles contain caldesmin which slows down ATPase activity.

Electromechano coupling is important.

In smooth muscles, Ca2+ comes from extracellular and intracellular

sources
Intracelluklary from sarcoplasmic reticulum (IP3) and extracellularyly via
ligand and voltage gated ion channels.
Ca2+ - Calmodulin complex activates MLCK.
In smooth muscles, myosin head is not active until MLCK phosphorylates
myosin head.

MLCP can make myosin head inactive by cleaving the phosphate group
from myosin head.

Higher the cAMP, more relaxed is the smooth muscle.

Nitric Oxide relaxes smooth muscles.

Single unit is activated by mechanical, electrical, neuronal way.

Adregenic receptors are receptors for adrenaline (hormone) and

noradrenaline (neurotransmitter).
Receptor can be alpha or beta.
Alpha 1: Gq
Alpha 2: Gi
Beta 1,2,3: Gs
Adregenic receptors are metabotropic. This means its a GPCR

G protein is a trimer.
Its subunits are alpha, beta, gamma,

Gq activates Phospholipase C. Phospholipas C makes IP3 and DAG (both

are secondary messengers) from the phospholipid membrane.
DAG: Activates Protein Kinase C which phosphorylates.
IP3: Activates IP3 gated Ca2+ channels on sarcoplasmic reticulum
membrane
Ca2+ is also a secondary messenger. It can bind to troponin (Skeletal
muscle) or calmodulin (smooth muscle) for muscle contraction.

Gs activates Adenylate Cyclase which makes cAMP from ATP.

cAMP is a secondary messenger.
cAMP activates protein kinase A.

Gi works opposing Gs.

Gi decreases the activity of cAMP.
Alpha 2 receptors are Gi (inhibitory receptors)

Nicotinic receptor for acetylcholine is an ionotropic receptor

This means it is an ion channel that allows Na+ to flow into the cell usually.

Nicotinic receptors can be Muscle type or Ganglion type.

Curare blocks muscle type nicotinic receptors.

Muscarinic is a metabotropic type of receptor.

Muscarninc has 5 types.
M1, M3, M5 all activate Gq proteins.
M2 and M4 activate Gi proteins.

1 motor unit = 1 motor neuron + all the skeletal muscle fibres that it
innervates.

The synapse between motor neuron and a muscle is the neuromuscular

junction.
Axon of motor neuron is usually myelinated.
In the neuromuscular junction, in the pre synaptic neuron Ca2+ and
calmodulin bind to form a complex. This also happens in smooth muscle
cells.

Acetylcholine is the neurotransmitter of the neuromuscular junction.

Acetylcholine will usually bind to ionotropic, nicotinic (muscle type)
receptor which can hold 2 Acetylcholines each.
Due to the binding, ion channel opens (cuz its ionotropic) and Na+ flows
into the cell.
When Na+ flows in, electronic potential increases and due to summation,
depolarisation occurs.
Depolarisation will disperse to T tubules and cause muscle muscle
contraction eventually.

Motor End Plate - Part of the muscle fiber below the synaptic cleft.

Myosin has head, neck and shaft.

In skeletal muscles: Troponin C binds to Ca2+.

Troponin C - Ca2+ complex pulls tropomyosin away from the myosin
binding sites on the actin.
Higher the Ca2+ concentration, more myosin binding sites will be available
and more myosin heads can bind to actin.

Actin and Myosin are organized in sarcomeres.

Titin stabilizes the sarcomere.

T tubules are invaginations in the sarcolemma.

DHPR and RYR receptors are present. DHPR on T tubule sarcolemma. RYR
on sarcoplasmic reticulum.
DHPR is a voltage sensor.

Action potential spreads into T tubules.

DHPR changes its conformation after sensing depolarisation.
DHPR now activates RyR receptor on sarcoplasmic reticulum.
This allows Ca2+ to leave the sarcoplasmic reticulum and go into the
sarcoplasma.

Myosin head has ATPase activity and binds to Actin as well.

After myosin hydrolyzes ATP, its angle changes from 90 to 45 degrees.
Sliding filament mechanism causes shortneing of sarcomere and thus
muscle contracts.

As myosin pivots towards the center its called a power stroke.

SERCA pumps Ca2+ out of the cell and pumps Na+ into the cell.
Without Ca2+, skeletal muscles relaxes as tropomysin once again covers
action ke myosin binding site.
Without Ca2+, smooth muscle relaxes as Ca2+ calmodulin complex breaks
down and cant activate MLCK.

Smooth muscle can be single unit or multi unit.

Multi unit (Autonomic neuron is in between individual muscle cells)
Single unit (Autonomic neuron borders all individual muscle cell. Cells are
connected by gap junctions.)

Both skeltal and smooth muscle contraction uses Ca2+

In smooth muscles, there is calcium induced calcium release.
In smooth muscles, voltage gated and ligand gated Ca2+ channels allow
Ca2+ influx along with sarcoplasmic reticulum.

When there is increased Ca2+ concentration in smooth muscle cell, Ca2+

binds to calmodulin.
Ca2+ calmodlin complex activated MLCK
MLCK phosphorylates light chain of myosin.

Thus MLCK is dependent on Ca2+ and calmodulin.

MLCP dephosphorylates myosin light chain.

In smooth muscles contraction, Ca2+ can come from intracellular and

extracellular space.
Intracellularly, Ca2+ comes from terminal cisternae of sarcoplasmic
reticulum.

DHPR means dihydropyridine receptor.

RyR are Ca2+ gated receptors.
RyR get activated by change in conformation of DHPR.
Week 5
2 compartments are Intracellular, Extracellular.

Isotonicity:
concentration/osmolarity should be the same in all 3 compartments.
If the concentration or osmolarity is not similar in all 3, then there will be
movement of water.

Too much water in a cell leads to swollen cell and ruptured cell membrane .
Extracellular space (Interstitial tissue) can also be swollen.

Edema is due to changes in isotonicity.

Isovolemia:
Have to maintain same proprtion/ratio of things between all 3
compartments.

VIQ:
Total water in human body = 0.6 x body weight
Intracellular fluid = 0.4 x body weight
Extracellular fluid = 0.2 x body weight.

The interstital fluid - 0.75 of extracellular fluid

Intravasal (blood plasma) is 0.25 of extracellular fluid
Transcellular is part of extracellular compartment. Includes eye and inner
ear.

VIQ:
To measure volume of fluid compartments:

Amount of indicator/concentration of equilibrium

Indicator gets distributed in the body after administration. It can be
measured how much indicator is present after a while.

Intravasal measurement uses albumin because it stays in the intravasal

space. Evans Bkue or I131 can be bound to albumin.
For measuring extracellular space: Inulin is used.
Inulin is easy to absorb, not toxic or metabolized and doesn't go into the
cell.
To measure total fluid in every compartment: radioactive water is used.

Thrombosis:
Continuity of intravasal space is disturbed. There is no or reduced flow in
the blood vessel.

Ahead of the thrombosis there is decreased or no blood flow.

Behind the thrombosis there is congestion, increase in pressure and
edema (due to disruption of isotonicity and isovalemia of blood)

Centrifugation is required to separated blood cells and fluid.

Cells (RBC, WBC, Platelets) accummlatae at the bottom of the tube after
centrifugation.

45% of total blood volume is RBC

Less than 1% is WBC and platelets
55% is blood plasma. Yellow and top region. Blood plasma made up of
electrolytes, proteins, blood glucose.

Blood Sera = Blood plasma without the protein fibrinogen

Hematocrit: Proportion of cells (mostly RBCs) in the blood.

Males: 0.44-0.46
Females: 0.41-0.43
Difference is due to testosterone production

Components of plasma:
1) Inorganic electrolytes (Na, K, Ca, Cl, Mg ions)
2) Organic substances (proteins, glucose, urea, amino acids, lipids)

Proteins of blood plasma are mostly synthesized in liver and gut.

Blood plasma proteins regulate oncotic pressure, transport and act as
acid-base buffers.

Albumin. Has a huge and crowded surface.

Attracts/Binds to water
Tranpsorts/binds to drugs
Can donate protons cuz protons are present on their surface.

- Alpha 1 globulins: Bind to hydrophobic specific hormones and vitamins

(thyroxine, cortisol, Vitamine D)
- Alpha 2 globulins: bind to copper via the ceruloplasmin.
Importaant cuz free copper is toxic.
- Beta globulins: Includes transferrin (iron binding protein)
- Gamma globulins: Are aantibodies
- Fibrinogen: Works in blood coagulation

Electrophoresis is used to separate proteins according to their sizes and

electric properties.

60% of blood plasma proteins are albumin.

Liver Cirrhosis:
Liver cells are dead and replaced by connective tissue.
There is less albumin and increased gamma globulin (antibodies) in the
blood plasma.

Nephrosis syndrome: Kideny can no longer keep albumin in circulation

and thus albumin is secreated out in urine.

Multiple myeloma: Albumin and gamma globulin are present at the same
level.

Transport of hydrophobic substances in blood is with lipoproteins of

plasma.
Hydrophobic core is triglycerides and cholesterol.
Hydrophilic periphery has phospholipids and apoliproteins.

Lipoproteins can be chylomicron, VLDL, IDL, LDL, HDL

This is in increasing density and protein content.
Chylo means absorbed from intestines.

HDL is the good cholesterol.

syntheitized in liver.
It picks up cholesterol from the blood vessel walls and protects against
atherosclerosis.

Mature RBCs have no mitochondria, no nuclei, no endoplasmic reticulum.

Glycolysis is the only metabolism in mature RBCs.
Mature RBCs are filled with hemoglobin.

There are 4-5 million RBC per microlitre.

Lifespan of a RBC is 120 days
Diameter of RBC is 7-8 micrometer

RBCs are made in bone marrow and their synthesis is facilitated by the
growth factor erythropoietin.

Reticulocyte is another name for young, non matured RBCs.

Reticulocytes have endoplasmic reticulum.

Parameters of RBCs:
MCH (mean corpuscular hemoglobin):
Amount of hemoglobin in a single cell
MCV (mean corpuscular volume):
volume of a single RBC

Price Jones Curve shows the distribution of MCV in RBCs.

Can show narrow and wide variancies.

Blood sedminetation rate is less than 20 mm/hr

In sedimentation, RBCs aggregate with plasma globulins.

Anaemia - Decreased RBC number.

RBC membranes are fluid and flexible.
They have Band 3 (Cl- / HCO3 -) transporter and GLUT 1 (glucose
transporter)
Both are transmembrane proteins
GLUT 1 needs no insulin and has high capacity.
Ankyrin is a very important stabilizing protein in the RBC membrane

Glycolysis is the only metabolism inside RBC

Under the membrane is a cytoskeleton (mesh) which provides flexibility.

This mesh is made up of spectrin.

The required iron uptake is 1-2 mg/day.

Fe2+ is better absorbed than Fe3+ and this is why Fe3+ is converted to
Fe2+.

Free iron is toxic.

In cells, iron binds to ferritin.
In circulation (plasma), iron binds to transferrin.
Iron is stored in the liver and the spleen inside macrophages. This iron
storage complex is called hemosiderin

Ferroportin causes the release of iron from storage cells.

Ferroportin is inhibited by hepcidin which is produced by the liver.

Iron deficiency causes Microcyter Hypochrom anaemia.

RBCs will be pale as there is less iron and less hemoglobin in the RBC.
MCH and MCV will be low.

Before binding to ferritin, Fe2+ must become Fe3+.

Vitamin B12/Folic Acid is used in the synthesis of DNA.

Vitamin B12 binds to R protein in saliva and then to intrinsic factors in
intestine.
Intrinsic factors are protecting proteins for B12. Prevent B12 from bein
destroyed by acid.
Deficinecy of B12 or intrinsic factors causes Macrocyter Hyperchrom
Anemia

Hemoglobin is made up of Beta globulin + heme (in the middle)

Fe2+ is in the middle of the porphyrin ring.
If Fe3+ is in the center of the porphyrin ring, there is loss of function.
(Methemoglobin)

Hemoglobin has 4 subunits.

Main type of hemoglobin is hemoglobin A

Hemoglobin has up to 97% saturation.

Hemoglobin affinity to oxygen is variable.
When hemoglobin affinity to oxygen decreases then oxygen is released by
the hemoglobin. Factors that decrease the affinity:
- Increased temperature
- Bohr Effect (CO2 and protons increase, pH reduces) [ muscle contraction]
- Presence of 2,3 bisphosphoglycerate (by product of glycolysis)

An increase in haemoglobin affinity for oxygen means that oxyegn is not

released by hemoglobin.
- Fetal hemoglobin (keeps oxygen of mother)
- Carboxyhemoglobin (CO + hemoglobin binds oxygen and doesn't let it go)

CO2 diffuses from the tissue to the RBCs

In RBCs, carbonic acid is made from CO2 due to the enzyme carbonic
anhydrase.
Carbonic acid dissociates to give a free proton ion in RBC.
Free proton binds to hemoglobin
Oxygen bound to hemoglobin is now released to the active tissue.
63% of oxygen transport is done by this mechanism.

Hamburger shift - Bicarbonate is exchanged for chloride on RBC

membrane. (Band 3)

In old erythrocytes: hemoglobin is released .

Haptoglobin binds to it in circulation.
Fe2+ is dissociated and stored.

Porphyrin is toxic.
For its degradation biliverdin (green) and then bilirubin (yellow).
Bilirubin binds to albumin. (indirect bilirubin)
Liver can take up bilirubin and join it with glucuronide (direct bilirubin)

From the liver to gut, bilirubin becomes urobilin and stercobilin.

Some of them are reabsorbed to liver (Enterohepatic circulation)
Most is secreated as feaces (stercobilin) or urine (urobilin)

Week 6
Normal WBC count: 4000 - 10000 cells per microlitre of blood.
Differential leukocyte count: Determination of the ratio of vatrous WBCs.

Staining of bloodmear (Pappenheim model):

Concentrated May Grunwald solution (3 minutes)
Dilute with equal amount of distilled water (1 minute)
Add freshly diluted Giemsa solution (1:20 ratio with distilled water)
Wash off Giemsa solution after 15 minutes

All blood cells originate in the bone marrow (multipotential hematopoietic

stem cells)
Gives rise to either common myeloid progenitor or common lymphoid
progenitor.

Granulocytes:
1) Neutrophils
60%-80% of WBC
Segmented nucleus
Have specific granules (phospholipase, lyzosime)
Act as phagocytes, produce cytokines

2) Eosinophils
1%-5% of WBC
Bilobed nuclei
Pro inflammatory cells
Produce cytokines & lipid mediators
Fights against viruses and parasites.

3) Basophils
(0.5% of WBC)
Largest granulocyte
Segmented nucleus
Have large granules with histamine and heparin.
Inflammatory response, inhibition of blood clotting, Allergic reactions,
produces pro inflammatory cytokine.s

Monocytes (5% of WBC)

Biggest white blood cell.
Bean shaped nucleus
Have lysosomes and phagosomes in its cytoplasm
Carry out phagocytosis and are antigen presenting cells.
After entering tissues, monocytes become macrophages.

Lymphocyte (20%-30% of WBC)

Smallest white blood cell
Have large nucleus
T lymphocyte - 80%
B lymphocyte - 20%
Primary lymphoid organs: Thymus, Red Bone Marrow
Secondary lympoid organ: Tonsils, spleen, lymph nodes, Peyer Patches.

T lymphocytes: Adaptive Cellular immune response

B lymphocyte: Adaptive Humoral Immune response. Plasma cell production

Natural Killer Cells kill tumor cells and infected cells using perforin.
Humoral innate system: Lysozyme, Complement System
Cellular innate system: NK cells, phagocytes (recognize pathogens
associated molecular pattern (PAMP))

Adaptive immunity is by lymphocytes.

B lymphocytes differentiates into plasma cells which produces antibodies.
Antibodies neutralize and opsonize toxins. Antibodies also activate
complement system.

Neutrophils and macrophages defend against infections participating in

the inflammatory process.

Chemokines attract WBC to the site of penetration.

Phagocytosis is an innate immune response.

Recognition of pathogen associated molecular pattern (PAMP) or antigens
labelled with antibodies.
Phagosome is formed within the cell. Phagosome merges with lysosome.
Destruction of pathogen within the phagolyzosome.

Neutrohils carry out cytokine production and release. Also do

degranulation by exocytosis. Releases proteolytic enzymes and defenzins,
ROS (reactive oxygen species) and Netosis (traps pathogens)

Complement system - Humoral system of innate immune system

Made up of proteolytic enzymes till C4. C5-C9 proteins are a part of MAC
(membrane attack complex) and have no proteolytic effect.
MAC create a hole in the membrane of the bacteria.

T cells - Adaptive Immune response

T lymphocytes recognize antigen only when the antigen is on the surface
of an antigen presenting cell (MHC I, MHC II)
Activated T cells proliferate (clonal expansion) and differentiate into Tkiller
and Thelper cells.

Tkiller cells have CD8 maker and are on MHC I.

Tkiller cells destroy infected cells by apoptosis (perforin, granzyme)

Thelper cell have CD4 marker and on MHC II

Thelper cells produce cytokines (inflammation) and activate B cells
Tregulator cells (CD4 marker) inhibits autoimmune reactions

B cells are adaptive humoral immune response.

Activation of B and T cells happens in the secondary lymphoid organ.
B cells transform into antibody (immunoglobulin) producing plasma cells,
Some activated B lymphocytes are converted into memory cells.
Memory cells helps the efficient and rapid development of a repeated
immune response.
B cell activation can be both T cell dependent(Thelper cell) and T cell
independent.

Antibodies aka Immunoglobulins.

There are 5 types.
IgM (pentamer) - antibody of primary response
IgG (monomer) - antibody of secondary response
IgE (monomer) - antibody of allergic reactions
IgD (monomer) - B cell receptor
IgA (dimer) - Secretory immunoglobulin.

Antibodies can:
- Neutralize toxins
- Opsonization, phagocytosis of microbes
- Trigger inflammataion
- ADCC - antibody dependent cellular cytotoxicity

If an antigen is present on red blood cells then the corresponding

antibody will not be present in the plasma.
Eg: Antigen B on RBC so Antibody A in plasma

ABO antigens are carbohydrates

Presence or absence of antigens A & B determines the 4 blood groups.

A, B antigens appear during the 5th-6th week of embryonic development

A, B antibodies appear 3-6 months after birth due to bacterial
colonisation of GI tract.
D antigen is the most important antigen of the Rh blood groups system.
In immunization, Rh+ and Rh- blood mixes.

Due to hemolysis, hematocrit levels reduce and bilirubin levels increase.

Total body water content - 42 litres (60% of human)
Intracellulcar fluid - 25 litres
Extracellular fluid can be:
Blood plasma (3 litres)
Interstital fluid (13 litres)
Transcellular fluid (1 litre)

There is more protein in the blood plasma than in the interstitial fluid.

Blood:
Erythrocytes: Approx 5 million per microlitre
Leukocytes: 4000 - 10,000 per microlitre
Thrombocytes: 150,000 - 300,000 per microlitre.

Blood is made up of plasma and corpuscular elements.

Hematocrit is the:
volume of corpuscular elements/total blood volume.

Since the leukocyte and thrombocyte number is negligible hemttocrit

practically measures the erythrocyte quantity only.

Usual hematocrit level: 0.41-0.46

Leukocytes can be granulocytes, monocytes, lymphocytes.

Granuclocytes can be neutrophils, basophils, eosinophils.

Neutrophils (50-70%) have segmented nucleus. Phagocytosis. Cytokine

production
Eosinophils (1-6%) have bilobed nucleus. Attacks parasites
Basophils (Less than 1%) have many granules. Invoved in inflammation

Lymphocyes make up 20-40% of leukocytes

B lymphocytes do antibody production.
T lymphocytes do cellular immune response.

Monocytes (2-10%) of leukocytes.

Form macrphages in tissue.
Largest leukocyte. Has large nucleus.

Blood sedimentation rate is up to 20mm/hour

If greater than 20mm/hour then patient has a problem..
Blood sedimentation rate depends on albumin globulin ratio.
More the albumin, higher is the blood sedimentation rate.

Plasma proteins do transport, nutrition, blood clotting and buffer function.

Especially transport function. Transport can be specific or non specific.
Albumin. Alpha, Beta, Gamma family of globulins are all plasma proteins.

Hemoglobin concentration of blood is 150g per litre.

Hematopoeitic stem cell gives rise to progenitor cells (erythrocytes,

monocytes, platelets, granulocytes) and lymphocyte precursor cells (B and
T lymphocytes).

Developed erythrocytes have no nucleus, mitochondria or endoplasmic

reticulum. They transport oxygen and CO2

Hemoglobin has heme and globin.

Heme has a porphyrin ring with Fe in the middle

In osmosis, solvent flows from low osmolarity to high osmolarity.

If erythrocyte is in a hypotonic solution, solvent flows into RBC and

hemolysis occurs.
If erythrocyte is in a hypertonic solution, solvent flows out of the RBC and
crenation occurs.

Due to the RBC shape it has osmotic resistance.

Due to the erythrocyte shape, volume can increase with the same surface
area. Thus there is osmotic resistance. Water volume of erythrocyte can
increase without immediate lysis.

Reticulocytes can be found in the blood. 0.5% of erythrocytes are

reticulocytes.

For hemoglobin you need iron.

Fe2+ goes into enterocyte via carrier protein. Leaves enterocytes via
ferroporta.
In blood F2+ becomes Fe3+. This Fe3+ is bound to transferrin in the blood.

Erythropoeitin enhances the production of erythrocytes.

Erythropoeitin is made in the kidney.

Vitamin B12 enhances the production of DNA and cell division.

Anaemia - low number of erythrocytes.
Due to vitamin B12 deficiency, RBC precurosrs don't divide and keep on
growing. Thus number of erythrocytes is low and there is a certain type of
anemia.
Intrinsic factors are made by the stomach wall.
Intrinsic factors are essential for the absorption of vitamin B12.
Lack of intrinsic factor will mean lack of B12 absorption meaning the above
mentioned anemia problem.

RBC lifespan is 120 days.

Then it is broken down in the spleen.
1) Hemoglobin is taken up by the macrophage.
In the macrophage, globin is separated from the heme.
2) Biliverdin formed. 3) Then bilirubin formed.
Jaundice - too much bilirubin. skin becomes yellow.
Bilirubin normal levels - 17micromol/litre
4) In blood plasma: Bilirubin + Albumin ----> Unconjucgated (indirect)
bilirubin
5) In liver: albumin leaves and Bilirubin + Glucoronic Acid ---------->
Conjugated (direct bilirubin)
Conjgated bilirubin sent to bile and excreted as
urobilinogen (urine) and stercobilinogen (faecese)

Transition of unconjugated bilirubin to conjugated bilirubin is the rate

limiting factor.

Antigen - A substance that evokes an immune response.

Immune response can be specific (acts on only one substance) or non
specific (acting on wide range of substances).
Memory cells are created during the first infection. These memory cells
cause a quicker response during the 2nd infection.

Monocytes - Form macrophages (kupfer cells, alveolar macrophage) in

tissues. Monocytes have an unspecific immune response.
The phagocytes are directed to a certain place (opsonization)
In opsonization there is marking of tissues for phagocytes.

Neutrophils also have non specific immune response.

Basophils release heparin (blocks blood clotting) and histamine

(inflammation)

Eosinophils attack parasites and cause inflammatory reactions.

Only B and T lymphocytes can produce a specific immune response.

B lymphocytes mature in the bone marrow and T lymphocytes mature in
the thymus.
After contact with the antigen both T and B lymphocytes will form memory
cells. B lymphocytes form plasma cells which produce antibodies.
T lymphocytes can become:
T helper cells (CD4 receptor) - produce cytokines which enhance the
immune system. Activate B lymphocytes
T regulatory (CD 4 receptor), T suppressor cells - produce substances
which decrease the intensity of the immune reaction
T cytotoxic cells (CD8 receptor) - destroy virus infected cells

Antigen presentation is done by MHC I and MHC II proteins.

T and B lymphocytes will only become active after antigen presentation.

CD 4 receptors bind to MHC II

CD 8 receptors bind to MHC I

T lymphocytes have cellular immune response.

Antibodies have heavy and light chains.

IgA (dimer) - secretory immunoglobulin
IgM (pentamer) - Blood group antibodies
IgG (monomer) - Small. Can pass through placenta barrier
IgE (monomer) Releases histamine
IgD (monomer)
Secondary immune response is much faster than the primary immune
response due to the presence of memory cells.

Cytokines - Humoral and non specific

Complement system has 9 proteins that activate each other.

The complement system opsonizes, activates mast cells and basophils.
C1-C4 are proteolytic enzymes.
C5, C6, C7, C8, C9 do the lysis of cells together via MAC (membrane attack
complex).

upto 60% of body weight is water

Of all this water, 60% in intracellular and 40% extracellular
Extracellular:
Intravasal (10%)
Interstitial (28%)
Transcellular (2%). Eg of transcellular is Cerebrospinal fluid.

Plasma expanders are only in intravasal compartments .

Crystalloid (saline) is in extracellular compartments.
Glucose solution is in every fluid compartment.

To increase blood pressure use crystalloid (saline) or plasma expanders.

Adding these fluids increases the strain on patients heart.

Adema (swelling of cells due to fluids going into cells)

Intravasal compartment can be measured using I131 (radioactive isotope)

albumin.
Extracellular compartment measurements uses inulin.
Extravasal measurement = Extraceullular volume - Intravasal volume
For whole body fluid measurement, tricium (radioactive water) is used.
Intracellular measurement = Total body - Exrtacellular volume.

Hematocrit = volume of RBC / volume of blood

Female hematocrit level: 0.37 - 0.42
Male hematocrit levels: 0.44 - 0.52
Roughly 45% of blood is erythrocytes

1% of blood volume is buffer coat (WBC + platelets)

55% of blood is plasma.

Serum does not have fibrinogen.

Plasma has fibrinogen.

Inorganic elements of plasma:

Na+ : 138-151 mmol/L
K+ : 3.4-5.2 mmol/L
K+ is the most permeable to cell membrane due to K+ leaky channels.
Cl- : 101-111 mmol/L
Ca++free : 1.5 mmol/L
Ca++all : 2.5 mmol/L
1 mmol/L of Ca2+ is bound to proteins.
HCO3- : 21-28.5 mmol/L
H+ : 10^-4 mmol/L

Organic elements of plasma:

Urea
Glucose : 4.6 - 5.9 mmol/L
Triglycerides
Cholesterol
LDL - creates plaques. Bad cholesterol
HDL - Remove cholesterol from plaques. Good cholesterol.
Bilirubin
Proteins : 60-80 g/L

Albumin is the most common protein in blood plasma. Albumin has

35-45g/L
Albumin does non specific transport (eg: drugs, bilirubin).
Albumin also regulates oncotic pressure (osmotic pressure caused by
proteins)
Liver produces albumin.

The other groups of plasma proteins are:

Alpha 1 globulins
Alpha 2 globulins
Beta globulins
Gamma globulins

Alpha 1, Alpha 2, Beta globulins are all transporter proteins.

Alpha 1 globulin: Thyroxine, Cortisol
Alpha 2 globulin: Ceruloplasmin
Beta globulin: Transferrin

Gamma globulins are produced by plasma cells. Gamma globulins are

immunoglobulins (antibodies)
Plasma cell aka activated B lymphocyte

Antibodies have 2 heavy and 2 light chains.

Light chain sequence is variable. This binds to pathogens
IgG (monomer) Anti D antibody
IgE (monomer) for allergic reactions, parasitic infections
IgD (monomer)
IgA (dimer)
IgM (pentamer) for blood group antibodies

Erythrocytes: 4.8 - 5.2 million per microlitre

Erythrocytes cant perform aerobic respiration.
Erythrocytes have GLUT 1 transporter (passive, facilitated diffusion) on its
membrane
Aquaporine channels also present in RBC membrane for water transport.
Band 3 transporter also present on RBC membrane

RBC diameter: 7-8 micrometer

MCV (mean corpuscular volume) - Volume in a RBC

94 x 10^-15 litre
MCH (mean corpuscular hemoglobin) - Amount of hemoglobin in a RBC
29 x 10^-12 g
MCHC (mean corpuscular hemoglobin concentration) - MCH/MCV
usually 333 g/L
RBc is made in the bone marrow from hematopoietic stem cells. These give
rise to erythroblasts (erythrocyte + nucleus).
Erythroblast loses nucleus to become reticulocyte (has endoplasmic
reticulum, golgi apparatus)
Reticulocytes loses its organelles to become erythrocytes.

Erythropoeitin ( produced by kidney), growth hormone and testosterone

increases erythrocyte production.

Vitamin B12 and folate are used for DNA production

Stomach makes intrinsic factors.
Vitamin B12 is only absorbed if it is bound to intrinsic factor.
Lack of B12 or intrinsic factor causes macrocytic hyperchromic anaemia.
Fewer and larger RBC created. RBC contains lots of hemoglobin.

Fe2+ is needed for hemoglobin production.

Lack of iron causes microcytic hypochromic anaemia.
RBC are small and there isn't enough hemoglobin.

There is 8-27 micromol of iron in blood plasma.

Recommended daily intake of iron: 10-12 mg.

From the diet, humans absorb Fe2+, Fe3+ and Heme-iron

Heme-iron enters the enterocytes via HTP 1
Fe3+ cant go into enterocyte so it is reduced by ferrireductase enzyme
(Fe3+ ----> Fe2+)
Fe2+ is absorbed into enetrocyte using DNT 1 transporter on enterocyte
membrane.

Iron in cells are bound to ferritin protein.

Iron ferritin complex leaves the cell via ferroportin and foes to blood.
In blood, iron is bound to transferrin.

Iron is stored in the liver.

Iron enetrs the liver via ferroportin and is bound to ferritin within the liver.

Liver produces hepcidin which inhibits ferroportin transporters. This

ultimately reduces iron content.

RBC lifespan is 120 days. After this it is filtered out by the spleen.
In macrophages, hemoglobin breaks down to globin (used in amino acid
synthesis) and heme.
Macrophage stores the iron from the heme. (hemosiderin)
Porphyrin of heme becomes bilirubin in macrophage.
Bilirubin is not water soluble and binds to albumin to form indirect
bilirubin.
Indirect bilirubin goes to the liver. Here albumin gets detached.
In liver, due to glucoronin attachment direct bilirubin is formed.
Bilirubin is yellow.
Direct bilirubin goes to gall bladder and then blood.
Urobilinogen is excreted with urine. Could be reabsorbed by liver.
Stercobilinogen is excreted with feaces.
Normal bilirubin range: 15-17 micromolar.
Higher than this will cause jaundice. (yellow skin)

Week 7
Transport of respiratory gases is by diffusion.

Partial pressure is the pressure the gas would exert alone in a given space.
It depends on the total pressure of the gas and its fractional
concentration.

In inspired air:
total partial pressure = 760 mm Hg
Oxygen partial pressure = 160 mm Hg

In deoxygenated blood:
Oxygen partial pressure is 40 mm Hg

The difference in partial pressures drives the diffusion of O2 into the

blood stream.

During respiration, gas molecules go through a gas phase (air) and a fluid
phase (blood) by simple diffusion until equilibrium is reached. At this
equilibrium, partial pressure of fluid and gas is the same.

Rate of diffusion is proportional to the diffusion coefficient and diffusion

surface area. It is inversely proportional to membrane thickness.
d = diffusion coefficient

D = diffusion capacity
V = Gas Transport Rate
ΔP = Partial pressure difference

V = ΔP x D

- Partial pressure of oxygen in alveoli is 100 mm Hg

- Partial pressure of oxygen in deoxygenated blood is 40 mm Hg
Due to the difference in partial pressures, blood gets oxygenated and the -
----- partial pressure of oxygen in oxygenated blood becomes 100 mm Hg
Blood then distributes oxygen to respiring tissues and becomes
deoxygenated again (40 mm Hg)

- Partial pressure of CO2 in alveoli is 40 mm Hg

- Partial Pressure of CO2 in deoxygenated blood is 46 mm Hg
- Partial pressure of CO2 in oxygenated blood is 40 mm Hg

Clearly, the partial pressure for CO2 is much less

Partial pressure of gases is different in alveolar air compared to inspired

air. This is because air is warmed and becomes saturated with water vapor.

Ventilation: Increase partial pressure of oxygen. Decreases partial pressure

of CO2
Metabolism: Increases partial pressure of CO2. Decreases partial pressure
of oxygen.

At rest, the partial pressure for oxygen in alveolus is 100 mm Hg.

At rest, the partial pressure for CO2 in alveoli is 40 mm Hg.

Gas transport could be limited due to too little perfusion or too slow
diffusion

Gas equilibration takes 0.25 seconds. Reserve time is 0.5 seconds.

Total time = 0.75 seconds.

Lung gas transport is always limited by cardiovascular system.

Not all alveoli are equal.

Basal part has better perfusion gradient and is more flexible (expands
more) than the apical part. Thus ventilation is more efficient at the base of
the lungs.

There are different rates of perfusion.

Apical parts of lungs doesn't have an as effective gas exchange as the
basal part.
Better the perfusion, better the ventilation.
The basal part is underventilated
The apical part is underperfused.
V/Q mismatch leads to a slight fall in partial pressure of oxygen.

Partial Pressures of Oxyegn:

In systematic venous blood: 40 mm Hg
In pulmonary capillary (after ventilation): 100 mm Hg
In systematic arterial blood: 90 mm Hg
Falls to 40 in systematic capillaries and venous blood.

Euler Liljestrand mechanism - Local vasoconstriction in the hypoxic lung

regions.

For every 200 ml of oxygen per litre blood:

Total oxygen content = Hemoglobin bound oxygen + Dissolved oxygen
200 = 197 + 3

1 gram fully saturated hemoglobin carries 1.34 ml oxygen.

The amount of oxygen in the blood depends on the amount of hemoglobin
in the blood.
Low temperature, partial pressure of CO2, 2-3 DPG and high pH increases
the affinity of oxygen to hemoglobin. Makes it harder for oxygen to be
released from hemoglobin.
High temperature, partial pressure of CO2, 2-3 DPG and low pH decreases
the affinity of oxygen to hemoglobin and makes it easier for oxygen to be
released from hemoglobin.

Hypoxia: Not enough oxygen in the body

can be
Hypoxic: Inspired air contains less oxygen
Anemic: Hemoglobin concentration is reduced
Ischemic: Blood flow is not fast enough
Histotoxic: oxygen utilization is impaired.

If the concentration of deoxygenated hemoglobin is less than 50g/L then

the skin will get a bluish discoloration.

CO2 in blood is transported as bicarbonate (85%), carbamino groups

(haemoglobin bound - 10%), dissolved (5%)
Hemoglobin oxygenation promotes the release of carbon dioxide.

Normoventilation: Ventilation is normal

Hypoventilation: Ventilation is too low
Hyperventilation: Ventilation is too high

Eupnea: Normal breathing rate

Bradypnea: Lower than normal breathing rate
Tachypnea: Higher than normal breathing rate
Dyspnea: Subjective feeling of not being able to breathe
Orthopnea: Can only breathe while sitting and standing straight

Enzymes foe antigens are inherited in the ABO blood group system.

There are no anti D antibodies in the blood plasma of a Rh - person.

Immunization can happen while giving birth and due to incompativle

transfusion.

Agglutination reaction 0 between antigens and antibodies. Cross link

Hemostasis has 2 parts: primary and secondary.

Primary: Local vasoconstriction, activation of platelets, plug formation,
adhesion, activation
Secondary: Blood coagulation

Platelets change shape upon activation due to actin-myosin interaction.

In the body, platletes are activated by thrombin.

Phosphodiesteras breaks down cAMP and cGMP.

Factors II and VII are vitamin K dependent.

Vitamin K converts inactive proteins with Glu residue to active proteins
with Gla residue. Vitamin K gets oxidized.

Vitamin K1: Phylloquinone is known well for clotting.

Vitamin K2: Menaquinone is an activator for calcium directing proteins

Vitamin K dependent Gla amino acid containing factors stick to

phospholipid membranes .

Heparin is an anticoagulant in the human body. Produced by mast cells,

heparin has an antithrombin effect

In blood clotting, prothrombin is converted to thrombin.

Thrombin creates fibrin monomers from fibrinogen.

Factors V and VIII are cofactors.

Factor IV is calcium

Intrinsic and Extrinisc pathways both use Factor IV, V, X.

- Extrinisc pathway produces little amounts of thrombin.

- This amount of thrombin activates the intrinsic pathway which makes a
large amount of thrombin - enough for fibrin formation.

Thrombin is an universal activator. Activates factor V and XIII

Detached plasmingen is quickly inactivated thus it is always attached.

Platelet activation is uslaly blocked by NO.

There are 4,000 - 10,000 WBC per microlitre in the blood.

Thymus - site of production of T lymphocyte
Red Bone Marrow - site of production of B lymphocyte
Neutrophils are phagocytes - produce reactive oxygen metabolites,
cytokines
Eosinophils - Fight against parasites
Basophile granules have heparin (antithrombin effect - anticoagulant) and
histamine (inflammation, allergic reaction)

At the site of infection there is vasodilation.

In phagocytosis, phagosome organelle is formed and it fuses with

lysosome to digest foreign particle.
Phagocytes do antigen presentation.

Proper antigen presenting cells: Dendrite cells, macrophages, B

lymphocytes

Natural Killer cells are large T lymphocytes.

Effector T cells: T killer and T helper cells

T regulator and T mediator cells also exist.

T lymphocytes become functional/activate after antigen presentation

which is done in a secondary lymphoid organ.

MHC I and MHC II does antigen presentation.

T killer cells have CD 8 marker. MHC I binds to CD 8 marker.
T helper cells have CD 4 marker. MHC II binds to CD 4 marker.

After activation, T cells proliferate.

T killer cells kill pathogens by secreating granzymes and perforins .

Perforins create a hole in the pathogen membrane. Granzymes go through
this hole.
NK cells also produce perforins and granzymes.
Capazes induce apoptosis.

T helper cells bind to antigens presented by B lymphocytes.

T helper cells then produce cytokines which activates B lymphocytes to
produce antibodies
Cytokines are signal molecules for the immune system (Interleukins)

B lymphocytes produce immunoglobulins (antibodies). Antibodies are

gamma globulin
Antibodies can be IgM, IgA, IgE, IgD, IgG
IgM is a pentamer - ABO antibodies
IgA is dimers
IgE, IgG, IgD are monomers.
IgD - Rh antibodies

Antibodies have Y shape with 2 heavy and 2 light chains.

There are disulfide bonds between heavy and light chains.

FAB part on antibody is for antigens

FC part is for NK cells.

Complenet system is a part of the humoral immune system.

Immune system:

Innate Adaptive
Cellular Phagocytes T, B lymphocytes

Humoral Complenet System Antibodies

Complenet system acts as a cascade

Have C1-C9
C1 to C5a are proteolytic enzymes. They hydrolyze next protein in the
cascade

Opsonization: marking of the pathogen

C5b - C9 forms the MAC (membrane attack complex) which makes a hole in
the membrane of the pathogen.

1st Landsteiner rule is valid for ABO and Rh

2nd Landsteiner rule only valid for ABO

Immunization occurs when Rh+ blood of fetus goes into Rh- blood of
mother.
Henolysis occurs (erythroblastolis fetalis) RBC of fetus is destroyed.

Every time Rh- mother is expecting Rh+ baby, Rh profilaxis has to be done

Rh antigens are proteins encoded by genes.

AB antigens are sugar chains.
A antigen produced when someone genotype is AA, AO
B antigen produced when genotype: BB, BO
AB antigen produced when genotype: AB
Neither A or B antigen made when genotype: OO

Rh antibodies are IgG type. Monomoric.

ABO antibodies are IgM. Pentameric.

Blood group A:
Have A antigen, anti B antibodies
Blood group B:
B antigen, anti A antibodies
Blood group AB:
AB antigen, neither anti A or anti B antibody
Blood group O:
Neither A or B antigen, both anti A and anti B antibody.

Hemostasis: Process which leads to cessation of bleeding

Includes blood clotting.
1) Vasoconstriction at site of injury
2) Thrombocyte function (Adhesion, Activation, Aggregation)
Steps 1 and 2 are called primary hemostasis. Ends with the formation of
white clot.
3) Blood clotting produces red clot.
4) Fibrinolysis (breakdown of fibrin mesh)

Prothrombin becomes Thrombin.

Thrombin adheses to sub endothelial collagen fibres.
Thrombin causes shape change in platelets.

ADP, adrenaline, serotonin are vasoactivatiom factors. They are released

by activated thrombocytes.
Thrombocytes aggregate to form white thrombus.

Factor III - tissue factor

Released by injured endothelial cells. Factor III starts extrinsic pathway of
blood clotting.

Calcium (Factor IV) is essential for blood clotting.

Calcium anchors clotting factors to membrane of thrombocytes.

Clotting factors V, VII are produced by thrombocytes

Vitamin K is important for blood clotting as there are Vitamin K dependent
factors for blood clotting

- Blood clotting is initiated by tissue factor (Factor III) as it activates

extrinsic pathway.
- The extrinsic pathway creates very little thrombin
- This little amount of thrombin is enough to start the intrinsic pathway
which creates a lot of thrombin.
- Thrombin then splits inactive fibrinogen to active fibrin
- Thrombin also activates production of Factor 13 which makes fibrin
polymers.

Fibrinolysis is important. After healing from injury, red clot has to be

removed.

Plasminogen binds to lysine residue of fibrin mesh.

Tissue Plasminogen activator activates plasminogen to plasmin.
Plasmin breakdown fibrin mesh
Week 8
inputs of respiration:
- Lung receptors
- Arterial blood (chemoreceptors) - O2 and CO2 conc
The information goes to the medulla
output:
- Ventilation
- Bronchiol muscles
- Secretory glands

Driving force if normal respiration is the increase in CO2 in the blood.

For CO2 removal, effectors are respiratory muscles.

Controlled system - lung/blood gas exchange

Respiratory centres are in the medulla and 2 in the pons. These centers
are loose networks of different cells.

Dorsal respiratory group projects to diaphragm and external intercostal

muscles (muscles for inspiration). The dorsal respiratory group is used in
normal inspiration, coughing.
The pneumotaxic centre has an inhibitory effect on dorsal respiratory
group.

Ventral respiratory group is only activated when high frequency or deep

breaths are needed and exhalation is made faster. (Exercise)

Due to inspiration, lung volume increases, pressure decreases and thus air
flows in. Muscles involved are diaphragm and external intercostal muscles

In expiration, lung volume decreases, pressure increases and air flows out.
Internal intercostal muscle is used.

When the diaphragm constricts, the nerve going to the diaphragm

(phrenic nerve) increases its activity. This happens during inspiration.

Dorsal respiratory group - Inspiratory area. Connected to diaphragm and

external intercostal muscles.

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

Increases in blood CO2 level causes an decrease in pH (increase in H+
conc).
H+ stimulates the medulla.
Blood brain barrier only allows CO2 to pass into the cerebrospinal fluid,
not H+.

Peripheral chemoreceptors primary sense O2 partial pressure levels.

Then CO2 partial pressure levels. Then blood pH.
Chemoreceptor examples - Glomus Caroticum, Glomus Aortica
These chemorecptors have receptor cells, synaptic transmission and
capillaries.

If there is a change in O2, CO2 partial pressures and pH then there will be
accumulation of positive charge in receptor cells cuz Na+/K+ pump will still
be working but K+ channels sensitive to O2, CO2 and pH might close. This
increases + charge and entry of Ca2+ causes action potential to form.
partial pressure of O2 and partial pressure of CO2 have synergic effect,
they amplify each others effects.

More the CO2, lower the pH, stronger the effect will be on chemorecptors
High amounts of CO2 is a very strong stimulus for respiration.

CO2 content of air - 0.04%

If 1% - respiratory function increases
If 10% - headache
If 15% - Black out
If 20+% - CO2 nacrose

Increase in CO2 causes decrease in pH.

Increase in CO2 causes alveolar ventilation to increase
Neurons don't work at pH below 6.9

CO2 in blood and blood pH are inversely proportional.

Decreased partial pressure of oxygen increases alveolar ventilation but

not linearly.
Increased partial pressure of CO2 increases alveolar ventilation linearly.

High CO2 levels is a more potent stimulus for respiration, ventilation than
low O2 levels.

Hering Breur reflex (stretch receptor) prevents overstreching of lung.

This reflex can change the respiratory rhythm

To protect airways: coughing and mucus secretion is done.

If there is an edema in lung tissue, J receptor blocks blood flow
temporarily
and tries to wash out the blockage of the capillary.

Kussmal respiration - when one has acidosis

Tries to remove CO2 by deep and high frequency ventilation

Cheyne Stokes respiration - amplitude gradually increases and decreases

in sleep and at high altitudes. Sensitivity of CO2 is lower thus CO2 levels
rise to higher level than usual

Apneusis - Chest is fixed in inspiratory position

Medulla is the rhythm generator
Cerebral cortex can act on medulla

Mechanoreceptors present in the lung and thorax. (has feedback)

Chemoreceptors present in blood (has feedback)
Mechanoreceptors in joints (no feedback. feedforward)

If CO2 levels is too low (less than 20 mm Hg), there is not enough
respiration stimulus
Alveolar surface - 70m^2, 10,000 L per day air inspired.

Biology fo airway:
- protection of the airway (sneezing and coughing in upper airway,
surfactant production by clara cells and making air wet. Alveolar
macrophages eat up dust, smoke. Tissue mast cells create histamine
- Mucociliar clearance - mechanism by which airway clears itself. Cilia
present which moves mucus (traps small particles) up towards pharybx.

Lung has physical filtering (trapping things),

chemical filtering (heparin, plasminogen activator),
neutralizing vasoactive substances (serpotonin, adenozin),
Converting Angiotensin I (inactive) to Angiotensin II (active). Does blood
pressure control.

Airways have a conducting and respiratory zone.

Conducting zone: Nasal cavity, nasopharynx, trachea, bronchi,

bronchioles. Voluem is 150 ml
Epithelial cells in this zone are ciliated and produce mucus.'Their function
is to trap foreign particles in the mucus and move the mucus with foreign
particles out of the airways. This is wth rhythmic movement of cilia which
moves foreign particles stuck in mucus.
Smooth muscles present in the conducting zone.

The respiratory zone has alveoli.

In alveoli there are Type I and Type II pneumocytes.
Type I pneumocytes do gas exchange
Type II pneumocytes produce surfactant.
This surfactant lines the inside of alveoli and reduces surface tension.

Lung volume is measured using spirometry.

Normal breathing: Inhale and Exhale 500 mL

Forced inspiration (Inspiratory reserve volume) - 3000 mL
Forced expiration (expiratory reserve volume) - 1200 mL
Volume which remains in the lungs after forced expiration(residual volume)
- 1200 mL
Functional Residual Capacity - 2400 mL
Everything except residual volume (Vital Capacity) - 4000 - 5000 mL
Total lung capacity - 6000 mL

Helium dilution technique is for the measurement of residual volume and

functional residual capacity.

Ventilation rate: Volume of air moved into and out of the lung per unit time
Breathing rate = 14 per minute
Minute ventilation = Tidal volume x breathing rate = 7000 ml/minute
Alveolar ventilation = 4000 ml/minute

Alveolar ventilation is directly proportional to CO2 partial pressure &

directly proportional to volume of CO2

Forced Vital Capacity: Total volume of air that can be forcibly expired after
maximal inspiration = 80%

Inspiration
Inspiration is an active process and requires active muscle contraction.
Diaphragm helps in inspiration and external intercostal muscle helps in
forced inspiration.
The diaphragm contracts, flattens and goes downwards. Ribs move
outward and thus the chest expands and so do the lungs. Lung volume
increases, lung pressure decreases and air flows in.

Expiration
Expiration is a passive process. The inspiratory muscles relax. Chest
volume decreases cuz the diaphragm moves upwards back to dome shape.
Ribs move downward and inward so lung volume decreases, lung pressure
increases and air flows out.
Internal intercostal muscles and abdominal msucles helps in forced
expiration

Surfactant (by type II pneumocytes) decreases surface tension. Prevents

the collapse of alveoli. DPPC is the most important component of
surfactant.

Smaller alveoli will have higher collapsing pressure than larger alveoli.
Surfaactant reduces surface tension and collapsing pressure.

Lungs have a tendency to collapse and surfactant prevents the collapse.

Compliance - Distensibility of lung and chest wall

Compliance is inversely proportional to the elasticity of the lungs.

Transmural pressure - pressure across alveoli wall. Keeps the alveoli open.

Hysteresis: Difference between inspiration and expiration compliance

curves
Hysteresis arises due to surfactant production
Surfactant increases the distensibility during inspiration.

COPD - chronic obstructory pulmonary disease

Fibrosis: Lung compliance decreases.

Lung tissue and alveoli stiffens and lung volume decreases
This is because fibrotic connective tissue replaces the alveoli.
Happens due to smoking.

Q = ΔP/R
Q = airflow
ΔP = pressure gradient
R = resistance of airways.

Greater the radius of airways, lower the resistance.

Medium sized bronchi have the greatest resistance

Sympathetic innervation decreases resistance in airways (bronchodilator)

Parasympathetic innervation increases resistance in airways
(bronchoconstriction)
Histamine (from mast cells) cause bronchoconstriction.

The pressure if one single gas in a mixture is called partial pressure.

Fick Diffusion Law:

V = (D x A x ΔP) / X
V = volume of gas transferred
D = gas diffusion coefficient
A = surface area
P = partial pressure difference
X = Membrane thickness.

Partial pressures of O2
Inspired air = 100 mm Hg
Arterial blood = 95 mm Hg
Venous blood = 40 mm Hg

Partial pressures of CO2

Plasma = 46 mm Hg
Alveoli = 40 mm Hg
Arterial blood = 40 mm Hg

CO2 is transported in plasma in the form of bicarbonate.

CO2 + H2O -------------> H2CO3 (carbonic acid)
H2CO3 -------------> HCO3 - + H+

There is bicarbonate-chloride exchange. Is antiport

Chloride (hamburger) shift
H+ binds to haemoglobin.

oxygen diffuses from alveoli to capillaries due to partial pressure

difference.
O2 binds to the hemoglobin and this binding causes the hemoglobin to
releases its H+.

CO2 goes from plasma to alveoli due to partial pressure difference.

Respiration has neuronal and chemical control.

Neuronal control center is in medulla and pons.

Dorsal respiratory group (dorsal side of medulla) - is the center of
respiration (inspiration)
Ventral respiratory group - rhythm generator of breathing. Used during
exercise
Pontine respiratory group - Regulates breathing rate

Chemoreceptors are present in the medulla, carotid and aortic bodies.

These cells are sensitive to changes in oxygen partial pressure and then
changes in pH and CO2 partial pressures.

CO2 diffuses into cerebrospinal fluid and binds with water.

HCO3- and H+ produced.
Chemoreceptor cells recognize higher H+ concentration and activates
inspiratory center to remove CO2 and bring in O2.

Lung Metabolic Functions - Produce and eliminates local vasoactive

substances. Such substances cause vasoconstriction and vasodilatoin
Lungs can eliminate vasoactive hormones (vasopresisn)

Week 9
Blood flows down the pressure gradient which is made by the heart.
Heart valves have only a passive role.

Cardiac muscles have gap junctions between them.

Cardiac muscles are involuntary.
Cardiac muscles have sarcomeres, many mitochondria, sarcoplasmic
reticulum and many capillaries.
Gap junctions are made up of connexions and thus longitudinal
conduction is very fast.
Cardiac ventricle cells have a much larger refractory period than other
cells (approx 200 ms)

There is no tetanic contraction in cardiac muscle cells. Only in skeletal

muscles due to the difference in refractory period.
During repolarization, Ca2+ permeability reduces and K+ permeability
increases.

After a fast depolarization (Na+ enter the cell), Ca2+ ions flow into the cell
and prevent repolariztion from happening and thus extends the refractory
period.

Myocardiac cells also have T tubules along with gap junctions.

1) Na+ channels open, Na+ flows into the cell and causes depolarisztion
2) Ca2+ channel open and Ca2+ ions from extracellular space flows into the
cell. This triggers the release of Ca2+ in sarcoplasmic reticulum via
Ryanodine receptors
3) Intracellular Ca2+ levels increases
4) Contraction between actin and myosin fibres
5) Removal of Ca2+ ions via 3 mechanisms.
i) Ca2+ ATPase takes up intracellular Ca2+ and pumps it into sarcoplasmic
reticulum
ii) Ca2+ ATPase on membrane takes up intracellular Ca2+ and pumps it out
of the cell
iii) Na+ Ca2+ antiport exchanger on the membrane removes intracellular
Ca2+
6) Repolarisation via opening of K+ channels

Ca2+ has a critical role on cardiac muscle function.

Cardiac muscle is the only muscle type wherein Ca2+ required for muscle
contraction comes from extracellular and intracellular sources.

Sympathetic stimulation works on the heart and causes Ca2+ to flow into
cardiac muscle cells. This is an intrinsic regulation and is + inotropic
(increases contraction force)

Na+ Ca2+ antiport exchanger and be influenced indirectly.

To make this exchanger less active (so Ca2+ stays in the cytosol and
contraction continues) intracellular Na+ has to increase.
By slowing down the Na+/K+ pump, we can slow down the Na+ Ca2+
exchanger.

Sympathetic stimulation causes phosphorylation of Ca2+ chanells causing

them to open.
Human heart has very low parasympathetic innervation.

Contraction of myocardium:
- No external neural impulse
- Gap junctions present so very fast conduction
- All fibres contract
- Ca2+ required for muscle contraction is from extracellular space as well
as intracellular space
- Removal of Ca2+ is by 3 methods (Ca2+ ATPase on sarcoplasmic reticulum,
membrane and Na+ Ca+ pump

Contraction force depends on the sympathetic stimulation and

extracellular Ca2+ levels.

Rhytmic contraction causes cardiac cycle.

During systole (contraction) pressure increases - 120 mm Hg
Pressure decreases just before diastole (relaxation) - 0-2 mm Hg
Diastole takes longer, more time.
Pressure gradient causes blood flow.

In the pressure graphs, whichever curve is higher, that compartment has

higher pressure so blood will flow out of that compartment to the graph
below it.
Blood flow causes a change in volume of both compartments.

Ventricles have isovolumetric contraction and isovolumetric relaxation.

In this volume doesn't change but pressure does.

Cardiac Cycle (with reference to ventricles):

A) Mitral valves open
Pressure doesn't change but volume increases.
Ventricle gets filled with blood from the atria
Period of filling

B) Mitral valve closes

Pressure increases, volume stays the same
Isovolumetric contraction

C) Aortic Valve opens

Pressure increases, volume decreases
Blood flows out of ventricles
Period of ejection

D) Aotric Valve closes

Pressure decreases, Volume stays the same
Isovoluetric relaxation

A) Mitral Valve opens

A---->B: Filling period

B------->C: Isovolumetric contraction
C---------->D Ejection period
D-----------> A: Isovolumetric relaxation

Cardiac Cycle takes 0.8 seconds.

Systole - 0.27 seconds
Diastole 0.53 seconds

Systole: Isovolumetric contraction, maximal & decreased ejection

Diastole: Isovolumetric relaxataion, Rapid & Slow filling.

End Diastolic volume: 110-160ml

End Systolic volume: 40-80 ml
Stroke volume (volume of blood that moves): 70-80 ml
Ejection fraction: SV/EDV. Should be 50-70%

If ejection fraction is lower then heart is not healthy

Atrial contraction (atrial systole) contributes to 20-25% of pumping blood

into ventricles towards the end of filling period.

In filling period, valve plane moves backwards causing ventricles to

enlarge and thus ventricular pressure decreases so more blood flows into
the ventricles.
Jugular venous pulse is directly connected with the atrial pressure.
When there is atrial contraction, Jugular venous pulse increases
When there is atrial relaxation, jugular venous pulse decreases.

Cardiac Output (volume of blood leaving the ventricle in one minute):

5.5 litre/min

Body Surface area usually = 1.7, 1.8 m^2

Cardiac sounds
1) Systolic sound - Contraction, ejection of blood, closing of mitral valves
(At start of systole. Louder)
2) Diastolic sound - Relaxation, closing of semilunar valves.
(At start of diastole. Less loud)
There are also 3rd and 4th sounds which are very very soft. These are
another diastolic and a late diastolic sound

More the venous blood that flows in, higher is the contraction force.

Druring diastole: Volume increases and pressure is mostly the same

During systole: Volume decreases

I: Filling period (V inc, P same)

II: Isovolumetric contraction (V same, P inc)
III: Ejection period (V dec, P increases a bit)
IV: Isovolumetric relaxation (V same, P decreases)

The resting length of cardiac muscle determines how powerful contraction

would be.

Preload - Volume Value. (Volume of blood that flows into heart)

Afterload - Pressure Value (Pressur that the ventricle must overcome to
circulate blood.)

Higher the venous return, higher the preload.

Increased heart rate alone will not increase cardiac output.

More the blood that flows into the heart, stronger will the contraction be
(up to a certain limit)
Contraction force could increase without change in muscle length sue to
sympathetic stimulation and an increase in external Ca2+ conc.

Rhythmic excitation of heart is due to natural pacemakers (SA node, AV

node)

SA node --------> AV node -----------> AV bundle -----------> AV bundle

branches ---------------> Purkinje Fibres

Fast action potentials are Na+ channel dependent.

More negative, steeper, larger amplitude (0.3-0.4 m/s)
Slow action potential are not Na+ channel dependent.
Less negative, less steep, lower amplitude (0.1-0.2 m/s)

Slow action potential don't have a resting potential value.

Influx of Ca2+ causes depolarisation.

Heart rate decreases during during vagal nerve stimulation.

(Parasympathetic). Vagal stimulation delays repolarisation and prevents
Ca2+ ions from flowing in.

In the heart, sympathetic and parasympathetic works against each other.

Sympathetic innervation of heart is diffuse and more spread out.

Parasympathetic innervation (through vagus nerve) innervates the SA and

AV node.

Neuronal regulation:
Vagal innervation decreases heart rate and contraction force.
Sympathetic innervation increases heart rate and contraction force

Humoral regulation:
Adrenaline increases heart rate and contraction force.

Ca2+ and K+ concentrations also regulates heart activity.

More the Ca2+ in cardiac muscle and extracellular fluid: higher the heart
rate and contraction force.
Higher the K+ conc in extracellular fluid, lower is the heart rate and
contraction force.
During ventricular systole: Pressure increases, volume decreases
Semilunar valve is open, so blood flows out of the ventricles.

Heart Action potential:

Steep depolarisation (influx of Na+)
Long plateau phase - delays repolarisation. Is due to slow Ca2+ channel
opening and closing. Long plateau phase delays repolarisation.

Cardiomyocytes:
Resting cell is -90 mV inside. Extracellular is +ve.
Active cell is +20 mV inside. Extracellular is -ve

Heart has pacemaker cells and contractile cells.

Plateau phase action potential is only for contractile cells.

Pcaemaker cells depolarisation is due to influx of ca2+. Before this is slow

depolarisation due to influx of Na+ cells.

SA node is the source of electrical activity in the heart.

Electrical signals spread through atrium, go to AV node. Slight delay at AV
node. Then His bundle. Bundle branches. Purkinje Fibres.

PQ interval from start of atrial activation to start of ventricular activation.

(atrioventricular conduction)
QT interval from start of ventricular activity to end of ventricular activity.
RR interval - One complete cycle.

PQ interval - 0.12-0.2 s
QRS complex - less than 0.1s
QT interval - 0.33-0.45s

Cardiommyocytes have gap junctions and are smaller than skeletal

muscles.
Ebert lines contain the gap junctions in cardiomyocytes.
Gap junctions have fast conduction of impulses.
Striations present in skeletal and cardiac muscles. Not in smooth muscles.
Anulus Fibrosis separates atria and ventricles.

SA node creates impulse. Goes to AV node, Bundle of His, Bundle branches,

Purkinje Fibres, Ventricles.

Skeletal muscles can undergo tetanic contraction.

Action potential duration: 10ms
Contraction duration: 100 ms

Heart muscles don't undergo tetanization.

Cardiac Muscle Contraction:

Action potentials (from SA node) spread into T tubules.

On T tubules are DHPR (Ca2+ channels).
Due to action potential , DHPR opens and extracellular Ca2+ enters
cytosol.
On ER membrane are Ryanodine Receptors (Ca2+ channels)
Ryanoide Receptors open due to extracellular Ca2+
Called Ca2+ induced Ca2+ release.

In skeletal muscles, only intracellular Ca2+ needed for contraction.

In cardiac muscles, intra and extracellular Ca2+ needed for contraction.

In the plateau phase, action potential is constant due to inflow of Ca2+

(through DHPR)

Cardiac muscles (like skeletal muscles) use Ca2+ for actin, myosin cross
bridge formation.
Ca2+ binds to troponin C which moves tropomyosin and exposes myosin
binding sites on the actin so binding and contraction can happen.

Na+ Ca2+ antiport transporter present on cell membrane. Removes one

Ca2+ (to extracellular space) and brings in 3 Na+. This reduces
intracellular Ca2+ levels
There are also Ca2+ ATPase on cell membrane and ER membrane which
reduce intracellular Ca2+ levels.

The only difference in cardiac and skeletal muscles contraction is the

source of the Ca2+
Power of contraction (inotropic effect).
Higher power = + inotropic effect
Due to sympathetic stimulation and adrenaline.

Higher the extracellular Ca2+ concentration, stronger the contraction

force.

Inhibition of the Na+/K+ pump pumps leads to extended contraction

because Na+ levels stay high in the cell.
Due to this Na+ Ca2+ antiport exchanger doesn't need to work as
efficiently so
Ca2+ is not pumped out resulting in higher Ca2+ concentration
intracellularly causing a stronger, longer contractions.

When there is more venous blood returning, heart contracts stronger.

Preload is also the maximal tension of ventricular wall before systole

Afterload: Maximal tension of the ventricular wall during systole because if
pressure of heart that has to be overcome to eject blood.

Luzitropic effect: Relaxation of ventricular muscle

Inotropic effect: Contraction force
Chronotropic effect: Impulse rate
Dromotropic effect: Condcution velocity
Bathmotropic effect: Excitability of Purkinje fibres

A positive effect causes faster or increased of the above. Positive effect

due to sympathetic stimulation and adrenaline (which acts on SA node).

Protein Kinase A can phosphorylate ion channels of the SA node.

Channels become more active, SA node becomes more active
Impulse generation increases. (+ chronotropic effect. Uses adrenaline)

Heart has 2 types of cells: Impulse generating cells and contractile cells.
Action potential times:
Contractile cells: 200-300 ms
Pacemaker cells: 150 ms
Contractle cells have the plateau phase in their action potential

Dromotropy (conduction velocity) due to cells of AV node

Chromotropy (Impulse rate) due to cells of SA node.

Sympathetic stimulation causes +ve Luzitropic, Inotropic, Chronotropic,

Dromotropic, Bathmotropic

Atria has parasympathetic innervation but the ventricle has no

parasympathetic innervation.

Thus parasympathetic stimulation only causes -ve chronotropy,

dromotropy effects.

Cardiac cycle refers to mechanical changes, pressure and volume

changes.
Duration of cardiac cycle = 0.8 s
Systole = 0.3 s
Diastole = 0.5 s

During systole, stuff contracts and volume decreases.

Durinf diastole stuff rlaxes and volume increases.

Atrial pressures are always lower than ventricular pressure

Maximal pressures:
Right atrium: 2 mmHg
Left atrium: 8 mm Hg
Right ventricle: 24 mm Hg
Left ventricle: 120 mm Hg

All the below is with reference to ventricular pressure and volume

1) During Isovolumetric Contraction

Aortic and Mitral valves are closed.
Volume stays the same, pressure increases.
No outflow of blood

2) Period of ejection:
Aortic Valve opens.
Volume decreases. Pressure increases a bit
Blood flows out of the ventricle

Isovolumetric Contraction and period of ejection makes up Ventricular

Systole.
3) Isovolumetric relaxation
Mitral valves closed
Volume stays the same, Pressure decreases.
No inflow of blood

Once pressure of ventricles drops below pressure of atria, mitral valves

open

4) Period of Filling
Mitral valves are open
Volume increases, pressure same.
Blood flows into venticles

Isovolumetric relaxation and period of filling makes up ventriccular

diastole

P wave - Atrial depolarisation

QRS complex - Ventricular depolarisation
T wave - Ventricular repolarisation

QRS complex covers the curve of atrial repolarisation

1st heart sound is due to closure of mitral valve

2nd heart sound due to closure of semilunar valve.

Jugular venous pulse follows the pressure changes of the atria.

Week 10
Fluctuations in the right atrial pressure causes changes in jugular pulse.
Stroke volume is 70-80 ml. Its the volume of blood that leaves the heart
after systole

When describing pulse waves:

1) By frequency
Frequents x Rarus
2) By amplitude
Altus x Parvus
3) By speed
Celer x Tardus
5) By compressibility
Durus x Mollis
7) By rhytm
Regularis x Irregularis
9) By similarity
Aequalis x Inaqualis

ECG - For measuring electrical activity of the heart

Inside cell Outside Cell

Resting - +

Depolarization + -

Repolarization - +

Every cardiac fibre produces vectors

Propogation of electric vector must be in the plane of the eCG lead.

Atrial depolarisation spreads and causes P wave (Activation of atria)

P wave is completed when all of atria is activated.

Q wave - Starting of depolarisation of ventricles

R wave - Activation of cardiac muscle. Biggest wave of ECG curve.
S wave - When almost all the ventricles have been active.
T wave - Ventricular repolarisation

QRS complex - Ventricular depolarisation

Atrial repolarisation takes place at the same time as QRS complex and
thus is hidden and cant be seen in the ECG.

Normal ECG, Cardiac Cycle = 0.8 seconds.

PQ segment shows how much time it takes for atrial depolarisation to

spread to ventricles.
ST segment: Plateau of ventricular action potential
In the ECH paper
1 large box = 0.2 seconds
1 small box = 0.04 seconds
5 small boxes make up 1 large box.

Einthoven - Bipolar between 2 limbs.

When reading ECGs look for:

Rhythmicity, Frequency

Normal ranges:
P wave = 0.08 seconds
PQ interval = 0.16 second
QRS complex = 0.08 seconds.

Week 11
The length and radius of blood vessels affects the resistance.
Blood vessels are elastic and branching.
Greater the radius of the blood vessel, lower is the resistance.

Transmural pressure: Differenece between blood pressure and pressure

outside the vessel wall (interstitial pressure)
Transmural pressure keeps the vessel circular.

Vascular Compliance: Increase in vessel volume in response to unit

increase in pressure.
Venous compliance is 20 times higher than arterial compliance. This is
because venous system has higher volume and lower transmural pressure.

Critical closing pressure (20 mm Hg): If transmural pressure falls below this
value, blood vessels collapse.

Wall tension is a force that could tear the vessel wall.

Veins are at low risk of wall rupture (large radius and low blood pressure)
Capillaries at low risk of wall rupture (small radius, low blood pressure)
Aorta, large elastic arteries have high risk of wall rupture (large radius with
thin walls + high pressure)

Vessels of the same class are connected in parallel.

Vessel classes are connected to one another in series.
Organs of systemic circulation are connected in parallel.
Arterioles have the highest resistance.

In series: R(total) = R1 + R2 + R3 .....

Total resistance is the sum of all resistance.

The blood pressure drop is greatest in the arterioles because the

arterioles have the largest vascular resistance.
Control of arterial blood pressure & blood flow is taking place in arterioles.

Velcoity of blood flow:

Aorta: 22.5 cm/s
Capillaries: 0.03 cm/s
Vena Cava: 11 cm/s
Velocity and cross sectional area are inversely proportional.
Capillaries have the highest cross sectional areas thus they have the
lowest velocity of blood flow.
Aorta has the lowest cross sectional area thus it has the highest velocity of
blood flow.

2/3 of total blood volume is in the venous system.

Blood volume distribution depends on pressure and compliance.

In invasive blood pressure determination, needle tipped cannula is

inserted into artery and then blood pressure is measured.
In non invasive blood pressure determination, the first sound is systolic
blood pressure. Last sound is diastolic blood pressure.

Critical Reynold number: 2200

Greater than this then flow becomes turbulent.
Lesser than this, then the flow is laminar.

Cardiac cycle: 0.8 s

Systole: 0.27s
Diastole: 0.53s

Length of cardiac cycle (pulse rate) affects the mean arterial blood
pressure.
Longer the cardiac cycle, longer the diastole and systole, higher the mean
arterial blood pressure.

During diastole, aorta passively contracts and pushes blood forwards.

Aging decreases aortic elasticity.

Compliance decreases as one becomes older. Compliance especially
reduces in high blood pressure range.

Arterial blood pressure is affected by:

- Stroke Volume (higher the stroke volume, higher the pulse)
- Elasticity of aorta (compliance): (decreased elasticity, higher pulse)
- Total Peripheral Resistance (higher TPR, higher pulse)

During propagation, as propagation moves towards the periphery, systolic

peak increases and diastolic peak appears.

Pulse wave velocity is increased by decreased wall elasticity, decreased

vascular resistance, increased wall thickness.

Propogation velocity of pressure pulse is much faster than velocity of

blood flow.
Pressure changes in aorta are transmitted along the arteries as a pressure
pulse. This pressure pulse creates a volume pulse that can be palpated.
Capillary Bed - where microcirculation happens.

Arteriole is covered by smooth muscle.

Smooth muscle is also present at the beginning of capillaries. (precapillary
sphincters.)
Metarterioles are a bypass to precapillary sphinctres
Arteriole Venule anastomosis is another bypass to precapillary sphinctres.

Diameter:
Arteriole: 20-30 micrometer
Capillary: 4-7 micrometer
Venule: 20 micrometer

Venules don't have smooth muscles around it.

When precapillaty sphincter is relaxed, blood flows from arteriole to

venules.
If the sphincter is closed, metarterioles are used.

Resistance vessels of microcirculation: Arterioles, metarterioles,

precapillary sphincters.
These vessels control the total peripheral resistance, systemic blood
pressure, local blood flow, local capillary pressure.
Vascular smooth muscles in these vessels have a resting tone that can be
modified.

Capillary types:
1) Continous (in skeletal muscle, skin, lung, myocardium)
2) Fenestrated - fenestrations visible, small proteins can pass through
(in renal, GI tract)
3) Mediscontinuous - large pores between epithelial cells. Even RBCs can fit
through these (in liver, spleen, bone marrow)
All capillaries service the tissues to meet their metabolic demands.
Diffusion is done by:
Respiratory gases in transcellular pathway
Water soluble solvents in paracellular pathway

Capillary wall is impermeable for plasma proteins.

Thus plasma proteins are transported in part by vesicular transport.

There are several pressures acting on capillaries.

Inside the capillary:
- Capillary pressure (acting on capillary wall)
- Plasma colloid osmotic pressure (acting against from capillary wall)
Outside the capillary:
- Interstitial fluid pressure (acts on capillary wall)
- Interstital fluid colloid osmotic pressure (acts against capillary wall)

Capillary blood pressure

Start: 25 - 40 mm Hg
End: 10 - 15 mm Hg
Mean: 17.3 mm Hg

Interstital hydrostatic pressure varies in different tissues from -4 to +8 mm

Hg
Mean is 3 mm Hg

Colloid osmotic pressure is made up of protein anions + associated

cations.
These 2 cant cross capillary wall.
Plasma colloid osmotic pressure = 28 mm Hg
The plasma colloid osmotic pressure is made up of albumin (21.8 mm Hg),
Globulin (6 mm Hg), Fibrinogen (0.2 mm Hg)

Interstitial colloid osmotic pressure : 8 mm Hg

Thus the net filtration pressure is 0.3 mm Hg in general in continuous

capillaries.
Net flow out of continuous capillary is 2L per day.

Lymphatic vessel is also present in microcirculation.

Lymphatic vessels collects fluidsnfrom microcirculation.
Lymphatic capillary endothelial cells form valves allowing interstital fluid
to enter.
Larger lymphatic vessels contain smooth muscles displaying intrinsic
pumping activity.
Lymph vessels flow through lymph nodes

Main function of lymphatic system:

Drainage of interstital proteins
Return of excess filtrate
Absorption of lipids
Moving lymphocytes

Interstital tissue space has many connective tissue fibres and non fibrous
adherent matrixproteins
Interstitial fluid levels vary in different tissues.
Muscles: 12 %
Skin: 35-40%
There is hydraulic resistance present in interstital tissue space.

Increased filtration ------------> Increased interstital pressure --------->

increased lymph flow -----------> Excess fluid accumulates in interstitium
(interstital compliance increaseS)
Due to this edema develops.
Edemas can compress lymph vessels causing a cycle.

Thus edema is due to filtration or reabsorption imbalance.

Due to:
- Inncreased intracapillary hydrostatic pressure
- Decreased plasma colloid osmotic pressure
- Increased permeability
- Lymphatic obstruction

Post capillary venules have important immune function.

From venous end of capillary to right atrium, only 10 mm Hg pressure

gradient is needed to maintain flow.
Such low pressure is needed because there is low venous resistance.

Because of the high venous compliance, 64% of total blood volume resides
in the venous system.
Veins have thin, distensible walls and thus low blood pressure.
Compliace: How volume of vessel changes when the pressure changes.

In venous system: small pressure changes cause a relatively much larger

change in volume thus this means it has higher compliance than arterial
system.

Stress relaxation is a feature of venous smooth muscle

Venous smooth muscle adapt to increased volumes by active relaxation (in
response to stretching of vessel)

Blood pressure is reduced above the heart and elevated below the heart

Arteries don't dilate much but veins do.

Veins can be compressed easily at vulnerable points thus elevating
resistance.

What provides venous return?

Heart activity (pumping, sucking)
Muscle pumps + Valves
Sympathetic venoconstriction

Walking and movement decreases venous pressure.

Sitting and standing in one place for a long time increases venous
pressure.

Vericose veins:
Incompetent veins,
Vein valves fail and edema is frequent.

Control of compliance by sympathetic system:

Venous constriction will reduce compliance, promote venous blood flow to
the heart and mobilize blood from venous stores

Blood reservoirs:
Venous system: 64%
Pulmonary circulation: 9%
Heart: 7% (sent out by increased ejection)

Venous blood reservoirs:

Cutaneous venous plexus
Liver
Spleen

On the right side of the heart:

During expiration, venous return decreases. During inspiration, venous
return increases.
On the left side of the heart:
During expiration, venous return increases. During inspiration, venous
return decreases.

Valsalva maneuver: Forced expiratory effort

Whenecer thoracohumeral muscles are used.
This maneuver evokes complex cardiovascular reflexes. There are large
fluctuations in vebous flow during this manoeuvre.

Purpose of cardiovascular system:

Facilitates exchange of gases, fluids, electrolytes between cells and
outside environment.

Flow output of right and left heart do not differ significantly.

Output of right and left heart are independent of each other.

Circulation of most major organ systems are in parallel.

Except portal circulation.
Because the circulation is parallel, adjustment of blood flow to 1 organ
does not create major disturbances in the blood supply to other organs.

Pressure gradient is the energy that drives movement of the fluid.

Flow (Q): fluid volume flowing through the cross section of a vessel in a
given time period (ΔV/ΔT)

Hagen Poiseuille Law:

Q = ΔP x pi x r^4 / 8 x n x l
n = viscosity
l = length of vessel
r = radius of vessel

At a given pressure gradient, flow will be determined by hydraulic

resistance.
Hydraulic resistance is determined by fluid viscosity, tube length and tube
radius.
When this statement is applied for systemic circulation, it is called total
peripheral resistance.

In parallel circuit, total resistance is less than sum of resistance

Organ blood flow is not driven by the output of the heart but instead by
the pressure generated within the arterial system.

Blood is a non Newtonian fluid.

Transmurla pressure within the vessel exerts a force on the vessel wall
causing it to be stretched
This wall tension could tear the vessel wall.
Small vessels are able to withstand higher pressures.

Aorta and large, elastic arteries are at high risk of a tear in the vessel wall
due to high blood pressure and a large radius with relatively thin walls.

Distensible nature of arteries allows them to accommodate the pulsatile

output of the heart.
Veins are the most distensible vessel. Veins are 8 times more distensible
than arteries. Thus even a slight increases in venous pressure causes the
veins to store lots of blood.
Thus veins can acts as blood reservoirs.

Compliance - Ability of vessel to respond to an increase/decrease in

pressure by distending or not distending and thus increasing/decreasing
the volume of blood that it can hold.

Veins are the most compliant vessel.

They hold the more blood at lower pressure than arteries.

Similarly, aging arteries have a lower compliance than a young artery.

Both arteries and veins have:

Tunica Intima (endothelieum, internal elastic membrane only in arteries)
Tunica Media (smooth muscle cells in circular arrangement)
Tunica external (Collagen fibres)

In veins, tunica externa is relatively musch thicker.

In arteries, tunica media is relatively much thicker.

Diameters
Aorta - up to 25 mm
Arteries - up to 100 micrometer
Arterioles: 10-100 micrometer
Capillary: 8 micrometer

Arterial walls are thick, capillary walls are not thick.

Veins and venules carry deoxygenated blood.

Distribution vessels: Aorta, large arteries

Resistance vessels: small arteries, arterioles
Exchange vessels: capillaries
Capacitance vessels: veins, venules.

Arteries transport blood under high pressure

Thus arteries have strong vascular walls and blood flows through aorta at
a high velocity.
Elastic arteries are near the heart. Muscular arteries connect elastic
arteries to arterioles
Arterioles do blood pressure and local flow control. They act as control
conducts.

Capillaries is where exchange of nutrients, fluids, electrolytes happens

Capillary walls are very thin and have numerous small capillary pores.

Venules collect blood from capillaries.

Veins do transport of blood from venule back to the heart. Veins serve as a
major reservoir of extra blood.

Blood pressure is not equal throughout the cardiovascular system.

Mean pressure in aorta = 95 mm Hg
Pressure remains high in large arteries (due to high elastic recoil of
arterial wall).
There is a significant decrease of pressure in arterioles.
At the end of arterioles, mean pressure in arterioles = 30 mm Hg
In capillaries, venules and veins pressure decreases further
pressure in vena cava = 4 mm Hg
pressure in right atrium = 0-2 mm Hg

There are pulsations of arterial pressure.

These pulsations reflect the activity of the heart (systole and diastole)

84% of blood is in systemic circulation.

7% of blood is in the heart
9% of blood is in pulmonary vessels.

Of the 84%
64% is in the veins
13% in arteries
7% in capillaries

Veins are highly distenisble capacitance vessels. They can acts as

reservoirs for blood.

TPR (total peripheral resistance)

19% in great arteries
50% in small arteries and arterioles
27% in capillaries
7% in venules, veins
Flow velocity = Flow/Cross sectional area
Flow of blood is always constant.

Mean arterial pressure = diastolic pressure + 1/3 pulse pressure.

Stroke Volume = EDV - ESV
Cardiac output is stroke volume per minute

Capillaries have the largest cross sectional area and lowest flow velocity.
Aorta has smallest cross sectional area and highest flow velocity.

ECG - Eelctrocardiography
limb leads are Einthoven (3) and Goldberg (3)
6 chest leads: V1-V6 Wilson leads
Thus ECG has 12 leads.

Leads can be unipolar or bipolar.

Einthoven is bipolar lead (2 active points)
Goldberg and Wilson is unipolar leads.
For the limb leads, we put the electrodes on 3 limbs: both the arms and the
left leg.
Since einthoven is bipolar, in that method we measure the potential
difference between 2 points.

P wave: <0.1 s
R wave: <0.1 s
In ECG we have waves, segments and intervals.
P wave - atrial depolarisation
QRS Complex - Ventricular depolarisation. This complex also hides the
atrial repolarisation.
T wave - ventricular repolarisation.
PQ segment - conduction of AV node.
ST segment - Time between ventricular depolarisation and repolarisation
Segments are isoelectirc (no potential change, flat line)

Intervals contain at least 1 wave and 1 segment.

In a complete cardiac cycle, there are 2 intervals.
1) PQ interval: from start of P wave to end of Q wave
200 ms (0.2 s), Atrial depolarisation
2) QT interval: From start of Q wave to end of T wave
320 - 390 ms (0.32 - 0.39s). Ventricular depolarisation and repolarisation.
QT interval contains QRS complex, T wave, ST segment.

In ECG paper:
1 small block is 0.04s long and 0.1 mV tall.

Heart axis:
aVR: -30
aVF: +90

Pressure graident is the driving force of flow.

Inverse proportionality between resistance and blood flow.
Blood flow = Pressure gradient/Resistance

Transmural pressure = Pressure in capillaries - Pressure in interstitum.

When transmural pressure is high, vein cross section is circular

When transmural pressure is low, vein cross section is elliptical
Possibility of Rupture of vessel wall is high in aorta and large, elastic
arteries.

Blood flow = Blood flow velocity x cross sectional area

Q=VxA

Inverse proportionality between blood flow velocity and cross sectional

area.
Flow (Q) is constant. About 5.5 l/min
Flow velocity and cross sectional area varies depending on the vessel type.
Eg:
Aorta velocity = 22 cm/s.
Vena cava velocity = 8 cm/s

Compliance: Volume change for a given pressure change.

Compliance of vessel depends on distensibility of vessel
Veins have higher compliance than arteries, thus veins are called
capacitance vessels.

2/3 of blood is in the venous system.

Aorta has windkessel effect.

Week 12
Systemic control of circulation: Maintains constant perfusion pressure by
regulating mean arterial blood pressure.

Local control of circulation: Maintains adequate blood flow to tissues to

meet their their metabolic and functional tissue needs.

Systemic control of circulation is done by renal and hormonal regulation

of mean arterial blood pressure. Done by volume regulation, pressure
diuresis. Is long term.

Delta P = Q x R
Q = cardiac output
R = Total peripheral Resistamce

A small increase in blood pressure causes a massive increase in urine

output. This is diuresis.
Increased urine output decreases blood pressure cuz an increased urine
output means decreased extracellular fluid volume.
A decrease in blood pressure also causes a decrease in urine output.
Opposite is true.

Renal and Hotmonal blood pressure control: slow, powerful

Central Nervous System blood pressure control: fast, adaptable.

Blood pressure regulation by volume regulation is done by hormones.

Renin-Angiotensin-Aldosterone axis and Vasopressin.
These 2 hormones retain salts and water respectively and thus the activity
of these 2 hormones decreases the urine output.

Thus vasopressin and RAA decreases diuresis and increases mean arterial
blood pressure.

ANH (atrial natriuretic peptide hormone) is secreated by the heart. It

inihibts salt retainance by kidney and thus increases urine output

Thus ANH increases diuresis and decreases mean arterial blood pressure.

ANH also causes vasodilation, thus reducing mean arterial blood

pressure. (NPR 1 receptor, cGMP coupling)
Angiotensin 2 causes vasoconstriction, thus increasing mean arterial
blood pressure (AT 1 receptor - IP3, DAG coupling)
Vasopressin also causes vasoconstriction, thus increasing mean arterial
blood pressure (V1 receptor - IP3, DAG coupling)

Neural regulation of mean arterial blood pressure via reflexes of the

autonomic nervous system is short term.

Efferebts of systemic neural regulation of circulation:

Sympathetic fibres innervates the heart (atria + ventricles) and the vessels
(arterioles + veins)
Parasympathetic fibres innervate the heart (atria only)
Only sympathetic system has a role in the rehilation of total peripheral
resistance when it comes to blood pressure control.

Systemic effect of catecholamines on circulation:

We are using noradrenaline/adrenaline
- Stimulation of the heart (causing increased cardiac output)
- Contraction of veins ---> Increased venous return (causing increased
cardiac output)
- Contraction of arterioles (increases total peripheral resistance)

All above 3 increase the blood pressure.

Normal peripheral resistance is made up of the sum of resistances.

Resting tone (in arteriolar smooth muscles) = Basal tone + Neurogenic Tone
Neurogenic Tone - Sympathetic vasoconstrictor tone
Basal Tone - Systemic hormones, Myogenic tone, local vascular factors,
local tissue humoral factors)

Increase in sympathetic tone -------------> Vasoconstriction

Increase in parasympathetic tone -------------> Vasodilation.

In the sympathetic vasoconstriction innervation of smooth muscles, there

is role of norepinephrine and ATP cotransmission.

Sympathetic vasoconstrictor effect is most powerful in kidney, gut, spleen,

skin. (These can tolerate a temporary reduction in blood pressure)
Cerebral and Coronary vessels don't have significant sympathetic
vasoconstrictor tones. (These cannot tolerate a temporary reduction in
blood pressure)

Sympathetic system maintains a normal sympathetic vasoconstrictor tone.

Origin of sympathetic tone is in the medulla.

The rostral ventrolateral medullar (RVLM) is the generator of the
sympathetic tone.
Caudal ventrolateral Medulla (CVLM) inhibits RVLM and stimulates the
cardiac parasympathetic tone.
Baroreceptors are pressure sensors.
Present in the carotid sinus and aortic arch.
Baroreceptors keep the blood pressure within a narrow range.
Baroreceptors are primary sensory neurons, pseudounipolar and are
interaceptive mechanoreceptors.

Baroreceptors respond to pressure induced changes in wall tension and

thus indirectly respond to mean pressure, pulse pressure and rate of
change in pressure.

Baroreceptors have an initial input to nucleus tractus solitarius.

Then an excitatory connection to CVLM and an inhibitory connection to
RVLM>

Thus increased baroreceptor input leads to lower sympathetic activity and

higher parasympathetic activity.

Due to the baroreceptor control system:

if there's increased blood pressure, increased parasympathetic activity,
decreased cardiac output so blood pressure decreases.

Baroreceptor activity increases if blood pressure increases.

Baroreceptor activity falls if blood pressure decreases.

Baroreceptor input inhibits RVLM, sympathetic output.

The set point can be shifted however. Increased set point for
baroreceptors will allow for higher blood pressure. This happens in
response to exercise, sense of danger or if PO2 decreases and PCO2
increases

Carotid sinus reflex is a defense against oscillation in blood pressure.

Reflex is active in normal range of blood pressure.
Carotid sinus receptors are more sensitive than receptors in the aortic
arch.

Carotid sinus reflex cannot correct chronic alterations in blood pressure. It

only prevents sudden changes in blood pressure due to sudden changes
in posture.

Chemoreceptor reflex function is the stimulation of breathing.

Long term control of blood pressure is by volume regulation. (renal &
Hormonal)

Local control of circulation: Maintains adequate blood flow to meet local

metabolic and functional needs of tissues.

Local vascular resistance is the key determinant of local blood flow.

Basal tone of arteriolar smooth muscle is controlled by local vascular and

tissue hormonal factors and myogenic tone.

Vasodilatory innervation can increase blood flow locally.

Myogenic tone - spontaneous contraction maintained by arteriolar

smooth muscle.

Bayliss effect: Some arteriolar smooth muscles are sensitive to stretching.

They respond to stretching with contraction. Thus blood pressure reduces.
Increased transmural pressure induces arteriolar contraction.

Endothelial factors regulating arteriolar smooth muscle tone can be

dialators or constrictors.
Dialators: Nitric Oxide, prostacyclin, EDHF
Constrictor: Endothelin.
All this is produced by the endothelial cells.

Local vasodilator tissue metabolites are released from active cells that are
not getting enough blood flow/ not getting enough oxygen (hypoxia) /
getting too much CO2 or lactic acid (acidosis).

K+ ions, NO, PGI2, PGE2, ATP, ADP are all signals for vasodilation.

Hyperemia - Increased blood flow above the base line.

Can be active hyperemia (to meet metabolic/functional demands)
Or
Reactive hyperemia (following an interruption to flow)

Blood flow autoregulation is present in every organ and is most prominent

in cerebral and coronary circulation. This is where systemic circulation
doesn't happen.

Blood flow regulation is based on the parallel increase or decrease of local

vascular resistance with changes in arterial blood pressure.

Change in perfusion pressure -----------> Sudden increase/decrease in

local blood flow ---------------> appropriate constriction/dilation of
arterioles
(The appropriate constriction/dilation of arterioles is an autoregulatory
response)
Autoregulation is unable to prevent sudden changes in blood flow is blood
pressure changes drastically (more than 1 mm Hg/s)

Autoregulation:
1) Myogenic (Bayliss effect)
2) Metabolic (accumulation or washout of vasodilatory metabolites)
Long term accumulation (takes weeks to months): new vessel growth, vessel
degenration

Active hyperemia:
Increase in tissue metabolism will proportionally increase tissue blood flow.
Due to the release of vasodilatory tissue metabolites -------------> Arteriolar
dilation ----------> Local vascular resistance decreases ------------> blood
flow increases ---------> O2 and nutrient supply increases.
This only happens as long as tissue metabolic rate is increased.

During active hyperemia, endothelial cells of the arterioles proximal to the

tissues will sense the increased flow due to increased shear stress. They
will release NO inducing vasodilation. Due to this, even arterioles that are
not exposed to the tissue metabolites are involved in active hyperemia.

Reactive hyperemia:
Ischemia occurs ---------> Vasodilatory tissue metabolism accumulate
-----------> Arteriolar dilation ----------> Occlusion is removed ------------>
Blood flow increases ------------> Vasodilators are washed away. Arterioles
constrict and blood flow returns to normal.

Chronic elevation of metabolic activity or hypoxia triggers angiogenesis

(making new vessels)

Hypoxia also triggers vascular endothelial growth factor, fibroblast growth

factor, angiopoeitins.

Capillary density is determined by maximum flow need.

Hemostasis induced vasoconstriction:

Loss of functional endothelieum -----------> Reduced releases of NO,
prostacyclin and EDHF -------------> Vasodilator mediators will be
ineffective.

Inflammation induced vasodilation is done by:

histamine, PGE2, Bradykinin, Substance P

Histamine is the most important inflammatory mediator.

Released by mast cells, basophils.
Causes vasodilation. Is endothelieum dependent.

Kinins (Bradykinin & Lysil bradykinin) also cause endothelium dependent

vasodilation.

Locally important vasodilatory autonomic innervation:

- parasympathetic innervation of salivary glands, external genitalia
- Enteral nervous system innervation of arterioles in GI tract glands.

Factors determining cardiac output:

Heart
Blood volume
Venous Compliance
Total Peripheral Resistance

Cardiac Output does not have homeostatic regulation.

Cardiac Function Curve: As right atrial pressure increases, cardiac output

increases.

Vascular function curve: As venous pressure increases, cardiac output

decreases.

Increased blood volume ------> Venoconstriction (compliance reduces)

Decreased blood volume ------> Venodilation (compliance increaseS)

Lung gas pulmonary circulation. It is the organ with the highest blood flow.

Pulmonary circulation ha smuch lower pressure values than systemic

circulation.
Pulmonary systolic pressure = 24 mm Hg
Pulmonary diastolic pressure = 9 mm Hg
Pulmonary mean pressure = 14 mm Hg

In pulmonary circulation, arterial compliance is similar to venous.

Thus blood volume is evenly distributed between pulmonary arteries and
veins.
Bronchiol arteries provide nutritive blood flow to the larger airways.

Pulmonary vascular resistance is affected greatly by passive mechanisms

due to the low pressures and large compliance values present in the
pulmonary circulation.
Pulmonary vascular resistance decreases if blood pressure or cardiac
output increases.

Blood flow per alveolus is much higher in the base of the lung compared to
the top.
Blood flow in pulmonary capillaries surrounds the alveoli like a sheet of
blood flow.

If lung is inflated (too much air), alveoli inflate and blood vessels get
compressed.

Pulmonary microcirculation have very thin capillaries that are permeable

to fluid.
Rich lymphatic vascularization protects against edema

Pulmonary circulation has no autoregulation.

Factors that affect the cardiac output also effect the pulmonary
circulation.

There is unique hypoxic pulmonary vasoconstriction.

Usually if there is hypoxia (lack of oxygen) there will be vasodilation but not
in the lungs.
Hypoxic pulmonary vasoconstriction regulates the distribution of blood
flow within the lung. It optimizes gas exchange. It is used if a bronchi is
blocked.

Vasoconstriction is an inherent, intrinsic feature of pulmonary circulation.

Long lasting hypoxia leads to pulmonary hypertension.

Many vasoactive substances that are wahsed out of organs are degraded
by the pulmonary endothelial cells
Pulmonary endothelium does the metabolic clearance of serotonin, PGE2
and bradykinin.
Distribution of resting cardiac output:
Cerebral + Coronoary blood flow: 20%
Renal blood flow: 20%
Skeletal muscle blood flow: 20%
Skin blood flow: 20%
Splachnic & rest blood flow: 20%

Left coronary artery has 85% of heart blood flow.

Right coronary artery has 15% of blood flow.

In left ventricle, blood vessels are compressed during systole so most

blood flow in the left ventricle happens only during diastole. (Blood
actually goes backwards a little bit in the left coronary arteries during
systole)
In right ventricle, blood flow happens during diastole and systoole both.

Resting tone of arterioles in coronary circulation is determined by basal

tone only.. There is no sympathetic vasoconstrictor tone here.

Blood flow is regulated by metabolites released from cardiomyocytes. This

metabolite is adenosine.

When oxygen extraction is maximal (80%), increased metabolism must be

supported by increased flow.

Coronary blood flow increases proportionally with the cardiac output.

Cardiac work:
The heart increases momentum of blood by 15% and also increases the
pressure of the blood by 85%

In general: higher the metabolism of the organ, higher the oxygen uptake.

Skeletal muscle:
Takes up 15% of cardiac output during rest (1/ / minute)
Takes up 80% of cardiac output during exercise (20l / minute)

20% oxygen consumption during rest.

80% oxygen consumption during exercise.
Regulation of skeletal muscle circulation:
Resting muscles have sympathetic vasoconstrictor tone, sympathetic
cholinergic, anticipating vasodilation and active hyperemia by
metabolites. (K+, acidosis, adenosine, PGE2)
Skeletal muscles have significant capillary recruitment during exercise.

Aorta and arteries have similar blood pressure. 120/80 mm Hg

Aortic pressure never drops to 0.

Heart spends longer in diastole than in diastole.

Mean arterial blood pressure is 93 mm Hg.

Venous pressure is 3 mm Hg.

The pressure difference is generated by pumping of heart and sucking of

venous blood by heart.
Thus heart action increases arterial pressure and reduces venous
pressure.

Filling pressure is 7 mm Hg.

In organs, if volume increases then pressure increases.

How much pressure or volume will increases depends on compliance.

Veins are more flexible (compliant) than arteries.

If you increase venous pressure even a little, venous volume increases
massively.

Arteries have much lower compliance than veins.

EDV - ESV = Stroke Volume. (70-80 ml)

Heart pumps out: Stroke volume x Heart rate = Approx 5 l/min

Resistance against flow in a tube depends on length, radius, viscosity.

Vasodilation/Vasoconstriction of blood vessels is done by smooth muscle

cells.

Lower the radius, greater the resistance.

Higher the length, greater the resistance.

Organs are connected to the circulatory system in parallel.

1/Rtotal = 1/R1 + 1/R2 + 1/R3...

Thus total resistance is smaller than the individual resistances.

As resistance increases, blood flow decreases.

As resistance decreases, blood flow increases.
This all can be done to meet the local blood flow needs (due to metabolic
needs) of certain tissues.
Week 13
Kidney functions:
- Homeostasis of fluid compartments
isosmia - regulation of osmotic concentration
isovolemia - regulation of blood pressure and blood plasma volume
isoionia - regulation of ion concentration in blood plasma
isohydria - regulation of pH in blood plasma

pH of blood plasma = 7.37-7.43

- Elimination of non required substances. Endogenous (metabolic end

products) & Exogenous (organic and inorganic substances)
- Endocrine function (renin, erythropoietin, calcitrol)
- Gluconeogenesis
Functional unit of kidney is nephron.
1 kidney has approximately 1.2 million nephrons.
Nephrons have:
- glomerulus + Bowmans capsule
- Proximal Convoluted Tubule
- Loop of Henle
- Distal convoluted tubule
- Collecting Duct

All glomerulus + Bowmans Capsule is in the cortex.

Superficial nephrons are called cortical nephron.
Deep nephrons are called juxtamedullary nephrons.
Loop of Henle is always in the medulla

Cortical nephron (aka short looped nephron): Has a short loop of Henle.
The loop gores to the border between inner and outer medulla.
Juxtamedullary nephron (aka long looped nephron): Has long loop of
Henle. Loop goes into the inner medulla.

Malphigian Corpuscle: Ultrafiltration - 180 litre/day.

Proximal Tubule: Large quantities transported, gradient not built here.
Transport processes are not regulated here. No hormones act here.
Phosphate is an exception.
Loop of Henle: Concentration & Dilution of tubular flow. Building of
medullary gradient which is needed for water reabsorption.
Distal convoluted tubule: Fine adjustment of urine composition.

1-2 litres of urine is produced everyday.

20-25% of cardiac output goes through the 2 kidneys.

Perfusion of the renal cortex is very high compared to the renal medulla.

Blood supply of kidney:

Renal artery -------> Lobular artery --------> Interlobar artery ----> Arcuate
artery -------> Interlobular artery ------> Afferent arteriole -------> Glomerular
capillaries (filtration fo blood plasma) -------> Efferent arterioles -------->
Peritubular capillaries and vasa recta.
Cortical nephrons use peritubular capillaries and juxtamedullary
nephrons use vasa recta.

Perfusion of kidney always remains constant due to autoregulation.

Renal blood flow is fairly constant between the mean arterial pressure
values (80-180 mm Hg)

Kidney autoregulation has:

- Bayliss effect (biogenic vasoconstriction) (regulates perfusion of kidneys)
- Production of local vasoactive metabolites (regulates resistance of
arterioles in kidney)
- Tubuloglomerular feedback

If mean arterial pressure is less than 60 mm Hg, there is no urine

production in the kidney.

Glomerular function - Filtration

Tubular function - Reabsorption & secretion (between capillary blood and
kidney tubule)

Glomerulus
At the glomerular capillaries there is ultrafiltration of blood plasma.
Gets blood from afferent arteriole and blood taken away by efferent
arteriole.
Beginning of proximal convulated tubule connected here.

Juxtaglmerular apparatus - Renin and Adenosine production.

Glomerular filtration: 180 litre /day

Glomerular Filtration Rate: 100-130 ml/minute

Factors determining filtration:

1) Extension, permeability of glomerular membrane
2) Effective filtration pressure (this is the driving force of filtration cuz
ultrafiltration is passive)
3) Properties of filtrating substances. (Diameter, radius, shape of
substances)

Glomerular membrane (blood plasma transported through it) has:

- Capillary endothelieum
- Basal membrane
- Podocytes.

Capillary endothelium has large fenestrations

Pores between fenestrated endothelial cells (50-100 nm)
Pores between podocytes (25 nm)

Ultrafiltration depends on pressure difference.

Glomerular capillaries have relatively high pressure for normal

ultrafiltration

Vasoconstriction: Vasopressin, Angiotensin II, Adenosin

Vasodilation: PGE, PGI2

Proteins cannot be filtered through the glomerulus.

The glomerular filtrate is protein free and phospholipid free blood plasma.

Pressure in bowmans capsule is pretty much constant.

To check filterability, we use filtrate/plasma concentration ratios.

Lower the molecular weight, molecular radius and molecular diameter,
greater the chances it'll be filtered.

Inulin clearance: 120-130 ml/min

Creatine clearance: 90-150 ml/min

Renal plasma flow: 600 ml/min

Renal blood flow: 1300 ml/min.

Urine production: 650-3500 ml/day or 0.5-20 ml/min

pH of urine: 4-6

Transport from tubular fluid to peritubular capillary is reabsorption.

Transport from peritubular capillary to tubular fluid is secretion.

90% os filtered substances are reabsorbed.

For Na reabsorption
70% in proximal convulated tubule
20% in Loop of Henle
9% in distal convulated tubule

For water reabsoroption

70% in proximal convulated tubule
10% in loop of Henle
19% in distal convulated tubule.

Less than 1% of filtered water, Na, Cl ions are excreted.

Epithelial transport processes transport stuff through the epithelial

monolayer of tubules.

The basal part of epithelial cell has capillary near it.

Epithelial cells have luminal cell membrane projecting into lumen of
tubule.
Basal membrane has more mitochondria and Na/K pumps and
interdigitations.

Proximal Convulated tubule.

It has 3 parts.
Basal membrane has interdigitations, many mitochondrial, tight junctions
are relatively open. Brush border present..
In the proximal convulated tubule, there is high transport capacity.
Lots of active transport in proximal convulated tubule.
Paracellular and Transcellular transport happens here.

Loop of Henle
Has 3 parts (descending thin, ascending thin, ascending thick)
Both thin segments have small epithelial cells, no brush border and no
intedigitation.
Small membrane surface thus transport capacity is relatively low.
No mitochondria, only passive transport happens in these segments.
In the ascending thick segment: no brush border, plenty of mitochondria.
Membrane surface is smaller than PCT so transport capacity is less than
PCT. Active transport can happen here. Paracellular and Transcellular
transport takes place.

Distal Convoluted Tubule

Has juxtaglomerular apparatus - renin production.
DCT has big epithelial cells, many mitochondria and no brush border.
Less transport capacity than PCT.. Active and PAssive transport happens
here. Only transcellular transport in DCT as the tight junctions are closed
here.

Collecting duct
Mitochondria present, closed tight junctions, large epithelial cells with no
brush border.
Thus only transcellular transport here

All regulated transport is in DCT except for phosphate ions whos

regulation happens in PCT.

In the PCT, there is highly water permeable epithelium.

Water impereable epithelium is in the ascending limb of loop of Henle.
(hyper osmotic absorption. Salt removed from luminal compartment into
interstital fluid without changing fluid volume in each compartment)

If tight junctions open, paracellular transport can happen. This type of

transport is exclusively passive.
Transcellular transport isn't dependent on tight junctions because
movement is through the cell. Transcellular transport can be active or
passive.

Epithelial cell -------> Capillary : Efflux

Capillary ------------> Epithelial cell: Influx

Tubule Lumen ----------> Capillary: Reabsorption

Capillary ---------> Tubule Lumen: Secretion

Tubule lumen -------> Epithelial cells :Influx

Epithelial cells ---------> Tubule lumen: Efflux..

Solvent Drag Mechanism:

As water moves to another compartment via aquaporines, ions move
along with the water current to other compartments via aquaporines.
50% of Na reabsorbed is due to solvent drag mechanism.
Small, polar substances are transported by facilitated diffusion (requires
carrier proteins). This can be saturated.
Ion channels cannot be saturated.

Primary active transport can build up gradients

Secondary active transport uses the gradient made by primary active
transport and can build up gradient of its own.
Tertiary active transport uses the gradient made by secondary active
transport and can build up gradient of its own.

Ca2+ ATPase (Ca2+ pumps) can be found in DCT

Clearance principal: Amount of plasma that is cleared of a substance

during one minute (ml/min)
Clearance gives information about the kidney function.
Inulin, Creatine are completely filtered and nothing is reabsorbed
(completely cleared).

Things are reabsorbed by tubular transport processes.

Renal plasma flow = 660ml.

This is the theoretical maximal value of clearance.

Osmotic Clearane - Amount of plasma that will be cleared by the kidney of

the osmotic active substance in a minute.

Glomerular filtrate Urine

Volume 180 l/day 1.5 l/day
Glucose 16 g/day 0
Protein 20 g/day 0
Sodium 700 g/day 5-15 g/day
Cells 0 0

Proximal Tubule
Epithelieum is maximally permeable to water.
Transcellular and paracellular pathways both happen here.
70% of Na, H20 reabsorbed here from glomerular filtrate
All filtrated glucose, amino acids, proteins, Ca2+, Mg2+, K+, phosphate ions,
water soluble vitamins and components of Krebs cycle are reabsorbed in
PCT.
In the proximal tubule, there are 2 secondary active transport and 1
passive transport for Na+ reabsorption.
Active transport:
Na+ solute symport (solute can be glucose, amino acids phosphate)
Na+ proton antiport (bicarbonate, Cl- reabsorption)
Passive transport:
Cl- driven Na+ transport

Water reabsorption in PCT is paracellular, transcellular and there are

aquaporine water channels (ADH channels). All this reabsorbs 70% of water
of glomerular filtrate.

Glucose reabsorption
Reabsorbed entirely in proximal tubule.
Reabsorbed into epithelial cell by Na+ solute symport (cotransport).
Glucose is the solute here.
In the basal membrane of epithelium, GLUT transporter is used to
transport glucose out of the cells to the capillaries.

Glucose can only be reabsorbed if blood glucose level is 10mmol/l or lower.

Glucose transporter is only in PCT.

Renal Blood Flow of kidney is equal to 20% of the cardiac output.

Arteries:
Renal ------> Interlobar -----------> Arcuate ----------> Interlobular ---------->
Afferent arteriole --------> glomerulus ------------> Efferent arteriole ------>
Peritubular capillary

Glmoerulus - Ball of capillaries

Nephron is the functional unit of kidneys.
They have single epithelial layer

Malphigian corpsucle: Glomerular capillaries withing Bowmans Capsule

Macula Densa is a part of the thick ascending limb of loop of Henle.

Macula Densa is involved in hormonal regulation and feedback
mechanism.

Cortical Nephron:
In the cortex, has short loop of Henle. No vasa recta. Does relatively less
filtration.
Juxtamedullary nephron:
Near the border between cortex and medulla. Has long loop of Henle. Has
Vasa Recta. Can do more filtration relatively.

In glomerulus, there are fenestrated epithelium + basement membrane +

podocytes.
These 3 make up the filtration apparatus.

After filtration, soluts can undergo: partial reabsorption, complete

reabsorption or secretion.

PCT does rough adjustment.

DCT does fine adjustment.

Renal Clearance: Amount of plasma which is cleared from a given

substance in a minute.
Clearance = urea conc x urine flow rate / plasma conc
Concentration is of a particular substance.

GFR (glomerular filtration rate)

- If a substance is not reabsorbed at all after filtration, it is completely

cleared.
In this scenario, clearance = GFR
- If a substance is filtrated and less amount is excreted then GFR >
Clearance
This is due to tubular partial reabsorption.
- If a larger amount of substance is excreted than filtrated then Clearance
> GFR.
This is due to tubular secretion
- If total filtrated amount of substance is reabsorbed, Clearance = 0
There is complete reabsorption.

Creatinine, Inulin is used to calculate GFR

RPF = renal plasma flow

PAH is used to measure RPF.

Afferent and efferent arterioles make up nearly 70% of total renal vascular
resistance.

Glomerular hydrostatic pressure acts in one direction. (favors filtration)

Glomerular colloid osmotic pressure and Bowmans capusle pressure act in
the opposite direction. (opposes filtration)
Glomerular hydrostatic pressure - 60 mm Hg
Glomerular colloid osomotic pressure - 32 mm Hg
Bowmans capsule pressure - 18 mm Hg

Thus net filtration pressure is 10 mm Hg

Autorgeulation of Renal Blood Flow:

- Myogenic Tone (Bayliss Effect)
- Tubuloglomerular feedback (dependent on NaCl change in tubular fluid.
Sensed by macula densa, alters GFR and afferent arteriole resistance.)

Glucose, amino acids are reabsorbed fully in the proximal tubules.

This means usually, glucose and amino acid clearance = 0.
Bicarbonate ions almost completely reabsorbed in PCT too.

Urine made up of urea, creatinine and small amounts of ions.

In the proximal tubule, epithelial cells are polarized cells (they have
different transporters on apical and basal membrane)
In the proximal tubules, Na+ reabsorption is by:
Na+/proton exchanger
Na+ solute symport transporter.
(these 2 are primarily in the 1st half of the proximal tubule)
In the 2nd half of proixmal tubule is:
Na+/proton exchanger and paracellular transport

Water can be reabsorbed paracellularly and transcellularly in the proximal

tubule.
Starling forces can change water reabsorption.

Organic cation transporteres are present.

Vasa Recta surrounds the loop of Henle.

Nephron: Morphological and functional unit of kidney

Malphigian corpuscle: Glomerulus + Bowmans capsule.

Glomerulus wall made up of podoctes + fenestrated endothelial cells +
basal layer.

Macula densa of DCT is near the afferent and efferent arterioles where
they are close together at the Bowmans Capsule.
Macula Densa - Na+ & Cl- sensors. part of the juxtaglomerular apparatus.
Macula densa is modified epithelial cells.

Tubuloglomerular feedback:
Macula densa sends information to renin producing cells and afferent
and efferent arterioles.
Renin produced in response to low blood pressure as renin increases
blood pressure.

If blood pressure is high, macula densa senses the increased Na+, Cl-
concentration in blood.
Macula densa cells swell, ATP leaves them and is converted to adenosine.
Adenosine constricts afferent and dilates efferent arterioles. This allows
for more time for Na+ reabsorption because now the flow is slower.

Renin hormones also breaks down angiotensinogen to angiotensin I and

then angiotensin II.
Angiotenisn II causes:
- vasoconstriction of arterioles
- Na+ reabsorption in proximal tubules
- increased vasopressin concentration
- increased aldosterone concentration

Both vasopressin and aldosterone increase blood pressure.

In the proximal tubules, epithelial cells have luminal and basolateral

membrane.
Basolateral membrane has Na+/K+ pump.

Na+ reabsorption happens in the PCT using 3 mechanisms including

Na+/proton antiporter on luminal membrane.
Na+ draws water with its movement.

Glucose is completely reabsorbed in proximal tubule.

Glucose and amino acids are reabsorbed in PCT using Na+ solute
cotransporter.

If blood glucose level is above 10 mmol/l, not all glucose will be taken up
by the cell as glucose transporters will be saturated. Glucose stays in the
filtrate.

15% of filtrated water is reabsorbed in the descending limb of the loop of

Henle.
The thick ascending limb of the loop of Henle is impermeable to water. It
makes the filtarte hypoosmotic. Na+ and Cl- reabsorption happens here.

Distal convulated tubule does reabsorption of 15% of filtrated water.

Reabsorption of Na+, Cl-, Ca2+ happens here.

There are 2 types of collecting ducts: Inner medullary and cortical.

Inner medullary collecting duct: Na+ reabsorption happens without K+
secretion.
Cortical collecting duct: Na+ reabsorption and K+ interstitium secretion
are coupled.

Diuretic drugs do:

decrease Na+ reabsorption
Increase urine volume
decrease blood pressure
decrease cardiac output
Na+ reabsorption:
67% in PCT
25% in thick ascending limb of Loop of Henle
5% in DCT
3% in collecting duct
1% of filtrated Na+ is leaves the body in urine.

Urea: end product of protein metabolism.

Gives 50% of osmolarity in kidney.

Urea transporters - UT1

Upto 40% Urea can be reabsorbed from the collecting duct if ADH present.
Urea recycling is only high if ADH is present.

ADH - anti diuretic hormone.

Released by hypothalamus, reduces diuresis (urination)
Vasopressin and ADH are the same.
Stimiuls for ADH release is increased plasma Na+ concentration.

Clearance: Volume of plasma cleared from a given substance in 1 minute.

GFR = glomerular filtration rate = 180l/day (120 ml/min)

Inulin and creatinine is used to determine GFR.

Countercurrent exchange (in vasa recta) and countercurrent multiplication

(between thin descenind limb and thick ascending limb) maintains the
osmotic layer of kidneys.

If low blood pressure, there is decreased Na+, Cl- concentration in distal

convulated tubules.

If
increased Na+ intake
lesser Na+ reabsorption
Increased Na+ excretion.
Week 14
In proximal tubule:
peptides with small molecular weight are reabsorbed by carrier mediated
mechanisms.
Peptides, proteins with larger molecular weight are reabsorbed by
pinocytosis.

Only very small peptides and proteins pass through into the glomerular
filtrate.
Epithelial cells in proximal tubules have peptidases which digests peptides
to amino acids.
Basolateral membrane of epithelial cell has amino acid transporters.

Peptides are taken from the lumen by peptide proton symport (tertiary
active transport).
This and pinocytosis removes all filtered proteins/peptides from tubules.

Uric acid is completely filtered and then completely reabsorbed in the

proximal tubules first 2 parts. in the 3rd segment of proximal tubules, uric
acid will be secreated.
Secreated amount is then excreated (10% of filtered amount).

Uric acid, K+, H+, organic acids, organic bases are secreated into the
proximal tubules.

Clearance of PAH = RPF = 660 ml

70% of filtered water, Na+, Cl-

90% of filtered bicarbonate
All filtered glucose, proteins and peptides have been reabsorbed by
proximal tubules.
Osmolarity is unchanged in the entire proximal tubule.

Loop of Henle has thin descending, thin ascending and thick ascending
segments.

Both thin segments have exclusively passive transport cuz of very few
mitochondrial present.
thick segment has many mitochondria present so here, active and passive
transport both happen.

Loop of Henle reabsorbs 20% filtered Na, 10% filtered water

Lets hypotonic fluid go into the distal tubule
Does concentration (descending segment) and dilution (ascending
segment) of tubullary fluid.
Medullary gradeint is produced here (50% NaCl, 50% urea)

There is counter current mechanism between ascending limb and

collecting duct.

Thin descending limb:

- No active transport
- Freely permeable to water
- Osmolarity increases from 300 to 1200 due to water leaving tubular fluid
(water reabsorption)
- Na+, Cl- in tubular lumen. Urea in peritubulat space.

Thin ascending limb:

- impermeable to water
- Freely permeable to Na+, Cl- (passive reabsorption of them)
- Osmolarity decreases but volume of fluid doesn't change.
- Na+, Cl= diffuse into peritubular space, urea diffuses into the tubule.

Thick ascending limb:

- 0 water permeability
- Actively and passively reabsorbs Na+, Cl-
- Osmolarity decreases in tubular fluid
- Concentration of urea unchanged because of low water permeability.

Thick ascending limb has many mitochondria. Na+/K+ pump on its

basolateral membrane which causes Na+ - K+ - Cl2- symport (secondary
active transport) on luminal membrane.
There is also paracellular Na+, Ca2+, Mg2+ transport in thick ascending
limb

Hyperosmotic fluid with high urea concentration leaves the loop of Henle.

50% of filtered urea will be reabsorbed in proximal tubule.

Descending limb - no urea transport
Ascending limb - urea transported from interstitium to tubular fluid.
Distal tubule - Concentration of urea in the tube increases due to water
reabsorption

Urea permeability transporters are observed in the medullary part of

collecting duct. These transporters are ADH dependent.
They can take urea from tubular fluid to intersitium.

Distal nephron
- Macula Densa segment (regulation of renal blood flow, contains
juxtaglomerular apparatus - renin, adenosine production)
- Distal convoluted tubule. Has many mitochondria and tight junctions are
closed.
Active Na+ reabsorption in DCT by Na+ - Cl- symport
Low water and urea permeability in DCT

No paracellular transport in distal tubule

Na+ - Cl- symport is in luminal membrane is secondary active transport.
At basolateral membrane, there is Na+/K+ pump and K+ - Cl- pump.

Ca2+ and Mg2+ reabsorption is regulated at the distal tubule.

Both go through respective ion channels present on lumina membrane by
diffusion. This is passive.
At the basal membrane, there are Ca2+ and Mg2+ pumps (primary
transport) and Na+/Ca2+ and Mg2+/Ca2+ antiport exchange (secondary
transport)

Vitamin D3 regulates Ca2+ reabsorption.

10% of filtrated Mg is excreted.

1% of filtrated Ca is excreted.

In the late distal tubules and collecting ducts, Na+ reabsorbed and K+
secreated. This by separate Na+ and K+ channel;s.
All this is regulated by aldosterone.
Basal membrane once again has Na+/K+ pump

Na+ intake from drinks and food.

Na+ loss mostly due to urine. Also due to sweat, stool.

Na+ regulated by:

changes in GFR (weak regulation)
Renin - Angiotensin - Aldosterone system
ANF

Renin is produced in kidneys. Angiotensinogen produced in liver.

Renin breaks angiotensiongen to angiotensin I (inactive form) in the blood.
Angtiotensin Converting Enzyme (ACE) converts angiotensin I (10 amino
acids) to angiotensin II (8 amino acids) in the lung.
Angiotensin II is a strong vasoconstrictor in arterioles so it increases
blood pressure.
It also stimulates thirst, salt appetite centers in hypothalamus
Also regulates aldosterone production in adrenal cortex.

Aldosterone causes Na+ reabsorption and K+ secretion in collecting ducts

ANF/ANP/ANH (Atrial Natriuretic Factor/Peptide/Hormone)

comes from the right atrium.
Increases ADH, atrial stretch and adrenalin.

ANF causes:
- vasodilation
- increased GFR (due to dilation of afferent arteriole)
- inhibits renin, aldosterone, ADH secretion
- thus water and Na+ diuresis increases
- Due to increased urination there is decreased blood plasma volume in
body and hence decreased blood pressure.

99% of filtered Na is reabsorbed by kidney.

Proximal tubule:
Paracellular passive transport (solvent drag mechanism)
Na+/proton antiport
Na+ - Solute symport

Loop of Henle:
Paracelular passive transport through tight junctions
Na+ - K+ - 2Cl- symport

Distal nephron:
Na+ channels
Na+ - Cl- symport

All these mechanisms which reabsorb Na+ from tubular fluid into blood will
increase the blood pressure.
Water in urine output is 1000 - 2000 ml per day

Thirst sensation by angiotensin II, hypothalamic centers (barorevptord

affect these - decrease in blood pressure sensed by baroreceptors causes
thirst)

Vasopressin (ADH) mainly regulates control of water loss from the body.
ADH comes from the hypothalamus (supraoptic and periventricular nuclei)

Renin-Angiotensin system stimulates ADH

ANP inhibits ADH.

ADH does water reabsorption from collecting ducts through aquaporine

channels using V2 receptors.
ADH can also cause weak vasoconstriction using V1 receptors.

Collecting duct is impermeable to water and urea in the absence of ADH.

Only transcellular transport happens at the collecting duct. No
paracellular transport.

In the absence of ADH, up to 15 of of filtrated water will be excreted. This is

diabetes onspidus.

Proximal tubule: Water reabsorption

Ascending limb of loop of Henle: Dilution of tubular fluid as its
impermeable to water
At the turn of the loop of Henle and in the medullary collecting duct there
is minimum water content and maximum osmolarity.

Urine concentrations are affected by length of loop of Henle and the % of

long loop and short looped nephrons

Hyperosmolarity in renal medulla (needed for water reabsorption) comes

from ions and urea.

Between the 2 limbs of loop of Henle there is couter current mechanism.

Na+ and Cl- accumulation.

Between ascending limb of loop of Henle and collecting duct there us

counter current mechanism. Urea accumulation.
Renal medulla is hyperosmotic. Renal cortex is isosmotic.

Medullary gradient originates from active Na+ reabsorption in ascending

thick limb of loop of Henle.
Cl-, Na+ recirculates from ascending to descending limb in loop of Henle.

Urea recycling is essential for building hyperosmolarity.

Urea concentration increases in distal tubule due to water getting

reabsorbed
Urea reabsorption in medullary collecting duct is ADH dependent.

Thiazide acts on distal tubules.

Vasa Recta also has counter current mechanism.

It absorbs Na+, Cl- and urea in its descending limb and secreates it in its
ascending limb.

Concentration of urine decreases (more water present in urine) due to:

- increased blood pressure
- Diabetes insipidus
- Thiazide (inhibits Na+ - Cl- cotransport)
- Loop Diuretics (inhibits Na+ - K+ - 2Cl- symprt)
(ions not reabsorbed so medullary gradient not built and thus water is not
reabsorbed.