Lecture

Summaries PHSI2006

Lecture 2: Endocrine System
The Endocrine System
One of two regulatory systems in the body
• The other is the autonomic system

Controls activities that do not require immediate adjustment
- Duration rather than speed

Homeostasis
• the tendency towards a relatively stable equilibrium between interdependent
elements, especially as maintained by physiological processes.

Endocrine system
• Releases hormones into the blood stream
• Hormone levels rise
o Looking for receptors
• Eventually once reach a certain point the levels of these hormones are lowered
o Negative feedback
• Endocrine hormones stay elevated for a significant amount of time
o Duration rather than speed

Autocrine signaling
• Release hormone that acts back on that cell type

Paracrine signaling
• Small amounts of a cytokine or a protein act on cells in their local vicinity
o Cells of different lineage next to each other

Endocrine signaling
• Cells release hormone for which levels rise
• Act on tissue in different parts of body
• Can detect increase of hormone in body
• All hormones are transported via blood

Hypothalamus
• (Generally) Releases tropic hormones which act on the pituitary gland






Cell to Cell Communication
- Long distance signaling may be electrical signals passing along neurons or chemical
signals that travel through the circulatory system
- Endocrine system
o Hormones secreted by endocrine glands à blood
§ Only target cells with receptors respond

Body Processes Under Hormonal Control
- Metabolism
- Internal environment regulation (ions, water balance, temperature)
o Ions
o Water balance
§ Blood pressure
o Thermoregulation
§ By sensory system and hormones
§ Changing how much cells metabolize energy
- Reproduction
- Growth and development

3 mechanisms of action once binding to receptor
1. Control rate of enzymatic reaction
2. Control ion and molecular transport across the membrane
a. Ion channels
b. Vit D acts on cells in guts to ensure calcium absorption
3. Control gene expression and protein synthesis
a. Bind in nucleus
b. Receptor hormone complex has special place in DNA
c. Affects transcription

Endocrine reflex
1. Internal or external change acts as stimulus
2. Endocrine system sensor integrating centre identifies the trigger
3. Release a hormone
4. Hormone moves into blood to find target tissues
5. Hormone binds to receptor (cellular mechanism of action)
a. Cascade
b. Downstream phosphorylation
6. Response depends on type of receptor and signal transduction pathway
7. Hormones eventually degraded by enzymes
a. Levels of hormones drop

Tropic hormones
- Regulate the production and secretion of another hormone
o E.g. Thyroid stimulating hormone secreted by the anterior pituitary
o Function: Stimulates thyroid gland to secrete thyroid hormones










Non-tropic Hormones
- Act directly on non-endocrine target tissues
o E.g. Thyroid hormones itself

Types of hormones
1. Polypeptide hormones
a. Composed of amino acids
b. E.g. insulin
2. Steroid hormones
a. All derived from cholesterol
i. Parent molecule
3. Amines
a.Amino acid derived
b. Only from tryptophan or tyrosine

Hormones Grouped in Terms of Solubility
- Peptide and amines are hydrophilic
o Can’t pass through membrane

- Steroid hormones are lipophilic
o Easily pass through fatty membranes

Peptide Synthesis


Peptide Synthesis Overview
1. Signal comes from DNA which creates mRNA works with ribosome to create pre pro
hormone (protein)

2. Moves into endoplasmic reticulum
- Enzymes chop of the signal sequence of the pre pro hormone
- Left as a pro hormone
- Still bound on either end by peptide fragments which stop from being active
- Need to come off before hormone can bind to receptor

3. Endoplasmic reticulum pinches off a transport vesicle carrying pro hormone
a. Through golgi complex
b. Pinches off into secretory vesicle
c. Golgi has provided enzymes that chop off peptide fragment
d. Now have active hormone and waste peptide fragments

4. Secretory vesicle excreted into extracellular fluid and into the blood to take action

Peptide and Amine Mechanism of Action

- Cannot enter their target cells as they are hydrophobic
- So they must combine with a membrane receptor to instigate a response




Receptors on cell membrane
o G-Protein coupled receptors
• Sub units take action (downstream phosphorylation)
§ Open ion channels
§ Activate amplifier enzyme
§ etc
o Tyrosine kinase receptors
• Auto phosphorylated upon binding
• Cascade of phosphorylation
• Expression of proteins
§ E.g. insulin

Steroid Hormone Production
- Cholesterol is the parent molecule for all steroids

1. Side chains chopped off by enzymes
2. Production of hormones like DHEA (testosterone) which can be hydrolyzed into
estrogen or progesterone (hydrolyzed into cortisol or corticosterone)
3. Move easily through membranes
a. Into cytoplasm to find a receptor
b. Or all the way into nuclei
4. Either directly or via downstream signaling bind to response elements on the gene
a. Affecting translation
b. Production of new proteins

- Can have cellular membrane receptors
o Can have immediate responses from binding to membrane receptors
o Faster
- Producing proteins takes longer
o Hours to days
- Kinase cascades are seconds

Steroid Hormone Mechanism of Action
- Act on intracellular receptors

Amines
- Most derived from tryptophan or tyrosine
o Most from tyrosine
§ Dopamine
§ Adrenalin
§ Noradrenalin
§ All modifications of side groups

- Thyroid hormone = 2 tyrosine and iodines attached


How are Hormones Triggered for Release?
- Hormones can be released through a clear stimulus
o Parathyroid hormone
§ Calcium concentration controlled

- Release can be controlled by reflex pathways
o All have a stimulus, snesor, input signal, signal integration, output signal,
target and response

- Simple reflex pathway
o Sense stimulus --> release hormone

- Hormone serves as negative feedback signal to switch itself off
o Don't want hormone levels to be too high
§ Hypersecretion

Reflex Pathways

Endocrine Pathologies
- Want balanced (basal) hormone levels
o Reference range
§ Almost never 0

Endocrine Pathology Classes
1. Hypersecretion
a. Gives excess levels

2. Hypo-secretion
a. Too little secretion

3. Abnormal response from target tissue

Causes of Hypersecretion
1. Benign tumors
a. Tissue removes
2. Cancerous tumors
a. More rare
b. Need full resection of endocrine organ
3. Iatrogenic (Exogenous Application)
a. Medical practitioner interfering with the hormone
b. Giving the hormone for some other reason
c. Or another medication which increases secretion

Causes of Hyposecretion
1. Genetic
2. Diet deficiencies
a. Iodine
i. Lack of causes growth problems in infancy
b. Vitamin D
3. Immunological
a. Autoimmune problems
b. Antibodies attack the gland and inhibit the production and secretion of the
hormone
4. Removal of gland
a. Benign or malignant Tumour
b. Will now need important hormones administered











Endocrine pathologies
• Problem associated with target tissue responsiveness
• Down regulation
o If hormone levels are too high for long periods of time
• Tissues start to downregulate receptors
• Internal compensation, stop the production of receptors
o Slows responsiveness to excessive hormone
o E.g. Hyperinsulinemia
• Receptor and signal transduction abnormalities
o Mutations of protein sequence of receptor make the binding between hormones
and receptors inefficient
o Or mutation to membrane binding domain
• Cant insert into membrane
o Receptors may be absent all together or non-functional
o Many G-protein linked effects

Lecture 3: Hypothalamus and Pituitary
Hypothalamus (“below the thalamus”)
- Receives information from other parts of the brain and the sensory system
o Changes in homeostasis
- Releases tropic hormones
o Are in control of releasing next set of hormones
§ Secondary hormones all released from the pituitary in this case

Sagittal Section of the Brain

Pituitary Gland
- Two glands fused together

1. Anterior Pituitary (Adenohypophysis)
a. Anterior section
b. True endocrine tissue
c. From epithelial cells
d. Able to secrete hormones
e. Secretes 6 hormones into the blood involved with growth, reproduction and
metabolism

2. Posterior Pituitary (Neurohypophysis)
a. Posterior pituitary
b. Pinched section of neural tissue which fuses to anterior section
c. Secretes neuro endocrine hormones
i. 2 main neurohormones


Anatomy of Pituitary Gland

Link Between Hypothalamus and Anterior Pituitary Gland
1. Neurons synthesising trophic hormones release the hormones into the capillaries from
the hypothalamus into the portal system of vessels
2. Portal system is a bed of capillaries supplies by a larger artery
a. Carry neurohormones into anterior pituitary
b. Which then act on endocrine cells
3. When endocrine cells in the anterior pituitary are stimulated they release their own
secondary hormones into another set of capillaries
a. Into bloodstream to target tissue


Link Between Hypothalamus and Anterior Pituitary Gland


Anterior pituitary secretes 6 hormones

- GH = Growth Hormone
- TSH = Thyroid stimulating hormone
- ACTH = Adrenocorticotropic hormone
- LH = Leutinising hromone
- FSH = Follicle stimulating hormone

Posterior Pituitary
- Pinched out section of neural tissue that secretes neuroohormones made in the
hypothalamus
o Neural hormones that are made in hypothalamus come through the neuron
and move their way down the neuron to be packaged in vesicles
§ Vesicles then exocytose to release neurohormones from the posterior
pituitary into the blood
- Main hormones produced
- Oxytocin
o During pregnancy and birth

- Vasopressin
o Acts on kidneys to control blood volume
o Secretion and reabsorption of ions

Hypothalamic Pituitary Pathways
- Hypothalamus Anterior pathways
o Hypothalamic releasing hormones (trophins) are transported to the anterior
pituitary by the portal system of vessels
§ Hypothalamic-hypophyseal portal system
 o Anterior pituitary endocrine cells release their hormones also into the portal
system
§ This drains out into the general circulation to target organs
Trophins
- Act on other endocrine glands to release a secondary hormone
















Hypothalamic Hormones
- Go to the anterior pituitary gland via portal systems
o Then initiate release of anterior pituitary hormones
- Dopamine
o Inhibits prolactin
- Thyrotropin releasing hormone
o Initiates release of thyroid stimulating hormone
- Corticotropin-releasing hormone
o Initiates release of Adrenocorticotropic hormone
- Growth hormone releasing hormone
o Acts on endocrine cells to release GH
o Inhibitor of growth hormone somatostatin
- Gonadotrophin releasing Hormone
o Initiates release of leutinising hormone and Follicle stimulating hormone



Complex Endocrine Pathway
- Complex endocrine pathway
o Hormones negatively feedback to downregulate their own production
1. Stimulus
2. Hypothalamus releases trophic hormone
3. Acts on anterior pituitary to release secondary trophic hormone
4. Acts on endocrine glands
a. Which release hormone to act on target tissue

- However, the trophic hormone released by anterior pituitary gland and the hormone
released by the endocrine gland act on the hypothalamus and the anterior pituitary
gland to downregulate the production of the original trophic hormone
o GHRH
The Growth Hormone Pathway
 - Hypothalamus stimulated to
release growth hormone
releasing hormone via the portal
system into the anterior pituitary

- Growth hormone releasing cells
then release GH into circulatory
system to act on target tissues
o I.e. Liver
o Liver releases growth
factors

- Growth hormone acts via
1. Anabolic activities
2. Catabolic activities
3. Bone growth































Growth Hormone
- Has effects on
1. Muscle
2. Liver
3. Adipose

Muscle
- Increases protein synthesis and decreases glucose uptake

Liver
- Can produce glucose to send into blood system
- Gluconeogenesis
1. Production of glucose into the blood
- Somatomedins
1. Insulin like growth factor family
















Adipose
• Decrease glucose uptake
• Lipolysis
o Breakdown of fatty tissue so that other systems can have fatty acids and proteins
for growth
o Often when there is a lack thereof from diet

Somatomedins
- IGF1- Bone Growth plates

- IGF2- Many organs
- Protein synth
- RNA and DNA synth
- Cell growth
o Size and number

Bone Growth
- Linear growth of bones takes place at the epiphyseal plates

- Epiphyseal plates
o One at either end of each long bone
o Place at which growth takes place

- Diaphysis
o Where marrow is stored
o Shaft of the long bone
o Can fill with adipocytes as we get old

- Growth plate full of proliferating chondrocytes when young
o Older cells found closer to the cartilage
o Younger cells found closer to the compact bone

- Middle of the bone is mineralized
o Growth does not occur from middle

- The bone plates are mineralized and growth occurs here at either end of the long
bone
o Growth occurs at either end
o Driven by growth hormones

Metabolic Action of Growth
• Hypothalamus releases the hormone releasing hormone
• Also secretes the inhibitory hormone
o Somatostatin
o Gives feedback mechanism
• Anterior pituitary releases growth hormone on stimulation by GHRH (from
hypothalamus)
o Have direct effects on liver and other tissues to produce insulin like growth
factors
o Also has anti insulin actions
• Because whilst trying to grow the growth hormone is trying to provide
tissue with the energy the protein and the FA necessary for their
proliferation and maturation
• Insulin on the other hand is trying to put glucose and protein away back
into muscle and fat for storage
§ Anti-insulin effect thus provides the energy for growth
§ Acts on fat and carbohydrate metabolism





Long loop and Short loop Feedback Mechanisms
 - IGF’s are the long loop feedback mechanism
o To inhibit growth hormone releasing hormone and growth hormone itself
- Growth hormone itself is the short loop negative feedback mechanism
o To the pituitary gland and hypothalamus, inhibits GHRH and GH itself

Increasing Secretion and Inhibition of GH
 • Stimulating the hypothalamus to release growth hormone inhibiting hormone
• Exercise
• Stress
• Drop of blood glucose

• Increase in blood AA and decrease in blood FA will stimulate the hypothalamus to
release growth hormone releasing hormone
o Heads off to anterior pituitary to stimulate growth hormone itself
• Which has metabolic action unrelated to growth
§ Decreases glucose uptake by muscles, (thus increase blood glucose)
anti insulin effect
• And metabolic action related to growth
§ Liver stimulated to produce IGF-1's which increase cell division,
protein synthesis and bone growth whilst reducing blood AA levels

• IGF-1's
o Can inhibit the anterior pituitary production of GH and GHRH
• Somatostatin
• Can inhibit the anterior pituitary from releasing GH
• We have pathways which inhibit via long and shorter loops to control growth
hormone release from hypothalamus and anterior pituitary gland
• And we have positive stimulation pathways

The Endocrine Pathologies

 • Hypersecretion
• Over secretion in hypothalamus, pituitary or in target tissue
• In target organ is called primary hypersecretion
• In hypothalamus or pituitary is called secondary hypersecretion
• Exaggerates the effect of the hormone
• Can lead to receptor downregulation
• Become more resistant
• Reduction in amount of receptors which target tissue produce

• Secondary hypersecretion – In Hypothalamus or Pituitary
• E.g. Hyperprolactinemia
• Excessive prolactin in the blood
• Affects 1% population
• In women
• Abnormal menstrual cycles
• Milk production when no breastfeeding occurring
• Increase in body hair
• In men
• Infertility, production of breast tissue, loss of body mass, loss
of body hair
• Causes
• Benign pituitary tumor
• Tissue dividing rapidly, more cells than usual,
producing lots of prolactin
• Dopamine disorders
• Intrinsic or iatrogenic
• Use of antipsychotic drugs (dopamine inhibitors)
increases prolactin production
• High TRH secretion secondarily increases prolactin secretion
• Treatment
• Bromocriptine
• Dopamine agonist
• Turning back on the inhibition of prolactin
• Treat underlying thyroid problem
• Surgery
• Spontaneous disappearance












• Primary hypersecretion – Occurs in Target Organ
 • Cushing syndrome (excess cortisol production)
• Caused by large adrenal tumor which produce excess cortisol
• Excess cortisol remodels the body to produce glucose, so
• Muscle is broken down
• Protein and fats in skin are broken down
• Diabetes can be mimicked
• Treatment is removal of tumour
• Symptoms
• Facial roundness
• Pink/purple marks where adipose tissue is deposited
• Muscle weakness
• Osteoporosis
• Slow healing wounds
• Menstrual disorders and hairiness in women
• Infertility and impotence in men

Hyposecretion in a target organ exaggerates the effect of the trophic hormone
- E.g. no production of thyroid --> hypothalamus and pituitary gland are not getting
negative feedback --> keep producing trophic hormones

- Hypothyroidism
o Primary or secondary hyposecretion
o Most commonly caused by autoimmune problems
o Iodine deficiency can cause this
§ Where diet is not high enough in iodine
o Affects men less frequently
o Affects 6-10% women at some point in their life
- Symptoms
o Fatigue, cold intolerance, hair loss, menstrual disorders, bradycardia (slow
heart rate)
- Treatment
o Administration of exogenous thyroid hormones

Removing Thyroid Hormone
- No thyroid hormones à no action on tissues à slow metabolic rate à no thermal
regulation à sensitivity to coldness

- Also have no feedback to anterior pituitary or hypothalamus
o So thyrotropin releasing hormone and thryoid releasing hormone are
excessively secreted to compensate to get thyroid to produce thyroid
hormones



Lecture 4: Hormonal Control of Circulating Nutrients
- Glucagon, cortisol, adrenalin and growth hormone all oppose the effects of insulin

Pancreas and Islets of Langerhans
- The pancreas is where enzymes of digestion are secreted
- Insulin is secreted by glandular structures embedded within the tissue of the
pancreas called islets of Langerhans
o Where the endocrine are that produce insulin, alpha cells, beta cells,
somatostatin cells and F cells
o Contain
§ alpha cells
• Secrete glucagon
§ beta cells
• Secrete insulin and amylin
§ D cells
• Secrete somatostatin
§ F cells
• Secrete pancreatic polypeptide



Insulin and Glucagon from Pancreatic Islets

- Food intake has spikes throughout the day

- If nutrient availability in blood were determined solely by consumption of food, then
it would mirror the times at which you ate
o However, the highly irregular input of food is converted to a relatively narrow
range of nutrients by glucagon and insulin
§ No serious lows
§ No serious spikes
§ Yellow line








Blood Glucose Homeostasis
- Why is this important
o Empirically blood glucose is between 3-5 mmol/L
o Consequences of hypoglycemia (low blood glucose) are really bad
§ Impairments to central nervous system
§ Brain needs glucose to function
o As glucose drops
§ Disorientation and hunger --> death
- What can you do
o Take a readily absorbable form of sugar

Hyperglycemia (High Blood Glucose)
- In an acute situation significant hyperglycemia will increase urine flow which can
cause significant dehydration
o Also draws water osmotically from cells
§ Increase urine flow à dehydration
§ Intracellular dehydration
§ Affects CNS
o Long term problem of glucose covalently bound to proteins e.g. basement
membrane proteins
§ Can cause disease


Sources of Nutrients for Blood
- There are 2 sources of nutrients for the blood stream
1. What you've eaten
a. Eating causes insulin to be released
b. Insulin promotes the uptake and storage of nutrients
c. At the same time it inhibits the release of endogenous stores
2. Endogenous nutrients stores
a. Fasting releases all of the counter hormones to insulin (listed above)
b. This is a time when not getting nutrients
c. Glucagon releases endogenous nutrients at this time



What are endogenous nutrients stores and how are they converted?

How long can you go without food?
• 3 weeks (ish)
• However body stores without glucose are 1 day!!

Glycogen found in muscles
• Can be broken down and used in the cell

Liver stores glycogen as well
 • Broken down into glucose 6P, can go into citric acid cycle
• ONLY TISSUE THAT CAN LOCK THE PHOSPHATE GROUP OFF AND EXPORT FREE
GLUCOSE TO BLOODSTREAM

Glycogen stores in liver
• About 1 day

Also comes from skeletal muscle
• Most important source of glucose in starvation
• Gluconeogenesis
o New formation of glucose

Most tissues don't need glucose
• Many can break down fats into FA --> citric acid cycle --> energy
• Glycerol backbone
• Can be used to form glucose through gluconeogenesis
• Don't have to breakdown too much skeletal tissue because the majority of glucose is
used by the brain
o Other tissues use other sources

Ketones
• If fasting they are used by the body and don't build up
• Are strong acids so if they do build up it can be lethal

Fuel stores
• Glycogen 1800kcal
• Fat 140,000kcal
• Protein 41,000 kcal

Glycogen can be converted to glucose
• Only liver can release stored glucose to the bloodstream

The Inability to convert fatty acids into glucose is overcome by
1. The oxidation of fatty acids inhibiting the oxidation of glucose
o so we don't waste glucose
2. Glycerol released from lipolysis is converted into glucose by gluconeogenesis in the
liver
3. Ketone bodies formed from fat oxidation can be used as an alternative to glucose by
many families

- Purpose of the three points above is to limit the amount of protein breakdown that
you need to get adequate glucose for brain to survive
o Leads to immune system problems




Stimulators of Insulin Secretion
1. Increase in blood glucose concentration
2. Increase in blood AA concentration
3. Food intake
a. Releases hormones from gastrointestinal tract and causes parasympathetic
stimulation
i. Both release insulin

Incretins
- Stimulate insulin release
- Inhibit glucagon release
- Leading to reduced blood glucose
- Make you feel full

- GLP-1
o Glucagon like peptide
1

- GIP
o Gastric inhibitory
peptide


- One of the most effective
ways of reducing food intake
is to slow the rate at which
you eat
o Give time for these
hormones to be
released
o Feel full part way
through the meal

- Mechanism for incretin breakdown
- DPP4
o Enzyme which inactivates GLP-1
o 1st round of additional diabetes treatments










Islet Beta Cell Insulin Secretion
- Major control is blood glucose level

Insulin Secretion
- Insulin secreted as a singular polypeptide chain which folds in on itself
o Held in the new conformation by 3 disulfide bonds
- In Golgi converting enzymes act on insulin to break it at two points release the seal
collecting peptide and insulin proper which now appears to be 2 polypeptide chains
which are linked
o Released in equally molar concentrations as insulin
o Little physiological impact
o Used to measure insulin secretion levels

Insulin Release
• Unlike most hormones it is not released into peripheral circulation
• Insulin is released to the portal circulation
o Circulation that goes from one tissue to another without going to the heart
o E.g. Hypothalamus to pituitary gland
o Very important
• Means that the liver gets exposed to the highest concentration of insulin
(and glucagon) under normal circumstances
• Islet cell transplants
o Often try put the cells close to the liver
o Rather than getting hormones secreted into general circulation
• The liver is exposed to higher concentrations of insulin (and glucagon) than
peripheral tissues

Insulin Action
Insulin is a peptide (protein)
• Doesn't get through membrane well
• Receptor therefor sits on exterior of membrane
• Heterodimer
• Insulin binds to receptor and alters conformation
o Altering its functional state
o Insulin acquires the action of tyrosine kinase enzyme
• Which add phosphate group to tyrosine residue on a protein

Tyrosine kinase response depends on
• Adequate insulin
• Normal receptors
• Normal cellular responsiveness
o Highly complex system
o Easily disrupted

Insulin is Anabolic
• Increases uptake and storage of any nutrient and inhibits breakdown of stored
nutrients at the same time - Insulin is building up

Insulin Effect on…
- Glucose
o Increases glucose uptake
o Increased concentration of glucose transporters
§ Assist glucose in crossing membrane
§ Facilitated diffusion
o Stimulates enzymes involved in glycogen synthesis
§ Inhibits glycogenolysis
- Fats
o Increase uptake
o Fats packaged into lipoproteins so that they can easily sit in water based
cytosol
o Increases uptake of glycoproteins into cells
o Increases storage of fats as triglycerides
o Inhibits hormone sensitive lipase
§ Enzyme which breaks down fats
- Proteins
o Increases AA uptake
o Stimulates protein synthesis
o Inhibits protein breakdown

Insulin Special Sites
1. Liver
a. Insulin doesn't stimulate glucose uptake by liver
b. Main actions are to stop stored nutrients from being released bloodstream into
whilst you are eating
c. Inhibits glycogen breakdown and enzymes involved in gluconeogenesis
d. Inhibits liver output of glucose when eating
e. Also inhibits ketone production by inhibiting the enzymes which produce ketones

1. Kidney
o No effect on glucose transport in the kidney
o Glucose filtered is proportional to blood glucose concentration
§ This glucose that is filtered into tubular fluid is largely reabsorbed
o If you have high levels of glucose in the blood you filter so much glucose that
you exceed the maximum capacity to absorb
§ Cannot reabsorb anymore
§ Glucose will be in urine
• Consequences
o Lose source of calories and lose weight



3. Brain
- Absolutely dependent on glucose
- Mostly glucose transport
- Insulin independent
o Except the satiety centre

4. Brain
- Glucose absorbance is insulin independent

5. Muscle
- Glucose uptake with exercise is insulin dependent

• There are currently drugs on the market which inhibit glucose uptake
o Allows you to lose weight
o Stop reabsorbing glucose

Glucose as an Osmotic Diuretic
• Holds water by hydrogen bonds and prevents reabsorption
• Result is decreased water reabsorption so you end up with a large volume of sweet
urine
o Diabetes mellitus
• Polyuria
• Lots of urine
• Dehydration
 • Polydipsia
• Excessive drinking

Fasting
- Releases counter regulatory hormones
o Glucagon
o Adrenalin
§ Also released by stress
o Cortisol
§ Also released by stress
o Growth hormone
§ (Does not increase protein breakdown)
- All of these hormones antagonize insulin actions

Glucagon
- Secreted by alpha cells
- Release stimulated by
o Decreased blood glucose
o Decreased levels of fatty acids
o Increased levels of amino acids
- High protein, low CHO meal
- Catabolic
o Increases release of stored nutrients
Catabolic Nature of Glucagon

Eating food
• Releases insulin
o Regardless of whether high in carbohydrate

- Insulin also releases glucagon
o Increases glucose output from liver
o By itself would cause hypoglycemia however is counteracted by release of
insulin
 o Counteract each other

Metabolism – Eating vs Fasting

- Never a time when one dominates
o A balance

- Eat a meal
o Have relatively more insulin than glucagon

- Overnight
o Relatively more glucagon than insulin



Diabetes Mellitus
- Too much glucose in blood resulting in a large volume of sweet urine
o Standard test
§ Measure glycated haemoglobin
• Has glucose bound to it depending on prevailing glucose
• Gives an idea of what the glucose has been over the last few
months
• >48mmol/mol = diabetes










Pathogenesis
- Type 1 diabetes
o Autoimmune condition
o Absolute deficiency of insulin because beta cells destroyed
o Genetic susceptibility, also environmental effect leading to insulitis
§ Causes beta cells to express 'non-self' proteins
§ Autoimmune beta cell destruction
o Zero insulin
§ Too many ketones
§ Can be lethal

- Type 2 diabetes
1. Insulin resistance
o Insulin doesn't work as efficiently
2. Inability to increase insulin sufficiently
o Insufficient compensatory insulin output
o Beta cell exhaustion

1 + 2 = Type 2 diabetes
• If you cannot top up insulin to overcome insulin resistance then you get
diabetes



Lecture #5: Other Hormones
- Hormones can be secreted from glands endocrine cells, or neurons

Endocrine gland composition
- generally made up of epithelial cells
- very good at secreting things

Posterior hypothalamus
• Just neurons
o Releases oxytocin and vasopressin

Adipose tissue
• Isolated endocrine cells

Pineal gland
• Produces melatonin

Thyroid gland
• Located in neck
• Butterfly shaped
• Stimulated by a hormone from APG
o Releases T3 and T4
o Bind to almost every cell type in the body controlling metabolism

Parathyroid Gland
• Releases parathyroid hormone in response to low calcium
• Increases calcium in blood by stimulating osteoclast reabsorption of mineral releasing
calcium and phosphate, increasing active form of vit D, stimulating kidney to release
enzyme that hydroxylyses 2nd form of vitamin D which acts on gut to increase Ca
absorption


Thymus gland
• Produces thymicin
o Mostly capable of maturing T cells and dendrites
o Gets smaller as we get older

Heart
• Atrial naturitic peptide
o Endocrine cells
o Controls blood pressure

Liver
- Endocrine cells
- IGF1 and 2
- Enzymes which help production of hormones from cholesterol

Stomach and small intestine
• Also produce a lot of hormones
o Many to do with controlling digestion
o Hormone enzymes
• Break down food
• Convert other proteins into enzymes which help food breakdown
• Endocrine cells
• GLP 2
o Controls glucose levels in our blood

Pancreas
• Produces glucagon when we are fasting and insulin when we have eaten a meal
• Glandular

Adrenal cortex
• Glandular
• Produces cortisol, adrenalin, noradrenalin etc.

Kidney
- Endocrine cells
o Produces enzymes which breakdown nutrients
o Produce some hormones



Skin
- Endocrine cells
- Formation of vitamin D

Testes
• Glandular
• Produce testosterone

Ovaries
• Glandular
• Produce estrogen and progesterone

Adipose tissue
• Endocrine cells
• Hormones which help control or enhance appetite
• Fat deposition

Placenta
• Endocrine cells
• Rich source of hormones

Renin
• Renin angiotensin
• Controls blood volume and pressure

Parahormones
• Act on adjacent cells

Renal hormones
• Act local and systemically

Cardiac hormones
• Regulate blood volume and pressure

Gastrointestinal hormones
 Act within the gut
•

Adipokines
• Adipose tissue hormones
• Metabolism and body weight
• Control appetite

Thymus gland
• Act locally
• Thymocin
o Matures T cells



Kidney as a Source of Hormones
• Produces hormones which control blood pressure, Vit D, oxygen saturation and
prostaglandin and nitrous oxide
• Renin
o Juxtaglomerular and granular cells in the afferent and efferent arterioles
• In response to drop in blood pressure
• Get rise in sympathetic nervous system stimulation
o Acts to increase blood volume
• Erythropoietin
o Stimulates blood cell formation (RBC) in bone marrow
o As they pass through pulmonary system can transport more oxygen
o Detects gas pressure drop
• Vitamin D
o Conversion into active hormone occurs in kidney
o Acts at gut to transfer more calcium to gut
o Helps bone formation and maintenance
o Changes concentration depending on calcium and phosphate in the blood
• Prostaglandins
o Released from different renal cells when vasoconstriction occurs due to
SNS/angiotensin release
o Inflammatory response
• Endothelins and Nitric oxide
o Released from renal endothelial cells


















Erythropoietin Mechanism

Stimulus = RBC numbers are decreased
• Brain detecting lack of O2
• Decreased availability of oxygen to blood or increased requirement for oxygen

Kidney releases erythropoietin
• Moves into bone marrow
• Stimulates red blood cells
• Increase RBC count
• Increases oxygen carrying ability

Adipose Tissue Hormones
- White adipose tissue releases a number of hormones which affect both local fat cell
metabolism and central appetite
o Main hormones are
§ Leptin, resistin and adiponectin
 § Becoming increasingly important in terms of the mechanisms of
insulin resistance in obesity
- Fat hormones
o Adipocytes come from white adipocytes
§ WOT

- Adipokines
o Affect local fat cell metabolism
o Work in brain to control appetite

- Brown adipose tissue goes away as we grow and is involved in thermal regulation


Adipose Tissue Hormones – Leptin
- Leptin released from white adipocytes
o Tells brain we are full and suppresses appetite
o Signals “satiety” and down regulates appetite areas in the hypothalamus

- Reproduction
o Signals whether a woman has appropriate energy for reproduction

- Leptin receptors are found in different parts of the hypothalamus

o Leptin acts on receptors in hypothalamus
§ ARC, DMH and VMH
• All release different signals to the sympathetic nervous system
o BAT Thermogenesis
o Heart rate
o Blood pressure

- Main action of leptin is on
o Arcuate nucleus and ventral medial hypothalamus
o What occurs at dorsal medial hypothalamus still under investigation

 - Leptin binds to leptin receptors
o Without leptin or the leptin receptors we can end up obese
o Don't know when to stop eating










Adipose Tissue Hormones – Resistin (ADSF)
- 2nd Adipokine
- Named due to its implication in insulin resistance
o Increase in resistance in patients with type 2 diabetes
- Target tissues are not responding to insulin very well
- Released from white adipose tissue, immune cells and epithelial cells
o Involved in insulin resistance, energy homeostasis, immune cell recruitment
and inflammation
- Works in opposite way to leptin
o Increases insulin resistance/reduces insulin sensitivity
- However, can increase levels of low density lipoproteins
o Bad
§ Get stuck in arteries
• Plaques
o Evidence to show obese people have increased levels of resistin
§ When these people lose weight this level of resistin drops

Adipose Tissue Hormones – Adiponectin
• Affects glucose regulation and fatty acid oxidation
o Decreases gluconeogenesis
o Increases glucose uptake into cell
• Improves effect of insulin
• Concentration in plasma is inversely related to obesity
o More adipose (fatter) = less adiponectin
• Works in hypothalamus to control appetite with leptin

Adiponectin and Resistin
- Appear to be involved in signaling for reproduction
o In particular, in females has an effect on polycystic ovarian syndrome in some
women
o In some women it is purely genetic
- Over-expression of adiponectin levels leads to increased insulin resistance and
infertility
 - If secretion of adiponectin and resistin is disrupted, fertility appears to be affected in
both sexes












Pineal Gland and Melatonin
- Melatonin
o Comes from pineal gland
§ Situated above the cerebellum
o Part of the bodies clock system

- Circadian rhythm
o Any biological process that displays an endogenous, entrainable oscillation of
about 24 hours

- Suprachiasmatic Nucleus (SCN)
o Is the master clock
o 24hr cycle
o Regulated by several genes

 - Photoperiod = daylight
o Melatonin can reset SCN to tell brain we are tired or awake
o The pineal gland responds to the daily cycle of photoperiod to secrete
melatonin which resets the SCN and other hypothalamic nuclei










Melatonin Derivation
- Melatonin is an amine
hormone derived from
tryptophan
o Also produces
serotonin
o Which can be
converted into
melatonin

Pineal Gland and Melatonin
- The pathway from the
eye to the pineal gland
is convoluted and
involves many steps
- Pineal gland is regulated
by the sympathetic
nervous system
o Pinealocytes
(pineal gland
cells) have both
beta-1 and alpha-1 adrenergic receptors for the catecholamine noradrenalin
§ When noradrenalin is present -> melatonin is produced and released
into the circulation
- Increases and decreases in catecholamine’s effect the pineal glands secretion of
serotonin
o Get a bit of an increase in noradrenalin at the end of the day
§ Slows things down

Light and the Suprachiasmatic Nucleus
- Light acts at the SCN
o Synapses at the paraventricular nucleus
o Which then sends a message to the intermediolateral cell column
 § In our thoracic spine
o Signal heads to superior cervical ganglion
§ Signals pineal gland to increase or decrease melatonin depending on
what is coming through the eye
§ Light
• Inhibition of the pathway between superior cervical ganglion
and pineal gland
§ Dark
• Stimulation of the pathway between superior cervical ganglion
and pineal gland
• Increase in noradrenalin release in pineal gland onto alpha and
beta 1 adrenergic receptors to increase melatonin secretion
§ Melatonin heads into the periphery, brain and
hypothalamus to initiate recovery
- Light

- Dark


Melatonin throughout the Day
- Low during day when awake
our outside
o Increases as
darkness forms

- This is why you should read
phones at night
o Response is same as
sunlight

- "The darkness body clock
hormone"



Pineal Gland and Melatonin
- Melatonin should have a
nice rhythm
o Down in day, drops at night, rises in morning
- Is affected by Jet lag/shift work
o Opposite light and dark cycles
o Melatonin secretion issues
o Increase in adrenalin pathways
 o Hypertension, accidents, immunosuppression

- Peripheral effects of melatonin pathways create heart problems

o Mostly hypertension
§ Which can lead to associated problems
• Heart attacks, strokes etc

Melatonin and Circadian Biology in Human Cardiovascular Disease

Melatonin can be prescribed to help with sleeping
• Must be prescribed by GP
• Can however interrupt natural melatonin if used over a long period of time

Circadian Rhythm is Controlled by Melatonin
 • Levels rise at night
• Drop as we start to wake up
• Melatonin levels can be measured through blood (best) saliva and urine
• Effects of melatonin may be to regulate core body temperature
• As melatonin levels increase it is believed that blood fat levels increase

Reaction Time: Alcohol Consumption vs Tiredness

Pineal Gland and Melatonin
- Melatonin can be exogenously administered through a tablet
o Good for elderly people with circadian rhythm problems
o Good for jet lag and shift work
§ To reset biological rythms

- However
o Can down regulate endogenous production of melatonin and melatonin
receptors

Lecture #6: The Adrenal Gland
Anatomy of the Adrenal Gland
- Adrenal glands sit above our kidneys
o Have 2 that sit within a capsule

Capsule
- Membrane that holds them in place
- Made of epithelial cells


The Adrenal Cortex
- Adrenal cortex secretes steroid hormones (made of cholesterol)

• Zona glomerulosa
o Where we get aldosterone
• Kidney hormone which controls blood pressure and water volume
• Zona fasciculata
o Largest part of adrenal cortex
o Produce glucocorticoids
• Cortisol (mostly) and cortisone
• Cortisone is inactive cortisol
• Zona reticularis
o Another change in morphometry
o Produce sex hormones here
• Estrogen in males
• Some testosterone in males (not much, mainly produced in testes)
• Female testosterone produced here

The Adrenal Medulla
- Secretes catecholamine’s
- Most interior region
- Below adrenal cortex
- Where we get amine hormones
o Noradrenalin and adrenalin
- Can be divided into two layers
o 1 producing adrenalin and the other producing noradrenalin

Functions of the Adrenal Medulla
- Inside of the adrenal gland = Adrenal medulla
o Sympathetic nervous system
§ Releases adrenalin and noradrenalin into the bloodstream which act
on the adrenergic receptors
• Alpha 1 and 2 and Beta 1 and 2
• Sit on different parts of CNS and respond to secretion of these
2 hormones differently
o Elicit different responses depending on which
catecholamine binds to them

Adrenal Medulla Mechanism of Adrenalin Release
- Adrenal medulla is acted upon by neuron coming from spinal cord
o Single synapse and acts on preganglionic receptors in the adrenal medulla
o No synapse in between the spinal cord and the medulla
§ Spinal cord neuron releases acetyl-choline
• Which binds to its receptors and stimulates Chromaffin cells
which are inside the adrenal medulla (similar to neural cells,
have small dendrites)
o These cells release adrenalin, a neurohormone which
enters the blood stream and acts on target tissues

Somatic Motor Pathway
- Acetyl Choline binds to nicotinic receptors
o Action potential moves down t tubules in muscle
§ Releases calcium from endoplasmic reticulum into muscle cells
causing contraction

Autonomic Pathways
1. Parasympathetic pathway
a. ACh binds to nicotinic receptors and muscarinic receptors
b. Downstream effects on target tissues
2. Sympathetic pathway
a. ACh binds to nicotinic receptor
b. Noradrenalin binds to androgenic receptors
c. Downstream effects on target tissues
3. Adrenal Sympathetic Pathway
a. Releases Ach into adrenal medulla
b. Adrenalin released into bloodstream to act on target tissues
i. Acts mostly on beta receptors to change flow of the blood
1. Acute response --> blood flow away from vital organs

The Adrenal Medulla secretes adrenalin
• Which acts on beta 1 and 2 g-protein coupled receptors
• Transformation of conformation of internal structure of receptor
• Activation of the g-protein
o Several subunits
• Elicit several downstream effects
• Stimulation of Beta-1 receptors
o Initiates the upregulation of activities
o E.g. Heart contraction
• Stimulation of Beta-2 receptors
o Can initiate relaxation of target tissue
o E.g. Vasodilation of smooth muscle around blood vessels


Functions of the Adrenal Cortex
- Contains three anatomical zones each secreting different steroid hormones
- Zona reticularis
o Closest to medulla
o Produces sex steroids, mostly androgens
o Production of testosterone in females

- Zona fasciculata
o Largest section
o Bigger cells, larger diameter
§ Because producing lots of glucocorticoids
• Cortisol in humans (cortisone inactive version)

- Zona glomerulosa
o Closest to surface/capsule
o Produces mineralocorticoids

Steroid Molecules Origin and Transformation
All steroid molecules come from cholesterol
• Cholesterol can be converted into pregnenolone
• All arrows represent represent an enzyme adding or taking away part of the molecule
o Enzymes tend to be hydroxylases
• Diseases where people are lacking 1 or more of these enzymes can be
linked together

Males get their estrogen from estradiol

Aldosterone
• Comes from the outer part of our cortex in the adrenal gland
• From conversion of corticosterone from aldosteronesynthase into aldosterone


Zona Reticularis Pathway

Zona Gomerulosa Pathway

Zonula Fasciculata Pathway
- Pregnenolone after cholesterol is broken down/added onto/hydroxylased
o Moves down through the pathway into deoxycortisol and is then
hydroxylased into cortisol

Functions of the Adrenal Cortex
- Zona Glomerulosa
o Produces aldosterone
o Specific to the glomerulosa
o Acts on the distal tubule of the kidney to retain water and salt
§ Increase blood pressure or volume, and to dilute blood by increasing
blood volume when dehydrated
o Activated by renin angiotensin system in response to dehydration

ANG1 and ANG2

- Liver constantly produces angiotensinogen in the plasma

- However, when blood pressure drops granular cells of the kidney produce renin
o Part of pathway that converts angiotensinogen into angiotensin-1 in the
plasma
- Blood vessel epithelium contains an enzyme called ACE
o Which onverts ANG1 in plasma to ANG2 in plasma










ANG2 can act on
o Hypothalamus
§ Vasopressin increases volume of blood and increases osmolality
• Increasing blood pressure
o Adrenal cortex
§ Aldosterone increases NA+ reabsorption
• Which in turn increases volume of blood and increases
osmolality
o Increasing blood pressure
o Cardiovascular control centre
§ Increased response
• Increased blood pressure
o Arterioles
• Constrict
§ Increase blood pressure

Aldosterone Mechanism of Action
- Aldosterone is lipophilic/hydrophobic
o Once crosses membrane it finds specific receptor
§ Aldersterone complex is the perfect shape to bind to response
element in the genes in the nucleus of P cells
• Leads to increased expression of mRNA and translation of
mRNA into proteins (channels, pumps and receptors)
o Luminal side of P cells where urine is being produce
and ready to be excreted
o Increases sodium uptake
§ Vasopressin increases water reabsorption from concentrated urine
o There are proteins which modulate channels and pumps which already exist


Functions of the Adrenal Cortex (continued)
- Zona Fasciculata
o Produces glucocorticoids
§ Cortisol promotes the formation of new glucose and is the main
glucocorticoid in humans
§ Corticosterone is the main glucocorticoid in many other species
- Zona Reticularis
o Production of sex hormones

The Hypothalamic-Pituitary-Adrenal Pathway for the Control of Cortisol Secretion
- We have an increase and decrease in cortisol levels when we are asleep and awake
respectively
o Stress increases cortisol levels

- Corticotrophin Releasing Hormone
o Released by hypothalamus
o Acts on the anterior pituitary to release ACTH (Adrenocorticotropic hormone)
§ To act on adrenal cortex to produce cortisol
• Cortisol acts on almost all tissues
o Acts on liver to initiate gluconeogenesis
- Lipolysis
o Breaking down fat into fatty acids for energy use





Actions of Cortisol

2. Protein Metabolism
a. Liver
i. In order to enhance steps for glucogen production we have protein
synthesis in the liver
ii. If ongoing and enough glucose you get glycogen production for later
use
a. Other cells
i. Breakdown and secretion of AA into blood
ii. Not more protein synthesis

3. Fat Metabolism
o Lipolysis in adipose tissue
§ Breakdown into FA for energy use
§ Enzymatic reactions require energy
§ Mitochondria functioning at high rate
§ A lot of fat stored in abdomen
• Get deposition of fat in torso
• E.g. Cushings disease --> central adiposity
Actions of Cortisol (continued)

4. Increases responsiveness of blood vessels to adrenalin and nurodrenalin
a. And to other organs which work to dilate or constrict blood vessels
b. Cortisol primes receptors and increases translation of mRNA into new receptors
for these hormones
i. Increases sensitivity of blood vessels to other hormones
1. By binding to internal receptor, then binding in nuclei to response
elements which are located on the promoters for the genes
responsible for production of other hormones

5. Immunosuppressive and anti-inflammatory activity
a. Glucocorticoids are by far and away the best anti-inflammatory drugs
b. Many risks
i. However benefits outweigh these risks

6. Permissive effect of normoglycemia

a. Required for glucagon to produce glucose
b. Also does itself by acting on liver
i. Increases blood glucose levels


Cortisol Negative Feedback
o Short loop to the anterior pituitary
• To decrease production of ACTH
o Long loop to Hypothalamus
• To decrease production of corticotrophin releasing hormone







Response to Decrease in Blood Glucose
• --> cortisol acts on the liver to increase gluconeogenesis
o Can only do this when it has enough amino acids for the production of enzymes
involved
• Breaks down protein in muscle and breaks down adipose to produce fatty
acids and glycerol
§ Increases blood glucose
• As does the direct effect of cortisol increasing resistance of
these organs to glucose uptake
• No longer going into muscle and fatty tissue

Adrenal Gland and Acute stress
• = flight or fight
• Response by adrenal medulla
• Spike in cortisol and thus blood glucose

Adrenal Gland and Chronic stress
• Long term
• Response by adrenal cortex
• Leads to many problems
o Similar response to cushings
o Always too much cortisol in blood system

Stress
- The non-specific response of the body to ay demand or change

Stressor
- Anything that promotes the stress response
o Stress response is the cascade of physiological responses in order to resist
the stressor



Stress and the Adrenal Gland

Acute vs Chronic Stress Responses

Cortisol is Higher with Stress
- In animals we can induce stress
o We get the same effect

- Very timid hare
o Big spikes in cortisol after very small changes
§ New people, temperature changes, light changes

- Penguins
o Cortisol levels at popular tourist times and off peak
§ Higher at peak periods
§ Lower when no tourists


Lecture #7 Calcium and Phosphate Metabolism
Calcium Content
- Average person has 1.1kg of calcium
o 99% of this in bones and teeth

Calcium Equilibrium
- There is an equilibrium between blood calcium and extracellular fluid calcium
concentration

- The majority of the food you eat is cells

o There is not a great deal of calcium in cytoplasm

Blood Calcium
- Very small range
o 2.3-2.5 mmol/L
- 50% in ionised form
- 46% is bound to protein
o Mostly albumin
o Can use albumin concentrations to determine concentration of ionised
calcium

Consequences of Increased and Decreased Blood Calcium
- The consequences of high and low calcium depend on
o Severity of change
o Sudden or long term change
- Blood calcium is nothing to do with intracellular calcium involved in signaling


Decrease in Blood Calcium
• A decrease (hypocalcemia) has an effect on protein conformation
o Effects the shape of the proteins that form the ion channels that let sodium in
and out of cell
o Increases sodium permeability
• Easier to get back into cell
• Partially depolarise
§ Muscle spasm
§ Pins and needles
§ Seizures







Increase in Blood Calcium
• An increase (hypercalcemia) has an effect on protein conformation
o Effects the shape of the proteins that form the ion channels that let sodium in
and out of cell
o Decreases sodium permeability
• Less able to get back into cell
• Hyperpolarization
• Nerves and muscles don't fire appropriately
§ Neurologic dysfunction
§ Cardiac arrythmias
§ Constipations, anorexia, nausea
§ Dehydration
o A lot of calcium is filtered at the kidney into the tubular fluid
• So when calcium levels are high in tubular fluid it interferes with water
reabsorption resulting in dehydration



Serum Inorganic Phosphate PO4-3

- 0.8-1.4 mmol/L
- Higher in children than adults

- Regulation of phosphate is less important than for calcium
o In the short term

- Not in long term
o Too high over long term
§ Soft tissue phosphate crystal deposition
o Too low over long term
§ Inadequate bone mineralisation
• Rickets

Calcium Homoeostasis
- We try to keep blood calcium very stable
o Is maintained by gut, kidney and bone

- Kidney
o Get some calcium losses every day
o <2% than calcium filtered load
o This obligatory loss is 150-200mg a day
§ Goes up after menopause in women

- Gut
o Can make up the loss in the kidneys by ingesting calcium
o Not much calcium in foods however and we aren't very good at absorbing it

- Bone
- Structural requirement for calcium phosphate
o Deformities and fractures without
- Bone mineral is an alternative store of calcium
 o If calcium is too low in blood, we will raid the bone for calcium
§ Parathyroid hormone, vitamin D hormone, fibroblast growth
factor and calcitonin regulate this












Calcium Homeostasis Review

The Parathyroid Glands

Parathyroid Hormone
- Parathyroid hormone is released when the parathyroid glands sense a low calcium
concentration in extracellular fluid
o Sensed by a g protein coupled receptor
o Important in regulation of bone mineralisation
o The release of parathyroid hormone is suppressed by calcitriol and high
calcium levels








Vitamin D Sources
- Sunlight
o Need UVb so make vitamin D
§ Breaks the b ring
• Vitamin D is essentially a steroid
o With an open ring
o If you continue irradiating skin, you begin to break down vitamin D
§ So you can’t get vitamin D intoxicated by staying in sun too long

o Need roughly 15% of body surface exposed to 1/3 erythemal dose
§ Erythemal dose = sunlight that would cause faint redness
- Diet
o Fatty fish, meat, liver, eggs, fortified foods

Vitamin D Metabolism
- Vitamin D is absorbed into the bloodstream and is converted (mostly) in the liver
into 25-hydroxy Vitamin D

- 25(OH) vitamin D
o Longest half life
o The vitamin D that we measure to asses vit D status

- Converted into the active hormone in the kidney
o 25(OH) vit D --> 1,25(OH)2D = calcitriol
o This conversion is triggered by
§ Parathyroid hormone (low Ca2+)
§ Low phosphate
§ Growth and pregnancy



Who is at high risk of Vit D deficiency
• Dark skinned people
• Older people
o In residential car
o In hospital
• People who wear modest dress for cultural reasons
• Chronically ill individuals
o Not outside
• Infants of babies with low vit D
• Obese people
o Distributes into fat and doesn't get out
• People who are mostly indoors


Fibroblast Growth Factor 23
• Produced in bone by osteocytes
o And by benign tumors
• Cause a phosphate wasting condition

• Acts predominantly in the kidney
o Causes phosphate dumping in urine
o Suppresses calcitriol (1,25 D) production
o Increases calcitriol (1,25 D) degradation

• Production stimulated by
o Calcitriol
o Parathyroid hormone
o High phosphate levels

 • Excess FGF23
o Low phosphate
o Low Calcitriol
o Osteomalacia
• Rickets in children

Calcitonin
- Peptide
- Found in parafollicular cells of the thyroid gland
- Released by same hormones triggered when you eat
o Gastric hormones
o Pentagastrin
- Also released by increases in Ca2+





The Gut
• Calcium is not plentiful in food
o Best sources are dairy, soymilk, nuts and seeds
o We are bad at absorbing calcium
• Active absorption is increased by vit D hormone

• Cells are high in phosphate and so phosphate is plentiful in food

- Main function of the vitamin D hormone is to acquire calcium and phosphate from
food
o Calcium has been a problem since we moved from the calcium rich sea onto
land

Bone
- Dual function
1. Calcium and phosphate are absolutely required for bone mineral and strength
a. Bones don't collapse because of calcium and phosphate
b. Mineralise the bones

2. Acts as a store of calcium to top up blood calcium when low

Bone Turnover
• Constantly remodeling in adulthood
o Reabsorbed and reformed
• In response to changing stresses

• Can become brittle and develop micro cracks
o Osteocytes which are embedded in bone can sense mechanical forces and micro
cracks
 o Will send out signals which results in new bone resorbing cells being recruited
from the blood stream
o Osteoclasts
• Release acids and enzymes to eat away at bone
• Releasing calcium and phosphate into the blood
o Then osteoblasts are recruited
• Bone forming cells
§ Lay down a collagen based matrix
§ Doesn't become mineralised for 3 weeks
§ Process of mineral being laid down (calcium and phosphate) takes
place extracellularly
• Coordinated by osteoblasts and osteocytes






Bone Resorption
- Calcium and phosphate is released from bone during bone resorption
o Stimulated by parathyroid hormone and vitamin D hormone (calcitriol)
§ You need some vitamin D for parathyroid hormone to work
o Although vit D does stimulate bone resorption its main function is to absorb
calcium and phosphate from the diet
o Bone resorption is switched off if there is enough calcium and phosphate
being absorbed from diet
o Osteoclasts are directly inhibited by calcitonin

Kidney – Calcium and Phosphate
- Function is to modulate calcium and phosphate losses

- Calcium Filtration
o Calcium is filtered at the glomerulus
§ Depending on calcium blood concentration
• If high, then you get a high filtered load
o Means more calcium ending up in the urine
o Good process
o Vast majority of filtered calcium is reabsorbed
§ PTH increases calcium reabsorption

- Phosphate filtration
o Phosphate is also filtered at the glomerulus
§ Reabsorbed by phosphate transporters expressed in cells of the
tubule
• Transporters have a maximum capacity to reabsorb phosphate
• Depending on number of transporters you will have a different
reabsorption capacity
 § Low phosphate increases phosphate reabsorption
• More transporters at the apical membrane
§ Parathyroid hormone
• Increases vitamin D production (calcitriol)
• Reduces phosphate reabsorption
o Causes phosphate dumping in urine












Low Blood Calcium Cascade
1. Low blood calcium
2. Will increase release of parathyroid hormone
3. PTH will go to the kidney
a. Increasing production of vit D hormone
b. To conserve calcium
c. To dump phosphate
4. PTH will go to the gut
a. To increase calcium absorption
b. To increase phosphate absorption
5. PTH will also increase bone resorption
a. Releasing calcium and phosphate into the blood

- Overall
o Getting an increase in calcium into blood
§ Which is what we need
o Also getting an increase in phosphate into the blood
§ We don't need this

- Extra calcium being pumped into the blood will be conserved
- Extra phosphate in blood will be dumped into urine
o Kidney
o So phosphate levels remain unchanged



Low Blood Phosphate Cascade
1. Low blood phosphate
2. Stimulates 1,25-D (calcitriol) production in the kidney
3. Calcitriol hormone will decrease phosphate losses
4. Calcitriol will act on the gut
a. To increase calcium and phosphate absorption
5. Will have a small effect on bone
a. To increase resorption release of calcium and phosphate
6. There is no parathyroid hormone so calcium is not conserved
a. The extra calcium is filtered into urine
b. Blood calcium is unchanged but blood phosphate levels increase (back to normal)



Too much parathyroid hormone leads to
• Hypercalcemia

Too little parathyroid hormone leads to
• Hypocalcemia

High FGF23 leads to
• Low blood phosphate
• Rare

Low vitamin D leads to
• More PTH
• Maintains blood calcium at the expense of bone
• May see fall in phosphate

Extremely low vit D leads to
• Cant resorb bone
• Not enough calcium and phosphate to mineralise bones
o Rickets, fractures
o At risk of low blood phosphate and low blood calcium

Lecture #8 Thyroid Hormone
Human Thyroid
- Two lobes connected by an isthmus across the trachea

Parathyroid Glands (4 of them)
• Are behind the upper and lower poles of the thyroid gland
• Not part of the thyroid gland
• Made up of follicles that look like footballs
• Cells of the follicles make up the skin of the footballs
• In the centre is this proteinaceous material called colloid
 • Where the synthesis of thyroid hormone takes place

• Other major cell type is parafollicular cells
• Which produce calcitonin
• Mineral regulating hormone
• Inhibits bone resorption

Calcitonin
- Has an inhibitory effect on osteoclasts
- And a minor stimulatory effect on osteoblasts










Hormones of the Thyroid Gland
- Major hormone that is released from the thyroid gland is
o Thyroxine, T4
§ Has 4 iodine atoms
§ 1 is removed to make the active hormone
§ If the wrong iodine is taken off by an enzyme we get reserve T3 which
is inactive

- This is converted to the active hormone
o Triiodothyronine (T3)

 - Ring structures
o Come from tyrosine residues

- Relative activity
o T3 > T4 >>> reverse T3

Iodine and Thyroid Hormone
- Iodine is important for making thyroid hormone
o Humans and animals require iodine
o Iodine is most plentiful in the sea
§ Further from the sea the harder it is to get iodine in your diet
§ Problems in central Asia
§ Lack of iodine à Lack of thyroid hormone à poor CNS development
in babies

Active Uptake of Iodide at Thyroid Gland
- Active uptake of iodide at the thyroid gland cell
o One of the few cell types that actively takes up iodine

- Cell produces the enzymes and the protein that cause conversions to occur in the
colloid
o Convert Iodide + tyrosine into Thyroxine














Active Uptake of Iodide at Thyroid Gland (continued)
- Iodide is actively taken up by thyroid gland
o Energy requiring
§ Sodium pump
o The iodide traverses the follicular cell and is pushed out into the colloid with
peroxidase
§ Where there are large proteins called thyroglobulins
§ Part of the protein chain is tyrosine residues
§ Peroxidase causes iodine to be covalently bound to a tyrosine residue
• Protein chain contains mono-iodo tyrosine
 • Same tyrosine residue can get a 2nd iodine to make di-iodo
tyrosine















- Phagocytosis
o Cell engulfs some of the colloid
o Vesicle fuses with lysosome
o Proteins are split and the mono-diodo tyrosine, T3 and T4 are released
§ T3 and 4 are secreted
o Mono and di-odotyrosines are recycled
§ Available to colloid again













Regulation of Thyroid Hormone Concentrations
 - TRH released in Circadian rhythm
o Promoted by the cold in babies, not once you're
older
o TRH travels to anterior pituitary gland via portal of
capillaries

- TRH stimulates secretion of TSH in anterior pituitary
gland (BUT WONT increase size of pituitary gland)
o TSH = Thyrotropin
§ Binds to receptors on the thyroid gland
and increases the release and synthesis of
thyroid hormone (TH)
o TSH secretion for prolonged periods
§ Will see increase in size of thyroid gland

- Negative feedback of thyroid hormone
o NONE to thyroid gland
o Predominantly to anterior pituitary
o A little bit to hypothalamus

Thyroid Hormone Metabolism
- Majority of thyroid hormone that is released from the gland is in the form of T4
o Has to be converted into T3 or rT3
§ In liver, kidney, pituitary
§ Via deiodinases
o T3 and rT3 are converted into di-iodothyronines
§ Iodine split off
• Taken back up by thyroid gland

-
T4 --> T3 or rT3 is highly regulated
o Physiological
§ Decreased food intake as well as stress hormones inhibit
o Pathophysiological
§ Inhibited by burns, trauma, renal failure, infarct
o Via drugs
§ Inhibited by propylthioracil
§ Propranolol (beta blocker)
o Stress hormones inhibit
§ Glucocorticoids
Thyroid Hormone in Blood
 - Small molecules are filtered in renal glomerulus
o TH circulate in blood largely bound to a protein called thyroid binding
globulin
§ Made by liver
§ Rarely found in free state
o Binding heavily favours bound T4 and T3

- However, the small concentration of free TH is relevant as this is what gets into cells
o If we have a lack of thyroid binding globulin
§ Get more free TH
§ Hyperthyroidism

- However, this doesn't happen because
o The higher free hormone concentration is sensed by the pituitary and TSH is
then reduced
§ Reducing thyroid hormone secretion

- Levels of thyroid stimulating hormone in blood tell you whether someone is
hypothyroid or hyperthyroid
o Hypothyroid = lot of TSH
o Hyperthyroid = little TSH

Thyroid Hormone Mechanism of Action
 - Thyroid hormones have steroid like rings but they aren't steroids
o The protein receptor they bind to are part of the family of receptors that
respond to steroids
§ Receptor is intracellular
§ When the hormone binds get a change in conformation
• Other proteins attracted to the complex
• Goes to promoter regions on target genes and up or down
regulates transcription
o Takes a while to see change in cells
o In general thyroid hormones have relatively slow on off
effect as a result

Thyroid Hormone Effects
1. Calorigenic actions
a. To generate heat
b. Come about through an effect on intermediary metabolism
§ CHO fat and protein metabolism
§ Has an effect on growth and development?

2. Sympathomimetic effects
a. Facilitates actions of catecholamines (adrenalin and noradrenalin)

Calorigenic Actions
- Heat Producing: Uncouples Oxidative Phosphorylation à Heat

- Metabolism

Thyroid Hormone and Protein Synthesis



Sympathomimetic Effects
- Thyroid hormones increase the number of beta adrenergic receptors expressed on
cell surfaces
o Controversy as to whether there is a resulting effect on affinity

- Too high or too low TH
o Effects on sympathetic nervous system
o Can be treated with beta blockers

- Excess T3/T4
o Overly anxious
o Fine hand shakes
o Higher pulse
o Higher systolic pressure
o Lower diastolic pressure
o Peripheral vasodilation

- Immunoglobulin
o Acts like thyroid stimulating hormone (thyrotropin)
§ Has no off switch
§ No negative feedback
o Essentially continuous thyroid stimulating hormone injections







Hypothyroidism
 - The child hasn't grown and has mental retardation
o As a result of lack of thyroid hormone caused by insufficient iodine
- Fetus underwent impaired central nervous system development

Basal Metabolic Rate
• Measure during rest when energy at lowest level
• Increased by thyroid hormones

Body Mass Index
- Weight (kg) /height (m)2
- Excess TSH increases basal metabolic rate and decreases BMI
- Insufficient TSH decreases basal metabolic rate and increases BMI

Goitre
- Increased size of the thyroid gland
o Can have a goitre with varying levels of thyroid hormone
o Size doesn't tell you how much hormone

- Can have hyperthyroid because of
o Thyroid stimulating immunoglobulins
o Iodine deficiency
§ Can’t make enough TH
• Poor negative feedback à more TSH than necessary
• Increasing the number and size of thyroid gland cells
o Autoimmune attack on thyroid gland resulting in inflammation of the gland
§ Destroys the gland eventually
§ For a short time results in a larger gland

Lecture #9 Mechanics of Breathing
Respiration Overview

Consumption and Production of O2 and CO2
- Determined by spirometry

- Respiratory quotients for carbohydrates and fats

- If your diet was entirely glucose your RQ = 0.8
- If your diet was fat RQ = 0.7
- Average diet RQ = 0.8









- Blocked nose
o Majority of congestion is a result of upper airway not performing its normal
function
§ Normal function of mucous membrane in upper airways is to heat and
humidify air
§ Mucous membrane is highly vascular

- Filtering and cleaning
o Cilia in airways for
§ Move at the same time to move mucous to the back of the throat
o Various tonsils
§ Immune tissue which deal with airborne pathogens

Concha
• Bones in nose that increase surface area
• Covered by mucous membrane
o Extensive surface
• When have a cold you don't have this surface
o So no heating and humidifying of air

Soft Tissue and Mild Muscle Contraction
- Majority of airways is soft tissue
o Problem because tissue would flop shut every time you breath in
o Under normal circumstances all muscles of side of throat and tongue are in a
state of mild contraction
§ So that soft tissue is not floppy
§ When breath in the same signal which causes diaphragm to contract
tells these muscles to contract and so airway doesn't collapse
Pharynx and Larynx Functions
1) Airway Maintenance
a. Intrinsic tone of pharyngeal muscles and tongue
i. Upper airway dilator muscles remain slightly contracted to prevent
airway collapse
b. Reflexes
i. Cough
ii. Swallowing
• Tongue moves backwards
• Epiglottis covers trachea and food goes down esophagus

2. Pharynx Immune Defence

Airway Maintenance Compromise
- If unconscious
o Put them in coma position
§ On side with head facing down
§ Gravity assists in pulling tongue forward and removing any vomit

- Alcohol
o Decreases the tone of upper airway dilator muscles
o Snoring, vibration of uvula

- Suppressants
o Suppress upper airway reflexes
o Morphene heroin related agents, old fashion sleeping pills and new sleeping
pills

- Sleep
o Upper airway dilator muscles relax and go floppy
o Airway closes a bit
§ CO2 builds up
• They arouse
o Then sleep again
§ Bad for sleep
Trachea – Bronchiole Division
• Trachea divides into right and left main bronchus
o Which divides into may branches airways
• Then get a sac (alveolus) at end of each branch
§ Capillary network on end of each alveolus
• Site of gas exchange






Arteries and Veins: Oxygenated and Deoxygenated Blood
- Arteries and veins are NOT named so because of oxygenated blood or not
o Artery
§ Takes blood to an organ
o Vein takes blood away from an organ

- Pulmonary artery (right side of heart) pumps venous blood to the lungs (to the
organ)
o Contains low oxygenated blood with high CO2 concentration
o Blood is then oxygenated in lungs and travels out of the pulmonary vein to
the left side of the heart heart

Inspiration
- Diaphragm contraction
o Moves down
§ Increases chest volume
§ Increase lung volume
§ Decrease in pressure

- Now have a temperature gradient
o High pressure outside, low pressure inside
§ Air is drawn into the lungs

Expiration
- Diaphragm relaxes
o Moves up
§ Decreases chest volume
§ Decreases lung volume
§ Increase in pressure

- Now have a temperature gradient
o Low pressure outside, high pressure inside
o Air is expelled out of the lungs

Pressure
- 1 mmHg = 13.6 mm H2O

Pleura Prevention of Lung Collapse
- Lungs can’t collapse because there are in a closed system
o Lungs slide on the inside of the chest wall when they expand
o Lungs and inside of chest are lined by epithelial cells called pleura
§ Parietal (outer) and visceral (inner) pleura





Pressure Change with Breathing
- Just started to breath in
o Diaphragm moves down
§ Pleural pressure falls
§ Alveolar pressure falls (but not by as much)

- Expiration
o Diaphragm moves up
§ Pleural pressure and alveolar pressure increases

- Moving air in and out of lungs requires very little pressure change

- Generate about +/-1mm mercury pressure gradient between lungs and outside
when breathing out/in

Lunge Excess Capacity
- Very large
o Maximum inspiratory effort can generate 50mm of mercury
o Forced expiration can generate a gradient of 100mm of mercury









Diaphragm and Phrenic Nerve
- Unlike most structures whose nerves come from areas the spinal cord close to them
o The diaphragm's nerves come from the phrenic nerve which comes from way
up high in the spinal cord
§ Means that you can have damage to lower spinal cord and still be able
to breath
§ Evolutionary advantage


Muscles of Respiration
- Light Breathing
o Inspiration controlled by diaphragm contraction
§ Phrenic nerve
o Expiration controlled by relaxation of diaphragm

- Breathing when exercising (Heavy Breathing)
o Accessory muscles
§ Neck muscles contract
§ Shoulders move up
o Inspiration
§ External intercostal contract and pull rib cage upwards and forwards
§ Assisted by neck muscles
o Expiration
§ Internal intercostal contract and pull rib cage downwards and
backwards
• Assisted by abdominal muscles
o Generate high pressure gradients during exercise

Spirometry
• When person breathes in drum goes down and pen goes up
• Down line = breath out
• Up line = breath in

Spirometry Terminology
- Tidal volume = volume of air breathed in or out each breath
o Vt

- Vital capacity = maximum volume of air able to be exhaled after maximum inhalation
o VC

- Functional residual capacity
o The volume of air left in the lungs at the end of a normal breath (exhalation)

- Residual volume
o Volume of air left in lungs after maximal exhalation
o Can’t be read with normal spirometry

- Total lung capacity = Vital capacity + residual volume
o Affected by many things
o General size
§ Height

- Ethnicity
o African Americans have bigger frames than Asians

- Minute ventilation = Tidal volume X breaths per minute
o 500ml x 12 = 6,000 ml in males

Lecture #10 Work of Breathing
3 Major Components of Breathing Work
1. Compliance work
• 65%
2. Airways resistance work
• 30%
3. Moving tissues
• 5%
• Normally <1-3% of total energy (E)

Compliance
- Compliance = stretch ability
o Change in volume / change in pressure

- X axis = trans pulmonary pressure
o Pressure created by diaphragm as it moves down and expands the chest

- Y axis = lung volume

- Not a linear relationship
o Compliance is the tangent to the line graphed

- Easy to take 1st breath in
o Then gets harder to take 2nd 3rd 4th … breaths

The Lungs Resist Stretching
- Tissue expansion (minor component)
o The lung acts like a pair of balloons in the chest cavity
§ They resist stretch due to elastic recoil
o Mostly when the lung expands the fibres change their orientation to one
another rather than getting longer
§ Only a small component of stretch resistance

- Surface tension (major component)
o Surface tension is what causes lungs to collapse
o Fluid lined sac with gas mixture in centre
§ Fluid air interface creates surface tension because water attracted to
one another by H bonds and they resist being pulled apart
o To reduce surface tension, you add a chemical (surfactant) which gets
between water molecules and reduces attraction

Lung Surfactant
- Lung surfactant is a detergent which reduces surface tension
o Water soluble protein with phospholipid
- Sits in between water molecules at lining fluid of alveolus and reduces surface
tension
o Means we have a thinner skin to our balloon (lungs) and it takes less energy
to expand the balloon (lung)
- Protein-Phospholipid
- From alveolar Type 2 cells
- Decrease surface tension to allow lungs to expand with normal muscle activity

Causes of Increased Compliance Work
1. Lack of surfactant

2. Scar tissue in lungs (means you can’t expand)
a. Typical after inhalation of matter which cannot be removed easily
i. Coal dust
ii. Asbestos
§ Fibres are surrounded by scar tissue, so can’t expand

0. Where chest wall expansion is limited
a. Scoliosis
i. Deformity of spine
1. Limiting expansion of lungs
b. Tight bandages

1. High long volumes
a. 1st breath in easy, 5th breath in hard



Fibrosis
- Occurs when scar tissue limits the ability of an individual to expand their lungs

Airway Resistance

Air is a "fluid" which flows through the airways
• We have a physical setup which has resistance to flow
• Gas flow is a function of the pressure gradient from one end to the other over
resistance to flow

Laminar flow
• Parallel airflow in same direction
• Possible to demonstrate that resistance is proportional to 1/r^4
o ^4 indicate a big effect
• Small changes in diameter have a large effect on resistance to laminar flow
Laminar Flow and Airway Size
- Someone takes in a puff of coloured air at the top (trachea)
o Generation 1 (trachea)
§ Big airway but mall cross sectional area
o Generation 3
§ 8 Bronchi
• More narrow
• Cross sectional area similar to trachea
- Generation 16
o Airways are tiny
§ But there are thousands
• So cross sectional area is massive
• Initial coloured air is dispersed over thousands of airways and
a massive area

• So small peripheral airways are where you get lamina flow because the small packet of
air is spread across such a large cross sectional area

Large Airways
- Turbulent airflow
- High resistance

Small Airways
- High cross sectional area
- Lamina flow
- Low resistance
- Reactive smooth muscle in airway walls
o Has a degree of contraction
§ Heart beats faster
• Muscles relax
o Further reduce airway resistance as they have gotten
larger
Airway Resistance is Affected By
1. Structure of the Lungs
• Resistance is negatively correlated with cross sectional area
♦ Greater in bronchus
♦ Lower in bronchioles
2. Mechanical Factors
• Airway resistance is greater in expiration vs inspiration
♦ Inspiration
⇒ Expanding spongy lung tissue pulls airways apart
⇒ Decreased airway resistance
♦ Inspiration
⇒ Squeeze down on lungs, airways move together
⇒ Increase airway resistance
• Airway resistance is lower at high long volumes
⇒ Airways are held open already
⇒ So lower resistance
3. Smooth Muscle Tone in Small Airways
♦ Sympathetic input
⇒ Beta adrenergic agonists --> relaxation of airways
♦ Parasympathetic input
⇒ Constrict airways
♦ Asthma
⇒ Highly responsive airways
4. Local reflexes
• If you have an area of lung with low CO2 (poor blood flow)
♦ Sensed by cells in lung
⇒ Signals to spine
⇒ Through synaptic junction signals sent back to nerves that effect
smooth muscle contraction (reducing airflow)
⇒ The airways to that part of the lung do go down in size reducing
airflow to this part of the lung (reducing airflow)
⇒ You only want gas exchange where there is good airflow and blood
flow
⇒ Helpful reflex

Emphysema
• Lung tissue destruction
o Reduced ability for gas exchange
• Floppy airways
o Caused by lack of support from lung tissue (due to its loss)
• Floppy airways will close during expiration
o Squeezing lungs, airways have nothing to maintain them
o Can’t get all the air out
o Air trapping
o Large residual volumes
o Can’t maintain normal oxygen and co2 levels



Spirometry in Normal and Obstructed Airways

X axis = time

Y axis = litres

On left
• FVC = 5 litres
• FEV = 4 litres
o FEV/FVC = 0.8 so normal

On right
• FVC = 3.1 litres
• FEV = 1.3 litres
o FEV/FVC = 0.42 so has airways resistance






Peak Flow Rate

- For two identical subjects
o The one with normal airways will have higher peak rate than the individual
with damaged airways

Expiration Peak Flow
- Occurs almost immediately

- Y axis = air flow of expired air
o Peak flow occurs immediately
§ 400L/min
§ Doesn't last long
- Then as airways compress during forced expiration you see an almost linear
decrease in flow rate until you've exhaled to residual volumes
o You can use predicted normal values for respiratory flow








Normal vs Damaged vs Restrictive

- If you can’t expand your lungs from deformities or scarring you have low vital
capacity

- If it’s pure restriction
o Airways perfectly normal (e.g. tight bandages)

- Restrictive lung disease (fibrosis and kyphosis)
o FVC will be low
o FEV1 will be lower
§ BUT FEV1/FVC will still be > 0.8 so you can’t tell there is nothing
wrong with the airways, this person just has restricted ability to take
air in

- Middle diagram indicates damaged airways
o Not just restrictive lung disease
o FEV: FVC ratio very low

Overall Work of Breathing
1. Compliance work is greatest at high lung volumes
2. Airways resistance is greatest at rapid airflow rates






Lecture #11 Gas Exchange
Partial Pressure of a Gas
- Regardless of the gas

- Partial pressure of multiple gasses gives the total pressure of a gas mixture
o Each gas will exert partial pressure
o If gas A contributes 50% of total number of molecules, then it contributes
50% of a mixtures pressure

§ 760mmHg is Pressure of Air
§ 21% of air is Oxygen
§ Oxygen pressure is therefor 160mmHg




Henry’s Law
- In the body we have partial pressure exerted by gases which are dissolved in liquid
- Henry's law
o Tells you that the concentration of dissolved gas = the partial pressure of
the gas x the solubility index of the gas

o Refers to concentration of dissolved gas
§ Directly proportional to partial pressure of the gas

Diffusion
- From areas of higher partial pressure to lower partial pressure
o Concept allows us to follow a gas from an air mixture right through to the
tissues
- Important that partial pressure of the gas is related to the concentration of
DISSOLVED gas
o Not the total concentration of gas in the liquid
§ Since gas may be combined with other agents, such as haemoglobin

Composition of Air Once Inhaled
• When inhaled, air gets water vapor added to it
o Slightly dilutes the other gases
• Partial pressure of oxygen falls as it moves through the system towards the tissue
• Partial pressure of oxygen falls as it moves from tissue to an open system
o Highest in tissues
o Lowest in open system
• Almost negligible

- Expired air consists as alveolar gas and inspired gas
o Arterial oxygen is similar to alveolar oxygen
§ Slight drop because some blood goes straight back to left side of heart
without going back to lungs


Diffusion of Gas
 - Gas molecules diffuse on the basis of concentration of dissolved gas molecules
o I.e. partial pressure

- The rate of diffusion of gases across biological membrane will be proportional to

Respiratory Membrane
- Alveolar lining cells with protrusions making up the wall
o Surfactant secreting cells

- On the other side of the alveolar cell cytoplasm is a thin basement membrane
o The capillary with single endothelial cell and its cytoplasm

- Gas needs to diffuse across thin cytoplasm and thin respiratory membrane

- Fluid buildup, infection, scar tissue will all increase the thickness of the respiratory
membrane
o Reducing the efficiency of gas exchange considerably

Overall Diffusion Capacity
- Highly dependent on how well ventilation (airflow) and diffusion (blood flow) are
matched
- Airflow and blood flow to the lungs are not evenly distributed under normal
circumstances at rest due to the effects of gravity
- Exercise
o Improves the evenness of blood flow and airflow
o Thus improves gas transfer
- Pulmonary pathologies
o Result in uneven air and blood flow and thus cause poorer transfer of gases

Alveolar Ventilation



- Not all of the air that you breathe in goes to the alveoli
o Air in airways is not taking part in gas exchange
o Anatomical dead space = spaces containing air which is not involved in gas
exchange = volume of air in airways

- Anatomical dead space in mls is roughly equivalent to body weight in pounds
o 2.2 pounds is 1 kg
o 70kg person has dead space around 150ml

- Physiological dead space
o Air that goes to alveoli which do not have an optimal blood flow
o So some airflow is wasted





- Air to alveoli = Tidal volume - dead space
- Alveolar ventilation = (Tidal volume - dead space) x breaths per minute
o = roughly 4.2L/min
- Extra tubing --> increased effective dead space
- Lung pathology (airflow but no blood flow) --> increased effective dead space

Pulmonary Artery/Vein Gas Exchange

 - Pulmonary artery brings blood from right side of the heart to the lungs
(deoxygenated)
o Gas exchange takes place
o Capillaries collect blood again
o Pulmonary vein
§ Takes blood away from lungs via the left side of heart
§ Arterial blood
• High oxygen and low in CO2

Pulmonary Circulation
• Although total volume of the lung circulation is lower than the systemic circulation
o The flow rate in the pulmonary circulation needs to be at the same rate as blood
flow rate in the systemic circulation

• Blood pressure in pulmonary circulation is much lower than the blood in the systemic
circulation
o Pulmonary hypertension is very dangerous and means >15mmHg in pulmonary
blood pressure

Pressure in Different Lung Vessels

 - Pumping from the right side (less muscle than left ) results in systolic values of 25
and diastolic values of 8
o Drops when you get to pulmonary capillaries

- Mean pressure stays below 30 even when exercising

Maintaining Low Blood Pressure with High Flow Rate
• The capillaries in the pulmonary circulation have capacity for considerable expansion
• Can get opening up of previously closed vessels during exercise (recruitment)
• And distention, further widening of vessels

Vessel Openings at Rest
- Sitting upright (pressure of gravity)
o Zone 1 top of lungs, apex
o Zone 2 Heart
o Zone 3 at base of lungs and heart



- Blood vessels at base of lungs are always open

- At top of lungs pressure in alveoli is higher than pressure in vessels, due to gravity
o So blood vessels are closed

- In the middle you have sometimes open and sometimes closed

- When the right side beats more strongly during exercise you can increase pressure
within these vessels so they exceed pressure in alveoli and blood vessels are always
open

Shunts
- Shunts = blood returning to left side of heart without being oxygenated
o Hasn't gone to the lungs
o Anatomical reason
§ About 2% which goes to left atrium goes directly to the heart from
central chest tissues
§ This accounts for slight drop in partial pressure of oxygen from alveoli
and arterial blood overall
o Physiological reason
§ Blood coming from areas of lung where blood flow is greater than
airflow
• So blood not used in gas exchange


Factors Disturbing Ventilation/Perfusion Ratio
- 1 and 2 are gravity effects, 3 is a pathological effect

1. Non uniform pulmonary blood flow
2. Non uniform ventilation
3. Pathological
a. Localised variations in airflow or blood flow due to infection, lung tissue
damage etc.

 - Effects of Gravity
o At normal breathing volumes
§ Alveolar ventilation at bases > alveolar ventilation at apices
§ Blood flow at bases > blood flow at apices

Problem with Non-Uniform Airflow and Blood Flow
- Airflow and blood flow can be non-uniform
o If this were really not matched
§ Car accident
• Right lung collapsed
o So no air flow
• Blood clot to left lung

- Would have all blood going to collapsed lung
o All oxygen going to lung with no blood flow
o Would be dead very quickly

- Collapsed lung could be life threatening because you have a limited capacity to carry
oxygen
o Usually isnt, why?
§ Protective reflexes which match blood and air flow


Protective Reflexes Which Match Ventilation with Perfusion
1. Hypoxic pulmonary vasoconstriction
- In an area of the lung which has low oxygen, you get blood vessel constriction
- If blood flow is greater than airflow at a part of the lung (low airflow)
o Oxygen partial pressure will fall
§ Reduced airflow
o This is sensed and creates a neural response which initiates
vasoconstriction
§ Which reduces the blood flow

2. Partial pressure of CO2 effects control of airway smooth muscles
- If airflow is greater than blood flow
o Partial pressure of CO2 falls in lung tissue
§ Broncho constriction is initiated
§ Air flow is reduced


Diffusing Capacity
- “The volume of gas that diffuses through respiratory membrane per minute for
each mmHg of gas partial pressure difference”
- Increases with
o Exercise and capillary diameter
§ Because you have better matching of blood (perfusion) and
airflow (ventilation)


Lecture #12 Gas Transport
Transport of O2 in Blood
- Gas exchange and diffusion of gases is determined by partial pressure gradients
which are related to concentration of dissolved gas

- Only a very small % of oxygen in the blood is in dissolved form
- Bulk is combined with hemoglobin

Haemoglobin
- Hemoglobin is a complex peptide
o 2 alpha chains
o 2 beta chains

- At the centre of each haemoglobin peptides (there are 4) is a porphyrin
o 4 porphyrins in the middle

Porphyrin Structure
- Fe2+ ion at the centre
o Ion containing the heme group
2+
- Fe
o Is what carries/binds to oxygen
- The combination of oxygen gas with the Fe2+ is a fully reversible process
o "Oxygenation"
§ Not oxidation
• Oxidation would convert Fe2+ to Fe3+ (rust)

Oxygen Binding to Fe2+
- Process of oxygen binding to Fe2+ ion is complex
o Oxygen carried on haemoglobin does not increase linearly with oxygen
partial pressure

- X axis = oxygen partial pressure
 - Y axis = percent saturation

- Shape of haemoglobin affects how readily oxygen can access Fe2+
o When oxygen partial pressures (levels) are low (and other factors) there is a
steep increase in oxygen being carried on haemoglobin
o This flattens out when we get to higher oxygen partial pressures
§ Saturation

- Physically dissolved oxygen does increase linearly with partial pressure of oxygen

- Assumptions
o Each gram of haemoglobin binds 1.34ml Oxygen (not true for all
haemoglobin)
o Each 100ml of blood has 15g haemoglobin

Implications
1. Blood is nearly fully oxygenated from any partial pressure of oxygen > 65mmHg
a. Close to 100% saturation doesn't mean PO2 is close to 100
2. As blood flows past capillaries in tissues, small drops in local partial pressure lead to
large unloading of oxygen
a. If PO2 goes from 40-->20mmHg then a large amount of oxygen is released from
haemoglobin


Changes from Standard Oxygen Fe2+ Binding Graph
- Polycythemia
o For a given partial pressure of oxygen, we have a greater level of oxygen
binding to haemoglobin
o Saturation reached at higher partial pressure

- Anemia
o For a given partial pressure of oxygen, we have a lower level of oxygen
binding to haemoglobin
o Saturation reached at lower partial pressure


Breathing Oxygen ay high Partial Pressures
- If you are breathing oxygen at higher partial pressures
o E.g. in scuba gear
§ You can increase the total amount of oxygen in blood
§ Nearly all in the form of dissolved oxygen
§ 100% oxygen will increase dissolved oxygen in blood

- Too much oxygen in blood
o Overstimulate oxygen reactive tissues
o Overwhelm these tissues ---> oxygen poisoning
§ E.g. Retina damage in children

Factors Affecting O2 Binding to Haemoglobin
- Affinity decreased by
1. Increased PCO2
2. Decreased pH acidosis
3. Increased temperature
4. Increased 2,3 diphosphoglycerate

- A decreased affinity shifts oxygen haemoglobin curve to right
o Means easier unloading of oxygen

Exercising Muscle
• More CO2
• Glycolysis --> drop pH
• Increase temperature
• Increase in 2,3 di-phosphoglycerate (glycolysis byproduct)

All lead to easier association of oxygen

Oxygen Content and Saturation in Tissues and Lungs

 - Right curve
o Higher CO2
o More acidotic
o Higher temperature
o Increased 2,3 diphosphoglycerate

- Left curve
o CO2 is lower
o Less acidic
o Lower temperature
o Little change in 2,3 diphosphoglycerate

- Biggest difference in these curves is at oxygen partial pressures which prevail in
tissues
o As a result, the oxygen carried on haemoglobin at any partial pressure is less
under the conditions of the tissues
- As the blood goes through a muscle, partial pressure of oxygen drops (more CO2,
more acidic), carrying capacity also drops
o Get massive oxygen unload

- Doesn't affect loading


Bohr Effect
- O2 carrying capacity of Haemoglobin at a particular PO2 is decreased by an increase
in PCO2
o Get easier unloading of O2 in tissues
o Get easier unloading of O2 in lungs

Carbon Monoxide
- Colourless and odourless, no irritant, no cyanosis (blue colour of desaturated
haemoglobin)
o Very dangerous gas

- CO combines with haemoglobin at the oxygen binding site
o CO affinity for haemoglobin is 200x that of oxygen

- Only require a very small increase in carbon monoxide for a massive increase in CO
haemoglobin binding
o Very dangerous

Oxygen Transport Summary


CO2 Transport in Blood
- CO2 much more soluble in water and lipid membranes than oxygen
o Making it easier to dissolve

Carbamino-Haemoglobin Formation

- CO2 diffuses across membrane readily
o Combines with haemoglobin to form carbamino- hemoglobin
§ Reversible process
o Binds to hemoglobin at terminal ends of polypeptide chains
§ Not a heme group in site
§ Not at same site as oxygen
• At end of polypeptide chain
- Effect of oxygen
o Forward reaction is facilitated by lower oxygen concentration
- Not facilitated by any enzyme
o So reaction is relatively slow
 - Not as important in carrying CO2 as the bicarbonate process

CO2 Diffusing Across Red Cell Membrane

• When bubbled through water get reversible reaction to form carbonic acid
• RBC has enzyme called carbonic anhydrase
o Presence of enzyme facilitates reaction in either direction
o Agnostic enzyme (either way)
o Rapid carbonic acid production as CO2 diffuses from tissues
• Due to carbonic anhydrase

• If nothing else happened, you would reach an equilibrium where the reverse reaction
would occur just as fast as the forward reaction

o 2 other things which allow this reaction to generate more CO2

1. Carbonic acid dissociates into carbonate and hydrogen ions
a. H ion taken out of free circulation by being buffered on haemoglobin
+
• Decrease H concentration
• Helps facilitate the forward reaction
o Happens to be favoured when haemoglobin is not
carrying as much oxygen
§ More appropriate shape for binding

2. Deoxygenated haemoglobin has a greater carrying capacity for carbon dioxide
 a. Haldane effect

- Bicarbonate diffuses out of the red blood cell
o We have a problem because we are losing a negative charge
o To maintain electronic neutrality a chloride ion enters RBC
§ Cl- ions tend to bind to water
• So takes a water molecule with it
o So RBC’s in veinous side of circulation have more CL-
ions and are slightly larger than RBC's in the arterial
side of the circulation

Haldane Effect

 - X axis = partial pressure CO2
- Y axis = mls CO2 per 100ml blood

- Nearly linear

- Thick line describes situation when blood in capillaries
o Partial pressure oxygen = 100mmHg

- Dotted line describes situation when blood in tissue capillaries
o Partial pressure of oxygen = 40mmHg
o When blood goes through tissue capillaries
§ Partial pressure CO2 goes up
§ Oxygen given off, so
• There is a lot more CO2 which can be carried by blood in these
circumstances

- The carrying capacity for CO2 in blood is low when partial pressure oxygen is high
o In lungs
§ When carrying capacity is low more CO2 can be unloaded

- The carrying capacity for CO2 in blood is high when partial pressure oxygen is low
o In tissues
§ Carrying capacity for CO2 is high when oxygen is low
§ Easier loading




CO2 and O2 Content in Blood vs Partial Pressure
1. Blood can carry a lot more CO2 than O2 at any partial pressure
a. Blood is thus a reasonable store of CO2
2. The relationship between CO2 partial pressure and CO2 content in blood is roughly
linear over physiological range
3. For oxygen there is a steep initial increase and then a plateau

- 1 lung collapsed
- Blood went to that lung would be carrying low levels of oxygen
o No fresh oxygen coming in
- Blood leaving good lung would not be carrying significantly more oxygen
o Blood coming back to heart will have lower levels
o Despite higher partial pressure of oxygen in that lung

- For CO2
o Collapsed lung will have venous levels of CO2
o Blood going to good lung which is ventilating more
§ Will be getting rid of CO2 and blood will have less CO2 than it
would normally carry
 o Without hypoxic-pulmonary-vasoconstriction
§ Arterial Slightly higher CO2 but way lower Oxygen

Buffers

- pH = -log[H+]










Biological Buffers
- Proteins can accept or donate a hydrogen ion at the C terminal end or the terminal
end

- Histidine has a ring structure
 o Which can accept a hydrogen ion or donate a hydrogen ion (in a reversible
reaction)
o Effect of partial pressure on haemoglobin shape allows you to show that
when haemoglobin is carrying less oxygen it is a better buffer

CO2 à Carbonic Acid à Bicarbonate

- CO2 Dissolves in water to form carbonic acid
§ Dissociates into hydrogen ion and bicarbonate

- Convert to Henderson-Hasslebach
o Concentration of CO2 is proportional to its partial pressure
- pK1 = 6.1
o Buffers work best around their pK
§ Less than 6.1 is not useful as most people operate at around 7.2
Isohydric Principle
• In a closed system all buffer systems are in equilibrium with each other
• Can describe pH of the body as a constant that is affected by
o Kidney function
• Altering bicarbonate
o Lung function
• Altering PCO2

Respiratory Disturbances
- Problems with lung function may cause changes in pH
1) Reduced ventilation
2) CO2 build up
 3) Decrease pH (more acidic)
4) Respiratory acidosis
5) Bicarbonate retention by the kidney
6) Higher bicarbonate levels in blood
7) Tends to return pH to normal (renal compensation) in a few days

Respiratory System pH Compensation
- Respiratory system can compensate for other causes of pH changes
o Over production of lactic acid
o Over production of ketones
o Losses of bicarbonate from severe vomiting of intestinal contents, severe
diarrhoea

- Response is like someone injecting acid (H+)
o Drop in pH
o Small increase in ventilation
o Reduced CO2 in blood
o Tends to return pH to near normal



CO2 Transport Summary

Lecture #13 Control of Ventilation

Respiratory centre
- Respiratory centre is in the midbrain
- Integrator which receives inputs from chemoreceptors, other receptors and higher
centres and then provides outputs to respiratory muscles and muscles of upper
airway

- Inputs
o Chemoreceptors, other receptors, higher centres

- Outputs
o Diaphragm, muscles of upper airways (to create airway contraction during
inspiration to avoid collapse)

Regulation of Ventilation


Many factors effect respiration
• Brainstem and pons contain various nuclei which work together to control ventilation
• Receive a series of inputs from receptors
• Then provide output to
o Muscles of respiration
• which effect rate and depth of respiration
o Smooth muscle airways
• Constriction/dilation
o Muscles of upper airways
• Especially during inspiration





Major factor which controls breathing
• Speaking
o Take a breath when it is suitable
o Can’t keep talking forever, eventually we need to inspire
o Can hold your breath for a certain amount of time (obviously not indefinitely)
• CO2 rises
§ Acidic build up
• Oxygen drops
§ More sensitive to higher CO2
• Voluntary hyperventilation
o Low CO2 causes cerebal vasoconstriction
• Fainting

Why does breathing rate increase with exercise?
- Obvious answer
o Higher oxygen demand
o Producing more CO2
- However, this is not the most important reason



Most important reason for higher breathing rate when exercise
• At the start of exercise
o Alveolar ventilation rises
• At this point there is no higher CO2 or oxygen demand at this point
• If anything there is a drop In CO2
• Eventually alveolar ventilation falls before rising again
• So right at the start of exercise the motor cortex is sending signals to
o The muscles of the feet to move on the treadmill
o The respiratory centre to increase ventilation in anticipation of the changes and
demands that are likely
• When the treadmill stops alveolar ventilation stops
o CO2 goes up
• With relatively mild exercise motor cortex has important effect on breathing
• In longer exercise buildup of CO2 has a bigger effect
Chemoreceptors
- 2 sets of chemoreceptors
o Peripheral and central

- Peripheral
o Carotid bodies
o Respond to changes in
§ Partial pressure of CO2
§ pH
§ Partial pressure of oxygen
§ Blood pressure

- Central chemoreceptors
o Located in brainstem near 3rd ventricle, behind blood brain barrier
o Bathed in CSF
o Near respiratory centre
o Respond to
§ Changes in partial pressure of CO2 only
• P(CO2) in the cerebral spinal fluid
 § Partial pressure of CO2 and partial pressure of CO2 in CSF are roughly
the same

For Partial Pressure of CO2, Changes are Sensed By


- CO2 has a major effect on ventilation
o If you remove the peripheral chemoreceptors you take away 20% ventilatory
response to high CO2

- Peripheral receptors responsible for rapid response to CO2

- Central receptors are much more powerful
o 80% of changes are due to central chemoreceptors
§ However, they are slower to respond than the peripheral receptors

- Neural cells in chemoreceptors sense the change in hydrogen ion concentration

- Arterial CO2 on x axis
o Can see that an increase in CO2 increases ventilation
o A decrease in CO2 decreases ventilation










Slope of Relationship Between PCO2 and Ventilation
- Many things affect the slope of relationship between ventilation and CO2




• C = Increase in sensitivity
o Low partial pressure of CO2
• Hypoxia
• B = Decrease in sensitivity
o Sleep
o Respiratory depressants
• Chemical depressants
§ Alcohol
§ Sleeping pills
§ Anaesthetic gases
§ Heroin, morphine, opium

• Gender and ethnic origin also effect the slope

• Respiratory depression decreases tone of upper respiratory dilator muscles
• Leads to airway floppiness











Ventilatory Response to CO2
- CO2 is more straightforward than oxygen
o Increase partial pressure increase ventilation
 § Up to a point

- Too high CO2 acts as a respiratory depressant itself

- Tolerance occurs
o Constant exposure to high CO2
§ Arterial CO2 will be higher but ventilation will eventually fall
§ Decrease CO2 partial pressure
§ Decreases ventilation

Tolerance to Changes in PCO2
- Response comes about due to central chemoreceptors
o Close to CSF within blood brain barrier
§ Like a closed system
§ Acts like a small kidney
§ Cells lining and secreting the CSF can act to adjust pH

- Arterial CO2 goes up after constant exposure to higher CO2
o Hydrogen ion concentration is sensed

- But after a few days the cells lining the 3rd ventricle will pump out bicarbonate
into the CSF
o Pushes reaction back to left
o H ion concentration falls
o Less stimulus to promote ventilation
§ Ventilation falls

- After another few days the kidneys kick in to retain bicarbonate in the body
o Again pushes reaction to left
o H+ concentration falls
§ Ventilation falls
§ pH returns very close to normal
§ No longer any trigger to increase ventilation
• Thus causing tolerance






Oxygen Response via Carotid Bodies (Peripheral Chemoreceptors)
• Small collections of neural tissue
o Divides into 2 from the common carotid artery

• Bodies get an enormous amount of blood flow
o 2L/100g/min directly from heart
o Flow rate is so fast that there is no time for oxygen to dissociate from
haemoglobin
o So neural cells are responding to dissolved oxygen
• To the partial pressure of oxygen
• Not to oxygen content (oxygen on haemoglobin)

• Consequences of responding to dissolved oxygen
o Don't see much of an increase in ventilation in someone with anemia
• Low haemoglobin doesn't affect response to dissolved oxygen
o Also don't start increasing breathing in CO poisoning even though oxygen binding
sites on haemoglobin are occupied
• Not affecting dissolved oxygen (Oxygen partial pressure)
• Empirically you don't get a change in ventilation under these circumstances

• You DO get a ventilationary response if blood flow decreases or blood pressure
decreases
o E.g. Myocardial infarct

• Chemicals which interrupt oxidative phosphorylation
o Cyanide blocks oxidative phosphorylation
• People with cyanide poisoning will undergo a period of increased
ventilation

Total Ventilation vs Alveolar O2
• There are 3 curves
o Difference depends on alveolar or arterial CO3
• High CO2
o You respond to small drops in oxygen
• Common in a confined space or for a
blockage in airway
• CO2 up whilst oxygen going down
• Normal CO2
o
• Low CO2
o Don't get an increase in ventilation until
oxygen drops to about 65-60
o Very brisk response

- All curves
o Increase ventilation at low oxygen, flatten
off at high oxygen
Response to Hypoxia (low O2)
1) If CO2 stayed in normal range
a. A drop in CO2 doesn't stimulate ventilation until PO2 falls to 60mmHg
 b. E.g. Going up a mountain
i. Low oxygen increases ventilation
ii. Increase ventilation results in CO2 falling

2) If PCO2 is high, sensitivity to hypoxia is increased

3) High oxygen does not inhibit ventilation

4) Tolerance does not occur
a. Don't become tolerant to low oxygen
b. It will stimulate your ventilation but you won’t become tolerant

pH
- Mainly sensed by peripheral chemoreceptors
o CO2 gets across the blood brain barrier well but hydrogen ion does not
§ So you are left with peripheral chemoreceptors
§ Which have a relatively limited ability to affect ventilation

- In particular, a decrease in pH tends to increase ventilation
o Mild response compared to changes in ventilation with changes in CO2


Acidosis
- People with acidosis typically present with an increase in ventilation
o Blows off some CO2 and helps to return pH almost to normal

Visceral receptors
- Visceral reflexes affect ventilation

• Cough and sneeze
o We use breathing to protect the airway

• Vomiting and defecation
o Contract
o Chest in fixed position
• Contract abdominal muscles to get expulsion of stomach and intestinal
contents or expulsion in defecation

• Stretch receptors in lung
o Hering-Breuer reflex
• Big breath in
• Activate stretch receptors in lung which send signals via the vagus to the
respiratory centre to stop inspiration
o Prevent over inflation of lung in babies
Outputs of Respiratory Centre


- Outputs of the respiratory centre go to
o The muscles of respiration rate and depth
o Smooth muscle airways
o Muscles of the upper airways
§ Especially during inspiration

Airway Tissue Composition and Consequence
- Lots of soft tissue and muscle which needs to be contracted
o When the pressure in the column of air drops during inspiration we need the
muscles to be tensed in order to prevent airway collapse
§ E.g. Sleep apnea
- When you swallow tongue rolls back pushing epiglottis over entrance to trachea to
prevent inhalation of food

Cough and Sneeze Reflexes

Cough and Sneeze Reflexes (continued)

 - Important for protecting the airway from obstruction mostly but also from noxious
chemicals (sneeze reflex)
o Have a sensory input
o Have a centre which integrate these inputs and generate an output

Sneeze reflex
- Generated by sensory endings in nose and upper pharynx
o Input goes via cranial nerve 5 to the brainstem
o Triggers deep inspiration followed by a forced expiration
o Breath air out quickly (not as fast as cough)
§ More air comes out your mouth than nose

Cough reflex
• Sensory input which goes to the brain is sensed by sensory endings in the wall of the
extra pulmonary respiratory tract
o Trachea upwards
o Senses foreign matter or excess mucous
• Triggers signals sent to the brain via vagus
§ This input triggers a deep inspiration
§ And then a moment where you are trying to expire forcefully but your
vocal cords are closed
§ Sudden glottic opening
• Very rapid expulsion of air through mouth (cough)
Flaw in the system
- If you completely block the airway with a solid you cannot take the deep inspiration
and so you can’t cough
- Under these circumstances
o Heimlich maneuver
§ Chest thrust from behind
• Trying to get some air expelled to mimic a cough
• Weak cough, not that effective, generally causes broken
ribs
o Chest thrust
§ Lean over a chair
§ Push yourself over it
• Use gravity to squeeze down on the lungs and expel the object

Emergency tracheostomy
- Cut through skin
- Insert knife between tracheal rings
- Low down away from voice box







Lecture #14 introduction to Respiration Practical

- Respiratory Quotient
o Eating an average diet
§ 0.8
§ Approximately the same amount of CO2 produced as oxygen is
consumed
o All fat = 0.7
o Only carbs = 0.1


Alveolar Gas Equations

- To measure alveolar gas

o You sample the end tidal volume
o What has been deepest in the body
- PiO2 = Inspired oxygen partial pressure
- PaO2
- PB = Barometric pressure
Alveolar Oxygen Under Normal Conditions

- If inspired oxygen goes up
o Alveolar oxygen will go up

- If alveolar ventilation goes down
o Taking in less inspired oxygen
§ Alveolar oxygen falls

- Hyperventilation
o Alveolar ventilation goes up
§ Alveolar oxygen will go up
• Highest theoretical value = PiO2

- Metabolic consumption goes up VO2
o Alveolar oxygen goes down












Alveolar CO2 Under Steady State Conditions

Alveolar Gas Composition
- Measure
o Basal values for
§ Alveolar oxygen and CO2
§ Oxygen saturation
o Breath hold
o Hyperventilation
o Hyperventilation then breath hold
o Breathing pure oxygen
- For each of
o PAO2
o PACO2
o O2 Saturation
o Time of breath hold

Oxygen Partial Pressure vs CO2 Partial Pressure
- Oxygen partial pressures may change considerably more than CO2 partial pressures

- Asphyxia
o Sensed by carotid body rapidly increases respiratory effort

- Can store very little additional oxygen in the blood
- Can store a great deal more oxygen in the lungs

- When occlusion occurs with additional oxygen provided
o Respiratory rate will increase because PCO2 increases
o But blood remains oxygenated for a much longer period of time



CO2 in blood
• Mainly carried as bicarbonate
• Large carrying capacity
o Much much larger than carrying capacity for oxygen

Hyperventilation
• The PCO2 in blood is very low
o Powerfully inhibits carotid body
• Only slightly more oxygen
• Won't start breathing again until PCO2 increases to normal
o Partial pressure of oxygen falls very low before we have enough CO2 to
initiate breathing
o Dangerous

Spirometry

- Various predictions for males and females
o FEV1/VC
§ Is the important ratio














Spirometry in normal airways, obstructed airways and restrictive lung disease
- Normal person on left
o Large total volume
o FEV1 high
proportion of FVC

- Obstructed airways
o Lower total
volume
o FEV1 very low
proportion of FVC

- Just expansion problem
o Low vital capacity
o Low FEV1
o Normal ratio

Peak Flow
- Measured by taking deep inspiration followed by forced expiration
- Used as a measure of airways obstruction and/or dynamic airway compression
- Smaller for females and as you get older

- Doesn't distinguish between airway resistance and small fibrotic lungs
o Is helpful if you already know what the issue is

Lung Function: Normal Flow-Volume Loop
- Possible to us peak flow, FVC and FEV 1 to get a normal flow-volume loop
o Measuring inspiratory and expiratory flow
§ Y axis
o Measuring FEV1 and FVC
§ X axid
o Also measuring time
§ 3rd dimension
§ Tick on the curve


- Peak expiratory flow occurs early
o Followed by linearly decreasing
flow

- Peak inspiratory flow occurs midway
through inspiration
o Gradual decrease and increase either side of this max




Increasing CO2 vs Ventilation
- Typically see that CO2 increases pretty much linearly with ventilation

Physiological Ventilation Feedback Loop
1. Measure minute ventilation
2. Related to alveolar ventilation
a. Which determines Alveolar CO2
3. We have made alveolar CO2 high
a. Arterial CO2 will be the same
4. High CO2 detected by carotid
5. At start we see a brisk response in ventilation to higher CO2
a. In order to reduce CO2 and pH
6. Bicarbonate pumped into CSF
a. Slowly reduces pH over a few days

Lecture #17 Haemotology 1

What is blood?
• Blood is a connective tissue
• Cellular elements (RBC, WBC, platelets) in a fluid matrix
o Plasma
§ A component of our extracellular fluid
§ Separated by blood vessel walls
§ Presence of plasma proteins differentiates from interstitial fluid
• Acts as a buffer
o Between cells and external environment
• Part of the cardiovascular system
• Makes up ¼ of extracellular fluid
• Carries material from one part of the body to other areas

Blood Composition
• Plasma composition
o Predominantly water 92%
§ Very viscous
o Proteins 9%
§ Albumins 60% of proteins
o Dissolved organic molecules 1%
o Trace elements <1%
o Gases < 1%

- Fibrinogen very important in clotting process

- Plasma is different to serum
o Serum is the fluid portion when blood clots
o Whereas plasma has the clotting portion

- Gases
o Dissolved component
o Very small level of Oxygen and CO2












Plasma Proteins
• Key difference between interstitial fluid and plasma
• Cant cross endothelial wall of blood vessels
o Creates colloid osmotic pressure
• Creating a gradient
§ Promotes fluid exchange at the capillary level
• Allowing gas exchange
• Predominantly produced in the liver
o Albumin 60% most prolific
• Carriers for other molecules within the blood
o Globulin
• Immune system function
§ Antibodies and clotting functions
o Fibrinogen
• Forms fibrin protein to join clots together
o Transferrin
 • Iron transport

Cellular Composition – Cellular Elements
• RBC's
• WBC's
o 5 types (MELBN)
• Lymphocytes
• Monocytes
• Neutrophils
• Eosinophils
• Basophils
§ The actions of these
are external to the
blood
§ Although they travel
within the blood
• Platelets





Cellular Constituents of Blood
o Red blood cells (Erythrocytes)
o Oxygen and Carbon dioxide transporters
o No nuclei
o White blood cells (leukocytes)
o Not all leukocytes are in the blood
o Immune function
§ Act on or in tissues out of the blood
• Phagocytosing etc.
§ Transported in the blood
o 5 types
o Platelets (thrombocytes)
o Very important in clotting (coagulation)
§ Lump together
o Cell fragments of a mega cell called Megakaryocytes

Haematopoiesis – Blood Cell Production
o Blood cell production occurs in the bone marrow
o Begin with pluripotent stem cell
§ Which develop into uncommitted stem cells (very very few in
number, form committed cells very fast so difficult to isolate)
o Then into Committed progenitor cells (pre-cells)
§ Which develop into their specific blood cells
o Erythroblast
o Immature form of red blood cell
o Almost a mature form of a progenitor cell
§ Then have release of cytokines and hormones which shrink the
cellular elements creating an immature red blood cell called a
reticulocyte
• Within 24
hours this
can form
a mature
red blood
cell
o Platelets
o Bud off a
megakaryocyte

Erythropoiesis
• Erythropoietin helps to develop erythrocytes in the bone marrow
• Erythropoietin is produced in the kidney in response to reduced oxygen carrying
capacity (loss of RBC)
o Hypoxia
• Travels to bone marrow to mature red blood cells at a more rapid rate
o Increase carrying capacity of blood
• Greater ability to bind oxygen to haemoglobin
§ Negative feedback to kidney to downregulate secretion of
erythropoietin
• Too many RBC's
o Thick sluggish blood
• Too few RBC's
o Can’t provide tissue with enough oxygen


Blood Doping
o Artificially improve ability to transport oxygen
o 3 methods
o Blood transfusion
o Remove 500ml of blood
§ Lowering oxygen carrying capacity ability
• Triggers release of EPO
o Then add back own blood
§ Higher EPO count
§ Greater oxygen carrying ability
o Commercial EPO Injection
o People with anemia actually need these drugs
o Injection of synthetic oxygen carriers
Haematocrit
o Hematocrit = packed red cell volume
o Hematocrit of blood sample
o Take a small blood sample
§ Centrifuge
• RBCs and WBCs fall to bottom
• Plasma stays on top
o Use as diagnostic to count RBCs
§ Males 40-54%
§ Females 37-47%
o Anemia
o Reduction in these values
o Dehydrated
o Higher value
o But lower plasma
o Overall
o RBCs 42%
o WBCs 1%
o Plasma 58%


Red Blood Cells
• Biconcave disk which promotes oxygen transport
o Large surface area
• Extremely thin surface
o Faster oxygen diffusion
• No nucleus, organelles or ribosomes
o However still have a structured cytoskeleton in the membrane
o Important because we don't want these cells to collapse
• Want to maintain the surface area
• Flexible membrane
o Allows travel through capillaries without rupturing
• Capillaries are about 1 cell wide
o So these RBCs filter through 1 cell at a time
o Need to be a bit flexible
o Cytoskeleton allows them to bend and move
• Actin
§ Important for contraction
• Allows the bending and moving
• Life span
o 120 days






Haemoglobin
- The major component of red blood cells
- A single haemoglobin molecule has
o Large protein with 4 protein chains
§ 2 alpha chains
§ 2 beta chains
o Each of these sub chains contain a heme group (4 heme groups)
§ All identical
• Porfirin ring with in iron molecule in the middle (4 iron
molecules)
§ Iron molecule
• Very important for oxygen binding
- Each haemoglobin molecule can carry 4 oxygen molecules
- Iron molecule can also bind to
o Carbon monoxide (greater affinity, dangerous)
o Carbon dioxide

Haemoglobin and Iron

- 70% of the body's iron is found in haemoglobin

- In order for humans to produce red blood cells we need to be able to consume
adequate iron

RBC Synthesis
1. Ingest iron
2. Active transport across membrane into gut
3. Transferrin binds iron and transports it to the bone marrow
4. Bone marrow uses Fe to make haemoglobin and RBC’s
5. RBCs live for about 120 days
6. Spleen destroys RBCs and convert haemoglobin to bilirubin which is excreted







Problems Associated with RBC’s
- Anemia
o Low haemoglobin levels
o Can’t transport enough oxygen to tissues
- Accelerated Red blood cell loss
o Losing blood by rapid numbers
- Or have a problem within the body
o Reducing red blood cell production

Sickle Cell Disease
- Exchange in beta chain amino acids of haemoglobin molecule (glutamine for valine)
o Results in haemoglobin crystalising when it gives up oxygen
§ Becomes sharp and obstructing
• Causes tangling and blockages

Blood Groups
• Determined by the presence of absence of antigens on surface of RBCs

Agglutination
- Occurs when the wrong blood type is given to a patient and a transfusion immune
reaction occurs
- Drop of blood on slide
o Add specific antibodies
o Will bind to corresponding
antigens if present we get
agglutination

In picture
• A Antibodies caused agglutination
o So blood type has A antigens
• B antibodies did not cause
agglutination
o So blood type has no B antigens
• D antibodies caused agglutination
o So Rhesus positive

- So we have A positive blood

Blood Donation

Rhesus Blood Groups

- Rhesus surface antigens
o About 49 of these
o Only worry about the D antigen
o Very important in pregnancy and maternal fetal interaction
- Presence of D antigen
o Positive blood group
- Absence of D antigen
o Negative blood group

- Mother can produce rhesus positive antibodies which can attack the D antigens of
fetus

Lecture #18 Haemotology 2
Haematopoiesis
- Platelets are regulated by thrombopoietin
o Which regulates the growth and function of megakaryocytes
- Thrombopoietin isn't as well understood as erythropoietin

- White blood cells
o 5 types
§ Not all controlled by same mechanism
o Number of different cytokines which control growth and development
o Lots of colony stimulating factors
§ To regulate WBC reproduction and development
o Interlukens
§ Signal to move these cells to their particular tissues

White Blood Cells
- Primarily responsible for immune responses of the body
o Leave the capillaries and function in underlying tissue
- 5 types in blood (MELBN)
- Differentiating cell types
o Different sizes
o Presence of dark staining granules
§ Basophils heavily granulocyted
§ Lymphocytes and monocytes aren't
o Nucleus
§ Round vs lobes
§ Size
o Must stain first to be able to see these differences

Grouping White Blood Cells
- Can group white blood cells based on whether they contain granules or not
o Granules are vesicles containing signaling cytokines
- Granulocytes (contain granules)
o Basophils
§ Responds to basic stain
o Eosinophils
§ Responds to eosin stain
o Neutrophils
§ Respond to a neutral stain
o Names don't reflect function
o Have multi-lobed nucleus'
o Single nucleus, just multiple lobes
§ Neutrophil often 5
§ Eosinophils usually 2
§ Basophils difficult to see due to highly granular


Grouping White Blood Cells (continued)
- Agranulocytes (contain no granules)
o Monocytes
§ Largest WBCs
o Lymphocytes
§ Smallest WBCs

Basophils
• Rare (small population)
• Have large dark blue granules in the cytoplasm
o Difficult to see nucleus
• Very similar to mast cells
• Release mediators important in terms of inflammation
o Histamine
• Causes inflammation
o Heparin
• Breaks down fat particles within our blood
o Other cytokines

Eosinophils
• Small in population (1-3%)
• Pink staining cytoplasm
• Produced in response to allergic reactions and parasitic diseases
o Granules contain toxic substances which attach to foreign pathogens
o E.g. intestinal worms
• Kill pathogens – cytotoxic

Neutrophils
• 1st line of defence against bacterial infections
o Most common infection so we have high numbers of neutrophils (50-70%)
• Multilobed nucleus
o 3-5
• Short life span
• Constantly produced
o Especially in gut and lungs
• Release cytokines to overcome pyrogens

Monocytes
• Largest cells
• Agranulocytes
• An immature version of a macrophage
• Circulate in small numbers (1-6%)
• Mature in tissues into macrophages
• Long lifespan upon maturity
o Months to years
• Live longer if dealing with less pathogens

Lymphocytes
• Highly important immune function
• Mediate the lymphatic system
• Smallest WBCs
• Make up 20-35% of WBCs
o Very common
• Categorised into
o B lymphocytes
• Produce antibodies
o T lymphocytes
• Latch onto cells and break them down
• Go through a maturation process so slower response
o Natural Killer Cells
• Similar to T lymphocytes
• Act in same way
• BUT no maturation process
§ So faster action than T lymphocytes
• All important in fighting viruses

WBC Diseases
§ Lymphoma
o Metastases (uncontrolled spread) of lymphocytes
o Cancerous
o Hodgkin's
§ Contains a particular cell that is metastasised
o Non-Hodgkin's
§ Don't contain a particular cell that is metastasised

§ Leukimia
o Cancer or disease of progenitor cells
o Issues in producing mature white blood cells
o Many different types
§ Acute
• Quick
§ Chronic
• Slow acting

§ Myelodysplastic Syndrome
o Category of blood cell diseases
o Bone marrow associated
o Affects RBCs and platelets as well as WBCs

§ Neutropenia
o Low neutrophil levels
o Often a secondary condition to a more primary condition
o Harder to fight bacterial infection

Platelets and Megakaryocytes
§ Megakaryocytes
o Mother cells of platelets
o Platelets are cell fragments which break off
o Undergo DNA replication many times (up to 7)

§ Large venous sinuses
o Pick up blood cells as they are produced

§ Megakaryocyte stays within bone marrow
o Sticks out cytoplasmic protrusions through endothelial layer of sinus
o Platelets bud off from there into the sinus to circulate

§ Platelets
o Small, colourless, no nucleus
o Have mitochondria, smooth ER and vesicles containing cytokines and growth
factors
o Budding off bits of cytoplasm from megakaryocyte
o Contain actin and myosin
§ Allows them to contract during the clotting process
o Have a major role in blood clotting but also have a minor role in immune
function

Haemostasis
- Process of keeping blood within a damaged blood vessel
- Circulatory system
o Need to keep blood in our vessels at all times
o To maintain blood pressure so that tissues constantly have oxygen supply and
constantly have way to remove CO2
- We damage blood vessels all the time
o Cuts and bruises

- 3 major steps of haemostasis
o Happen in succession but trigger each other and overall all occur very quickly

1. Vasoconstriction
a. Upon damage specialised factors released from endothelial layer
b. Allow vessels contract
c. Two endothelial sides become sticky where damage has occurred
i. To reduce blood flow
ii. And reduce blood pressure






Haemostasis (continued)
2. Formation of platelet plug
a. Where lumen is damaged collagen is exposed within blood vessel wall
b. Starts to attract platelets which stick to von willebrand's factor
c. Release of platelet factors occurs
i. Release ADP and tyromboxane A2
ii. Attracting more and more platelets
d. This increases the size of the plug via platelet aggregation

Endothelial layer
• Releases NO and prostaglandins
• Stopping platelet adhesion at all times
• Stop clot formation at non damaged endothelium

3. Coagulation
a. Formation of clot
b. Turning fluid into a gel
c. Intrinsic and extrinsic pathway
i. Depending on what has caused the injury
ii. Each step converts an enzyme from inactive form to active form
iii. Driven by calcium
iv. These processes often interact
v. Collagen vs tissue factor 3

Haemostasis - Intrinsic pathway
• Internal pathway
o When collagen is exposed it activates factor 12
o This converts factor 11 into active factor 11
• Requires Ca2+
o This converts factor 9 into active factor 9
• Requires Ca2+
o Active factor 9 moves into common pathway

Haemostasis - Extrinsic Pathway
• External pathway
o Damage exposes tissue factor (III)
o Which activates factor 7 into active factor 7
o Active factor 9 and and tissue factor 7 cause activation of factor 9 into active
factor 9
o Active factor 9 then initiates clot formation in common pathway







Haemostasis Intrinsic and Extrinsic Pathways

Formation of Common Pathway
- Common pathway
- Produces thrombin
- Active factor 9 activates factor 10
- Active factor 10 initiates conversion of prothrombin (a plasma protein) into
thrombin
- Thrombin converts fibrinogen into fibrin
o Fibrin forms a mesh which sticks to platelet plug and captures anything in
its path
o Stopping blood loss
- Active 13
o Makes fibrin stronger by turning it into cross linked fibrin
- Calcium very important in facilitating all of these processes

Clot Retraction and Dissolution
- Clot needs to break down eventually
o Fibrinolysis
§ Driven by activation of thrombin (has 2 opposing effects)
• Which activates conversion of plasminogen into plasmin
• Plasmin gets trapped in the clot and then works to break it
down



Disorders of the Coagulation Pathwaysclot
- Often inherited
o Cause an inability to
- Any issue in the cascade
o E.g. one of the factors
- Haemophilia
o One of the factors in coagulation cascade is defective or lacking
o A, is the most common type 80%
§ Recessive and sex linked
§ Usually affects males

Lecture #19 Sexual Differentiation and Male Reproduction
Male Sex Chromosomes Determine Sex
- 22 somatic chromosomes
- 1 sex chromosome
- Diploid
o So gametes must be haploid
- No pairs
o 23 single chromosomes
o Thus we need genetic reduction
§ Meiosis
- Female gametes have only x chromosomes
- Male gametes can be x or y
o So the male gamete is the determinant of sex in the offspring










SRY gene on Y chromosome = sex determining region of Y
• Produces testis determining SRY protein
o Increases production of proteins that cause gonad medulla to differentiate into
testes, which contain
• Leydig cells
§ Secrete testosterone
• Development of wolffian duct
onto accessory glands
• Prostate, seminal
vesicles
• Development of male
external genetalia
• Scrotal sac and penis
• Sertoli cells
§ Secrete anti mullerian hormone
(AMH)
• Blocks differentiation of
reproductive duct which
develops into female
structures
• Causes regression of
mullerian duct
• Which would form
vagina and uterus

- Absence of testosterone
o Wolffian duct regresses

Male Reproductive Tract
- Testis
o Reservoir which exits fluid into epididymis
o Highly convoluted tube
§ 1 cm length
§ However, 1-meter-long when stretched out
o Sperm squeezed out vas deferens
§ Which extends into abdomen, around back of bladder, releases
contents through ejaculatory ducts into urethra
§ Urethra passage down through erectile tissue and out of the glans
penis
- 2 Major functions

1. Formation of gametes
a. In Seminiferous tubules

2. Formation of hormones
a. Testosterone
i. In extra tubular stroma
ii. By leydig cells

Testes Composition
- The testes are composed of the seminiferous tubules and extra tubular stroma
- Leydig cells
o Produce testosterone
- Also have fibroblasts and myoid cells

- Specialised basement membrane
o Sitoli cells on top
§ Essential for development of gametes
§ Germ cells are located in between sitoli cells
• Intimate contact enables sitoli cells to translate signals from
the blood
• For tight junctions with
- Spermatigonium
o Adult stem cell population
o Diploid
- Pass beyond blood testes barrier when they undergo meiosis
o Once a cell becomes haploid it becomes no longer recognized by the body
o So we get them beyond the blood testes barrier so we don't initiate an
immune response
- Round spermatids
o Gone beyond meiosis
o Go from round shape to elongated sperm cell
o Specialised with flagella
§ Enable them to swim

3 Stages to Gametogenesis
1. Mitotic proliferation (clonal expansion)
2. Meiotic division
3. Spermiogenesis (germ cell remodeling)

- Different in male and female

- Differentiation of reproductive tract
o Prior to formation of sitoli and leydig cells in fetal gonad
§ Have migration of primordial germ cells
• Once we have specification of gender we will get development
of these primordial germ cells into male or female
• Get proliferation
o Once specialised
§ Male
• Stop dividing and lie dormant until puberty
§ Female
• Undergo replication and enter meiosis
• Stop at meiosis
• Remain dormant until puberty
o Once we reach puberty
§ Around every 12 days
• Each spermatigonia will be stimulated to enter several rounds
of mitosis (clonal expansion)
• About 6 rounds
o After these 6 rounds of mitosis they enter meiosis
§ Diploid --> haploid
o Clonal expansion followed by meiosis is why we produce huge numbers of
sperm
§ 60 million per ejaculate
• Only useful if they can migrate to the uterine ducts
o Half a meter for something that is less than a micron
long
o So need to be streamlined
§ Torpedo shape
o Need a flagella
o Need to get rid of a lot of the cytoplasm and organelles










Gametogenesis Overview

Endocrine Regulation of Male Reproductive Physiology
- Gametogenesis is dependent on sitoli cell function
o Which itself is dependent on 2 key hormones
§ FSH and Testosterone
• Have a classic negative feedback system

- Hypothalamus
o Secretes Gonadotropin releasing hormone
§ Stimulate anterior pituitary to secrete FSH and LH
• FSH targets sitoli cells and stimulates them to produce factor
important in spermatogenesis maintenance
• Sitoli cells will also produce inhibin which acts as a negative
feedback mechanism to reduce secretion of FSH
• LH stimulates leydig cells to produce testosterone
o Which negative feedback to reduce GnRH secretion

- Low testosterone --> increase GnRH secretion
- High testosterone --> decrease GnRH secretion

Leutinising Hormone Mobilises Cholesterol to Enter Steroidogenic Pathway
- All steroids are formed from cholesterol
- Action of LH on receptors on surface of leydig cells that drives 1st step of
steroidogenesis
o Production of steroid acute regulatory protein is responsible for movement
of cholesterol from outer mitochondrial membrane to inner mitochondrial
membrane where it is then converted to prognenelone
§ LH allows this 1st step to happen
• Cyclic AMP signalling cascade
o Prognenelone moves out of the mitochondria into the ER
§ Where other enzymes are present to facillitate steroidogenesis

Testosterone and FSH are both Required for Spermatogenesis

- If we Deprive rats of
o Testosterone
§ Maintain normal levels of spermatogenesis
o Testosterone and follicle stimulating hormone
§ Lose numbers of early germ cell types of spermatogenesis

Hypogonadotropic Hypogonadism
- Little to no testosterone production
- No sperm in their semen
o Can occur for a number of reasons
§ Usually due to disruption of HPG axis
• Tumour or chronic steroid medication or opiods
- Low levels of gonadotropins and testosterone
o We need testosterone and FSH for normal sperm production
- Leads to infertility
- Normally treated by hormone replacement therapy


Epididymis and Ductus (vas) Deferens
- Epididymis functions
o Fluid absorption
o Sperm transfer
o Sperm storage
o Sperm maturation

- Once we have sperm
o We need to mature them in the reproductive tract
§ Develop motility
§ Develop surface profile to allow them to bind and fertilise the oocyte

- Peristaltic movement pushes sperm along length of epididymis
o Towards caudal region
§ Which is very important for storage
• Need to remain there for a certain amount of time for them to
become mature
§ A day or two in the cauda and all sperm will be motile
• Dependent on
o Absorption of proteins secreted by epididymis
§ Forward motility protein
o Transcriptional activity is switched off
§ Nucleus has been condensed to form the head
• Can’t make proteins
o Loss of cytoplasmic droplet
§ In caudal region
• Then phagocytosed

2 Major Events of Sperm Maturation
1. Forward progressive motility
a. Forward motility protein
b. Loss of cytoplasmic droplet

2. Attainment of fertilizing ability
a. Ability to bind and penetrate zona pelucida and oocyte
b. Requires absorption of proteins to sperm surface (secreted by epididymis)
and modification of sperm surface proteins (enzymes secreted by epididymis)

Epididymis and Ductus (vas) Deferens (continued)
- Function of ductus deferens
o Transfer of sperm from epididymis to prostatic urethra vi ejaculatory duct
- Function of both epididymides and ductus deferens
o Ejaculation
§ Inner and outer layers of longitudinal smooth muscle richly
innervated by sympathetic nervous system
§ Intense peristaltic contractions

Sperm Fluid
- Sperm aren’t enough for normal function
- Also need to supply them with fluid to help travel through female reproductive
system
- Fluid
o Components secreted by seminal vesicles and prostate which are required
for sperm function

Sex Accessory Glands
- Seminal vesicles
- Prostate gland

- Function
o Produce seminal fluid of the ejaculate
§ Secretions constitute 95% of the ejaculate
o Secretions maintain viability and motility of sperm and aid transfer to and
transport through the female reproductive system

Erection Reflex and Ejaculatory Response (EPOR)
- Excitory, plateau, orgasm, resolution

- Inputs
o Either somatogenic or psychogenic
o Effects both sympathtic and parasympathetic stimulation
o To initiate vasodilation of penile arteries




• Corpus cavemosum
• Resting state
• Sympathetic nervous system is telling
this muscle to constrict

• When we get excited we relax this muscle
• Get vasodilation within this muscle
• Get other changes which cause blood
flow to the penis to increased

• As a result, tissue expands
• Presses against deep dorsal vein
• Restricting outflow of blood
• Maintaining erection




Erection response dependent on
• Acetylcholine
• Vasoactive intestinal peptide
• Nitrous oxide
1. Activates guanylate cyclase to increase cGMP, relaxing smooth muscle of corpus
cavernosum
2. Testosterone

Viagra
• Blocks action of PDE5 so cGMP not degraded and erection maintained

Ejaculatory Response
• Stimulate enough beyond threshold then we have the ejaculatory response


Lecture #20 Non-Pregnant Female Reproduction
Endometrium
• Endometrium is lost at the onset of a menstrual cycle
• Rebuilt as the menstrual cycle progresses
• In absence of pregnancy shed again at beginning of next cycle

Fimbriae
- Sweep surface of ovary
- Ovary sits outside of the female reproductive tract itself (unlike testes in men)

Oocyte development
- A cycle
- Eventually leaves behind a corpus luteum

Oocyte
- Surrounded by granulosa cells (important endocrine cells)
- Then basement membrane
- Then layer of cells called theca cells (important endocrine cells)

Functions of the Female Reproductive Tract
1. Sex steroids
a. Estrogen and progesterone
2. Production of oocytes
3. Provide a conduit for gamete transport
4. Site of fertilisation
5. Maintain pregnancy
6. Birth

Steroidogenesis
1. Production of steroids is a sequential pathway
2. Cholesterol is the beginning of all steroids
a. Get cleavage of groups away from that structure and we get a reduction in size of
the molecule

- Sex steroids
o Progesterones come first
o Which are parental to androgens
o Which are parental to estrogens

- Certain cell types produce different steroids because of the enzymes they produce
- The reason cells of the adrenal gland produce aldosetrone, corticosterone and
cortisol is because they are the only cell types which produce the enzyme 21-alpha-
hydroxylase
o Similarly, for cells in reproductive tract with their specific steroids and
enzymes
Principal Ovarian Steroids
- Progesterone
o Implantation and pregnancy maintenance
§ Inhibits uterine contraction
o Controls endometrium activity
o Promotes glandular development of breasts
- Androgens
o Estrogen synthesis
- Estrogen
o Secondary sex characteristics
§ Development of breast ducts
§ Function and phenotype of reproductive tract at any one time

Biogenesis of Ovarian Steroids

- Enzyme profiles dictate the pathways we go down

Thecal cells
• Outside of follicle
• Produce androgens
o Convert them into testosterone by the granulosa (1st part of ovarian cycle)
• Testosterone is aromatised into oestradiol by granulosa cells
Corpus Luteum
- Produces progesterone

Granulosa
• Sit inside basal lamina of follicle and surround the oocyte
• Convert
• Androstenedione into testosterone
• Oestrone into oestradiol
When we have the structure that is the remains of the follicle (oocyte released) we form
corpus luteum
• Change from being a delta 5 dominated pathway to a delta 4 dominated pathway
• Under the delta 4 dominated pathway we get production of progesterone
Two Cell – 2 Gonadotropin Hypothesis
- The thecal cells produce androgens
- Granulosa cells stimulated by follicle stimulating hormone to convert androgen into
oestrogen (aromatization of androgen)

- Gonadotrophins
o Luteinizing hormone
§ Stimulating thecal cells
- Follicle stimulating hormone
o Inducing granulosa cells to express aromatase
o To then convert androgen into estrogen

- Rate of steroid production is dependent on 4 enzymes

- Granulosa cells only ones producing aromatase
o So only cells which can convert androgen into estrogen

- Key branch point down through to androgens is only driven by granulosa cells

Menstrual Cycle
- Time from commencement of one bleeding cycle to the onset of the next
- Shedding of endometrial lining à Gets reestablished à Enters secretory phase
àNo pregnancy àEnter next menstral bleed

- Underpinning uterine cycle is ovarian cycle
o Follicular phase (1st half)
§ Release of oocyte for ovulation
§ Variability in length
o Luteal phase (2nd half)
§ Punctuated by ovulation
§ Constant 14 days irrespective of individual
Follicular Recruitment
- The start of every menstrual cycle is marked by follicular recruitment

FSH and Follicular Recruitment
- At the beginning of every menstrual cycle
o Have a situation where we have elevated levels of FSH
o Stimulates recruitment of primary follicles
o Ovary has many primary follicles
o A few stimulated by FSH and start to develop
o Called follicular recruitment

- 4-5 days in
o One of the follicles becomes selected to be the dominant follicle
o Continues to grow
o Whilst rest of the cohort die off

- Estrogen increases with development of follicle until we get ovulation

Oogenesis and Follicular Development (Diagram list)

- 3 phases in every ovarian cycle to activate several primordial follicles
o Primary/pre antral
o Secondary/antral
o Pre ovulatory




Oogenesis and Follicular Development
In females
• Primordial germ cells migrate to gonad and become specified to become oocytes
• Oocytes enter into meiosis and then arrest

- All of the primordial follicles in the ovary is the total population of gametes that the
female can produce

- Dominant follicle out of the primary follicle population becomes the
developing/growing follicle
o Expansion in number of thecal and granulosa cells
§ Becomes the Graafian cell
• Becomes pre-ovulatory follicle
o Waiting for a signal before releasing oocyte

Menstrual Cycle (Ovarian and Uterine)

Endocrine Regulation of Female Reproductive Physiology
Early Follicular Phase
- Have have a classic negative feedback system
o Hypothalamic release of GnRH
§ Stimulating FSH and LH release from anterior pituitary
• LH stimulating thecal cells to produce androgens
• FSH stimulating granulosa cells to convert androgens
(produced by thecal) into estrogen
• Estrogen is the negative feedback to reduce FSH LH and GnRH
release

Late Follicular Phase
- Small increase in estrogen
o Levels of FSH and LH remain fairly constant
- As we get to ovulation estrogen levels are very high
o For some reason we switch from having a negative feedback pathway to a
positive feedback pathway
§ Estrogen begins to stimulate GnRH release
• Stimulating release of LH and FSH
• LH SURGE is what drives ovulation
o Start to get a change in follicle of structure
§ Breakdown in basal lamina that separates thecal cells from granulosa
cells
• Allows cholesterol to penetrate towards granulosa cells
o Allowing for the production of progesterone

- LH Surge
o Potential modulator
§ Gonadotropin surge attenuating factor
• This protein is at high levels during early follicular phase
o Has negative feedback response
§ As follicular phase progresses the amount of GnSAF starts to decline
• Until eventually we hit late follicular phase and we see almost
no GnSAF
o We think that this reduction in GnSAF is the cause of change from Negative
feedback mechanism to Positive feedback mechanism which creates the LH
surge








Luteal phase
- After we release oocyte
o We get the corpus luteum
§ "Yellow body"
• Highly active steroidogenic structure
o Granulosa cells can make progesterone because they are now exposed to
cholesterol after loss of basal lamina
§ Explains why we get changes in hormones which are being secreted
o Progesterone dominated phase
§ Negatively feeding back to reduce GnRH release and thus FSH release

Menses/Late Luteal Phase
- Corpus granulosa cells need stimulation from gonadotropins to maintain activity of
corpus luteum
o As the amount of the hormones fall (negative feedback) the corpus luteum
begins to die
o So we see a crash in hormone levels towards the end of the menstrual cycle
• Then we see an increase in gonadotropins because we have returned back to
classic negative feedback
• Increased levels of FSH
§ Start to induce follicular recruitment
• Estrogen and progesterone have dropped
§ So the endometrial lining of uterus is shed

Combined Oral Contraceptive Pill
- Suppressed gonadotropin levels
o FSH low so no follicular recruitment
o Not getting ovulation and oocyte release

- Barrier for sperm entry into the uterus
o Post ovulation we don't want to fertilize another oocyte that is in the system

Puberty
- Difficult to explain what drives puberty
o In humans
§ On set is early teens
• However, this varies
§ Pre puberty is a GABA ergic dominant phase
• Suppressing GnRH neurons
§ For some reason in early teen years we get antagonism of these GABA
systems
• So GnRH is released

- Peptin and kisspeptin
o Individuals with impaired production of Kisspeptin
§ Get delayed puberty
o Individuals with high levels of kisspeptin
§ Start puberty early

Menopause
- Cessation of sex steroid production
- Around 50 years of age

Lecture #21 Pregnancy and Lactation
Fertilisation Occurs in the Uterine Ducts
- Ovary sits outside reproductive tract

- End of follicular ovarian cycle is punctuated by ovulation
o Oocytes ejected from ovaries
§ Estrogen is very high at this point
• Important for activity of fimbriae and cilia lining epithelium of
uterine ducts
• Activity maximal at this point
• We need to vacuum up this oocyte
o Fimbriae sweep surface pf ovary
o Cilia beat in same direction
o Pulling oocyte through the duct and into the uterus
- Fertilisation takes place in uterine ducts
- Implantation occurs in uterine wall
Sperm Hyperactivation and Acrosome Reaction Allow for Oocyte Penetration
- When sperm are released from testes they are immature and unable to bind to
oocyte
o Mature in the epididymis

- Maintained as being immobile to stop them from swimming
o Don't want to use all their energy before it is necessary

- During ejaculation these sperm are activated
o Swim up female reproductive tract
o To fertilise in uterine duct

- Sperm become HYPERACTIVATED when the meet the oocyte
o Start to thrash around
o Reason for this is an influx of calcium due to PM receptors on sperm surface
which are activated when reach oocyte

- Layer of granulosa cells on oocyte
o Sperm need to get through this
o Reason for hyperactivation

- Once through the granulosa cells reach zona pellucida (glycoprotein coat)
o Sperm come capacitated
o Acrosome reaction

- Back in spermatogenesis
o Germ cell remodeling
§ Sperm form structure called aquasome cap which is filled with
enzymes important to degrade zona pellucida and reach PM of oocyte
§ Then get fusion and fertilisation

Sperm and Oocyte Nuclei to Establish the Diploid Zygote
- Polyspermy blocked by
o Na+ influx (fast block) across oocyte membrane
§ Depolarization of the PM
• Changes the nature of the membrane making it more difficult
for sperm to bind
o Signaling cascade results in an increase in Intracellular Ca2+ release (slow
block)
§ Activates processes which make PM more stiff and rigid take off
proteins which are important for sperm binding too oocyte

- Binding of the sperm initiates completion of meiotic division




Sperm and Oocyte Nuclei to Establish the Diploid Zygote

Morulla à Blastocyst
- Solid ball of cells
- Changes to blastocyst through process of compaction

Cells of the Blastocyst Have Distinct Embryonic and Extraembryonic fates
- Fate of the trophoblasts and embryoblast will have very different fates
- Inner cell mass is pluripotent
o Can become any cell except extraembryonic tissues
§ Those tissues which become chorion and placenta
- Trophoblast are multipotent
- Tight junctions between epithelial cells begin to break down
o To allow implantation
§ Start to form extraembryonic structures
• Chorion and placenta

Formation of the Placenta

- Changes in structures that occur towards the formation of placenta is what is

important
o Placenta becomes an extremely important endocrine structure
- Fetus is starting to grow
o Blastocyst is developing into different cell types
o We get expansion of membranes
§ Particularly chorion
 o As it expands outwards
§ Fills with amniotic fluid
§ Eventually fuses with opposite wall of endometrium

- The chorion fondosum (side which was originally fused to endometrium) will form
the placenta and tree like structures called chorionic villi

- Chorionic villi
o Covered with single epithelial cell layer have been bathed in blood from
maternal side
o Epithelium separates the maternal and fetal circulation
• To prevent immune response from baby
• Allows for exchange of gases and glucose and for the removal of
waste
o Vasculature that is coming from fetus
• Umbilical artery and vein branch into these tree like structures

Endocrinology of Early Pregnancy

- Luteal phase
o Oocyte released and leave behind cells
o Producing lots of progesterone
§ Drops off in absence of pregnancy because we don't have
gonadotropins

- Chorionic fondosum and villi
o Produce HCG (human chorionic gonadotrpoin)
§ A copy of LH
§ Absence of LH from pituitary is compensated by HCG
• So we still get production of progesterone and estrogen
o Maintain uterin function
o HCG detected in urine
§ Used to predict pregnancy or not
o Still get negative feedback from progesterone and estrogen
Endocrinology of Mid/Late Pregnancy
- Progesterone maintains endometrium
o No progesterone we shed that lining
- Prevents uterine contraction
o To maintain fetus
- Placenta secretes peptide hormones
o hCG
§ Replaces LH
§ Described above
o hPL (human placental lactogen)
o Elevates levels of circulating glucose in the mother
o Need to provide an energy source to the energy requiring fetus
o Decreases insulin sensitivity, increases blood glucose
§ Gestational diabetes

Parturition (giving birth)
• Placental block hypothesis
o CRH
• Induces cervical contraction
• Primes prostaglandin synthesis to stimulate uterine contractions
• Removal of progesterone block
o Suppression of progesterone block
• Metabolism to less potent 20-alpha di-hydro-progesterone

Oxytocin and Parturition
- Positive feedback system
o Fetus drops lower in uterus
o Cervical stretch
§ Oxytocin releases prostaglandins from uterine wall
o Causes uterine contractions and further cervical stretch

Prolactin
o Produced in anterior pituitary
o Under normal conditions is prohibited by dopamine
o During pregnancy
o Partly suppression of dopamine
§ Increasing production of prolactin
o Once we have a baby sucking at the breast
o Chemoreceptors suppress dopamine releasing cells completely
§ Get high prolactin production
§ And secretion of milk






Prolactin
- During breastfeeding prolactin production suppresses GnRH
- Oestrogen increases the number of prolactin secreting cells during pregnancy
- Prolactin inhibiting hormone suppresses prolactin release
- PIH falls towards the end of pregnancy
o So Prolactin rises
- Following birth oestrogen and progesterone levels
fall
o Suckling stimulates prolactin release and
secretion of milk

Hyperprolactinemia
- Functional gonadotrophin deficiency
o Women
§ Menstrual disturbance
§ Infertility
o Men
§ Erectile dysfunction
§ Diminished libido

Oxytocin and Lactation – Let Down Reflex
- Milk produced by mammary gland lobules
o Need to get milk out of ducts
- OXYTOCIN
o Acini is surrounded by myoepithelial cells
and duct with smooth muscle cells both
with oxytocin receptors on them
§ Suckling releases oxytocin and causes duct to contract and squeeze
milk out of the nipple

Non-Classical Oxytocin Actions
• Modulating autism spectrum disorder
• Can improve cardiovascular function
o decrease blood pressure
• Clinical trial underway in terms of managing schizophrenia function
• Release at orgasm?
o Love?

The Maternal Brain
- Hormonal fluctuations thought to be involved in remodeling mothers brain
- Oxytocin and progesterone stimulate maternal behaviour
- Oestrogen and progesterone of pregnancy prime the brain for these actions
- Stress response is suppressed at parturition and during lactation



Lecture #23 Gastrointestinal Physiology Introduction
GIT: Constant Supply of Water, Electrolytes and Nutrients
- Constant supply
o Water
o Electrolytes
o Nutrients
- Neuronal and hormonal control
- GIT
o Very long muscular tubule
o Extremely high surface area
o External facing

GIT Specific Functions
• Passage of food
• Storage and breakdown
• Digestion and absorption
• Storage of wastes
• Secretion of enzymes/fluid

5 Major Processes of the Gut
• Motility
o Peristalsis
• Secretions
o From exocrine glands
• Digestion
o Breakdown of
macromolecules
• Absorption
o Of digested products
into blood
o Most important
• Elimination
o Indigestible materials and waste products removed

Use of Food
- Required as an energy source for ATP production
o Oxidative phosphorylation
o Organic molecules + O2 --> Energy + CO2 + H20

Main Components of Faeces
• Undigested residues
• Substances excreted by liver
• Cell debris
o Shows that the gut is turning over rapidly to renew itself
• Bacteria
• Water
Carbohydrates
• Ingest 300g per day
• Complex polysaccharides
o 64% starch
o 0.5% glycogen
• Disaccharides
o 26% sucrose
o 6.5% lactose
• Monosaccharides
o 3% fructose

- Hydrolysis reactions to break these things down
- Complete hydrolysis yields 80% glucose, 14% fructose, 5% galactose

Complex Carbohydrates – Polymeric Glucose
- Cellulose is broken down by bacteria not us
- Mainly amylase breaking down complex chains into simpler chains

Proteins
• Proteins are broken down by proteolytic enzymes
o Very strong enzymes secreted as zymogens
§ Inactive when secreted
§ Activated when get to site of digestion in order to protect internal
structures of the body
• Endopeptidases
o Cleave inside proteins
• Exopeptidases
o Cleave with the enzyme
• >100g protein ingested per day




Digestion of Protein
- Occurs via hydrolysis cleaving out peptide chains
o Removal of water molecule

Fats
- Triacyglycerols
o Digested by lipases
o Again via simple hydrolysis

Morphology of the GIT
- Serosa
o Secretes watery fluids to lubricate organs
o Is continuous with rest of mesentry
§ Contains blood vessels, lymphatics and nerves
§ Entry points to small intestine

Lamina Propria
- Connective tissue
- Nutrients enter blood and lymph here
- Immune cells
- Peyer’s patches
o Gut associated lymphoid tissue

GIT Integrative Control
- Only control is
o Upper esophageal sphincter
o And anal sphincter
- Autonomic control once in GIT
- Self-regulating system of organs (enteric nervous system and gut endocrine system)
o Coordinate motor secretory, digestive and absorptive functions
Enteric Nervous System
- A Separate autonomous division of the autonomic nervous system
o Has extrinsic and intrinsic control
o Short and long reflexes

- Enteric nervous system and gut endocrine system
o Long reflex
§ Sight or smell of food causes salivation
o Short reflex
§ Stomach starts to expand with food consumption and we signal the
excretion of digestive enzymes

Myenteric Plexus
• Runs entire length GIT
• Controls motor activity
• If stimulated
o Increases rate and intensity of contractions
• Peristalsis
o Inhibits valves

Submucosal Plexus
o Controls the local absorption, secretion and contraction
o Local control within each segment of the gut

Major Types of Neurons in Enteric Nervous System
• Cholinergic
o Normal motility pattern (Ach)
• Adrenergic
o Generally, relaxes GIT (NE)

• Stimulation of the sympathetic pathway can block movement through GIT

• NANC
o Non-adrenergic, non-cholinergic
o All enteric ganglia, mainly secrete Vasoactive intestinal peptide/Nitric oxide

Parasympathetic Innervation
- Arises in 2 separate sections of CNS
o Medulla
§ Controls upper GIT functions
o Pelvic nerves
§ Control of colon and large intestine
§ Come from sacral spinal cord




Sympathetic Innervation
- Arises in the spinal cord
o Synapses with superior cervical ganglion
o Project to various parts of GIT

Somatic (voluntary) Control of GIT
• Mouth
• Pharynx and upper oesophagus
• External anal sphincter

GIT Receptors
• Chemoreceptors
o Detect chemical composition of luminal fluid
o pH
• Mechanoreceptors
o Sense stretch or tension in the gut wall
• Osmoreceptors
o Sense osmotic composition of the luminal fluid

• All elicit both short and long reflexes

Gut Hormones
- Endocrine cells
o Secrete hormones
§ Paracrine
• Effect at the site of secretion
§ Endocrine functions
• Effect at alternate site after transport in blood
o Hormones are released in response to specific local changes
§ Gastrin, secretin, CCK, GIP, motilin

Gastrin
• Stimulates gastric acid secretion and mucosal growth

Secretin
• Stimulates bicarbonate secretion and inhibits gastric emptying and acid secretion

CCK (Cholecystokinin
• Stimulates gall bladder contraction and pancreatic enzyme secretion
• Inhibits gastric emptying and acid secretion

GIP (Gastric Inhibitory Peptide)
• Stimulates insulin release
• Inhibits gastric emptying and acid secretion

Motilin
• Stimulates migrating motor complex

GIT Short and Long Reflexes
- External influences
o Cause a long reflex through extrinsic autonomic nerves

- Local changes in digestive tracts
o Induce short reflex and long reflex
§ Intrinsic nerve plexus and hormonal system activates responses
§ As well as extrinsic autonomic nerves

Enteroendocrine Cells
- Secrete hormones and neurotransmitters
- Neuroendocrine cells rapidly convey information about the gut by releasing
neurotransmitters to excite vagal and spinal sensory neurons
o = Gastrointestinal synapse

Gut Microbiome Communication with Brain and Enteric Nervous System
- Via
o Production of
neurotransmitters
o Modulation of host
neurotransmitters
catabolism
o Innervation via vagus
nerve
o Activation of HPA axis







Abdominal Aorta
• Takes blood from the heart to the body
• All the blood from the gut is collected by the hepatic
portal vein and goes to the liver to be filtered
• Splanchic circulation receives about 25% of cardiac
output
o All in order to process food
o Increases during meals

GIT Musculature
- Longitudinal and circular layers which are
electrically coupled
o As membrane potential changes they
contract
o Never still
o Slow rhythmic changes

Gut Muscle Tone
- Slow waves
o Bundles are partly contracted generating muscle tone
o Tonically contracted due to spike
o Reaching threshold potential results in initiation of action spikes
contraction
o Controlled by hormones and para/sympathetic stimulus
Gut Muscle Tone

Gastrointestinal Motility
- Involves both contraction and relaxation
o It is a muscular tube
§ Need to contract to either propel, mix and stop things from moving
§ For propulsion to occur we need both relaxation and contraction
• On either side of the objects
§ Thus relaxation is an essential component of the peristaltic reflex and
accommodation reflex
Functional Movements in the Gut
- Peristalsis = propulsion
o Occurs in response to distension, irritation and parasympathetic stimulation

- Highly complex signaling process
o With classic short reflexes


- Peristaltic contractions occur against a
sphincter
o Results in churning
o Mixing movements
- Segmentation contractions
- Variable and random contractions
o Homogenize food
- Local constrictive contractions
o Result in chopping

Epithelium Function
- Acts as a barrier to diffusion
- Allows transport of materials that we want to move
- Synthesizing proteins and mucous etc

Transport Processes in Epithelium
- Tight epithelium has high membrane resistance
o Not much can get across
§ Electrical resistance is high

- Leaky epithelium
o Lower resistance
o Lower membrane potential

Water Movement Across Epithelium
- Water is on both sides
o Will move according to osmotic gradient which is created by nutrients
o Small intestine
§ Leaky epithelium
§ Water can move whichever way it wants
§ By moving nutrients via active transport we control the osmotic
potential and thus movement water
• Basis or reabsorption in gut and kidney

- If we can’t absorb osmotic components water becomes excreted
o Diarrhoea

Fluid Movement vs Excretion
- GIT is moving about 9L of fluid every day
o Only excrete around 100-200ml

Fluid Movement in the Intestine
• Intestinal membrane is highly permeable to
water
o H20 thus flows according to gradient
o Water will follow movement of ions
• Net fluid movements in the bowel
o It is a cycle of fluid rather than a turnover
of fluid
• Bowel fluid losses (vomiting and diarrhoea)
o Result in an isotonic contraction of the
ECF
o Electrolyte disturbances are common
and variable


Lecture #24 Ingestion of Food
Digestion Time
- Mouth and oesophagus = 10s
- Stomach = 1-3hrs
- Small intestine 7-9hrs
- Large intestine 25-30
- Rectum 30-120mins

Mani Functions of Chewing
• Mechanical disruption of food
• Mix food with saliva to start carbohydrate digestion by amylase
• Stimulate afferent receptors
• Form food into a bolus
o Easier to swallow

Main Salivary Glands
- Parotid
o Drains in between jaw
§ Serous
- Submandibular
o Serous and mucous
- Sublingual
o Mainly mucous

Serous vs Mucous
- Serous
o Water, electrolytes and amylase
o Fluid
- Mucous
o Secretes mucins, electrolytes and water
o Lubrication

Functions of Saliva
- Food functions
o Digestion
§ Secretion of enzymes
o Taste
o Bolus formation
§ Mucins and water
- Micro-organism functions
o Anti-bacterial
o Anti-fungal
o Anti-viral
- Teeth functions
o Lubrication
o Remineralisation
o Protection
o Buffer
- Irrigate

Exportable proteins from salivary glands
- Mucins
o Glycoproteins mechanically protect epithelium
§ Lubricate food
§ Trap microorganisms
§ Protect stomach lining
- Digestive enzymes
o A-Amylase which digests starch
§ Promoting oral hygiene
- Lipase
o From von Ebner's gland
§ Newborn milk digestion
Amylase
- Digests carbohydrates
o Mainly digest linear chains
o There are other enzymes for more complex carbohydrates
- Big function of amylase in oral hygiene
o If we have a lack of salivary secretion
§ No antimicrobial agent
• Terrible hygiene outcomes

3 Salivary cell types
• Acinus
o Secrete primary fluid
o Water permeable epithelium
• Mucous and enzyme movement
• Ducts
o Fluid modification membrane
o Impermeable to water
• Myoepithelial cells
o Prevent over distention


2 Stage Hypothesis of Salivary Formation
1. Primary juice that is very similar to blood plasma (Na, K, Cl and HCO3) is secreted by
water permeable acini
0. Fluid is modified by the water impermeable duct via absorption of Na and Cl and
secretion of K and HCO3

- Secretion à Modification

Aquaporins
- Channels for water to move throug
- Require energy
o Electrochemical gradient
§ Via Sodium Potassium ADPase
o Use sodium gradient drive chloride into a cell
§ Cl then enters lumen via aquaporins
§ Na+ them moves through to lumen to balance the charge
• Water follows to balance osmotic potential

- Without aquaporins
o Water can’t move at all
o However an move ions around actively
§ Use sodium potassium ADPase
• Sodium moves in via sodium channel (ENaC)
• Chloride also moves across via CFTR
o Net reabsorption of NaCl
o Secretion of K and HCO3-
o No net movement of water

Regulation of Aquaporins
- Via G-protein coupled receptor
o Activated by signal molecule
§ Alpha subunit activated and binds to activated phospholipase
• Triphosphate triggers opening of Ca2+ channel
o Which activates protein kinase C
§

Two Stage Hypothesis of Salivary Secretion
- Sodium and chloride being produced and being modified as it moves along the duct
- Sodium and chloride being reabsorbed
- Bicarbonate and potassium being secreted
- Duct has conductors for sodium and chloride
- Final composition of saliva is linked to flow rate

Salivary Composition is Dependent on Flow Rate
- Higher flow rate
o Higher ion concentration
o Less reabsorption
o More basic

- Lower flow rate
o Greater absorption
o Lower ion concentration
o More acidic



Nervous Control of Salivary Secretion
• Parasympathetic and sympathetic nerves
o Main stimulus is the parasympathetic pathway acting via signals from the salivary
nuclei
• Excited by both taste and tactile areas of the tongue
• Also excited via stimuli arriving at the salivary gland from higher centres of
the central nervous system
o Salivation can also be stimulated by gastric irritation
• Reflexes from stomach and upper intestines signal salivation in order to
dilute food

Simple and Conditioned Reflexes for Salivary Secretion
- both the pressure receptors and chemoreceptors in the mouth signal to the salivary
centre to cause stimulation of
o Automatic nerves
o Salivary glands
o Salivary reaction

- Also have more complex conditioned reflex
o Where cerebral cortex remembers inputs associated with requirement for
salivation
§ Pavlov's dog

Functions of swallowing
- Transport food from Pharynx to stomach
- Prevents oesophagopharyngeal reflux and gastroesophageal reflux

Swallowing involves
- Complex interactions between voluntary and involuntary nervous and muscular
systems
- Coordination with breathing and associated activities (talking)
















Four Phases of Swallowing - POPO
- Four phases of swallowing
o Preparatory
§ Voluntary and involves bolus formation and lubrication during
chewing
o Oral phase
§ Bolus propelled into the pharynx by the tongue
o Pharyngeal
§ A single contraction peak coinciding with the beginning of the
peristaltic wave
§ Soft palate elevates and seals the nasopharynx
• Preventing nasal regurgitation
§ Larynx ascends and epiglottis tilts downwards
• Facilitating closure of the laryngeal vestibule and removes
laryngeal inlet from oncoming bolus
§ Upper oesophageal relaxation commences with the onset of the
pharyngeal phase
o Oesophageal
§ Upper esophageal sphincter closes and primary peristalsis occurs
§ Then secondary peristalsis occurs
• Smooth muscle
• Purely intrinsic reflexes (distention)
§ Lower oesophageal sphincter relaxes shortly after swallow
• Due to cessation of tonic excitation to the sphincter
• As well as inhibition by NANC inhibitory neurons
§ Receptive relaxation of the LES ahead of the food bolus allows easy
propulsion of the food into the stomach

Causes of Vomiting
- Stimulation of back of throat
- Irritation of stomach
- Elevated intracranial pressure
- Motion sickness
- Intense pain
- Chemicals
o Emetics
- Emotions
o Phsychogenic

Vomiting Pathways
1. Neural
2. Hormonal





Mechanism of Vomiting
1. Diaphragm descends
a. Glottis remains closed
b. Negative intrathoracic & oesophageal pressure (retching)

2. 0.5s later stomach and lower oesophageal sphincter (LES) relax and the abdominal
wall muscles contract propelling the gastric contents through the LES

3. Contraction of the oesophageal longitudinal muscle shortens the oesophagus and the
thoracic cage expands further lowering pressure

4. Gastric antrum contracts and the UES relaxes with expulsion of vomit(us)

Lecture #25 Stomach Function

Main Functions of the Stomach
• Storage of food before emptying into small intestine
• Begin digestive process
o Releases 2-3L of gastric fluid per day
• Homogenise food
o Forming chyme
o Semifluid paste
• No absorption except alcohol and aspirin

Stomach Structure
- 4 parts total
o Fundus, body, antrum, pyloris
- Rugae
- Increase surface area
- Allows expansion

- Muscular layers
o All of GIT except the stomach we have 2 layers of muscle
§ One circular and one longitudinal
o Stomach also has an oblique muscle layer
§ 3 layers total

- Lower oesophageal sphincter
o So don't get reflux

- Pyloric sphincter
o Stop things leaving stomach uncontrollably







Stomach Musculature
- Proximal stomach
o Maintains a steady tone
o Relaxed during swallowing
§ Receptive relaxation
o Distention allows bulge up to 1.5L
§ Accommodation without pressure increase
o Fundus
o Corpus
§ Pacemaker zone
• Splits proximal and distal
§ Responsible for rhythmic waves of contraction

- Distal Stomach
o Peristaltic waves driven by the pacemaker region
§ To homogenise the food
§ Driven by intrinsic neurons
o Corpus
o Antrum

Intragastric Pressure vs Volume
- Stomach can expand a lot without you feeling like you are full
o Until you hit a threshold
§ Around 1500ml
- Once you hit the threshold
o Pressure rises fast
o Can't eat anymore

Basal Electric Rhythm
- Stomach has basal electrical rhythm
o 3 electrical waves per minute

- Antral peristalsis begins as the stomach fills

- Peristaltic ring is very strong
o Gets very narrow

- Retropulsion against pyloris
o Pyloric sphincter remains
constricted
o Contractile ring pushes chyme into
the pyloris
§ Eventually into the duodenum




Main Components Involved in Digestion
- HCL
o Acid denaturation of digested food
§ Amylase deactivated
o Activate pepsinogens
o Convert ferric salts into absorbable forms
o Kill ingested bacteria
- Intrinsic factor
o Absorption of dietary vitamin B12
o Absence of intrinsic factors can lead to anemia
§ RBC don't develop
- Pepsinogen
o Principle enzyme (from chief cells)
o Inactive when released
o When gets to stomach interacts with low pH to become active
§ Pepsin
• Protein breakdown
o Then inactivated by neutral pH of duodenum

Stomach Tubular Glands
- Oxyntic gland
o On the body of the fundus
- Pyloric glands
o In the antrum
o Secrete mucous to protect pyloris
- Parietal cells
o Large acid secreting cells
o Secrete intrinsic factor as well
- Chief cells
o Principle source of pepsinogen
- Mucous neck cells
o Secrete mucous glycoprotein
- Surface mucous cells
o Secrete mucous bicarbonate HCO3
- G cells
o Secrete gastrin











Secretory Cells of the Gastric Mucosa
- Self-regulating endocrine system that can control acid production

Gastric Mucosal Protection Barrier

- Surface epithelium
o Secrete a thick alkaline mucous in order to protect the stomach
- Mucous
o Acts as physical barrier
§ Protecting gastric mucous cells and underlying tissue
o Secrete bicarbonate
§ pH gradient
§ So epithelium is at a neutral pH
§ Becomes more acidic in stomach lumen
- Cell turnover
o Layers turning over every week or so
o Replacing any damaged cells
















How Does the Stomach Make HCL?
- Parietal cells
o Utilise the ions in the extracellular fluid and the potassium-hydrogen ATPase
pump
o ADPase sets up an electrochemical gradient to allow movement of ions
§ Red circle bottom left
- Luminal Surface
o Hydrogen-Potassium ATPase pump
o Potassium channel
o Chloride channel

- In the cell
o Water and CO2
§ Get converted to bicarbonate + proton
- ECF surface
o Chloride bicarbonate exchanger
§ Allows Cl- in for bicarbonate
• Proton gradient builds up
o Protons enter lumen via ATPase pump