Physiology / Neuronal Structure & Communication

Lecture #1 W1

Cells: Function as the building blocks of the body (smallest living entity)

Tissues: Epitherlial, Connective, Muscle, Nervous/Neural

Organs: Consist of at least 2 primrary tissues

Systems: Comprosied of organs located in various regions of the body to perform related functions.

Basic Classification systems:

3 Functional classes of neurons: afferent, efferent, interneurons

 

Epithelial Tissues:

Tissue that surrounds our body and lines the inside of our body such as our respiratory tract. Is comprised of epithelial cells arranged in a continuous sheet.

Which of the following statement describes epithelial tissue? It is avascular (does not have a blood supply supporting it)

Function: protect, secrete, absorb and filter.

Epithelial cells are continueally being shed from the villi of the intestine because new cells are continually being propduces in the crypts at the base of the billi and migrate upwards.

3 Types of Epithelial Tissue:

Squamous

Function: Diffusion and filtration

Line oral cavity, pulmonary alveoli and the glomerulus  of the kidney

Cuboidal 

Function: absorption, secretion and excretion

Line kidney tubules, salivary and pancreatic ducts.

Columnar

Function: absorption secretion and excretion.

Line digestive tract, uterine tubes etc.

Any of the 3 can be either…

• Simple: One cell layer thick; Specialized for transport
• Stratified: Composed of a number of layers; Specialized for protection

Epithelial Other Characteristics:

The positions/sides:

• Apical (top) surface/Apical layer/luminal
• Basal (deep) surface – connected to basement membrane
• Lateral surfaces: connected by tight junctions, adherens  junctions, gap junctions etc

Basement membrane

• basal lamina contains collagen, laminin, proteoglycan and  glycoproteins etc; secreted by epithelial cells
• reticular lamina rich in collagen fibers; secreted by  fibroblast

Epithelial tissue is avascular (Doesn’t have any blood vessels within the tissue).

Connective Tissue: Types

2 Types of Connective Tissue:

Connective tissue proper:

Loose – More cells, less protein fibers

Dense – Mostly densely packed collagen  fibers and fewer cells (mainly fibroblasts)

Special connective tissue: cartilage, bone, blood.

• Regular Dense: found in tendons/ligaments that function for strength and support.
• Irregular Dense: in dermis (skin) and walls of  tubular organs that function for flexibility to moveent.

Connective Tissue: Components

Cells

• Fibroblasts: most common cell in connective tissue
• Adipocytes, macrophages, plasma cells, mast cells (produce  heparin and histamine)
• Infiltrated white blood cells during inflammation.

Matrix

Connective tissue cells are dispersed in a matrix. The matrix usually includes a large amount of extracellular material produced by the connective tissue cells that are embedded within it. The matrix plays a major role in the functioning of this tissue The major component of the matrix is a ground substance which is usually fluid, but can also be mineralized and solid, as in bones.

Main role is to connect epitherlial cells to the rest of the body.

• Protein fibers; examples:
• Collagen – strong and flexible
• Elastin – Allows for stretching and recoiling; makes tissue  elastic
• Reticulin – thin collagen fibers coated with glycoprotein

Ground substances: water and a variety of small and large  molecules (electrolytes, nutrients, glycosaminoglycan,  polysacchrides, proteins etc.);

Connective Tissue: Function

• Connects cells and organ together (e.g. connects skin to  muscle; form a network or lattice in organs such as spleen,  lymph nodes, liver)
• Provides strong flexible support (tendons and ligaments),  or provide elasticity to tissues (Elastic fibers ).
• Nourishes the cells and organs, and stores “body fluid“
• Fills spaces, store fat and provide cushion (the kidneys are  cushioned by adipose tissue; the eye is cushioned in the  orbit by adipose tissue.
• Protects body against infection; ‘loose one’ is main site for immune response.
• Involved in wound healing, tissue remodeling, cancer  metastasis and many more…

Muscle Tissue:

Skeletal: Voluntary: Long striat  cells with multiple nuclei

Cardiac: Involentary: Branching,  striated cells, fused at plasma  membranes

Smooth: Long spindle-shaped cells, each  with one nucleus; located in inte  hollow organs

Nerve Tissue:

Neurons:

Structure: cell body, Dendrites and axon

Function: produce and transmit electrical signals (nerve  impulse)

Supporting cells

Astrocytes: physically support neurons in proper spatial  relationship; induce formation of blood-brain barrier etc.

Schwann cells and oligodendrocytes: the myelin forming cells  of the PNS and CNS

Microglia: Function as the immune system of the CNS to remove wastes

Ependymal cells: line internal cavities of brain and spinal cord

Basics of Neural Regulation

 

How do nerve cells transmit signals?

Neurons transmit information through electrochemical signals and neurotransmitters.

• Neurons are excitable.
• Stimulus can alter their membrane permeability.
• Permeability changes lead to membrane potential changes,  leading to action potential.
• Action potential is conducted along the nerve as  electrical signals (nerve impulse).
• Neurotransmitters relay signals between neurons.

Resting membrane potential of cells

A- = Negative charged ions

Stimulus triggers action potential

AP stimulutes the depolorisation of  Na+ and K+ channels which depends on the magnitude of the stimlus. If the stmlius is strong enough you get more of a stimulus then you reach a threshold potential (all or nothing principle) then an AP is generated which causes a depolarization which causes a rapid influx of Na+ and some more stuff.

The opening of axon membrane voltage-gated potassium channels is responsible for which part of the action potential? Repolarisation of the membrane

Neurons transmit signals through synapses and  neurotransmitters are messengers in synapses

• Inter to intra neuron transmission needs a neurotransmitter.
• ACh binds to generate AP in the post synapatic cells.
• Then you need to deactive ACh after its been activated.

Autonomic nervous system

• A postganglionic neuron releases ACh neurotransmitter at the effector cell
• Postganglic means after the ganglion so it’s the one that goes straight to the effector tissue.
• Effector cells/organs are the one’s that carry out the response to glands and muscle.

Pre-ganglionic neurons release acetylcholine (ACh) that binds to the receptor on the post-ganglionic neuron.

The receptors on all the post-ganglionic neurons of both sympathetic and parasympathetic nerves is a nicotinic receptor. 

For parasympathetic nerves the neurotransmitter that binds to receptor in the target organ = muscarinic receptor.

For the target organs for sympathetic nerve post-ganglionic neuron they are adrenergic receptor.

All pre-ganglionic fibres are cholinergic: denoting to nerve cells where ACh acts a a neurotransmitter 

Neurotransmitters and Receptors for  autonomic nerves

Sympathetic

• Pre-G: acetylcholine (nicotinic receptor)
• Post-G: norepinephrine (adrenergic receptor) (except for  sweat gland)

Parasympathetic

• Pre-G: acetylcholine (nicotinic receptor)
• Post-G: acetylcholine (muscarinic receptor)

Homeostasis: foundation of physiology

Homeostasis is the maintenance of stable conditions (dynamic constancy) of the internal environment to allow cells to survive.

What is the internal environment? The Water in our body

The interstitial fluid is contained in the connective tissue.

What are the homeostatic conditions?

This is what we’re talking about when we talk about homeostasis.

• Concentration of nutrients
• Concentration Waste products,
• Concentration of O2 and CO2, pH,
• Concentration of water, salt  and electrolyte
• Temperature
• Volume and pressure

Mechanisms Regulating homeostasis

Intrinsic control: being regulated within the organ to  control a condition Example: low O2 in exercising muscle  dilates blood vessels to bring in more blood.

Extrinsic control: regulatory mechanism initiated outside the organ alters the activity of the organ. Accomplished by endocrine and nervous systems. E.G. Adrenaline production  via the HPA axis

*intrinsic + extrinsic can happen at the same time

3 types of control

• Negative feedback – common
• Positive feedback
• Feed-forward

Negative feedback

• Change in a controlled variable triggers a response that opposes change, driving the variable in the opposite direction of the initial change.
• AKA if something is too high you have a mechanism that brings it back to maintenance baseline homeostasis.
• E.G. An air-conditioner turning on and off to regulate precise room conditions.

Components of negative feedback

Positive feedback

Change in a controlled variable is further enhanced by the regulatory system so that the controlled variable continues to be moved in the direction of the initial change.

Examples

1. Blood clotting occurs as a result of sequential  activation of clotting factors.
2. Progressively heightened uterine contraction  during childbirth

E.G. Childbirth: Increased stretch of uteris which causes a contraction which causes increased stretching which causes contraction etc etc

Same with oxytocin and prostagladin (progesterone function inhibits contraction which oxytocin inhibits because you want the contractios)

Feedforward Mechanism

Change occurs in anticipation of a change in a controlled variable. E.G. Anticipating food (saliva) the body can anticipate the uptake of food in the  stomach before the food is assimilated into the gut thus it helps release insulin and GIP.

 

Indicate whether the following physiological event represents

 

• intrinsic control
• negative feedback control
• positive feedback control
• feedforward control

 

• increased blood flow into muscle tissue in response to a localized increase in carbon dioxide. A & B – can be considered intrinsic control (regulated via an organ) AND negative feedback because it’s trying to push back to normal homeostasis
• the release of a hormone to lower blood calcium levels when it gets too high. B – negative feedback control because the trigger response opposes the change back to homeostasis
• increased cardiac activity to elevate blood pressure when systemic pressure is low. B – negative feedback because its bringing blood pressure back baseline
• rapid clotting of blood due to increasing levels of platelet activity at a site of vessel damage. A – positive feedback to move in the direction of a
• Increase of insulin secretion in response to food in the digestive tract. D – feedforward – GIP goes to pancreas to promote release of insulin before the blood glucose levels are changed and increased

Integumentary system

Skin Renewal: The skin renews itself fast because the top layer sheds and the bottom layer proliferates and grows through which pushes the cells to the top and then the apical layer undergoes terminal differentiation.

Skin as We Age: Younger people usually have a thicker epidermis because its nourished with collagen and water .. as we age it thins out and becomes less hydrated and nourished which contributes to looking old

Structures of the Skin

Epidermis: epithelial cells (avascular – no blood vessels)

• Inner layer, rapidly dividing
• Outer layer, flattened and dead, keratinized
• Contains melanocytes, keratinocytes, langerhans cells and  Granstein cells etc.

Dermis: mainly irregular dense connective tissue

• Rich in elastin and collagen fibers, blood vessels  and nerve endings

Hypodermis = subcutaneous (under the skin) tissue

• Loose layer of connective tissue
• Where most fat in the body are stored

Functions of the skin

Protection: the skin barrier impede passage of most  materials into the body

Participate in immune response

• Keratinocytes are known to produce inflammatory cytokines  and kill microbes
• Langerhans and Granstein cells serve as antigen-presenting  cells.
• Connective tissue in dermis hypodermis is a important site for  immune response.

Production of melanin by melanocyte

Temperature regulation

Thermoregulation

Normal body temperature: Core temperature (of inner tissues) – Constant -Ranges from 36 – 37.5

Skin temperature: fluctuates depending on the ambient temperature.

Body can stand high temperature of up to ~ 43oC but is more tolerant to cooling

• > 45°C may destroy proteins and enzymes and lead to death
• < 34°C may cause slowed metabolism and arrhythmias (our heart beats too quickly, too slowly, or with an irregular pattern)

4 physical processes for heat gain or loss

Body temperature is controlled by thermoregulatory  center in hypothalamus that operates on a set point.

Responses to cold exposure

• Shivering thermogenesis to produce heat and get back to  homeostasis
• Skin vasoconstriction to minimize heat loss.

The arrector pili are associated with hair follicles. (Contraction of these muscles causes the hairs to stand on end, known colloquially as goose bumps via smooth muscle via the sympthatic NS)

Adrenalin stimulates Arecotr pili muscles to contract when we’re in a sympathetic state, cold or scared to make hairs on their ends. One previous function of this used to be to make ourselves look larger and more threatening when we were confronted with danger back when sapiens used to be covered in thick fur. This is called a vestigial reflex, meaning a reflex we used to have but no longer need. Goosebumps is known as the piloerection reflex.

Behavioral adaptations

• Non-Shivering thermogenesis – increase in brown fat activity; this is  especially important in newborns and hibernating animals. Brown fat produces heat to help maintain your body temperature in cold conditions.  Brown fat contains many more mitochondria than does white fat.

Responses to heat exposure

• Decreased muscle tone (also called residual muscle tension) is the continuous and passive partial contraction of the muscles, or the muscle’s resistance to passive stretch during resting)
• Skin vasodilation
• Sweating
• Skin vasomotor activity is highly effective in controlling heat loss in environmental temperatures between 20 – 30oC. Below this range, shivering makes the major contribution. Above this, sweating is  the dominant mechanism.

Disorders in Thermoregulation

• Hypothermia (too cold)
• Hyperthermia (too hot)
• Fever

Release cytokins which release  pyrogens .. More prostogladin  increases your core temp which  changes the set point via the  hypothalamus. Therefore you’ll  have a fever.

The onset of sweating during a fever is viewed as a good sign because it often indicates that the fever has broken. What is the physiological basis for this view?

• Heat is a very effective antimicrobial and the onset of sweating indicates that the bodies thermoregulatory pathways are active.
• The body wants to cool the body when the bodies above the set point it will attempt to cool the body via the hypothalamuses control.
• During a fever the release of cytokines release pyrogens .. More prostogladin increases your core temp which changes the set point via the hypothalamus. Therefore you’ll have a fever (heat loss mechanism – you sweat).

In fever production, cold response mechanisms are initiated by the hypothalamus to raise the body temperature to the new set point.

1. endogenous pyrogen released from neurons of the cerebral cortex in response to an infection elevates the hypothalamic “set point.” Why its wrong: it’s the neutrophils that release the endogenous pyrogens)

The Brown Fat Science

Brown adipose tissue, or BAT, is primarily found around your collar bones, sternum, neck, and upper back. It is a unique kind of fat that can generate heat by burning the regular white fat (adipose tissue) found on a your stomach, butt, hips, and legs.

Brown fat converts energy/calories into heat via NST.

Traditionally found in high amounts in infants, animals living in the cold (hibernating animals).

Brown Fat	White Fat
Smaller lipid droplets	Larger lipid droplets
Many mitochondria	Less mitochondria
Brownish colour due to the high presence of the iron rich organelle of mitochondria	White in colour
Protein Channel: Produces UCP1 (thermogenin) that functions to allow the proton to pass through its protein channel and the energy is lost in the form of heat.	Protein Channel: Protons pass through ATP synthase therefore the energy is used to synthesise ATP
Much less ATP Synthase	Much more ATP Synthase responsible for synthesising ATP
Cold induces brown fat activity to produce heat via NST.

Both UCP1 and ATP synthase are protein channels that allow the protons to pass through. The difference is the UCP1 uses the energy to create heat whereas ATP synthase uses it to create ATP. Thus scientist believe having more brown fat gives us a better advantage to facilitate fat loss as energy is lost in the form of heat.

But brown fat doesn’t work passively in the background. There needs to be a trigger for brown fat activity. The trigger is the cold. One mechanism is how Thyroid Hormone stimulates brown fat activity.

1. Brown fat activity is triggered by the sympatric nerve activity which is downstream of TH.
2. In response to cold TRH and TSH are released which will increase release of TH then the TH targets the hypothalamus
3. downregulates AMPK
4. which activates sympathetic nerve activity
5. which induces brown fat activity by stimulating the production of UCP1.

1. Brown fat is derived from a common precursor of muscle cells (Myf5 – myogenic factor 5 which is a transcription factor).
2. In the presence of BMP7 (Bone morphogenetic protein 7) this protein will stimulate the cell to express PRDM16 (transcription factor)
3. this will induce the differentiation of the progenitor cells (like a stem cell that can differentiation into a specific type of cell) into brown fat cells.
4. In the absence of BMP7 myogenin is then expressed which will stimulate the differentiation of the progenitor cells into muscle cells.

But it was also found that one could have some brown fat activity from white fat cells by giving it a special protein hormone called Irisin. Irisin can stimulate the production of UCP1 in the white fat cells therefore these cells will appear slightly brownish and turn into beige fat cells.

Irisin is cleaved from skeletal muscle. During exercise a large amount of Irisin is cleaved from this precursor protein (Fibronectin III domain) and Irisin in the blood is increased. During exercise Irisin will target the white fat cells and promote brown fat activity to increase energy expenditure. It is also known to improve insulin sensitivity. Therefore scientist came up with the idea of taking Irisin in capsule form to lose weight. But it’s receptor on the fat cells hasn’t been identified therefore we don’t understand the pharmacology of it. But it seems like a good theory if it can be put into practice.

Explain why the brown fat tissue is a potential target for treating obesity?

Brown fat produces heat to help maintain your body temperature in cold conditions. Brown fat can generate heat by burning the regular white fat (adipose tissue). Brown fat contains many more mitochondria than does white fat. Brown fat contains special proteins called UCP1 (Thermogenin is an uncoupling protein found in the mitochondria of brown adipose tissue. It is used to generate heat by non-shivering thermogenesis) and this UCP is a protein channel that allows the protons in the inner membrane space to pass to its channel and this energy is lost in the form of heat instead of synthesizing ATP, therefore calories are expended in the form of heat. This mechanism is a gateway to expend calories without having to convert to ATP. Compared to white fat cells where mitochondria channels use ATP synthesis; when protons pass through the channel ATP is created for energy.

Amount of cold-activated Brown Adipose Tissue in men is negatively associated with body fat or BMI

People with less body fat (white fat) generally have higher brown fat activity compared to those with higher body fat.

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Acids, Bases & pH in the Body

ACID –  substance that donates H+

BASE –  substance that accepts H+

pH is inversely related to the H+ concentration

Sources of H+

1. Carbonic acid formation

• metabolic formation of H+

2. Organic acids

• from intermediary metabolism

3. Inorganic acids

• catabolism of proteins

Regulation of H+

1. Buffers

• act very quickly, but do not eliminate excess H+

2. Respiratory System

• “buffers” H+ by removal of CO2 via  ventilation

3. Renal (Urinary) System

• removes H+ and adds HCO3- (bicarbonate)

• slow, complex system that exerts fine control (long term regulation)

1. Buffers

1. Phosphate buffer system

• inorganic phosphates have low buffering ability

2. Protein buffer system

• high concentration of proteins eg. RBC

3. Bicarbonate-CO2 system

2. Respiratory System

pH is regulated by controlling rate of CO2 removal via ventilation

• ­ H+ detected by peripheral and central chemoreceptors

• ­ rate of pulmonary ventilation

• ­ CO2 removal, ¯ PCO2

3. Urinary System

pH is regulated at kidneys by:

• H+ secretion (loss)

• HCO3- absorption/reabsorption (gain)

1. Bicarbonate reabsorption system
2. Phosphate buffer system
3. Ammonia system

• Act to maintain filtrate (urine) at pH 4.0-4.5

pH is regulated at kidneys by:
– H+ secretion (loss)
– HCO3- absorption/reabsorption (gain)

Bicarbonate reabsorption system
Phosphate buffer system
Ammonia system

• Act to maintain filtrate (urine) at pH 4.0-4.5

Acid-Base Disturbances

Respiratory Acidosis

ventilation is impaired – hypoventilation:

•   reduced neural drive
•   respiratory muscles
•   airway obstruction
•   pulmonary disease

hyperventilation:

•   anxiety
•   increased neural activation
•   high altitude (reflex – low PO2)

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Lecture 2 Endocrine System (I)

Lecture #2 W2

1. What is the endocrine system?

The endocrine system is slow release long lasting effects compared to CNS which is quick release shorter lasting.

Consists of ductless endocrine glands that secrete hormones that are essential for homeostasis.

• Specialized glands that secrete homrones: thyroid gland, adrenal glands, etc.
• Endocrine cells in tissues such as the hypothalamus, adipose tissue (leptin, a satiety  hormone ), gastrointestinal  tract (GIP, Ghrelin, a ‘hunger  hormone.

 

1. Chemical Classification of Hormones

Hormones

are chemical messengers that enter the blood and are transported in the blood to their target tissues

1. Peptides:

A peptide is a hydrophillic (water soluble) combination of short-chain amino acids derived from cholesterol. Not all peptides are alike.

• Small peptides: TRH (GluHisPro), vasopressin (nonapeptide)
• Proteins: insulin, growth hormone
• Glycoproteins – Long polypeptides (>100 KD) bound to 1 or  more carbohydrate groups (FSH and LH – female reproductive cycle).

Peptide/protein hormones: antimullerian hormone (AMH), adiponectin (also Acrp30), adrenocorticotrophic hormone (ACTH), angiotensinogen, angiotensin, antidiuretic hormone (ADH, arginine vasopressin, AVP), atrial-natriuretic peptide (ANP), calcitonin, cholecystokinin (CCK), corticotropin-releasing hormone (CRH), erythropoietin (EPO), follicle stimulating hormone (FSH), gastrin, glucagon, gonadotrophin-releasing hormone (GnRH), growth hormone-releasing hormone (GHRH), human chorionic gonadotrophin (hCG), growth hormone (GH), insulin, insulin-like growth factor (IGF, also somatomedin), leptin, luteinizing hormone (LH), melanocyte stimulating hormone (MSH), neuropeptide Y, oxytocin, parathyroid hormone (PTH), prolactin (PRL), secretin, somatostatin, thrombopoietin, thyroid-stimulating hormone (TSH), thyrotrophin-releasing hormone (TRH).

2. Amines:

derived from tyrosine and tryptophan Example: catecholamines, thyroxine.

Amine-derived hormones: adrenaline (or epinephrine), dopamine, melatonin, noradrenaline (or norepinephrine), serotonin (5-HT), thyroxine (T4), triiodothyronine (T3).

3. Steroids

Hydrophobic (water insoluble) hormones derived from cholesterol

Steroid hormones: cortisol, aldosterone, testosterone, dehydroepiandrosterone (DHEA), dehydroepiandrosterone sulfate (DHEAS), androstenedione, dihydrotestosterone (DHT), oestradiol, progestagens, progesterone, calcitriol.

Based on their mechanism of action, steroid hormones affect the synthesis of proteins and peptide hormones affect the activity of proteins.

Estrogen and Testosterone are very chemically similar. Estrogen is derived from T by an enzyme called aromatase.

Androgen binding protein concentrates Testosterone by 100x in the seminiferous tubule. 

2. Mechanisms of hormone action

• The effects of hormones are mediated by specific hormone receptors in the cell like a lock and key relationship. The receptor for T is adrogen recepors whereas estrogen binds to an estrogen recepotrs. 
• The location of the hormone receptor depends on  the chemical nature of the hormone
• Receptors for hydrophilic (cannot pass through the cell membrane) hormones/receptors are on cell surface membrane
• Receptors for hydrophobic hormones are intracellular (inside the cytoplasm or nucleus) and can pass through the cell membrane freely.

The action of hydrophilic hormones is mediated by receptors on cell surface (I)

• G-protein-linked: activate second messenger pathway  (cAMP or Ca++).
• Ion-channel-linked: mostly for neuropeptide  hormones.
• Enzyme-linked: Most are protein kinases (e.g. insulin receptor is a receptor tyrosine kinase)

How Hydrophillic Hormones Work Timestamp: 26min in – 10min)

Red box: Shows the hydrophillic hormones

How Hydrophobic Hormones / Steroid Work to produce a Physiological Response 

The action of hydrophobic hormones is mediated mainly by nuclear receptors

• Estrogen diffuses past membrane and binds to the estrogen receptor.
• These regulatory structures influence gene expression, usually in an inhibitory manner

3. Regulation of endocrine function can be regulated by…

1) Hormone secretion

• Can respond to changes in the internal and external environment (e,g, food in the stomach can produce a feedforward secretion to upregualte insulin)
• Negative and positive feedback and feed forward
• Neuroendocrine reflexes (e.g. the secretion of epinephrine by adrenal medulla is under the control of sympathetic nervous system)
• Diurnal/circadian rhythms (cortisol secretion)

2) Tissue sensitivity

• Tissue receptors (each hormone have specific receptors, therefore, is tissue receptor-dependent)
• transcription cofactors (co-repressors and co-activators)

3) Hormone binding to plasma proteins, metabolism and excretion (next slide)

as a way to regulate the ability of the hormone to function

Binding to plasma proteins, hormone metabolism and excretion regulates concentration of active hormones

Endocrine disorders…

result mostly from the  hyposecretion or hypersecretion of a hormone

Hyposecretion (low)

• Due to heredity, dietary deficiency, immunologic factors (autoimmune disease) etc.
• Causes can be primary (the defect occurs in the endocrine gland cell), or secondary (due to the deficiency of another hormone )
• Can be treated by Hormone Replacement Therapy in most cases.

Hypersecretion (high)

• Due to tumors of the endocrine gland, immunologic factors etc.
• Causes can also be primary or secondary.

Lack of Tissues response

• There is a lack of specific hormone recepor (e.g. an androgen receptor that can’t make T).
• Endocrine dysfunction can also arise from the unresponsiveness of target cells to a hormone (Testicular feminization syndrome,  type II diabetes – insulin resistance).

4. The central endocrine glands

• The hypothalamus
• The anterior pituitary gland
• The posterior pituitary gland
• The pineal gland

The hypothalamus

• Forms the lower lateral walls and floor of the third ventricle, above pituitary.
• is intimately connected to a number of structures within the limbic system (a number of brain structures that regulates mood/emotion/memory) and brainstem.
• A integrating center for  many homeostatic functions and serves  as an important link between the autonomic system and endocrine  system.
• Function: secretes hormones to help regulate homeostasis 

Leptin

• A satiety hormone produced by adipocytes (fat) and enterocytes in the small intestine
• Sends signals to hypothalamus about how much fat is stored in adipocytes.
• Adipocytes produce leptin in proportion to their quantity therefore, obese people have higher levels of leptin.
  • High levels of leptin tell your brain that you have plenty of fat stored, while low levels tell your brain that fat stores are low and that you need to eat
• Negative Feedback Loop: When you eat, your body fat goes up, leading your leptin levels to go up. Thus, you eat less and burn more. Conversely, when you don’t eat, your body fat goes down, leading your leptin levels to drop. At that point, you eat more and burn less. This kind of system is known as a negative feedback loop
• Leptin Resistance: While copious amounts of leptin may be present in obese people, the brain doesn’t see it. This condition — known as leptin resistance — is now believed to be one of the main biological contributors to obesity. When your brain doesn’t receive the leptin signal, it erroneously thinks that your body is starving — even though it has more than enough energy stored.
  • AKA leptin may be present but brain does not receive signals from leptin receptors → the brain erroneously thinks that body is starving → so it eats more.
  • Due to the high levels of leptin, there are not enough leptin hormone receptors (downregulation of receptors). Therefore, this makes the person leptin-resistant.
• As such, eating more and exercising less may not be the only underlying cause of weight gain but rather a possible consequence of hormonal defect

The pituitary gland

• The pituitary gland attaches to the hypothalamus by the  infundibulum. It is structurally and functionally divided  into anterior lobe and posterior lobe. Divided into…
  • The anterior lobe, or  adenohypophysis,  consists of glandular  tissue.
  • The posterior lobe,  or neurohypophysis, consists of neural tissue.
  • Adeno = gland

The anterior pituitary secretes trophic hormones

Trophic hormones are hormones that stimulate the secretion of other endocrine glands/other hormones (E.G. TSH, ACTH, FSH, LH)

 

Left hormones: are important for mammary gland growth and tissue growth

Technically only the hormones on the right are trophic hormones based on the definition of hormones that stimulate other hormones.

• Adrenocorticotropic hormone (ACTH or corticotropin) – stimulate the adrenal cortex (target tissue) to produce corticosteroids
  • Adrenocorticotrophic hormone is a trophic hormone secreted by the anterior pituitary. Its role is to stimulate adrenal cortex to produce corticosteroids. Prior to that, the hypothalamus regulates the secretion of anterior pituitary gland. To stimulate the release of ACTH Corticotropin releasing hormones is secreted. Corticosteroids are involved in suppressing inflammation, stress response etc. 6 trophic hormones : TSH, ACTH, FSH, LH, GH, Prolactin
• Thyroid-stimulating hormone (TSH or thyrotropin) – Stimulates thyroid  to produce thyroxine
• Luteinizing hormone (LH) – Needed for ovulation, formation of corpus  luteum in females; Stimulates testes to produce testosterone in males
• Follicle-stimulating hormone (FSH) – Required for development of  ovarian follicles in females (estrogen) and for sperm development in  males
• Prolactin – Induces lobulo-alveolar growth of the mammary gland and stimulates lactogenesis (milk production);
• Growth hormone (GH or somatotropin) – promote growth of tissues and  essential for metabolic regulation

Hypothalamus regulates secretion of  anterior pituitary gland

• Hypothalamus neurons secrete releasing and inhibiting hormones that regulate the secretion of theanterior pituitary glands.
• The hypothalamic hormones are transported to AP gland through the Hypothalamic-hypophyseal portal  system.
• Hypothalamic-hypophyseal portal system: blood vessels connecting capillaries in the hypothalamus with capillaries in the anterior  pituitary.

 

Hypothalamus regulates secretion of anterior  pituitary gland

• Thyrotropin-releasing hormone (TRH) – stimulate TSH release
• Corticotropin-releasing hormone (CRH) – stimulate ACTH release
• Gonadotropin-releasing hormone (GnRH) – stimulate FSH and LH
• Growth hormone-releasing hormone (GHRH) – stimulate GH release
• Growth hormone-inhibiting hormone (GHIH-Somatostatin) – inhibit  GH release
• Prolactin-releasing hormone (PRH)
• Prolactin-inhibiting hormone (PIH) = dopamine

HPA AXIS: The hypothalamus-pituitary-  adrenal/gonadal/thyroid axis

Negative feedback

• The hormone from target gland can act on the anterior pituitary and hypothalamus to inhibit the secretion of stimulating and releasing hormones.

The hypothalamus-pituitary Adrenal/gonadal axis is regulated by the higher brain

• Stress affects the timing of menstruation because the higher brain affects the function of hypothalumus which affects FSH and LH secretion > affects mensturation
• Stress – CRH (increase)  – ACTH (increase) – corticosteroid (increase) (CRH is a stress coping hormone)
• ‘Dormitory effect’ may be due to pheromones (females mensturation cycle lines up – why it happens is unknown but speculated to be related to pheramones)

Pheromones & Attracting a Mate

• Subtle chemical signals, or pheromones, have long been known to draw pairs together within the same species, and for a specific reason. In mice, for example, experiments showed that pheromones acted as attractants between males and females who were genetically similar except that they differed in a certain type of immune system gene. That difference is actually a survival benefit: The combination of two individuals’ different MHC (major histocompatibility locus) genes gives their offspring an advantage in beating back disease organisms.
• So the mice could smell a genetic difference. But could modern humans, who aren’t known for a particularly good sense of smell, also make that distinction?
• In the first “sweaty T-shirt” experiment, a Swiss zoologist, Claus Wedekind, set up a test of women’s sensitivity to male odors. He assembled volunteers, 49 women and 44 men selected for their variety of MHC gene types. He gave the men clean T-shirts to wear for two nights and then return to the scientists.
• In the laboratory, the researchers put each T-shirt in a box equipped with a smelling hole and invited the women volunteers to come in, one at a time, and sniff the boxes. Their task was to sample the odor of seven boxes and describe each odor as to intensity, pleasantness, and sexiness.
• The results were striking. Overall, the women preferred the scents of T-shirts worn by men whose MHC genes were different from their own.
• The experiment did not test men’s perceptions of female scents, but the results certainly suggest that evolution has provided humans, not just mice, with a transmitter and receiver for genetic information that could influence mate choice.

Circadian rhythms: Secretion of cortisol is highest during sleep and decrease during wakefulness

Growth hormone

Also known in its other forms as Somatrophin or Somatotrophin

Exerts direct and indirect effect on tissue growth and  metabolism.

• Direct effect via GH receptor.
• Indirect effect via secretion of IGF-I from the liver and other tissues. GH effect can stimulated via IGF-I. Justification for consuming amino acids to develop muscle mass.

Secreted from anterior pituitary (in short bursts) in response to:

• ion and nutrient concentrations (fasting)
• stress / exercise
• sleep (major stimulus)
• other hormones (testosterone, estrogen, insulin, thyroid hormones)
• secretory and inhibitory via short- and   long-feedback loops

Stimulates the growth (hyperplasia and hypertrophy) of  muscle, cartilage and bones.

Regulates metabolism

• increases protein synthesis
• maintains blood glucose level by decreasing uptake of glucose in peripheral tissues and enhances glucose synthesis in the liver.
• Mobilizes fat stores as energy via lipolysis by stimulating triglyceride breakdown and oxidation in adipocytes. A higher GH typically correlates to a leaner person.
• Stimulates IGF-1 secretion

Growth hormone and IGF-1 secretion

Read on the use of bovine growth hormone in dairy cows. Are you for or against the use? Why 

• After reading this it’s not worth the potential risk to humans and the actual adverse effects on the animals. But if I all I cared about was making money and feeding a larger population than I would be for it. 
• RBST, short for recombinant bovine somatotropin (growth hormone), is a type of artificial growth hormone that increases milk production. It is illegal for use in Canadian dairy cows, but is legal in the USA.
• Both the natural and recombinant forms of the hormone stimulate a cow’s milk production by increasing levels of another hormone known as insulin-like growth factor (IGF-1).
• Following a 1990s survey, Health Canada identified that, when using rBST to increase milk production in dairy cows, there was no risk to human health, but there was a risk to animal health.

What are the health concerns in humans?

• does drinking milk from rBGH-treated cows increase blood levels of growth hormone or IGF-1 in consumers? If it does, would this be expected to have any health effects in people, including increasing the risk of cancer? Several scientific reviews have looked at these issues and are the main focus of this document.

Risk To Cows

• Second, cows treated with rBGH tend to develop more udder infections (mastitis). had an approximate 25% increased risk of mastitis, a potentially fatal mammary gland infection, a 40% reduction in fertility, and 55% increased risk of developing clinical signs of lameness. (Canadian Journal of Veterinary Research in 2003)

Antibiotics:

• These cows are given more antibiotics than cows not given rBGH. Does this increased use of antibiotics lead to more antibiotic-resistant bacteria, and is this a health concern for people? This remains a concern, but it has not been fully examined in humans.

Summary:

Although it can increase the average milk yield by 10 to 15% and has no known significant impact to the health of the people drinking it, it is known to cause problems in the cows that have been administered the growth hormone and may also promote the development of antibiotic resistant bacteria.

The use of bovine growth hormone Bovine somatotropin (bST) in dairy cows slows the decrease of mammary cells in the udder and extends the period of peak milk production. According to an article by the National Center for Biotechnology Information(ncbi), the use of bST in milk is unlikely to impact human health significantly. The use of bST has no effect on the composition of milk such as the fat, protein, and lactose content. Although there may be slightly more Insulin-like growth factor-1 (IGF-I) in milk produced by cows that have been administered bST, the oral consumption of IGF-I by humans has little or no biological activity (as IGF-1 is a protein and will be broken down into amino acids when consumed) and the concentrations of IGF-I in digestive tract fluids of humans far exceed any IGF-I consumed when drinking milk.

GH added to cows doesn’t present any added risk to human’s because we don’t absorb the GH in its raw form. GH is broken down into amino acids via the stomach and gut. Therefore the protein in milk is treated just like any other protein from animal products so it has an equal weight for stimulating IGF-1 pathway compared to other amino acids, therefore dairy cows with added growth hormone don’t present any special added type of risk to disease.

Although it is a problem if the cows have to take antibiotics and then we assimilate part of the antibiotics.

Bone Structure

• Osteoblast – bone formation
• OsteoClast – mnemonic: bone Cracker
• Osteocytes – bone maintenace
• 90% of bone tissue are osteocytes.
• Osteoblasts built the bone and laid down the matrix and collagen fibre then deposit calcium phosphate crystals then osteoblasts are trapped inside the bone and transform themselves into osteocytes
• Chondrocytes: important for bone growth (don’t produce collegan)

Bone lengthens with the expansion of  epiphyseal plate

GH (and IGF-1) stimulates the proliferation of  chondrocytes and osteoblast activity

Epiphyseal plate (growth plates) made of cartilage cells that allow the bone to lengthen. The bone grows because the EP becomes widened/lengthen and are replaced by the hard bone.

During the bone lengthening the contracyte cells undergo cell division and hypertrophy. When that occurs then the epithelial plate widens. This widened plate will be replaced by hard bone? How? The conracytes will enlarge and the osteoblasts will swim up to lay collagen and calcium phosphate crystals to develop hard bone.

Growth & Development / Epiphyseal plates of the long bones ossify (form) at the end of adolescence. What is the physiological cause and consequence of this ossification?

During a growth spurt, there is a very rapid cell proliferation and bone-building activity such that the cells get exhausted from dividing and once the epiphyseal plates become hard bone we no longer stop growing.

• During adolescence, high levels of sex hormones eg. estrogen and testosterone increase production of GH & IFG-1
• GH and IFG-1 stimulate:
  • Chondrocytes: Chondrocyte cells in the epiphyseal plate undergo proliferation & hypertrophy → results in an increase in their number and enlargement in size
  • Osteoblasts move in to ossify the matrix to form bone:On the diaphyseal side of the epiphyseal plate, osteoblasts swell up and deposit collagen & calcium phosphate → causes cartilage to calcify and die → Replaced by bone
• Process continues throughout the adolescent years until the cartilage growth slows and finally stops → chondrocytes in the epiphyseal plate cease proliferation and bone replaces all the cartilage → epiphyseal plate completely ossifies so that only a thin epiphyseal line remains

Consequence: Epiphysis & diaphysis fuse & bones can no longer grow in length

How bones grow in width?

• Osteoblasts (bone builder) produce a matrix of osteoid  and deposit calcium phosphate.
• Osteoclast (bone breaker)  carry out bone resorption on  the inner side of the bone.
• IGF-1 stimulates the activity  of osteoblasts and  osteoclasts.

 

 

Control of Growth Hormone Secretion

• Secretion of growth hormone is highest during sleep and decreases during wakefulness
• Exercise stimuluate GH secretion,
• Intake of high amino acids
• Intake of low fatty acids and low glucose increase GH secretion
• Growth hormone deficiency: dwarfism
• GH hormone excess gigantism and acromegaly

Effects of growth hormone on glucose metabolism.

Growth hormone (GH) counteracts in general the effects of insulin on glucose and lipid metabolism, but shares protein anabolic properties with insulin. Under physiological circumstances GH does not affect total glucose turnover directly. There is however evidence that GH acutely decreases glucose oxidation (secondary to an increase in lipid oxidation) and suppresses muscle uptake of glucose, suggesting that GH redistributes glucose fluxes into a non-oxidative pathway, which could be a build up of glycogen depots through gluconeogenesis. Since GH secretion is inhibited in the fed state these actions are mainly important in the postprandial or fasting state. Under pathological conditions of GH excess (e.g. acromegaly, poorly controlled tp

Other hormones besides growth hormone are  essential for growth

• Thyroid hormone-permissive role; the effect of growth  hormone manifest fully only when sufficient thyroid  hormone is present
• Androgen – plays important role in prepubertal growth spurt  and stimulate protein synthesis. This role depend on the  presence of GH; Responsible for men’s musculature  development; promote  the ossification of epiphyseal plate so we no longer grow taller and have a defined set point
• Estrogen – prepubertal growth spurt; adult level stimulates  the ossification of the epiphyseal plate so as to stop bone  lengthening

The posterior pituitary hormones

The posterior pituitary is a functional extension of the hypothalamus.  It stores and releases vasopressin and oxytocin that  are produced by the  hypothalamus.

Paraventricular and supraoptic nucleus produce hormones that are transported to the posterior piturarity gland.

Functions of Antidiuretic hormone (ADH)/vasopressin

• Antidiuretic = inhibites urine production 
• Main function = conserve water/fluid balance and constriction of blood vessels
• ADH increases water permeability (water reabsorption) of the medullary collecting duct.
• Promotes water reabsorption by the kidneys by stimulating insertion of water channels (aquaporins) into the membranes of kidney tubules.
• Vasopressin has the function to constrict blood vessels therefore the high concentration  cause contraction of arteriolar smooth muscle to narrow blood vessels (Vasoconstriction).

Control of secretion of Vasopressin/ADH

• Its mission is to maintain blood osmolarity and blood volume.
• The major stimulus for ADH release is increase in plasma osmolarity (measures the bodies water-electrolyer balance) detected by osmoreceptors in hypothalamus.
• The less important input is the decrease in blood volume and blood pressure, detected by left atrial volume receptor which then sends the signal to the hypothalamus to trigger the release of vasopressin.

What would be the consequences of vasopressin deficiency?

Deficiency of ADH is usually due to hypothalamic-neurohypophyseal lesions (central diabetes insipidus) or insensitivity of the kidney to ADH (nephrogenic diabetes insipidus). These patients, if untreated, have the predictable result of dehydration, hyperosmolality, hypovolemia, and eventual death in severe cases because of the main consequences of passing an excess volume of water.

Function of Oxytocin

• Stimulates contractions of the uterus during labor;  Labor is initiated when the oxytocin receptor  concentration reaches a critical threshold.
• Stimulates contractions of the mammary alveoli to  facilitate milk-ejection reflex.
• Involved in love, trust? (next slide)

Oxytocin the hormone of Love and Trust?

• Play a role mother-infant bonding during breastfeeding
• Related to monogamous bonding in prairie voles
  • Oxytocin antagonist prevent pair bonding
  • Oxytocin infusion facilitate bonding
• Associated with positive emotions in humans and probably involved in human trust

http://www.psychologicalscience.org/index.php/news/releases/the-dark-side-of-oxytocin.html

https://www.scientificamerican.com/article/to-trust-or-not-to-trust/

Oxytocin receptor is a G protein-linked receptor

 

The pineal gland & Melatonin

• A tiny pine cone-shaped  structure in the center of the  brain
• Secretes melatonin (derived from tryptafan) which  increases with darkness and  peaks after middle night (~2  am)

How Light Inhibits Melatonin Secretion #Post

• Melatonin secretion is controlled by the  suprachiasmatic nucleus (SCN) of the hypothalamus, master pacemaker of circadian  rhythms > Receive input from melanopsin found in the retinal ganglion cells (retina) > light detection sends AP to SCN  suppressing melatonin secretion when light is detected

SCN receives input from Melanopsin signaling

• A special type of retinal ganglion cells (sRGC) detect light at the back of the eye controls the SCN and regulation of melatoin
• Melanopsin (protein) in RGCs is a circadian photopigment
• When melanopsin is activated in response to light, it triggers action potential that is transmitted as nerve impulse to SCN,  which in turn suppresses (inhibits) melatonin secretion.

Regulation of melatonin secretion in response  to light/dark cycle

Core components of the circadian  transcriptional clock in peripheral cells

The body cells itself appear to have inherent circadian cells and genes that are likely independent on the SCM shown by 2 groups of proteins (Per2, Cyr1 & Npas, Bmal1). This was recently discovered in 2018~ and won a Nobel prize.

How are these regulated? By negative feedback mechanism regulated during the day by the CLOCK genes, then those genes are inhibited at night.

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Lecture 3 Endocrine System II

Lecture #3 W3

Thyroid Gland

• The largest of the pure endocrine glands.
• Located in front of the neck just below the larynx.
• Secretes thyroid hormone.
• Thyroid gland made of millions of thyroid follicles made of epithelial cells, inside the gland is a liquid called colloid.
• Between these cells are parafollicular cells which are involved involved in secretion of calcitonin which regualtes calcium homeostasis

 

The 2 ingredients that have to get transported are iodine and thyroglobin. The iodine goes through the cell membrine (pendrin).

Throperoxidase function is to oxidise iondine to iodene.

Transport and conversion of Thyroid hormones

• Triiodothyronine (T3) and thyroxine (T4) are collectively called thyroid hormones.
• Thyroid secretes 90% T4 but T3 is 4 times more potent/more active form.
• T4 is converted to T3 in the liver and kidney
• Most of the thyroid hormone in the blood is bound to thyroxine binding globulin and albumin; only 0.3% T3 and 0.03% T4 are free and biologically active.
  • Why? T3 and T4 are hydrophobic, therefore they are poorly soluable in water so by binding to plasma proteins will increase the __ also this will prevent these hormones being eliminated in the kidneys. 

Functions of Thyroid Hormones

• Increases overall basal metabolic rate thus increases heat production 
• Stimulates consumption of glucose and fatty acids and increases metabolic heat (non-shivering thermogenesis).
  • Thus the disregulation of TSH (especially during menapause) can adversely affect body composition,
• convert glycogen into glucose and stimulates protein degradation.
• Sympathetic-mimicking effect – increase target cell responsiveness to Epi and NE
• Essential for normal growth and promotes the maturation of nervous system
• Hyperthyroidism function to increase overall metabolic rate so the symptoms that occur are usually: irritable, very synpathatic, big appetiate, if not treated may have muscle wastage.

Current understanding of how TH stimulates non-shivering thermogenesis

• Important function of TH is to stimulate NST.
• It can stimulate the metabolic heat production through various mechanisms in the bottom left of the image.

But brown fat doesn’t work passively in the background. There needs to be a trigger for brown fat activity. The trigger is the cold. One mechanism is how Thyroid Hormone stimulates brown fat activity.

1. Brown fat activity is triggered by the sympatric nerve activity which is downstream of TH.
2. In response to cold TRH and TSH are released which will increase release of TH then the TH targets the hypothalamus
3. downregulates AMPK
4. which activates sympathetic nerve activity
5. which induces brown fat activity by stimulating the production of UCP1.

How TH stimulates NST in brown fat tissue

A recent study has shown TH can activate sympathetic nerve activity that innervates the brown fat tissue. TH can target this special nuecleus in the hypothalamus – TH will decrease the levels of protein AMPK which will in turn increase sympathatic nerve acitivity to stimuluate brown fat activity to generate more heat.

Regulation of secretion of thyroid hormone

HYPOthyroidism

Etiology/causes: primary or secondary

• Inadequate supply of iodine.
  • Biosynthesis of thyroid hormone: Iodine binds to tyrosine residues in thyroglobulin molecules to  form thyroxine (T4) and triiodothyronine (T3) collective known as the thyroid hormones.)
  • Circulating level of thyroid hormone is very low, such that negative feedback mechanism is activated  on the anterior pituitary and hypothalamus. Thyroid-stimulating hormone (TSH) secretion is elevated  to act on the thyroid to increase their rate of secretion. However, no amount of TSH will be able to  induce these cells to secrete T3 and T4 if the thyroid cells lack a critical enzyme or iodine.This will trigger hypertrophy and hyperplasia of the thyroid, (increased in size and number of follicular  cells) leading to enlargement of the gland, known as a goiter.
• Goiters are associated with both hypothyroidism and hyperthyroidism but  plasma concentrations of relevant hormones are determinant factors if a  goiter will form. In some cases of both, a goiter need not necessarily be  present.
• Autoimmune disease (e.g. Hashimoto thyroiditis – body has developed autoimmune antibodies against thyroid gland)
  • At later stages of hashimoto’s gland will actually shrink because the thyroid gland gets destroyed.
• Deficiency of TSH, TRH or both
• Symptoms: Sluggishness and intolerance to cold

• A Goiter develops when the thyroid gland is over-stimulated by TSH
• Neonatal hypothyroidism can lead to Cretinism, a condition of severely impaired physical and mental growth in infant.

HYPERthyroidism

• Graves’ disease is the most common cause
• In Graves disease, the body erroneously produces thyroid- stimulating immunoglobulin (TSI) (against TSH receptor) which produces large amounts of T3 and T4
• TSI exerts TSH-like effects on thyroid but is Not subjected to negative feedback.
• Symptoms: can cause elargement of the thyroid and can stimuliate water retention at the back of the eye socket causing a progrution of the eyes out of the socket
• CAUSE/ETIOLOGY OF GRAVES DISEASE: Generation of an autoimmune antibody directed against TSH receptors

Which of the following would not support the diagnosis of Graves disease? 

• Increased levels of TSH
• Decreases levels of TRH and TSH would support the diagnosis of Graves disease due to an inhibition mechanism that…?

Parathyroid glands and hormones involved in calcium metabolism

• Parathyroid hormone
• Calcitonin
• Vitamin D

Majority of CA+ is in bone, only 1% in non-bone areas. Its crucially imporant that CA+ in the extracullular is mainatained constant otherwise it can be life threatening.

Homeostasis of Extracellular Matrix Calcium is vital

Hypocalcemia

• If there is not enough CA+ in the blood it increases neuromuscular excitability which causes too much muscle contraction which means __, therefore, you’ll get muscle cramps (could help explain why dehydration/high sweat rates can contribute to muscle cramps)
• May lead to muscle cramps
• Severe hypocalcemia causes spasm of respiratory muscles, leading to suffocation.

Hypercalcemia

• reduces excitability and can cause cardiac arrhythmia due to a defect on the AP Why? …

How can Hypercalcemia reduce excitability and why CA+ homestasits is critical

Practical implications to having adequate electrolyes (CA+) to support high sweat rate envrionments/exercise

If stimulus is strong enough you get influx of NA+ causing depolarisation caused by influx of K+, an AP and then repolseration which causes muscle contraction. That is fine with a strong enough stimulis. With not enough stimulus the membrane potential does not reacch the threshold potential unable to generate an AP. When the NA+ goes in to generate depends on how many NA+ channels are open. CA+ have the function to block the NA+ channel. Once you have enough NA+ ions blocking the … If you don’t have enough NA+ the small stimuus will cause enough NA+ channel to open .. (lecture not recorded)

Parathyroid Glands

Para = 4 (that’s why there’s 4 glands)

• 4 glands embedded in the lateral lobes of the thyroid gland.
• Secrete parathyroid hormone (PTH): A 84  amino acid polypeptide
• The most important hormone in the control of blood [Ca2+], essential for survival.
• Stimulated by decreased blood [Ca2+].

Parathyroid glands and hormones involved in calcium metabolism

On bones

• Promote the transfer of [Ca2+] from bone fluid to plasma (fast effect)
• Stimulate dissolution of calcium phosphate crystals to release [Ca2+] and PO43- (slow effect)

On kidneys

• Stimulate [Ca2+] reabsorption
• Promote PO43- elimination (to prevent re-precipitation of Ca++)

On Intestine

• Increase both [Ca2+] and PO43 (phosphate)- absorption via vitamin D activation in Kidneys (Vit D is important for CA+ absorption)

Abnormalities associated with Parathyroid Hormone (PTH)

PTH hyposecretion Causes

• PT removal mistakenly during thyroidectomy
• Rarely as a result of autoimmune disease and genetic defect of PTH gene etc.
• Fatal in complete absence

PTH hypersecretion Causes

• Chronic kidney failure
  • the main reason for this is because the kidneys are important for the elimination of phosphate so if the kidneys fail you get phosphate retention it will combine with CA+ to precipitate it on the bone which will decrease CA+ levels
• Parathyroid hypertrophy or malignancy

Vitamin D

• Also known as calcitriol; synthesized in the skin or from diet. 
• Converted to 25-hydroxy Vitamin D in the liver and 1, 25-dihydroxy Vitamin D (active form) in the kidneys
• VD is important for maintaining CA+ homeostasis
• Promote Ca++ and PO4 (phosphate) absorption from the intestine
• Increase responsiveness of bone to PTH
• Vit D deficiency may lead to rickets and/or osteomalacia (usually occur together).

Calcitonin

The opposite function to parathyroid hormone

• Secreted by the parafollicular cells of the thyroid to reduce blood CA+ levels 
• Secretion is stimulated by high blood calcium concentrations.
• Acts as a physiologic antagonist to PTH.
  • inhibits osteoclast (bone breaker) activity
  • delays calcium absorption from the intestine
  • increases calcium urinary excretion
• It has been used to treat osteoporosis to mobilise the CA+ onto the bone to increase bone density. How does that work? 

Estrogen (and androgen) inhibits bone reabsorption and promotes bone deposition

• Osteoporosis is characterized by low bone mass and deterioration of bone tissue.
• This leads to increased bone fragility and risk  of fracture.
• Osteoporosis is often known as “the silent thief”  because bone loss occurs without symptoms.
• Occurs more often in  postmenopausal women largely due to reduced estrogen levels and in older men due to low T

Adrenal Glands

• Each is embedded in a capsule of fat on top of each kidney
• Consist of outer adrenal cortex and inner adrenal medulla
• Produce 4 different hormones

Adrenal cortex

Each zone expresses a unique set of enzymes for the synthesis of the steroid hormones in that zone.

Steroid synthesis occurs in mitochondria and smooth endoplasmic reticulum

In the mitochondria, CHOL is converted to pregnenolone (pregnenolone is the starting material in the production of testosterone, progesterone, cortisol, estrogen and other hormones)

Remember: 21-hydroxylase and 11b-hydroxylase they are imporant…

Aldosterone

Function

• Most important function to Stimulate the kidneys to reabsorb Na+ and secrete K+
• The secondary effects are the osmotic retention of water (likely due to Na+ reabsorption) and expansion of ECF volume.
• Essential for life

Regulation of Aldosterone secretion

• Most important function is the decrease in Na+ Concentration and blood pressure activates Renin–Angiotensin-Aldosterone System (RAAS)
• Increase in extracellular [K+] directly stimulate the adrenal cortex to produce aldosterone
• If there is a decrease in NA+  sensed by the kidneys via the protein renin…
• Aldosterone is important for maintaining blood pressure because of the effect on NA+ absorption

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Abnormalities with aldosterone secretion

Aldosterone hypersecretion

• Primary cause: e.g. adrenal tumor of aldosterone-secreting cells (Conn’s syndrome)
• Secondary Cause: e.g. overactivity of Renin-Angiotensin system due to reduced blood flow to the kidney

Aldosterone hyposecretion

• Primary Cause: adrenal cortical insufficiency (addison’s disease) is mainly due to autoimmune disease; can affects all layers of adrenal cortex
• Secondary Cause: Congenital adrenal hyperplasia due to genetic defect of 21- hydroxylase or 11β-hydroxylase.

Glucocorticoid – Terminology

Glucocorticoids are a class of corticosteroids, which are a class of steroid hormones. 

• Cortisol is the primary glucocorticoid for most mammals including human
• Corticosterone/steroid serves the same function in rodents, birds, amphibians, and reptiles. Cortisone is a short form for corticosterone
• Glucocorticoid is often used for drugs that mimic the action of cortisol (e.g. dexamethasone)

Cortisol

Features of Cushing’s syndrome (hypersecretion of Cortisol)

Glucocorticoids – Functions

PRACTICAL: This is why you have to be careful about topical creams and drugs with cortisol and glucocorticoids because they can have minor versions of some of these symptoms… e.g. cortisol has an adverse affect on wound healing, fat storage etc

Q: what can this effect of creams actually have? 

Adaptation to stress: any stress is a major stimuli for cortisol secretion (Permissive role for catecholamines)

Metabolic effect

Glucose

• Stimulate hepatic (liver) gluconeogenesis.
• Inhibit glucose uptake and consumption by many tissues but not brain tissue.

Protein

• reduces protein stores in all tissues except the liver via promoting degradation and inhibiting synthesis

Lipid

• increase lipolysis in the limbs and promote fatty acid oxidation in some parts of the body therefore some can have very thin limbs
• However, it increases lipogenesis in the face and torso to people can have moon face and a large gut

Immunosupressive effects: Suppress all aspects of the inflammatory response (e.g. immune cell proliferation, cytokine secretion and fever production).

Glucocorticoid –  regulation of secretion: how cortisol is created

Abnormalities with cortisol secretion

Cortisol hypersecretion (Cushing’s Syndrome)

• Primary: adrenal tumor
• Secondary: excessive stimulation by CRH and ACTH.

Cortisol hyposecretion

• Primary adrenal cortical insufficiency (Addison’s disease)
• Congenital adrenal hyperplasia

Adrenal androgens

• DHEA (dehydroepiandrosterone) is the only biologically significant androgen from the adrenal cortex, but much weaker than testosterone

May play significant roles in females:

• • Growth of pubic and axillary hair
  • Pubertal growth spurt
  • Female sex drive
• Secretion is stimulated by ACTH
• Negative feedback to GnRH instead of CRH

Adrenal androgen hypersecretion

• Commonly caused by a deficiency of 21-hydroxylase (Congenital adrenal hyperplasia).
• Associated with hyposecretion of aldosterone and cortisol secretion.
• Can lead to adrenogenital syndrome

The secretion of adrenal androgen is increased in patients with 21-hydroxylase deficiency. 

Q) An infant was born with genetic defect of the gene coding for 21-hydroxylase. What disorder(s) would the infant experience and what treatment should the infant receive?

21-hydroxylase is an enzyme that is involved in the biosynthesis of the steroid hormones such as aldosterone and cortisol

21-hydroxylase deficiency = Decreased production of 21-hydroxylase = Affects biosynthesis of aldosterone and cortisol:

1. Decreased levels of aldosterone and cortisol
2. Increased levels of 17-hydroxyprogesterone = Excess androgens synthesised

 DISORDERS:

1.Addison’s disease

• Cortisol hyposecretion
• Aldosterone hyposecretion → Salt wasting crisis

-low sodium levels (hyponatremia) and high potassium levels (hyperkalemia)

-As infant loses large amounts of sodium in their urine → Life threatening in early infancy and require immediate treatment.

-Infant might experience poor feeding, weight loss, dehydration, and vomiting.

2. Adrenal androgen hypersecretion → Congenital Adrenal Hyperplasia

• In people with 21-hydroxylase deficiency, their adrenal glands produce excess androgens, which are sex hormones that give males their ‘male’ characteristics.
• Female infant → May have ambiguous genitalia (genitalia that is not typical female nor male appearing), with normal internal female reproductive organs (ovaries, uterus, and fallopian tubes);
• Male infant → Normal genitalia but may have small testes and an enlarged penis.

TREATMENT:

1.To prevent salt-wasting crisis, infant can be treated with hormones and steroids such as:

• Corticosteroids to replace cortisol → Main treatment
• Mineralocorticoids to replace aldosterone → Help retain salt and get rid of excess potassium
• Salt supplements to help retain salt

2. To treat Congenital Adrenal Hyperplasia, infants can take a form of cortisol called hydrocortisone.

Hormonal interrelationships in adrenogenital syndrome

Adrenal medulla (inner part of adrenal glands)

• Consists of modified postganglionic sympathetic neurons, also known as Chromaffin cells.
• Innervated by preganglionic sympathetic neurons.
• Sympathetic stimulation of the adrenal medulla is almost solely responsible for epinephrine (adrenalin) release

Hormones from adrenal medulla / Catecholamines

• Adrenal medulla produces 80% epinepherine (adrenalin) and 20% norepinepherine (noradrenalin), collectively known as catecholamines (also includes dopamine)
• Norepinepherine is more important as a neural transmitter for sympathetic post-ganglionic neurons.
• Catecholamines are important for the maintenance of blood pressure. 
  • The catecholamines alter the blood pressure by altering the vascular resistance.
  • Control of the vascular resistance is achieved through vasoconstriction and vasodilation.
  • Vasoconstriction is mediated through the α adrenergic receptors in liver, kidney, skin and gut & vasodilation is mediated through β adrenegic receptors in skeletal muscle

Receptors for epinepherine and norepinepherine are called adrenergic receptors that bind to α and ß adrenergic receptors which are the major classes.

In general, α1 and ß1 are coupled to stimulatory G protein,  whereas α2 and ß2 coupled to inhibitory G protein.

α1-receptors: Bind Gs (stimulatory) protein to activate phospholipase C pathway

α2-receptors: bind the inhibitory G protein (Gi), inhibit adenylate cyclase.

ß1 and ß2: Activate (by Gs) or inhibit (Gi) adenylyl cylase.

Functions of Adrenalin (epinephrine)

Epinephrine reinforces the sympathetic nervous system and exerts additional metabolic effects.

Fight-or-flight response:

• Increase rate and strength of cardiac (ß1 receptor) contraction.
• Dilates the blood vessels supplying the heart and skeletal muscles EXCLUSIVELY through ß2 receptor
• However, it constricts most blood vessels supplying internal organs such as the kidneys and intestine (via α1 receptor), raising the total peripheral resistance. 

Vasodilation: Enlargement in the circumference and  radius of a blood vessel as a result of smooth muscle layer relaxing.

Vasoconstriction: Narrowing of blood vessel, smooth  muscle layer contract. Causing arterioles to decrease blood flow through that vessel and veins increase blood flow.

Metabolic response

• Promotes hepatic gluconeogenesis (generation of CHO from non-CHO forms) and glycogenolysis (the breakdown of glycogen to glucose) (liver and skeletal muscles) and lipolysis
• Stimulates glucagon secretion and inhibits insulin secretion.

Q) Epinephrine causes vasodilation in cardiac and skeletal muscles but  vasoconstriction in digestive organs and the kidneys. 1) How does it achieve  the differential effect in different organs? 2) What is the physiological  significance of this?

Epinephrine actions has different stimulatory effects on  the two major classes of adrenergic receptors, namely alpha and beta  adrenergic receptors.

Alpha 1 receptors are located on:

• all vascular smooth muscle, although densities vary thoughout the body
• GI & urinary sphincters
• dilator muscle of the iris

Beta 2 receptors are located on smooth muscle in:

• gastrointestinal tract
• urinary bladder
• skeletal muscle arteries
• bronchial tree
• coronary vessels

B2 adrenergic receptors are present in cardiac and skeletal muscle blood vessels to cause vasodilation in fight/flight situations because those organs needs a high demand of nutrient/O2 supply.

Epinephrine combines with both 𝝱2 and 𝛂1 receptors. Activation of 𝝱2 receptors produces vasodilation but not all tissues have it. It is most abundant in the arterioles of skeletal muscle and the cardiac muscles. In contrast, arterioles in digestive organs and kidneys are equipped with 𝛂1 receptors, which leads to vasoconstriction.

Note that cardiac and skeletal  muscles has beta 2 receptors  while digestive organs and the  kidneys have alpha 1 receptors.

During sympathetic stimulation of the adrenal medulla which leads to epinephrine release,  this allows the contrasting effect of vasodilation in specific tissues (cardiac and muscles),  and vasoconstriction in other tissues (organs and kidneys) ultimately depending on what  receptors they are equipped with.

It should be noted that arterioles in digestive organs and kidneys do not have 𝝱2 receptors  and as such, there will not be the contradictory effect of simultaneous vasodilation and vasoconstriction. It is subjected to only vasoconstriction. Subject only to vasoconstriction via adrenalin release or period digestive organs cna’t vasoconstrict?

What is the physiological significance of this?

• This allows maintenance of arterial blood pressure. When the sympathetic system produces an increased amount of epinephrine, this leads to an increase in cardiac output by increasing the rate and strength of cardiac contraction, hence increasing arterial blood pressure. So its supports the SNS in producing movement.
• This is possible as vasodilation of cardiac and skeletal arterioles shifts blood to the heart and skeletal  muscles from other vasoconstricted regions of the body, shunting blood to the areas of most  immediate need or to support their increased metabolic activity.

Endocrine control of stress response

 

Vasopressin important for maintaining blood volume.

Renin important for maintaining blood pressure.

The Pancreatic hormonesT

• Beta cells secrete insulin
• Alpha cells secrete glucagon
• These cells are embedded in the pancreas that secretes many of the enzymes that assist digestion – therefore pancreatic health is important to support/help from supplements from people who have GI problems is important.

Insulin and Glucagon antagonize (oppose) each other

Functions of insulin

• Promotes entry of glucose, amino acids and fatty acids into cells and increases their anabolic process (glycogenesis, fat storage and protein synthesis)
• Acts on insulin receptors mainly in skeletal muscles, liver and adipose tissue
• inhibits glycogenolysis, lipolysis and protein degradation (inhibits catabolism) AKA inhibits CHO/FAT/PRO breakdown
• The effects results in the decrease of blood levels of glucose, fatty acid and amino acids. (decrease? really?)

Regulation of Insulin Secretion

Positive regulators (whats that mean?)

• High plasma levels of glucose and amino acid
• Glucogan and Glucose-dependent Insulinotrpic peptide (Gastric Inhibitory Peptide).
• Parasympathetic activation

Negative regulators (whats that mean?)

• Somatostatin
• Sympathetic activation

Insulin is a hormone known to lower blood glucose levels. Level of glucose in the body becomes high = the beta cells of the pancreas become stimulated to secrete insulin.

Glucgaon raises BG levels when it detects lower BG levels or needs to liberate more fuel from tissue during excessive heat production (activity/exercise).

Insulin causes:

1. Muscle cells, adipocytes (fat cells) and the red blood cells to take up glucose by the GLUT 4 transporters.
2. The liver to convert glucose to glycogen in a process called glycogenesis.

Hence the overall effect of the insulin hormone is to lower the amount of glucose present in the blood.

GLUT4 is a glucose transporter in muscle and adipose tissue.

Diabetes mellitus is the most common endocrine disorder

Insulin resistance is a common characteristic of T2 diabetes

• A condition in which the body does not respond to insulin – SHIT definition.
  • Insulin resistance, occurs when higher amounts of insulin are needed to reduce blood glucose levels following the administration of the same amount of exogenous glucose.
• Decreased expression, increased internalization or immune destruction of insulin receptor are among the causes of insulin resistance.
• There is also a loss of post-receptor components in insulin signal transduction pathway (next slide)  including a defect in GLUT4 translocation:  lipid-induced  insulin resistance (slide after next)

Insulin signalling Pathway

Insulin will activate PI-3-kinase > which will activate Akt-kinase > the activation of Akt-kinase causes the insertion of glucose transporter GLUT-4 onto the cell membrane so it can open the gate for glucose to enter the cell.

• Insulin is the only hormone that helps put maronutrients into storage.
• Glucagon, epinerpheran, thyroid hormone and GH all help liberte and utlilise fuel stores.
• This highlights the importance of managing insulin sensitivity/resistance (CHO consumption) over a lifetime to manage/mitigate fat gain (therefore all cause mortaility) and blood sugar disorders such as metaolbic syndrome and T2 diabetes. #Post

Lipid-induced defect in insulin signalling

• Intra muscle lipid level predicts insulin resistance
  • Kind of obvious inferring that fater people are generally going to have a harder time utlising and storing fuels considering it’s likely the habit of eating a high quantity of shit food a contributor 
• The free fatty acid inhibits GLUT4 translocation to membrane of muscle cells by inhibiting PI-3K signalling
• Too little fat is equally bad. Fatless mice manifest  liver and muscle insulin  resistance and develop  diabetes because they have high intracellular fat which develops intermediates which blocks the insulin transduction pathway thus the GLUT4 glucose transporter cannot be inserted into the cell membrane.

How Fat Affects Insulin Signaling & Insulin Resistance

Obese people tend to have high level of intra-cellular lipid. This intra-muscle lipid can be metabolised to generate some harmful intermediates (Long-chain acyl-CoA – an indicator of lipid metabolism) which then generates Ceramide and DAG – and these intermediates turn out to inhibit the activity of all these components along the insulin receptor transduction pathway. Once these are inhibited then GLUT4 cannot be inserted onto the cell membrane then the glucose cannot come into the cell and it’s stays floating around in the circulation and you’re left with high blood glucose and insulin resistive like state.

Endocrine control of fuel metabolism

Metabolism – synthesis, degradation and transformation

Key tissues in metabolism:

• The Liver: Primary role in maintaining blood glucose level (glycogenesis, glycogenolysis and glyconeogenesis)
• Adipose tissue: store fat to regulate blood fatty acid level
• Muscle: Primary site for amino acid storage and is the main energy user
• The brain: use glucose as the only source but can not store glycogen

Normal fuel metabolism

• Insulin Lower blood glucose, amino acid and fatty acid level, promote anabolism of these molecules
• Glucagon opposes the actions of insulin
• Thyroid hormone increase metabolic rate

In response to stress

• Epinephrine and cortisol – increase blood glucose and fatty acids
• Growth hormone – increase blood glucose and fatty acids; increase amino acid uptake and protein  synthesis.

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Reproductive Physiology #1

Lecture #4 W4

#1 goal is to ensure species survival and pass on genes

Structure of the reproductive system

 

Uterine tube = fallopian tube

Male and female both have…

• Gonads
• Internal genitalia (reproductive tracts and secretory glands)
• External genitalia

Reproductive structures in human fetus in  the first 6-7 weeks are indifferent – they have no sex

Gonad turns into an ovary or the testis 

Mesonphros partly forms into the gonads and the other part will degenerate

Mullerian Duct develops into the female fallopian tube then the Wolffian duct degenerates 

Wolffian Duct turns into the male reproductive tract vas deferens then the Mullerian degenerates 

Sex can be defined at 3 levels

Genetic sex does not guarantee gonadal sex (the structures of their genitalia and reproductive system) which in turn affects phenotypic sex (external genetalia)

Estrogen is not secreted by the fetal gonads but rather present as placental estrogen, it is the placental estrogen that induces the development of the female external genitalia.

Does the development of the female reproductive tract during sexual differentiation require estragon from the ovaries? No. Because if you castrate a male/female the foetus will develop a female reproductive tract. But why? Because it’s the placenta that provides a large amount of E that is why the female reproductive tract is default because E is in high supply via the placenta.

If androgens are absent in females the Mullerian ducts persist and develop into Fallopian tubes, uterus, cervix, and the vagina, and due to the absence of androgens, the Wolffian ducts regress. 

 

Genetic Sex: Your chromosone combination: XX = Female / XY = Male

Gonadel Sex: Your reproductive system 

Phenotypical Sex: External genitalia 

Genetic sex determines Gonad sex

The evidence – SOX9 mediates the  effect of SRY

• SOX9 is a direct target of  SRY
• SOX9 mutation is associated with male to female sex reversal in humans
• SOX9 induces testis development and male behaviour in XX human and  transgenic mice
• Sox9 is critical for the development of The testes. SOX 9 induces testis development and male behaviour in XX humans.
  • SOX9 > Testes > Testosterone > Wolffian Duct = It is responsible for the development of the testes which in turn secretes testosterone which develops the Wolffian duct
  • SOX9 helps regulate sex differentiation, and is indirectly responsible to the development of the Wolffian ducts: 

Testes: SOX9 (Sry-related HMG box) that encodes a transcriptional activator. Together with FGF and SF-1 → results in differentiation of primitive gonads into testes

Mullerian Ducts: AMH expression is upregulated by FSH via cAMP. SOX9 and SF1 binds to AMH promoter which is essential to increase the activity of AMH promoter in response to cAMP.

Wolffian ducts: SOX9 results in the testosterone which leads to the wolffian ducts in developing into male reproductive tract and seminal vesicle.

DEX1 in male (red) the levels drop once the sex deferentiation is initiated whereas in the female it rises and maintains a very high level. Therefore thats an indication that DEX1 may be important in ovary differentiation.

The absence of SRY gene in a XY male may lead to the development of female reproductive tract in the fetus. (In the absence of the SRY gene, there is no production of SOX9, FGF9 or SF-1 and therefore, the reproductive structures in a fetus develop into a female reproductive tract. In Addition, without an SRY gene, Wnt signalling is not inhibited. This results in the increase in ovary differentiation)

Not just SRY – is DAX1 anti-testicular or pro-ovarian?

• DAX1 is a transcription factor expressed normally in primitive gonads but  down-regulated in males.
• It has been found that the Duplication of DAX1 in an XY individual can was reported to cause male- female sex reversal in humans. Some evidence that DEX1 can inhihbit testies differentiation.
• Similar observations have been found in mice: XY mice carrying extra copies of Dax1 showed delayed  testes development; Complete sex reversal occurs when the transgene is tested against weak alleles of Sry gene (weak alleles, mean the expression levels are lower).

Not just SRY –  is RSPO1 critical for ovary development?

• R Spondins is a signal to a beta-catenin pathway.
• A family of four brothers with XX had no insertion of SRY but a mutation (Defective) in RSPO1 (Nature Genetics, 2006) because their RSPO1 doesn’t work/
• A 46XY individual with a duplication of chromosome 1 region containing RSPO1 had male-to-female sex reversal
• Similar sex reversals were observed in transgenic mice.

Sexual differentiation – Genetic sex determines Gonad sex

Antagonistic balance between SRY and Wnt signalling in sex differentiation?

In XX (female) the Sox9 and Fgf9 are NOT active

 

How SRY inhibits Wnt signaling in sex differentiation

 

Both M&F both have beta-catenin but in the male we also have SrY, and the SrY will bind the repressive complex so the beta-catenin can change the expression of the genes so you won’t become a women.

Alfred Jost showed that testes determine phenotypic sex irrespective of genetic sex

How does gonadal sex determine phenotypic sex?

1. If Jost removed the ovaries from the developing fetus that was starting to differentiate (to ovaries or gonads) it developed into a female reproductive tract.
2. If he removed the testes from the male foetus, the foetus also developed a female reproductive tract.
3. Therefore he concluded the testes determined the phenotypical sex irrespective of genetic sex.

He then wanted to discover why – what do the testes do to induce this phenotypic sex?

In this rabbit, the rabbit is supposed to develop female reproductive system and the Wolffian duct is supposed to degenerate into but it didn’t because of the presence of T, therefore, this shows that testosterone is important for the Wolffian duct to develop. Administering T after castration resulted in the development of the reproductive tract.

The SRY gene is responsible for the development of the testes.

He wanted to see what would happen if he grafted the testes next to the ovary. What he found the effect was ipsilateral, on the side without the testes graft the development follows as normal so you have ovaries and on the grafted side the Mullerian duct degenerated and the wolffian duct developed. The grafted testes do not produce high enough ___? factors that will affect the othe side. 

In the presence of the testes the Mullerian duct will degenerate and the wolffian duct will develop into a male reproductive system.

In the case of a female the wolffian duct will degenerate and the mullerian duct will develop into a female reproductive system.

• Mullerin duct is to be differentiated to the female reproductive tract.
• Wolffian duct is to be differentiated into the male reproductive tract.

Genetic sex is typically determined by SRY

 

Disorders of chromosomal sex -Chromosome Aneuploidy

• Turner’s syndrome: 44+XO – female, 1 in 2500.
  • this individual would lack an X chromosome
  • 99% of people with this don’t survive
• Triple X female (44 + XXX), 1 in 1000 .
  • Has an extra X chromosome
• Klinefelter syndrome: there is at least one extra X (44+XXY, 44+XXXY etc) chromosome in males (1 in 1000).
  • One of the most common causes of male infertility.
• XYY, Jacobs syndrome, 1 in 1,000 male births. 96% phenotypically normal.
• True hermaphroditism: an individual is born with ovarian and testicular tissue either fuse together (ovotestis) or one on each side.

Disorders of phenotypic sex due to endocrine disorder

• Defect in the androgen or its receptor would result in developmental failure of male reproductive tract.
  • Testes in a genetic male fail to secrete androgens
  • Or a defect in the androgen receptor gene (testicular feminization syndrome)
• Genetic deficiency of 5 alpha-reductase results in failure of the development of male external genitalia.
  • Catalises the conversion of T to dihydrotestostrone.

Testosterone is required for the development of the male reproductive system. In the body, testosterone is converted to dihydrotestosterone (DHT) in some target tissues by 5a-reductase. Target tissues for DHT include the prostate, external genitalia, and genital skin while target tissues for testosterone include the wolffian structures and the testes, among other tissues.

Testosterone Dihydrotestosterone

• Adrenal androgen hypersecretion (in the case of congenital adrenal hyperplasia) may cause genital ambiguity in female infant.

 

Male reproductive system

Components – The Accessory sex glands

Seminal Vesicles

• Provide bulk of the semen
• Supply fructose to nourish the sperm
• Secrete prostaglandins which stimulate contraction of smooth muscles of the ‘tract’ facilitate sperm transport
• Secrete fibrinogen to clot the semen

Prostate gland

• Secrete alkaline fluid to neutralize the acidic vaginal Secretion to facilitate the sperm’s survival
• Provide clotting enzymes to ‘clot’ the semen and fibrinolysin to degrade the ‘clot’

Bulbourethral glands: Secrete mucus for lubrication

Histology and function of the testes

Seminiferous tubules

• The Site of spermatogenesis (sperm production)
• Contains germinal cells and Sertoli cells
• Interstitial cells, also known as Leydig cells
  • Secrete testosterone

Functions of Sertoli cells

• Form tight junctions to provide testes-blood barrier to protect testes so they won’t be poisoned by things that are harmful to it
• Secrete chemicals and proteins to provide nourishment for spermatogenic cells.
• Establish the stem cell niche to ensure renewal of sperm cell precursors.
• Produce androgen-binding protein (ABP) which binds to testosterone to concentrate (100x) the hormone in the tubules.
• Secrete inhibin which inhibits FSH (follile stimulating hormone) release in a negative feedback loop
• Secrete AMH (Anti-Müllerian hormone)

image

Spermatozoon

• Head: contains the nucleus
  • Acrosome: contains enzymes  (hyaluronidase) for penetrating the  ovum
• Mid piece: contains mitochondria for the sperm to swim to get to the egg
• Tail: responsible for movement

Semen

• 10% sperm and testicular fluid,
• 30% prostate secretions,
• 60% seminal vesicle secretions.

Androgens: origins and target tissues

• Include adrenal and testicular androgens
• Testosterone is synthesized by Leydig cells
• Testosterone is converted to dihydrotestosterone (DHT) in some target tissues by 5α-reductase.
  • Prostate Cancer: 5a-reductase is used in prostate cancer becaue prostate grwoth depends on androgens, namely DHT therefore in order for prostate cancer to grow it reliaes . Treatment includes using a 5a inhibitor that blocks the conversion to DHT.
• Target tissues for DHT include the prostate, external genitalia, and genital skin. Target tissues for testosterone include the wolffian structures, the  testes, muscles, bone, kidney, and brain.

Functions of Androgens (1)

Sexual differentiation

• Induce the development of male reproductive  tract and external genitalia
• Promote descending of the testes into the scrotum (where have your ‘balls dropped’ saying comes from)

Spermatogenesis

• Essential for both mitosis and meiosis

Functions of Androgens (2)

• Growth and maturation of the reproductive system;
• Maintain the function of male reproductive tract.
• Development of secondary sexual characteristics.
• Male-pattern behavior
• Non-reproductive function
  • Signal protein anabolism and muscle development
  • Stimulate bone growth and closure of epiphyseal  plates

Hormones in male reproduction

Anabolic steroids

• Synthetic steroids similar to testosterone in function.
• Target androgen receptor
• Used for hormone replacement therapy
• Abused for performance enhancement and ‘muscle building’ etc.
• Has a similar function as T
• Anabolic steroids chemical can bind to andoregen receptor with high afinity and specifcity 

Negative effects of Anabolic steroids

Short term effects:

• Males: premature baldness, testicular degeneration, impotence, development of breasts…
• Females: irreversible masculinizing effect, menstrual irregularities, uterine atrophy…

Long term effects: cardiovascular disease, increased risk of liver cancer, hostility and aggression…

What are the possible side effects of anabolic steroids on the reproductive system of female athletes who take anabolic steroids for an extended period of time? Explain the mechanisms for these side effects.

Anabolic steroids:

• Androgenic steroids →  include natural androgenic steroids like testosterone as well as synthetic androgenic steroids. 
• Used to enhance performance such as muscle hypertrophy and strength
• historically commonly used by athletes.

The potential side effects of such steroids on the reproductive system of female athletes may include:

• Menstrual irregularities
• Uterine atrophy
• Inhibition of follicle formation and ovulation as a result of prolonged hypogonadotropic hypogonadism.

Mechanisms for Follicle Formation & Ovulation Dysfunction:

Ovulation Dysfunction:

Inhibition of follicle formation and ovulation as a result of prolonged hypogonadotropic hypogonadism (reduction or absence of hormone secretion via the gonads):

• Anabolic steroids suppress the release of gonadotropins via negative feedback mechanisms. 
• After prolonged use of anabolic steroids, the level of anabolic steroids in the female athlete’s blood increases and as a result, negative feedback mechanisms may be activated to reduce the production of gonadotropins such as LH and FSH.
• When there is negative feedback to the hypothalamus, the production and secretion of gonadotropin-releasing hormone (GnRH) is decreased. This results in negative feedback to the anterior pituitary gland, and the production and secretion of LH and FSH is inhibited.  

Menstrual Irregularities Dysfunction:

• As a result of the decreased LH levels, there is inhibition of ovulation (egg release) in females.
• As a result of decreased FSH levels, the development of ovarian follicles is inhibited. This results in decreased levels of hormones such as estrogen and progesterone. This thereby results in menstrual irregularities as the above hormones are critical for a healthy functioning menstrual cycle.

 Uterine Atrophy:

• Uterine atrophy is the thinning, drying and inflammation of the uterine walls that may occur when your body has less estrogen.
• As a result of decreased FSH levels, and hence, the decreased levels of estrogen secretion, the uterine lining of the female reproductive system is unable to thicken adequately, resulting in the thinning of the uterine lining.

 

Prostaglandins –chemical structure

• Chemical messengers produced in virtually all tissues;
• 20-carbon fatty acid derivatives from arachidonic acid (fatty acid)
• They can act locally and inactivated rapidly after action
• The prostaglandins are a group of physiologically active lipid compounds called eicosanoids having diverse hormone-like effects in animals.

Prostaglandins synthesis by  cyclooxygenases

E.G. Aspirin (and NSAIDS) ihibits the cyclooxygenases pathway because their designed to reduce inflammation/pain. 

Explain the mechanism by which aspirin reduces fever.

Prostaglandin production by the hypothalamus resets the hypothalamic set point and then the hypothalamus operates on a new set point therefore it will initiate increased heat production. During the fever the substances that stimulate prostaglandin are known as endogenous pyrogens which are a result of inflammation. Aspirin/NSAID is a COX inhibitor to inhibit COX2 activity to reduce inflammation, pain and reduce prostaglandin production. Therefore you will reduce the temperature set point which will reduce the fever.

 

Prostaglandins

Have very broad functions……

Reproductive function

• stimulate reproductive tract contraction that
  • facilitates sperm transport
  • Is associated with painful menstruation
  • Involved in parturition
• is important for ovulation

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Reproductive Physiology (II)

Lecture #5 W5

Ovarian Follicles & Oogenesis

Oogensis/Ovogenesis: Creation of the egg (ovum).

Structures of the Ovary

• Present in millions at birth as primordial follicles (ovarian follicles) with ovum arrested in the prophase of meiosis I.
• Covered by a layer of epithelium.
• Consists of Cortex and medulla
• Ovarian follicles are in the cortex
• Medulla contains major blood vessels and nerves

Ovarian Follicles

• Consist of oocytes and surrounding follicular cells and stroma.
• Follicular cells include Granulosa and thecal cells
  • Graulosa cells produce Zona pellucida (protein) to cover the oocyte.
  • Thecal cells are specialized connective tissue cells for T production then converted to eostrogen
    • These 2 together are called follicular cells 
• After puberty, some follicles develop each month; mature follicles are also called Graafian follicles.

Graafian Follicles

depends on the activity of estrogen and FSH because they stimulate granulosa cell proliferation and maturation of follicles.

Different stages of development of the ovarian follicles 

Primordial follicles surrounded by the granulosa cells – each follicle contains an egg in the centre and follical/stroma cells – then eggs develop under the presentation of LH/LSH

Graafian = a mature follicle BEFORE ovulation

Estrogen synthesis occurs in the ovarian follicles by thecal and granulosa cells

How estrogen synthesis in ovarien follicles works:

Under stimulation of LH Thecal cells produce T > T then uses CHOL to diffuse into granulosa cells > then converted to estrogen by the enzyme aromatase so then T then becomes estrodiol. This process is stimulated by FSH. Then this estorgen will either be in the cavity to stimulate the maturation of the egg or secreted into the circulation.

Oogenesis

Before ovolation it competes meiosis I

Right after fertilisation is complete miosis II initiates

Why meiosis during oogenesis?

Meiosis: A type of cell division that results in four daughter cells each with half the number of chromosomes of the parent cell, as in the production of gametes and plant spores.

A few follicles are activated to develop during the monthly cycle and usually only one matures to ovulate!

MENSTRUAL CYCLE

• Occurs during female reproductive period (puberty – menopause)
• Cycle lengths vary and average ~ 28 days
• Most conspicuous feature is vaginal bleeding
• Each menstrual cycle involves two cyclic changes
  • ovarian cycle (maturation of the ovum)
  • uterine cycle (the process of uterine preperation for implentation)
    • The cycle is completely driven by homrones

The ovarien and uterine cycle occur alongside each other but they occur at different sites in the body, one in the ovaries one in the uterus.

Ovarian Cycle

Phase #1: Follicular phase (day 1 – 13)

• Oocyte growth and proliferation of granulosa and thecal cells.
• Both LH and FSH stimulate estrogen synthesis.
• Estrogen and FSH stimulate granulosa cell proliferation and maturation of follicles.
• Moderate levels of estrogen exert negative feedback to inhibit FSH and LH secretion, but the FSH-producing cells are more sensitive to estrogen therefore you’ll see a more obvious decrease in FSH levels.
• Follicular phase varies in length from person to person, and generally gets shorter closer to menopausal age.

Phase #2 Ovulation (Day 14)

• Enlarged Graafian follicle bulge on the surface of the ovary, and the secondary oocyte is expelled.
• High concentrations of estrogen exert positive feedback to cause abrupt, massive increase in LH secretion (LH Surge)
• Therefore the LH levels can be used as a predictor of ovolation
  • What symptoms does this contribute to? Increased libido? 
• LH surge triggers ovulation by inducing local production of prostaglandin and activation of proteases (e.g. plasmin) through progesterone receptor. 

How does LH induce ovolation? Role of progesterone and prostaglandins in the modulation of proteolytic activity during ovulation…

LH will target this ovarian follicle where the ovum is attached to it will induce the expression of progesterone and COX2 (enzyme that makes prostaglandins). For progesterone it can increase the production of protelyic enzymes which can cause the destruction of the ovarian follicle wall. The progestoerone receptor is key for the process of ovulation. This is howLH promotes ovulation. 

Phease #3 Luteal phase (Day 15 – 28)

• Follicular cells are converted into steroidogenic cells that form the corpus luteum (yellow body) following ovulation.
• Secretion of a large quantity of progesterone and a moderate amount of estrogen to prepare the uterus for implantation of fertilized egg.
• LH triggers the differentiation of follicular cells into luteal cells (can store large amounts of lipids/CHOL) and stimulates the secretion of a large amount of progesterone and smaller (but large) amount of estrogen. During this phase, the progesterone plasma concentrations 1000x more than estrogen. We don’t know why we need so much progesterone during this phase. 
• Progesterone and estrogen exert negative feedback  on LH and FSH secretion.
• The fall of estrogen and progesterone following the demise of corpus luteum allows moderate secretion of  LH and FSH that initiate the next follicular phase.

Uterine Cycle

Proliferative Phase (Day 1 – 13)

• Correspond to follicular phase
• Estrogen stimulates growth of epithelial cells, glands and blood vessels.

Secretory phase (Day 15 – Day 28)

• Corresponds to luteal phase.
• Embryo implantation occurs
• Progesterone converts the thickened endometrium to highly vascularized, glycogen-filled tissue.
  • Estrogen responsible for stimulating growth of epithelial cells, glands and blood vessels in endometrium in proliferative phase: thickening of endometrium.
  • Progesterone responsible for conversion of thickened endometrium to highly vascularized, glycogen-filled tissue to sustain zygote. It also causes further stromal cell growth.

Menstrual Phase (Day 26~ – Day 1)

• Coincides with the end of luteal phase and onset of the follicular phase.
• Necrosis and sloughing of endometrium
• Due to the demise of corpus luteum and resulting withdrawal of estrogen and progesterone

Mechanism of negative and positive feedback on GnRH secretion by estrogen

It seems the reason is because estrogen has different effects in differnet types of neurons which in turn result in poisitve and negative feedback loop.

High levels of estrogen enhance GnRH secretion by stimlating Kisspeptin reelase from AVPV neurons. 

Questions

Moderate levels of estrogen inhibit the hypothalamus and anterior pituitary in negative-feedback fashion.

• Correct, as moderate levels of estrogen will inhibit Kisspeptin release from Arcuate KiSS-1 Neuron via negative feedback mechanism, which in turn inhibits GnRH neurons in the hypothalamus, which in turn suppresses LH and FSH secretion in the anterior pituitary.

At high level, estrogen stimulates LH secretion and initiates the LH surge.

Correct. High estrogen levels stimulate AVPV KiSS-1 Neuron, increasing Kisspeptin secretion, which induces GnRH Neuron to secrete more GnRH, which increases LH secretion in anterior pituitary.

Progesterone inhibits LH secretion.

Correct. Luteal cells differentiated from follicular cells secrete progesterone, which suppress LH via negative feedback. Demise of corpus luteum and corresponding fall of progesterone and estrogen allows moderate secretion of LH and FSH that initiates next follicular cycle.

Histological structure of the uterus

• Endometrium: stratified epithelium, stroma and glands (the inner most layer / thick)
• Myometrium: smooth muscle cells useful for assiting uterine contractions
• Perimetrium: connective tissue covered by simple  squamous epithelium covering the utereus

Disruption of menstrual cycle

Caused by many factors including abnormalities in the hypothalamus – pituitary – ovary axis, stress, low body weight, and vigorous physical activity etc. 

• Amenorrhea: Absence of menstruation
• Oligomenorrhea: irregular cycle or infrequent intervals

 

• Main health risks: premature osteoporosis (remember: estrogen is very important for bone health)
• Potential benefits: lower cancer risks in reproductive tissues? (No clear causation but some studies suggest it)
• Menopause: Cessation of menstrual cycle at the end of reproductive age marked by a plummet in estrogen.

Q: A young woman is given daily injections of a substance beginning on  the 16th day of her normal menstrual cycle and continuing for 3 weeks. As long as the injections continue, she does not menstruate. What is  the most likely identity of the injected substance?

Menstruation occurs due to the withdrawal of estragon and progesterone. The withdrawal of E & P happens because the corpus luteum degenerates. The CL won’t degenerate if you have continual high levels of LH so therefore by taking LH injections you stop the CL from degenerating therefore the withdrawal of E & P won’t occur therefore menstruation won’t occur.

Testosterone won’t affect the level of Estragon or Progesterone.

A 20-year-old female patient has developed the disorder of hypersecretion of androgen from the adrenal cortex. How would the condition affect her menstrual cycle?

Oral contraceptives

The ‘pill’ – synthetic estrogen and progesterone to prevent implantation

Usually take for 21 days then stop 7 days then take again

The commonly used birth control pill contains synthetic estrogen and progesterone. The pills are usually taken daily for 21 days. This is followed by 7 days with no pills. The schedule is repeated if contraception is desired.

How does the pull kind work to prevent pregnancy?

 

• The “Minipill“ – progesterone only
• Morning after pill: Plan ‘B’ and Ella
  • Plan B is said to be effective with 72h
    • high dose of progesterone, if there is ovulation high level of progesterone would be able to increase the secretion of the mucous in the uteris so the mucous so the sperm is unable to reach the site of fertilisation in time)
  • Ella is said to be effective within 5 days
    • Ella contains RU486 derivative Ulipristal acetate. It is reported to be effective in preventing pregnancy if taken within 5 days of unprotected sex.
    • Is a progesterone antagonist so progesterone doesn’t bind

Mechanism of How Ella & Plan B Work

Plan B: (Levonorgestrel emergency contraceptive (LNG-EC): 

• Primary mechanism: Its primary mechanism to prevent pregnancy is through the inhibition/disruption of ovulation.
• Ella is progesterone receptor antagonist that inhibits progesterone action.

It prevents pregnancy through its antagonist activity. Ella can prevent pregnancy through 2 mechanisms:

1.Before ovulation it can inhibit progesterone action to delay or prevent ovulation because progesterone is required to induce the proteolytic enzyme’s to digest the follicle wall – Ella inhibits this action of progesterone therefore prevents or delays ovulation

2.The second mechanism is that it inhibits progesterone activity on the endometrium. Progesterone is required for endometrium thickening, in particular for stimulating glandular secretion/development in the endometrium. Without it the endometrium is unable to receive the zygote / implanted embryo and support pregnancy.

Explanation:

• The synthetic progesterone, levonorgestrel, binds to the progesterone receptors which results in negative feedback to the hypothalamus. This results in the reduction of production of Gonadotropin releasing hormones (GnRH), which thus signals the anterior pituitary to produce lesser amounts of FSH and LH. The reduction in FSH prevents the stimulation of granulosa cell proliferation and maturation of follicles. While the reduction in LH levels inhibits the preovulatory luteinizing hormone surge, thus impeding the release of the egg itself. Thus, the primary mechanism of plan B and ella is to either impede follicular development or ovulation, depending on which part of the menstrual cycle the women is in.

Explanation 2: 

A secondary mechanism of preventing pregnancies is through the thickening of the cervical mucus. The cervical mucus, under the influence of progestins, becomes thick and opaque. This prevents the transport of sperm from vagina into the uterus and fallopian tubes. Thus, sperm motility is affected which interferes with fertilisation of the egg, thus preventing pregnancies. However, the decreased cervical mucus quality is a result of long term progestin only contraception pills such as ‘the minipill’. However, the mechanism of ella and plan b is a one time, post coital use and cannot be compared to long term daily administration of progestin only pills. Thus, this mechanism of action to prevent pregnancy is highly debated, with numerous papers refuting this mechanism.

Ella

• Primary mechanism: Inhibition/disruption of ovulation
• Progesterone Antagonist
• Higher binding affinity to progesterone receptor

Inhibition of implantation

• Ulipristal acetate can exert an anti-progesterone effect on the endometrium when given in the luteal phase.
• Decrease endometrial thicknes
• Prevents implantation

Lastly, Ella can also prevent pregnancy through the inhibition of implantation. Ulipristal acetate binds to progesterone receptors to produce an anti-progesterone contraceptive effect on the endometrium by decreasing the endometrial thickness. Progesterone converts the thickened endometrium to highly vascularised, glycogen filled tissues. Thus, the antagonist effects on the progesterone receptors delays this conversion and thus decreasing the possibility of implantation. However, alike the mechanism of the thickening of the cervical mucus, this mechanism is also highly debated on.

Interferes with ovulation

• Ulipristal acetate binds to the progesterone receptors, exerting antagonistic effects
• The progesterone receptors are thus unable to induce expression of proteolytic enzymes to rupture the Graafian follicles to release secondary oocyte.
• Fertilisation cannot occur as secondary oocyte is not released

WHAT ARE THE SIDE EFFECTS AND WHAT HAS THE LEAST SIDE EFFECTS? 

Hormonal Termination of Pregnancy

• • RU486/prostaglandin used to terminate early stage pregnancy
  • ru486 acts as a progesterone receptor antagonist to prevent progesterone from binding.

Side Effects of the pill

• Cardiovascular effects (estrogen increases the risk of blood clotting, etc.)
  • Blood Clotting: Proteins in your plasma (the liquid part of blood) work together to stop the bleeding by forming a clot over the injury
• The effect on cancer risks is not significant or controversial.

Fertilization, implantation and parturition

Fertilization: The action/process of fertilizing an egg.

Implantation: The attachment of the fertilized egg or blastocyst to the wall of the uterus at the start of pregnancy.

Paturition: The action of giving birth

Fertilization (I)

• The site of fertilization = ampulla
• Of the 300 million sperm ejaculated, ~ 100 reach fallopian tube, usually one fertilizes the egg.

Fertilization (II)

In order to fertilize the egg the sperm has to secrete enzymes to get past the zona pellucida and get to the egg

Block to polyspermy = the other sperm can’t penetrate the egg anymore once one sperm has entered

Implantation

• Zygote divides as it travels through oviduct.
• Occurs during the secretory (progestational) phase of the menstrual cycle(D15-D28)
  • Implantation occurs during mid- secretory phase, between cycle days 20 – 24 which is the Window of Implantation, where uterus is receptive from implantation of the free- lying blastocyst.
  • During secretory/ progestational phase, peaking levels of progesterone prepares endometrium for possible implantation by growing to a thick, highly vascularized tissue lining, providing an optimal environment for implantation.
  • Does that infer you cannot fall pregnant until this phase of the menstrual cycle comes around? Does this also explain why its harder to fall pregnant during the other phases of the cycle?
• ~ 6th day after fertilization, blastocyst (a hollow ball of  ~100 cells) attaches to the uterine wall.
  • Makes sense why the mini pill and regular pill are both <5 days if the blastocyst attaches to the uterine wall at day 6
  • Also, after ejaculation sperm can be alive for a maximum of 5 days.
• Trophoblastic cells break down the endometrial tissue and develop into fetal portion of the placenta (Chorion) and Inner cell mass differentiates to fetus

 

hCG (Human chorionic gonadotropin) maintains corpus luteum in first trimester

• Human chorionic gonadotropin is a hormone produced by the placenta after implantation. The presence of hCG is detected in some pregnancy tests.
• Trophoblast cells begin to  secrete hCG soon after  implantation
• hCG Exerts LH-like effect to signal corpus luteum not to degenerate
• Presence of hCG in urine is the basis for home-based pregnancy test
  • At the end of 1 month until 2 months there is a very sharp rise in hCG.

Proper function of corpus luteum is crucial for a successful reproduction. Explain the rationale for the statement

• Corpus luteum develops under the influence of luteinizing hormone (LH) after ovulation (rupture of secondary oocyte from mature follicle) It is fully functional within 4 days but continues to grow in size for another 4 – 5 days.
• Main function of corpus luteum is to prepare uterus for pregnancy in case fertilization and implantation occurs by secreting abundant amount of progesterone and slightly smaller amount of estrogen
• If no fertilization and implantation 14 days after corpus formation, corpus luteum degenerates which ends the luteal phase which signals a new follicular phase. It degenerates partly because progesterone is produced which inhibits LH secretion.
• If fertilization and implantation occurs, corpus luteum continues to grow instead of degenerating. It is now known as the corpus luteum of pregnancy which continues to provide the hormones essential to maintain pregnancy until developing placenta (2nd trimester onwards) can take over this crucial function.
• Post Pregnancy: *corpus luteum persists until pregnancy ends where it partially regresses as hCG secretion dwindles but will not converted into scar tissue until after delivery of the baby

 

Formation of the Placenta

Chorion aminion membrane becomes the fetal portion of the placenta

Baby Test: Amniocentesis testes for genetic abnormalities of fetal cells (especially for mothers 35+)

• As women increase in age chance for egg to have genetic abnormalities increases.
• There is no blood supply between the maternal and fetal circulation

Mechanism of Labor

When does the body know the fetus is mature enough to be delivered?

• As the fetus matures the fetal AP anterior pituitary increases secretion of ACTH > causes it to increase secretion of cortisol (cortisol is very important for maturation of fetal lungs) by stimulating the secrtion of pulmonary surfactant for lung maturation. Once the system know’s cortisol is at work the rest of the system can go to work.
• The adrenal cortex secretes a larger amount of DHEA stimulated by ACTH which is converted in the placenta to estrogen. Estrogen will #1 increase the gap junctions in the uterus, #2 increase oxytocin receptor levels so that the uterus is sensitive to oxytocin #3 you also increase prostaglandin production.
  • All this is to prepare for uterine contraction and delivery of the baby.
• Relaxin is released from placenta causes the dilation and softening of the cervix and pelvis so the baby can pass through.
• All this will cause uterine contractions which will give you a positive feedback loop to continue to heighten the frequency and intensity of uterine contractions.

Roles of Hormones in Paturation (Birth):

Oxytocin:

• During labour, as the cervix and vagina starts to widen, oxytocin is produced.
  • Oxytocin increases the motility of the uterus, hence promoting uterine contractions.
• Oxytocin also enhances prostaglandin production
  ○ Prostaglandin also involved in promoting uterine
  contractions

Prostaglandins

• Prostaglandins promotes contraction of the uterus smooth muscles. It also softens the cervix to promote dilation.

Estrogen

• Increase gap junctions
  • Coordinated contraction of the uterus
• Increase oxytocin receptors
  • Increases the sensitivity of the uterus to oxytocin
• Increase prostaglandin production
  • Involves in uterine contraction
  • Softens the cervix to promote labour

Placental Hormones

• hCG (Human Chorionic Gonadotropin)
• Estrogen: estriol is the main form
• Progesterone
• Placental lactogen (Human chorionic somatomammotropin)
• CRH (Corticotropin-releasing hormone) involved in the stress response. It is a releasing hormone that belongs to corticotropin-releasing factor family.

Estrogen and progesterone

Estradiol (non-pregenant females) / estrone (main estrogen in post menapuasal women) / Estriol ? 

• Stimulates endometrial growth and enlargement (thickening) of the mother’s uterus.
• Inhibit prolactin secretion.
• Stimulates growth of mammary ducts.

Progesterone:

• Suppresses uterine contractions.
• Stimulates decidualization and gland secretion.
• Promote formation of mucus plug in the cervix
• Stimulates development of mammary alveoli.
• Suppress  both LH and FSH secretion.

Placental lactogen

• Released by the placenta
• Maternal growth hormone of pregnancy
• The amount of secretion is proportional to the size of placenta (normally 1/6 weight of fetus)
• Structurally similar to growth hormone and prolactin
• Metabolic effect in mother: lipolysis, decrease of glucose utilization (diversion of glucose to the fetus)
• Prepare the mammary gland for lactation

Mammary Biology

• Structure of the mammary gland
• Hormonal regulation of mammary development
• Lactation

Structure of the mammary gland

• Consists of mammary ducts and alveoli that produce milk
• Made of alveolus is the functional (secretory) structure of the breast that produce milk
• clusters of alveoli are called lobules
  • Groups of lobules form larger clusters (Lobe)

Mammary Development

• Rudimentary mammary ducts are present at birth.
• development is limited to mammary ducts and buds before puberty
• Some development of alveoli in mature animals
• Extensive ductal and alveoli development during pregnancy
• After weaning, the mammary glands undergo involution , during which many mammary cells undergo apoptosis.

Like the seasons, Summer, Winter, Autnomn, Spring 

Endocrine regulation of mammary development (I)

• Without hormones mammary development does not take place 
• It’s understood that Em GH and AS are important for duct growth
• If you add PROGST and PROLAC alveolar growth is initaited

Hormones involved in mammary growth  and milk secretion in the  hypophysectomized-ovariectomized-  adrenalectomized rat https://academic.oup.com/jnci/article-  abstract/21/6/1039/876713, 1958).

Endocrine regulation of mammary development (II)

• Estrogen is essential for ductal morphogenesis (development of morphological characterisitcs)
• Progesterone is required for ductal branching and alveoli development.
• Prolactin promotes alveoli development
• Prolactin and cortisol are required for milk secretion.
• Oxytocin is essential for milk ejection.

If we delete the estrogen receptor gene there is very limited mammary gland development showing the importance of estrogen for mammary gland development

Hormonal regulation of mammary development during pregnancy and lactation

• Placentra supply E and PROG that stimualte growth of glands
• Insulin/cort/thyr stimulaute permissive effects on duct growth
• During pregnancy secretion is inhibitated of estrogen through the increase of PIH

Which of the following protein is required for lactose synthesis by mammary epithelial cells?

Lactose synthesis is catalyzed by Lactose Synthase complex, between galactosyltransferase and α -lactalbumin.

What is the correct order of protein synthesis and release in milk?

RER > Golgi > surface

Under the stimulation of prolactin and glucocorticoids, the ribosomes on the RER in the alveoli cells begin to synthesise milk proteins such as casein and pre-modification proteins such as the precursors proteins for lactose synthesis. These proteins are then transported to the Golgi apparatus for protein modifications, such as turning the lactose precursor proteins into lactose. Then these proteins are packed in a secretory vesicle and detach from the Golgi apparatus. These secretory vesicles travel to the cell membrane and fuse with it, releasing the milk proteins outside of the cell.

Lactation

Lactogenesis: process of milk synthesis and secretion.

• Prolactin and cortisol increase the expression of milk proteins and promotes lactogenesis (milk synthesis).

• Milk synthesis does not happen until 1-2 days before labour, not talking about lactation.

Lactogenesis I: Cytological and enzymatic differentiation  of alveolar cells before parturition.

• Before pregnancy there is a dramatic hypertrophy of the RER and Golgi and increase in the number of mitochondria.
• Increase in essential enzymes (e.g. acetyl CoA carboxylase,  fatty acid synthase) for milk synthesis
• Limited milk synthesis secretion

Lectogenesis II: Onset of Copious milk secretion

• Occurs in women at 1 – 2 days postpartum.

Lactogenesis III: maintenance of milk secretion

 

• Human milk contains two types of proteins: whey and casein.  Approximately 60% is whey, while 40% is casein. This balance of the proteins allows for quick and easy digestion.  If artificial milk, also called formula, has a greater percentage of casein, it will be more difficult for the baby to digest. Approximately 60-80% of all protein in human milk is whey protein.
  • But this is not true because there are many other proteins in milk, lactose, calcium .. figure out what the distribution is.

Suckling Reflexes and maintenance of lactation: How does the milk deliver to the baby

• Suckling stimlus is needed to activate mechanoreceptors to trigger neural relfex in the posterior pitruarty to increase oxytocin reelease causing contraction of myoepithelial cells
• Once the milk is empty it needs to be filled again. How? Prolactin inhibiting hormone stimulates alveoli cells to poroduce more milk via the anterior pituitary

Influence of stress on lactation

Stress will inhibit milk ejection via  epinephrine or norepinephrine from the adrenal gland or the sympathetic nerves by:

• It does so because it can reduce the myoepithelial cell response to oxytocin;
• It also contrsticts the blood vessels in the mammary gland decreasing mammary blood flow (hence the amount of oxytocin to the gland therefore the amount of milk that can be ejected is limited)

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Cardiovascular Physiology

Lecture #6 & Lecture #7 W6 & W7

The Heart

• Size of your fist (200-400g)
• Beats ~100,000 times a day
• Pumps about 5-7L of blood per min

Cardiac Anatomy

The heart sits between the lungs/orientated to the left in 80-90% of individuals but there is a condition called dextrocardia in which your heart ir orientated towards the right side.

It is the major circulatory system of the body.

Your heart returns to the body in two different ways via 2 large veins:

1. Superior Vena Cava
2. Inferior Vena Cava

Deoxygenated blood then travels from the inferior/superior venca cava through the R Atrium > R Ventricle > Out of the heart through the pulmonary artery which distributes deoxygenated blood to the lungs > it gets oxygenated in the lungs > pulmonary veins will bring back the oxygenated blood back to the heart through the L Atrium > L Venntricle > out of the Aorta to the rest of the body 

• Circulation is managed by heart valves: tricuspid, mitral, aortic and pulmonary valve.
• The valves allow the blood to flow in one direction and prevent back flow.

Veins carry blood towards heart (Note – not all venous blood is de-oxygenated/ Artery carry blood away. (A for AWAY)

Arterioles:

• Determine blood flow distribution to organs via vasoconstriction and vasodilation.
• Play major role in determining MAP (mean arteriole pressure) given that they regulate resistance to flow – hence name resistance vessels

Dual Circulation

Duel circulation splits your entire bodies circulation into two categories:

Pulmonary Circulation Purpose:

• Is the oxygenation of blood

Systemic Circulation Purpose:

• Delivers oxygenated blood to the organs through systemic arterial system.
• Collects deoxygenated blood from the organ system through the systemic venous system.

The pulmonary arterial system collects deoxygenated blood from tissues to heart.

The systemic arterial system brings O2 blood out of the heart to deliver to tissues.

Systemic Circulation

Systemic Circulation: Pulmonary veins > Left atrium > Left ventricle > Aorta  (Oxygenated blood)

Systemic Circulation: Aorta > Systemic arteries > Capillaries (Organs)  (Oxygenated blood)

Systemic Circulation: Capillaries (Organs) > Systemic Veins  (Deoxygenated blood)

The only communication between the arterial and venous system is via the capillaries in the lungs which picks up all the deoxygenated blood.

 

Systemic Circulation: IVC/SVC > R atrium > R ventricle > pulmonary artery  (Deoxygenated blood)

What’s the difference between the SVC and the IVC:

• The SVC brings all deoxygenated blood above your neck back to the heart.
• The IVC brings all deoxygenated blood from the neck down back to the heart.

Pulmonary Circulation

Pulmonary Circulation: Pulmonary artery (deoxygenated) > capillaries (oxygen exchanged in the lungs) >  brings oxygenated blood back through the Pulmonary veins (oxygenated)

Principles of Dual Circulation

• To separate the pulmonary and systemic circulation (they have minimal communication)
• To separate arterial and venous circulation which communicates via the capillary network.
  • The capillary network is where all the diffusion of gaseous exchange occurs.

When Things Go Wrong …

Abnormal communication between the arterial and venous system

Atrial Septal Defect – ‘Hole In The Heart’

• There is a hole (abnormal opening) between the left and right atria resulting in…
• Mixing of oxygenated and deoxygenated blood  “shunt”
• is a type of congenital (present from birth) heart defect in which there is an abnormal opening in the dividing wall between the upper filling chambers of the heart (the atria).
• If the hole is small enough most of the time it closes by the time they grow into a toddler. But some holes persist and cause growth and development stunting and/or cause children to turn blue when they cry or exercise.
• This issue can also persist in the L and R ventricle – ventricular septal defect.

Layers of the Heart

The heart (cardiac) muscle is broken up until 3 different layers.

• The innermost layer is the endocardium.
• Then the myocardium which is where the bulk of the heart muscle is located (hence ‘myo’).
• The pericardium (perry perry sauce) acts as a lining surrounding the heart (surrounding the myocardium) to protect the heart. In between, you have a pericardial space (cavity).
• Part of the pericardium is your myocardium, and that’s the epicardium.
• Epicardium is the outer most layer of the heart that folds upon itself.  The inner most layer that’s closest to the heart is the ‘visceral layer’ and the outer most layer is called the ‘parietal layer’.
  • The folding of the visceral and parietal layer creates a space/cavity is called the pericardial cavity. That’s all you need to know.
    • The pericardial cavity has fluid inside to reduces friction when your heartbeats.
• *The visceral layer of the pericardium forms part of the muscle wall. (EXAM Q)*

Heart Fiber Orientation

• The orientation of the hearts muscles fibres are different to each of the 3 layers of the heart to maximise torsion for contraction and relaxation. 
• Image shows a right-hand and left-hand helix such that when it contracts if you’re looking of the top of heart it goes in a clockwise direction and if your looking at the apex (bottom) of the heart it goe in a counter-clockwise direction.
• Why is this important? Because it gives you maximum torsion for the contraction to eject blood from the heart and when it relaxes it creates a suction to suck blood from the SVC and IVC back into the heart.

Mechanical Events of the  Cardiac Cycle

• Ventricular Systole: Ventricle contracts to eject blood out of aorta; LV pressure increases to open the aortic valve; mitral valve closes
• Ventricular Diastole: Ventricle relaxes and fills with blood from left atrium; LV pressure drops; mitral valve opens; aortic valve closes;
  • 2 phases: early/passive filling and active atrial contraction
• Isovolumetric ventricular contraction: all valves closed; LV pressure increases, no change in volume; before aortic valve opens
• Isovolumetric ventricular relaxation: all valves closed; LV pressure drops, no change in volume; before mitral valve opens
  • Think of isovolemic phases as preparation phases.

1. At end-diastolic volume where the line is flat there is no change in volume and an increase in pressure = the IVC.
2. The aortic valve opens and the LV ejects blood into the aorta (the LV pressure mirrors the aortic pressure).
3. Peak pressure in the LV – once the blood is ejected the pressure drops and the aortic valve closes to prevent backflow.
4. IVR occurs where the heart begins to relax. As the heart relaxes the volume doesn’t change – this is the point where all the valves are closed.
5. During the state of relaxation, the heart is waiting for the mitral valve to open. Now that the mitral valve is open it is receiving blood from the L atrium. This is where you have early filling and then the atrium contracts where it fills blood into the LV. Ending the diastolic phase.

Cardiac Excitation Contraction Coupling

1. AP triggers opening of L-type Ca2+ channels
2. Ca2+ influx from extracellular space
3. Intracellular Ca2+ release
4. Cystolic Ca2+ binds to troponin
5. Crossbridge forms as myosin heads bind to tropomyosin

The cardiac cycle is split into 2 different phases

• Systole: Contraction
• Diastole: Relaxation

Isovolumetric Ventricular Contraction (IVC): When your heart contracts and all your valves are closed where your heart is generating pressure.

In the beginning just before your heart contracts all your valves are closed. Your heart has to generate enough pressure to reject blood out of the aorta.

EXAM Q: On which valves open and close at which point: MC (1) – AO (2) – AC (3) – MO (4)

Left Ventricular Volumes and  Function

• End diastolic volume (EDV): Maximum LV Volume at end diastole when LV is the “largest”
• End systolic volume (ESV): LV volume at end systole (contraction) when LV is the “smallest”
• Stroke volume (SV) = EDV – ESV (the difference between the two)

 

• • Ejection fraction: Fraction of blood ejection with each cardiac cycle; [SV/EDV]*100
    • 60% EF is normal. Every time your heart contracts 60% of your hearts blood is being ejected
    • It’s not possible to get 100% EF because you need some residual volume in end systole.
    • Athletes typically have lower resting EF as their cardiovascular fitness is heigthtened and higher EF potential during exercise.
• Cardiac output = SV * HR [L/min] *amount of blood pumped out of the heart p/m (remember the equation)
  • If you don’t have SV you can use EDV – ESV = SV 
• Cardiac index = cardiac output/body surface area [L/min/m2] (reference to body surface area)

From Cardiac Cycle to  Pressure-Volume Loop

You can convert your whole cardiac cycle to a loop [right]. The loop tells us information about the physiology of the heart. 

Left Ventricular PV Loop

1. Beginning of diastole: mitral valve has to open
2. It begins to fill – ventricular filling.
3. The bump at 3 indicates atrial contraction
4. EDV is the point where your heart is the biggest filled with blood ready to pump-out
5. There’s no change in volume but there’s increase in pressure which is IVC
6. The aortic valve opens and then the…
7. Ejection phase occurs and then…
8. It peaks end systole where the aortic valve closes because the pressure drops.

• The important point is that peak pressure occurs in-between phase 6 and 8 BEFORE end systole.
• People have the misconception that peak pressure occurs at end-systolic but that’s not true.

 

You can corrospond the numbers of peak pressure lining up. The peak pressure occurs at the point of maximum ejection.

• 7 = systolic blood pressure
• 6 = diastolic blood pressure 

Left Ventricular PV Loop

• Requires pressure catheter in the left ventricle for accurate assessment (invasive procedure)
• Important for the understanding of cardiac physiology and diseases
• Mechanical properties of the heart: contractility, stiffness and compliance
• Guide diagnosis and treatment of cardiovascular diseases

Preload, Afterload and Inotropy

Preload: Giving more fluid to the heart. If we can give more fluid to the heart we can get increases in SV. Curve shifts to the right if it increases.

• Primary effects: If the preload increases the SV and EDV will increase
• Secondary effects: aortic pressure increases because you have more volume coming off the aorta

Afterload: Means your heart having to generate more pressure to overcome a certain amount of pressure being put on it e.g. hypertension.

• Primary effect: Increase in afterload = increase in aortic pressure and decrease SV. Shifts curve to the right 
• Secondary Effect:

How you differentiate afterload and preload is preload will increase SV and afterload will decrease SV. 

Contractility/Inotropy: How forceful your heart contracts.

• Increased preload on the heart: increased stroke volume, up to a certain point (Frank Starling Law: see next slide)
• Increased afterload on the heart: LV had to overcome the increased pressure ?> reduced stroke volume
• Increased inotropy: force of LV contractility increased ?> increased stroke volume
• The parameters are inter-related, change in 1 will affect the rest

Frank Starling Law

Know for exam

“Stroke volume of the heart increases in response to  an increase in the volume of blood in the ventricle,  before contraction (end diastolic volume)”

When all other factors remain constant

At a certain point you can only give so much volume to a heart. You put fluids in to put

Adaptation of the Myocardium

The myocardium is the muscular middle layer of the heart

• The myocardium adapts to various conditions to maintain cardiac output. When adaptation fails, decompensation and heart failure occurs
• Mechanisms in many cardiovascular conditions are multi9factorial and complex: combination of preload, afterload, contractility and compliance
• (Clinical application: cases studies in tutorial)

LaPlace’s Law of Wall Stress

You don’t need to know for exam 

• The way your heart adapts to stress is defined through LaPlace’s Law
• Your heart responds to two different types of stress:
  • Pressure stress
  • Volume stress
• LaPlace’s law states that your wall stress (T) is a function of pressure x the radius of the heart and inversely proportionate to the thickness of the heart.
  • Pressure Stress: E.G. If you have a pressure problem where you’re blood pressure is very high it exerts a certain amount of stress onto the heart. How does the heart cope with this stress? According to LaPlace’s law because the pressure is very high the only way to normalise T (pressure) is to thicken your heart. Because if your heart is thicker it lowers your wall stress. A term called concentric hypertrophy. 
  • Volume Stress E.G: Mitral/Aortic regurgitation where you have to much blood in the heart. What happens here is the radius of your heart increases and that increases your wall stress -the wall thickens to compensate = eccentric hypertrophy.

Concentric hypertrophy responds to pressure overload.

Eccentric hypertrophy: responds to volume overload.

 

Effects of Preload and PV Loop

Exam Q: Need to be able to identify what is changing, e.g. preload/afterload etc

Increase in Preload opposite for decrease

1. Shifts PV loop to Right
2. Increase in stroke volume**
   • If the SV increases its likely an increase in preload 
3. Increase in EDV
4. Secondary effects: Increase ESVD increase in LV pressure

Effects of Afterload and PV  Loop

Increase in Afterload

1. Shifts PV loop to Right
2. Increase in LV pressure
3. Reduction in stroke volume**
4. Secondary effects:  Increase in ESV and EDV

Changing Preload and Afterload

The two lines are slopes that we can generate from multiple PV loops. One is ESPVR (a measure of contractility) and the other is EDPVR (a measure of compliance).

ESPVR and EDPVR

ESPVR: End-systolic pressure volume relationship: a measure of contractility

• End-systolic pressure volume relationship (ESPVR) is a measure of LV contractility or inotropy
  • The Steeper the slope = the higher the contractility

EDPVR: End-diastolic pressure volume relationship: a measure of compliance 

• End-diastolic pressure volume relationship (EDPVR) is a measure of LV compliance
  • Steeper the slope = the less compliant the left ventricle (inverse relationship) AKA your heart is not able to fill as well 

Effects of Contractility and PV Loop

Increase in Contractility

1. Shifts PV loop to Left**
2. Increase in stroke volume**
   • Which makes sense considering increased contractility is going to increase the SV
3. Secondary effects: Smaller ESV and EDVB Increase in LV pressure

 

Effects of Compliance and PV  Loop

Increase in Compliance (fills more blood into the heart)

1. Shifts PV loop to Right**
2. Increase in stroke volume**
3. Secondary effects: Larger ESV and EDVD Increase in LV pressure

PV Loop Summary

1. First ask yourself: is there a change in slope? (ESPVR or EDPVR slope)
2. If there’s no change in the sloop, then we look at SV.
3. Whether SV is IN or DE and decide whether your PV loop is R or L shifted.
4. If SV has increased, there’s no change in slope and it’s shifted to the R you know you have increased preload.

PL/EDV = Preload / AL/ESV = Afterload 

EXAM QUESTIONS ON PV LOOP:

Figure out where SV is and then if it’s shifted to the left or right then work backwards 

Lecture #7 W7

Heart disease can be an intangible difficult concept for the layperson to grasp. This may help: imagine your heart as a house, the rooms of the house as the chambers of the heart (ventricles/atrium) > each room you have a door (these are the valves of the heart that help direct transportation of objects (blood) in one direction) > the plumbing system of the house are the coronary arteries > the electrical system is electrical conduction that causes the heart to beat. 

When people think of heart disease they typically think of heart attacks, but that’s only a ‘plumbing’ issue where arteries get clogged/blocked. But any component of the heart can break down (the rooms (chambers), doors (valves) and electrical system). You can have many breakdowns of the heart that can cause heart disease then heart failure. #Post

Blood Flow Through a Vessel

Blood flow through a vessel can be summed up into this equation.

Pressure gradient = the change in pressure. It is the difference in pressure between the beginning and end of a vessel.

You need the pressure difference between two ends for blood to flow.

Vessel 1 you have a beginning pressure of 50mmHg, end pressure of 10 so the difference (P) = 40.

Vessel 2 the blood flow has doubled.

• Vessel 3: the difference in pressure is still 80 and the blood flow is the same even though the starting and end pressures are higher. This illustrates that we should think in terms of pressure gradient not the absolute pressure. 
• If you pressure that’s the same on both ends then there is no blood flow.

Factors Influencing Resistance

Blood viscosity (friction)

If your blood is thicker than normal it IN friction, therefore, increases friction > increases resistance > therefore, blood flow is slower.

Vessel length: longer the vessel = greater the resistance

E.G. If you have twice the length your resistance will be twice as much, therefore, your blood flow will be lower.

Vessel size is the most important thing that determines blood flow.

If the size of the vessel increases your blood flow will increase.

Vessel radius (r): smaller the radius, greater the resistance

Blood Pressure

Blood pressure maintains blood flow.

Ventricular contraction ejects blood into the major arteries, resulting in flow from regions of higher pressure to regions of lower gradient for that to happen you need a pressure gradient.

Smaller people generally have lower BP compared to people are a larger.

Anatomy of the Vasculature

The aorta has to be able to withstand very high pressure hence it has a lot of smooth muscle and is very thick relative to other components.

EXAM: Be able to differentiate between an artery, capillary and vein.

Large Arteries:

• High smooth muscle content for pressure
• Elastin fibre content for recoil

Because arteries have to be able to withstand a lot of pressure from the heart it has to have a high proportion of smooth muscle, also the elastin fibres have to be high because when the aorta receives blood from the heart it has to be able to recoil – the elastin fibre allows the aorta to recoil – that recoil will generate your diastolic blood pressure, hence it requires elastin fibres.

As we move further from the heart vasculature doesn’t have to be as large.

Capillaries:

• Doesn’t have elastin fibres because it’s not dealing with high pressure
• Vessels which allow exchange of nutrients and waste products with cells
• Typically, a tube of endothelial cells one cell layer thick, resting on a basement membrane

Veins:

• Low resistance conduits to allow blood to flow from tissues to heart
• Veins aren’t dealing with high pressure so it doesn’t need elastin fibres to sustain the pressure.
• Contain valves to aid in venous return
• Venous pressure important in regulation of venous return and hence stroke volume

Systolic and Diastolic Blood  Pressure

Top image: With each contraction, it ejects blood into the aorta > the aorta expands > that generates a systolic BP > Bottom image: after expansion it recoils back via the elastin fibre and that generates the diastolic BP

Expansion and relaxation of arteries allows blood to flow effectively and smoothly.

Blood Vessels As We Age

As we grow older blood vessels become more stiff so the ability for arteries to recoil and relax is adversely affected. As a result your blood flow is not as smooth compared to a younger more elastic aortic fibres, so most of the blood pressure has to come from systole instead of diastole. 

Need to know how to recognise BP from a PV Loop

Disastlic BP is #6 (look at 80)

Capillaries

• Thin-walled, extensively branched in order to maximize surface area for diffusion
• Large cross sectional area results in slow blood velocity and maximize time for exchange of nutrients and waste products 

Veins

• Veins return blood, CO2 and waste products back to the heart
• Contains about 60% of blood volume (not 100% bceause it keeps bood in reserve for times of need such as wounds)

Mechanisms to counter the effects of gravity:

1. Valves to allow flow in one direction
2. Venoconstriction by sympathetic nervous system
3. External compression by skeletal muscles (walking, exercising, physical compression by squeezing a limb).

What Causes the Heart to Beat? Electrical Conduction.

SA is your intrinsic pacemaker of the heart > when your SA generates an impulse it generates an impulse across to the LAtrium > your SA also sends an impulse to the AV node (the AV nodes acts as a backup system to take over if the SA fails) > it goes down the conduction fibres called the bundle of His > as it goes down into the ventricles through the Purkinje fibres and then through the rest of the cells = THAT’S WHEN YOUR VENTRICLE CONTRACTS

Once you have an electrical impulse THEN you have a mechanical contraction. Without the electrical impulse, there is no mechanical contraction.

1. Cardiac impulse originate at the SA node
   • The SA node is the primary pacemaker of the heart
2. Spreads to the left and right atria (atrial contraction)
3. Impulse passes from the atria to AV node
4. Travels down the ‘bundle of his’ (left and right bundle)
5. Rapidly moves throughout the myocardium through the Purkinje fibers
6. Ventricular contraction

Transmission of Electrical  Impulses: 2 Types of Cells 

• Autorhythmic cells generate electrical impulse spontaneously
• Delivers electrical impulse (action potential) to the gap junction, which carries the excitation to neighboring cardiac muscle cell (contractile cells)

How does the impulse get passed on from cell to cell – through gap junctions.

Ions and Ion Channels

The heart is mediated by 3 positvely charged ions (ions are a charge)

Slower channels allows ions to pass through slowly and fast allow fast transmission of ions.

(1) Sodium (Na+) ions into cell

• Fast channel
• Funny channel (slow)

(2) Calcium (Ca++) ions into cell

• T type transient calcium channel (fast)
• L type long lasting calcium channel (slow)

(3) Potassium (K+) ions out of cell

• Many types

You don’t need to know the different types of channels for exam.

Pacemaker Action Potential  (SA, AV, and Bundle)

IN = ions goes in the cells / OUT = ions go out of the cells

Depolarisation = makes it less negative (more positive) – it helps muscle contraction.

Repolirisation = resets the whole process  – resets the cell so the cell is ready for a second contraction.

For an AP in a pacemaker cell to occur:

AP process is different from skeletal muscle contraction 

1. NA+ get into the cell
2. Then CA2+ goes in
   • This is to make the cell more positive
3. Up to a certain threshold (membrane potential) then CA2+ take over which is when it becomes more positive and generates an electrical impulse (AP)
4. Once the impulse is generated then muscle contracts
5. Once muscle contracts it needs to reset itself: it resets by leaking out K+ so it can become more negative which is when the repolarisation occurs.

Pacemaker cell is involuntary – it generates an impulse by itself which is exactly what you want the heart to do.

• SA node is the pacemaker in normal hearts
• Other conduction tissues such as the AV node “take over” when SA node is diseased – if the AV node then fails the then the bundles take over but that is a very unstable heart rhythm.

 

• Heart rate is modulated by the autonomic nervous system
  • Parasympathetic NS slow down heart rates (delay closure of the K+ channels = hyperpolarize)
  • Sympathetic NS increases heart rates (increases Na+ influx)

Contractile Cell Action Potential  (Atrial and Ventricular Cells)

• The resting membrane potential is about 90 in a contractile cell compared to a pacemaker cell is about 60.
• CS need something to stimulate it before it can fire compared to the pacemaker cells (PS) which don’t need voluntary contraction.
• The phases are different between CS and PS but ions used are the same.

 

1. Phase 0: Once NA+ comes in (overshoot phase where the membrane potential goe sover 0) and it hits a peak
2. Phase 1-2: Causing the K+ to leak out and CA2+ comes in (plateau phase one’s going in ones coming out – it’s having a competition between these two ions)
3. Phase 3: Eventually, more K+ is leaving the cell phase
4. The cell resets itself to repolorise and resets itself at -90 and is ready to regenerate another impulse.

Differences Between Autorhythmic  and Contractile Cells

Cardiomyocyte contains a plateau phase and is about 200 times longer than in other excitable cells. 

 

Refractory Periods

• Allows sufficient time between electrical activation and mechanical contraction
• Inappropriate activation during refractory periods can cause lethal arrhythmias
• The RP means at this period if there’s an impulse coming the cell wont react to it. It’s a safety mechanism for the cells that has practical imlicationsm to certain heart conditions.
• But there is no refractory period for the PM cells because it will generate contunuesely autonomously.
• Due to long absolute refractory period (250 ms) Cells can only be excited again when cardiac muscle twitch is almost complete.

Heart sounds

Two heart sounds:

First, soft low pitched lub: closure of AV valves & ventricular pressure exceeds atrial pressure

Second, louder dup: closure of pulmonary and aortic semilunar valves & arterial pressure exceeds ventricular pressure

Electrocardiogram (ECG)

Electrical activity of the heart can be captured on the surface 127lead electrocardiogram

Components of 12 lead ECG

• P wave represents atrial depolarization (atrial contraction)
• QRS complex represents ventricular depolarization (ventricular contraction; atrial relaxation hidden)
• T wave represents ventricular repolarization (ventricular relaxation)
• PR segment represents the AV node delay.

When Things Go Wrong …

SA node dysfunction (Sick Sinus Syndrome)

• SA node fails to fire impulse
• AV node or other electrical cells turn over function > unreliable and unstable

That’s where implantable pacemakers takeover…

Implantable Pacemaker

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Respiratory System

Lecture #8 W8

REST: ventilation accounts for ~5% of total body oxygen consumption

EXERCISE: ventilation may account for up to 20-25% of total body oxygen consumption

Function

Primrary:

1. gas exchange and gas transport (uptake O2 and expel CO2)
2. Short term regulation of blood pH (i.e. acidity)
3. pulmonary ventilation
4. regulation of respiration

Secondary:

• Speech (phonation)
• Smell (olfaction)
• Eliminates heat & water (thermoregulation)
• Modifies some hormone systems e.g. renin-angiotensin-aldosterone
• Modifies thoracic vascular flow e.g. assists venous return on inspiration

Two sets of blood supplies

Structure of the respiratory system

• Larynx is the opening to the trachea.
• Epiglottis is a flap made of cartilige that closes the glottis when you swallow
• Persistalsis: where muscles constrict at the top part of the eosphegeal column and relax at the bottom part of the column to allow the passage of foodwhich takes about 10 to 15 seconds.

What happens when food falls into the trachea when you’re talking while eating ?

•  When somebody feels like something went down the wrong pipe, it usually means that it went into his or her trachea, a process known as aspiration
• “In otherwise healthy people, the presence of foreign material in the airway is extremely uncomfortable and will stimulate immediate gag and coughing reflexes,” says Kim. “If these reflexes fail to clear the material, it may become lodged in and obstruct the trachea causing choking.” Even if you don’t choke, food that makes its way down the trachea into your lungs can lead to a very serious case of pneumonia.
• You should also take into consideration that liquids are much harder to swallow than solids, simply because they move faster and are more difficult to manage. “When people are having swallowing problems, liquids are their nemesis,” says Rosen. “When people get life-threatening pneumonia from their swallowing, it’s usually liquids, not solids.” Even if you don’t have problems swallowing per se, it’s a good idea to be extra alert every time you drink.

Pulmonary Alveoli is the functional unit of the lungs

• T1 alveolor cells make up the wall
• T2 alveolar cells secrete pulmoary surfactent which is important for inflating the alveolii and reducing surface tension
  • Pulmonary surfactant is a mixture of lipids and proteins which is secreted by the epithelial type II cells into the alveolar space. Its main function is to reduce the surface tension at the air/liquid interface in the lung.

Properties of the lungs

1. Compliance and elastance
2. Pulmonary surfactant reduces surface tension

Compliance and elastance of lungs are due to  abundance of elastic protein fibers

C&E operate on a reciprocal relationship – as one is done – the other is given in return 

Compliance: Refers to effort required to distend (swell) the lungs

• Lungs are 100 x more distensible than balloons which is due to the elastic fibres

Elastance: Lungs have the tendency to recoil after distension

• The compliance and elastic nature of the lungs facilitates alveoli interdependence: When an alveolus starts to collapse, the neighboring alveoli recoil to expand the collapsing alveoli

Pulmonary surfactant reduces surface tension

Surface tension

• There is a surface tension that tends to collapse the alveoli
• Generated by attracting force of water molecules  lining the alveolar surface
• Resists distension

Pulmonary surfactant

• A complex surface active material composed of lipids and  proteins secreted by type II alveolar cells that reduces the surface tension therefore increase compliance.

The inward pressure = 2 x surface tension/radius

When you add the surfactent the inward pressure is reduced because of the reduction of the surface tension

Smaller alveoli tends to collapse in the  absence of surfactant

 

Clinical Relevence of Pulmonary Surfactant:

Newborn ‘respiratory distress syndrome’ (RDS) is due to the lack of pulmonary surfactant

• Occurs mostly in premature infants because their lungs are not mature enough to produce pulmonary surfactant and they have very weak muscles that can’t expand their lungs which can result in death
• Characterized by the deficiency of pulmonary surfactant, causing increased surface tension and low compliance.
• Most common cause of death in the first month of life.
• Treatments:
  • Synthetic or natural surfactant through the breathing tube
  • Glucocorticoids (one sign of infant maturity is when the pituitary gland helps the lungs produce pulmonary surfactant)

Graham Liggins discovered glucocorticoid as stimulant of pulmonary surfactant secretion

• Studies on cortisol in sheep
  • Experiment he confucted was the Removal of fetal pituitary (which delayed ACTH) which he found delayed the onset of labor
  • He found the cortisol release triggers labor
• Studies on lungs in sheep
  • Lungs of premature lambs sunk in water.
  • Lungs inflated and floated if given prior injection of cortisol to ewes.
• Cortisol injection stimulated lungs to secrete pulmonary surfactant that saved the lives of  prematurely born lambs (and later clincally proven to help prevent premature infant death)
• Antenatal glucocorticoid therapy is now routinely  used to reduce the incidence of NRDS in premature or high risk infants.

Pulmonary Ventilation

Pulmonary pressures and intrapleural fluid

Atmospheric pressure = 760

Intrapleural Pressure = the space between the lungs and the chest wall) ≈ 756 at rest

• Interpleural pressure is always lower than the intrapulmonary pressure. Usually its -4 to the air pressure = 756 at rest. Therefore there is a transpulmonary pressure gradient.

EXAM Q: Why is the intrapleural pressure less than the intrapulmonary pressure? 

Because the tendency of the chest wall to expand – and there is also a tenedency for the lungs to recoil so that increases space a bit. Beause of this action the intrapleural pressure is always lower.

Intrapulmonary pressure = changes depending on the lung volume dictated by respiration.

Visceral pleura is the membrane covering the internal organs in the lungs

Parietal pleura is the membrane covering the chest/abdominal wall

What keeps lungs open to fill the larger thorax?

1. Intrapleural fluid’s cohesiveness
2. transpulmonary pressure gradient hold the lungs and the thoracic wall in tight apposition so that the lungs open to fill the thorax.

What happens if this pressure gradient is broken?

Pneumothorax occurs as a result of loss of transmural pressure gradient

• Scenario 1: If there is a puncture the lungs will collapse because the air enters in the inerpleural space
• Scenario 2: If there is a hole in the lungs the air will escape and enter the interplaural space because there is no longer a transpulmonary pressure gradient

Summary of the events of Ventilation

Ventilation occurs as a result of  change in pulmonary pressure

Ventillation discusses the expansion of the chest cavity creates a difference in lung pressure relative to whats outside and pressure moves from high to low pressure

AKA more volume = less pressure / less volume = more pressure relative to the same amount of molecules in each space

• Reduce lung volume = increase pressure
• Increase lung  volume = decrease pressure

 

• Increase in lung volume lowers pulmonary pressure – air in.
• Decrease in lung volume raises pulmonary pressure above  atmospheric pressure – air out.

The works of respiratory muscles  alter pulmonary pressure

3 group of respitoary muscles:

• Accessory muscles of inspriation
  • SCM
  • Scalenus
• Muscles of active expiration
  • Internal intercostal muscles
  • Abdominal muscles
• Major muscles of inspiration 
  • External intercostals
  • Diaphragm

 

Muscles of Respiration

Mechanics of ventilation – Inspiration

Mechanics of ventilation – expiration

• “When you breathe, you inspire. When you do not breathe, you expire”
• Passive expiration (at rest): After being stretched, external intercostal muscles and diaphragm relax,  and lungs recoil.

Active expiration:

• Internal intercostal muscles contracts to reduce  front-to-back dimensions of the thoracic cavity
• Abdominal muscles contracts to push diaphragm  upward, reducing vertical dimension

Lung volumes and capacities

• Tidal Volume: Volume of air we respire at rest
• Reserve Volume: Amount of air we can inspire and expire with maximal effort
  • Tidal Volume + Reserve Volume – *you expire all the air* = Vital Capacity 
• Residual Volume: Amount of air left in the lugns after voluntary maximal expiration (there is always a reserve)

Pulmonary ventilation  versus Alveoli ventilation

• Pulmonary ventilation (ml/min) = tidal volume x Respiratory rate
• Anatomical dead space: volume of air in conducting airways
• Alveoli ventilation (ml/min) = (tidal volume – dead space volume) x Respiratory rate (breath/min) (considers gas exchange)
• The conducting zone in the upper airways does not assist in gas exchange because it is too thick.

 

 

Why shallow breathing does not generate effective alveolar ventilation?

• If one has shallow short breathing then a portion of the air may be getting lost moving in and out of the conductive zone, thus you’re not taking in enough O2 for optimal gas exchange
• Shallow fast breathing at a respiration rate upwards of 40 p/m can result in 0 alveoli ventilation which has serious implications for gas exchange:
  • Alveolar ventilation is the exchange of gas between the alveoli and the external environment. It is the process by which oxygen is brought into the lungs from the atmosphere and by which the carbon dioxide carried into the lungs in the mixed venous blood is expelled from the body. #Post

Remember: The conducting zone in the upper airways does not assist in gas exchange because it is too thick.

TV = Total air displaced during normal inhalation and exhalation 

Control of Airway resistance

• SNS Stimlation: Epinephrine and sympathetic stimulation causes bronchodilation and inhibition of secretion via β2 adrenergic receptors.
• PNS Stimulation: causes bronchoconstriction and increase of secretion via muscarinic receptor.
• Local factors, e.g.
  • Increase of CO2 causes bronchodilation
  • Histamine and cold air cause bronchoconstriction

 

• Left is normal open airway
• Right is blocked because the smooth muscles contracts narrowing the airway + inflammation of the airway (red) + mucous secretion which are factors that affect airway resistance

Two types of common pulmonary Disorders

1. Obstructive disorders due to airway obstruction  (increased airway resistance)

• Asthma: airway blocked by
  • Chronic bronchitis – the inflamed bronchial tubes produce a lot of mucus
  • Emphysema – Alveolar tissue is destroyed by trypsin. Therefore the alveolir wall is broken – this most commonly occurs in smokers. Smoking causes increased amont of trypsin which consumes the alveolar.

2.Restrictive disorders (means lungs have reduced compliance due to reduced elastic fibres)

• Pulmonary fibrosis: Lung tissue disrupted by accumulation of fibrous connective tissue.
• Asbestosis: inflammatory and fibrotic lung  condition caused by inhalation of asbestos
• Can occur in people with prolonged inflammation

Gas Exchange

Refers to the gas exchange between the lungs, alveoli, the capillaries and the tissue. This is governed by the pressure gradient between these 2 compartments. 

Gas exchange follows Fick’s Law of Diffusion:

The rate (R) of gas diffusion across a membrane depends  on surface area (A), the diffusion coefficient of the  particular gas (D), the partial pressure difference  and the distance (d)

R = A X D X (P1 – P2) /d

Partial Pressures

• The pressure of individual gas is called partial pressure.
• Each gas in a mixture of gases exerts a pressure that is proportional to its concentration in the mixture.
• e.g. 21% of the atmosphere is oxygen, the partial  pressure of this gas is 0.21x 760 = 160

O2 and CO2 move across pulmonary and systemic  capillaries according to partial pressure gradients

You have more o2 in the alveoli when the blood arrives > the O2 goes to the blood > CO2 returns back to the alveoli for expiration and the opposite happens at the tissue level.

Gas transport

Oxygen Transport

Hb (heme) binds to O2 but it does not contribute to Po2. It’s only the non-bound form that bounds to Po2. 

Oxygen-hemoglobin dissociation (saturation) curve

How does Hb give up O2 when the body needs?

 

• *PO2 of the blood determines %Hb saturation
• The upper plateau portion ensures that variation of PO2 above 60 does not alter Blood O2 supply significantly.
• The Lower steep portion of the curve facilitate the release of O2 in capillaries surrounding the tissue.
  • At the PO2 of 40 , Hb saturation is 75% . Should the PO2  at the tissue falls further, O2 is readily released from Hb.
• * Oxygen already bound to Hb does not contribute to PO2

PO2 (partial pressure of oxygen) reflects the amount of oxygen gas dissolved in the blood. It primarily measures the effectiveness of the lungs in pulling oxygen into the blood stream from the atmosphere.

Factors affecting the affinity of Hb for O2

Why is Hb more willing to increase O2 for cell use at the tissue level?

The bohr effect: if you have more CO2 and H+ then the binding (affinity) of O2 to Hb is reduced. 

• We know during high intensity activity / heavy strength sets you can enter mild hypoventilation which faciliates the build of of CO2.
• The more we can breath nasally and deeply the more efficient our body is at uptaking/delivering O2. The longer we stay nasally breathing we can theoretically help buttress the bohr effect CO2 (+ lactate accumulation).

• 2,3-Diphosphoglycerate (2,3-DPG) is a special intermediate of glycolysis in erythrocytes which is rapidly consumed under conditions of normal oxygen tension. However, when hypoxia is encountered in peripheral tissues, the concentration of 2,3-DPG can accumulate to significant levels within hours.
• Functionally, fetal hemoglobin differs most from adult hemoglobin in that it is able to bind oxygen with greater affinity than the adult form, giving the developing fetus better access to oxygen from the mother’s bloodstream.

Transport of CO2 in the blood

• 10% Physically Dissolved
• 30% Bound to Hb:
  • CO2 binds to globin portion
  • Deoxygenated Hb has higher affinity for  CO2 (and H+) than HbO2 (Heldane’s effect)
• 60% as HCO3 (bicarbonate)

Abnormal Blood O2 and CO2 level

Hypoxia: insufficient O2 at the cellular level

Hypoxic hypoxia: Hypoxia due to insufficient  oxygen available to the lungs

Hyperoxia: above-normal Arterial PO2 level

Hypocapnia: Below–normal  Arterial PCO2 due to  Hyperventilation; May result in respiratory alkalosis

Hypercapnia: excess CO2 in arterial blood due to  Hypoventilation; May result in respiratory acidosis

Apnea and Dyspnea

Respiratory control centers

• Pre-Botzinger Complex (PBC) gives signals to respiratory neurons
• Pneumotaxic Center (PC) is to halt the inspiration at a certain point
• Apneustic Center (AC) is to prolong the inspriation

 

Respiration involves rhythmic firing from DRG

• Inspiration occurs when inspiratory neurons fire and activate the motor neurons supplying the inspiratory muscles
• Expiration occurs when inspiratory neurons cease firing
• The expiratory neurons stimulate the motor neurons supplying the expiratory muscle during active expiration

Respiratory center receives input from Chemoreceptors (CR)

• Receptor center receives signal from chemorecptors – peripheral CR are located in the aortic and cartoid bodies (a small cluster of chemoreceptor cells).
• CR responds to changes from Po2, H+ concentration and PCO2 (1-3 in the below table).
• Central chemoreceptors that control ventilation responsd DIRECTLY to the changes of pH in the cerobrospinal fluid.

Effects of Blood P02  on Ventilation

If you have a decrease in blood PO2 > centrel recetpors dont work > peripheral receptor is activated ..

 

 

 

Relationship between high altitude and Air PO2

Practical:

• Commercial aircraft cabin is similar to being at altitude in Denver, Colorado because they’re pressurised to 2000m.
• Why airlines tell you to put your air mask on first: if there is a sudden decompression of air pressure at 12,000m (aicraft is pressuresed to 2000m) human can only survive for 30 seconds 
• Aircrats operating at air pressure of 5000m you can only survive for 15 seconds 

Acclimatization to High Altitude

• Changes in ventilation: Hypoxic ventilation response produces hyperventilation and hypocapnia-induced alkalosis.
• Affinity of hemoglobin for 02 is decreased due to the action of 2,3-BPG  (Bisphosphoglyceri c acid so the body will experience hypoxic hypoxia (lack of O2 at lungs)
• Then the body will try and adapt…such as hyperventilation…

• Other adaptive changes include
  • Increase in heart rate, stroke volume, blood pressure
  • Increased hemoglobin and red blood cell production due to  increased secretion of erythropoietin by kidneys
    • Increased capillaries
    • Increase in lung sizes

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Renal/Urinary System I

Lecture #10 W10

Consists of the kidneys, ureters, bladder, and the urethra. The purpose of the urinary system is to eliminate waste from the body, regulate blood volume and blood pressure, control levels of electrolytes and metabolites, and regulate blood pH.

Functional structures

Three basic renal processes:

Filtration, reabsorption and secretion

• Urinary excretion and plasma Clearance
• Fluid balance
• Renal failure
• Regulation of kidney function

Homeostasis

Kidneys play a key role in homeostasis and regulating these factors: 

• Concentration of nutrients,
• Concentration Waste products,
• Concentration of O2 and CO2,
• pH,
• Concentration of ions,
• Temperature,
• Volume and pressure

Renal system regulates the internal envrionment

1. Regulate the volume of ECF.
2. Regulate the quantity and concentration of most ECF ions, including Na+, K+, Ca++, PO – and HC0 – .
3. Excrete waste products (urea, uric acid and creatinine) and foreign  compounds (drugs, pesticides).
4. Regulate pH by adjusting urinary acid  excretion.
5. Producing erythropoietin (EPO), renin, and  activating vitamin D, and converting T4 to T3. So the kidneys they function as endocrine organs as well.

Erythropoietin (EPO)

• It plays a key role in the production of red blood cells (RBCs), which carry oxygen from the lungs to the rest of the body.
• When there is a lack of O2 (e.g. at altitiude adaptation) the kidneys sense the reduced O2 carrying capacity > a special type of connective tissue in the kidneys produce EPO > that will travel to bone barrow which stimulates production of RBCs thus increasing O2 carrying capacity of the body.

 

Important functional structures of the renal system

• The kidneys
  • Contain The Nephrons
    • Contains the Juxtaglomerular apparatus

The kidneys

• Fist sized organs
• Receive 25% of blood supply every minute which is a lot compared to its size
  • Kidneys receive the most blood flow at rest than any other organ
• The function of the kidney is performed by millions of nephrons

The nephrons

Each nephron consists of two components:

• Tubular component: Where the urine flows throw. Bowman’s capsule, proximal tubule, loop of Henle, distal tubule and collecting tubule

Vascular component

• Afferent arteriole: delivers blood into the glomeruli.
• Glomeruli: capillary network that produces filtrate that enters the urinary tubules.
• Efferent arteriole: delivers blood from glomeruli to peritubular capillaries.
• Peritubular capillaries: deliver blood to renal tissue and are important in exchange between tubular system and blood in the production of urine.

The tubular component in yellow

The vascular component in blue, red and purple

The kidneys are supplied by the renal artery. Each of these nephrons are supplied by efferent arterioles.

There are 2 types of nephrons

1. Cortical nephron

• Glomeruli is at the outer renal cortex
• Short loop of Henle penetrating a short distance to medulla

2. Juxtamedullary nephron

• Glomeruli lies deep in the renal cortex.
• Long loop of Henle dip deeply into the medulla.
• Important in forming concentrated urine.

Juxtaglomerular apparatus

A cluster of specialized vascular and tubular cells in the region where the afferent and efferent arterioles come into direct contact with the distal tubule.

How do they Juxtaglomerular cells regulate function?

Juxtaglomerular is a baroreceptor so when the blood passes through it can sense the amount of blood pressure and produce renin accordingly.

So when the amount of blood passing through is decreased then the baroreceptor senses this and it will stimulate the cells to release more renin which activates the secretion of aldosterone which functions to secrete reabsorb Na+ and secrete K+. 

Macula densa cells serve as chemoreceptors which can sense the concentration of Sodium chloride to communicate to regulate renin release.

Messangial cells function is less undersood but it has a lot contracctile elements in order ot regulate the opening of the capiliries.

Three basic renal processes

Glomerular filtration

filtration of protein-free plasma through glomerular capillaries into Bowman’s capsules

Tubular reabsorption

Return of most of the solutes and H20 from the urine filtrate back into the peritubular capillaries.

Tubular secretion

Selective transfer of substances from the peritubular capillary blood into the tubular lumen lost into the urine to get rid of by products the body doesnt need that may be harmful

Glomerular filtration

• Glomerular Filtration Membrane is like the sieve that allows materials to be filtered through 
• A Filtraton pressure is needed for the lipid to go through
• This is a reguluated process that operates at a certain rate

Glomerular Filtration Membrane (I)

Blood runs through the capillary and there are slits in the basement membrane down to the Bowmans capsule that allow liquid to pass through

Glomerular Filtration Membrane (II)

Glomerular capillary

• Capillary pores are large fenestrae and 100 times more permeable than capillaries elsewhere.

Basement membrane:

• Basement membrane is the mechanism that selectively retains the stuff you don’t want to filter through
• If the base membrane is damaged you have proteins in the urine
• Composed of negatively-charged collagen and glycoprotein.
• Negatively charges prevent leakage of negatively charged plasma proteins.
• Common Infection: Post-streptococcal Glomerulonephritis is caused by streptococcal proteins deposited on glomerular membrane (symptoms = sore throat). Mozart is said to have died of this after they found he had swollen kidneys.

Inner layer of Bowman’s capsule

• This is the 3rd layer of this filtration membrane
• Consisting of octopus-like cells podocytes with intercalating foot processes.
• This forms the narrow slits between foot processes are filtration slits for filtered molecules to pass.

Filtration pressure (I)

• The Glomerular capillary pressure (55 mm Hg) plays the major part in filtration pressure which is determined by the diamter of the afferent and efferent arterioles 
• This capillary pressure is higher than anywhere else because the Diameter of afferent arteriole is wider than that of efferent arterioles.

Then there are pressures against this filtration:

• Plasma-colloid osmotic pressure gradient between the capillaries and Bowman’s capsule (30 mm Hg) opposes filtration to draw the liquid back into the capillary.
• Bowman‘s capsule hydrostatic (water) pressure (15 mm Hg) opposes filtration
• Net filtration pressure ≈ 55 – 30 – 15 ≈ 10 mm Hg

Filtration pressure (II)

• Influenced largely by glomerular capillary pressure which is determined by the diameter of the afferent and efferent arterioles.
• If the diameter of the afferent arteriole becomes narrowed less blood enters the capillary = less capillary pressure = decreases net filtration pressure 
• Afferent artioloes play a larger role on capilary pressure because they rececive more sympathetic nerve fibres  

 

Glomerular filtration rate (GFR)

• Filtration rate is predominantly determined by pressure 
• GFR = Kf X net filtration pressure.
• Kf is determined by glomerular surface area and glomerular membrane permeability.
• At any one time 20% plasma entering the glomeruli is filtered.
  • 125 ml/min on average = 180 liter/day (A LOT – the kidneys can filiter up to a bathtub filled of liquid a day) 

GFR is mainly regulated by filtration pressure

• GFR influences how much urine we make

What regualtes filtiration pressure?

1. Autoregulation – the purpose of autoregulation is to prevent change

• Renal infusion changes based on blood pressure daily fluctuations. The autoregulation is said to maintain a relatively stable GFR within certain blood pressure range (80-180 mmHg).

2. Sympathetic regulation – Make change in response to decrease in BP through baroreceptor reflex

3. Hormonal regulation e.g. epinephrine and angiotensin II by regulating the diameter of the affeerent and efferent arterioles

Regulation of GFR by autoregulation

1. Myogenic mechanism: arterioles constrict when stretched due to increased pressure.
2. Tubuloglomerular feedback mechanism: when detecting a rise in NaCl of the fluid of distal tubule, Macula densa is a chemoreceptor that senses change in NaCl, cells produce adenosine that causes vasoconstriction of afferent arterioles to reduce the filtration pressure to correct the increase in GFR to maintain a constant homestatic level. Adenosine also inhibits renin release to cause a decrease in aldesterone which remember absorbs Na+ and secretes K+.

Sympathetic regulation of GFR

• Significant fall in blood pressure is detected by baroreceptor, which leads to the activation of sympathetic nervous system and consequently vasoconstriction of the afferent arterioles [to reduce blood going in to reduce GFR to reduce filtration to conserve water] – that  receive more sympathetic innervations than the efferent arterioles.

EXAM Q: When blood pressure decreases/increases significantly what happens?

• In response to a decrease in BP > the baroreceptor will detect it > it will reduce the firing and GFR will decrease which would activate SNS to increase HR and SV
• In response to an increase in BP > the baroreceptor will detect it > it will increase the firing and GFR will increase which would activate PNS to slow HR and SV
• Sympathetic regulation can override autoregulation
• There is no evidence for parasympathetic innervation of the kidneys therefore sympatathic regulation of GFR is important.

Tubular reabsorption

• Describes the returning of most solutes and H20 from the urine filtrate back into the peritubular capillaries (into the blood).
• You have 180L going through the tubules everyday and most of it will be taken back by the process of tubular reabsorption

What and how much is tubular reabsorption?

• Components of value to the body are reabsorbed.
• The amount is tremendous: 180 L of is filtered/day and only 1–2 L of urine excreted. So most is reabsorbed.
• A small reduction in reabsorption can lead to large increase of urine volume.
  • E.g. 1% reduction in reabsorption (e.g. from 124 ml/min to 123 ml/min) can double the urine volume.

Percentage of various substances reabsorbed

Tubular reabsorption

• Barriers for Tubular Reabsorption
• Sodium reabsorption and regulation
• Water reabsorption and Aquaporin
• Glucose reabsorption and tubular maximum
• Reabsorption of urea, PO4 and Ca++ and other solutes

Barriers for Tubular Reabsorption

• This is the direction of tubular reabsorption through 1 to 5 membranes.
• These are considered barriers because the concentration of the fluid affects the reabsorption.

(1)Luminal membrane

(2)cytosol of the lumen cell

(3)Basolateral membrane

(4)interstitial fluid

(5)capillary wall of the peritubular capillary.

Mechanism of sodium Reabsorption

Describes the multiple membranes NA+ has to pass through to get reabsorbed in order to get diffused into the blood.

Only when the NA+ is getting pumped out of the cell does it need A LOT of energy. Na+ reabsorption uses 80% of total energy spent by the  kidney! However this energy consumption is worthwhile because Na+ reabsorption also brings about the absorption of other solutes that include glucose, amino acid, urea and water.

Sodium Reabsorption in different  segment of renal tubule

• Na+ reabsorption (~67%) in the proximal tubule is crucial for re-absorption of glucose, amino acid, Cl-, urea and H20.
• The descending limb of ‘Henle’ is not permeable to Na+.
• Na+ reabsorption in the ascending limb of the loop of Henle is critical for water elimination or conservation.
• Na+ reabsorption in the distal and collecting tubule is subject to hormonal control.
  • About 8% of the filtered sodium depends on aldosterone for re-absorption.
  • With maximum aldosterone secretion, all filtered Na+ is re-absorbed.
  • That increased Na+ reabsorption is facilitated through increased Na channels and Na-K/ATPase

Regulation of sodium reabsorption (I)

When we need to increase blood pressure and we need more fluid in the body the kidneys will increase the release of renin which will increase this cascade of angiotensin’s.

Regulation of sodium reabsorption (II)

• Systemic input – a fall in BP triggers increases in the activity of sympathetic nerves that innervate the granular cells to cause the release of renin

Local input

• Baroreceptors in juxtaglomerular cells detect a fall of pressure in afferent arterioles
• The macula densacells detect decrease of NaCl concentration –increase of PGE2 release stimulation of juxtaglomerular cells

Both systemic and local input lead to  the release of renin which will  activate Renin-angiotensin-aldosterone system

Renin aldosterone system is life saving to maintain blood pressure. E.G. For when we would be in fight/flight situations where you don’t have enough water and you lose blood, therefore aldosterone is a life saving mechanism.

• Is there a mechanism that opposes the renin aldosterone system?
• The ACE system is a peptide hormone that opposes this system.
• Triggers increased Na+ excretion and decreased arterial blood pressure
• Initiates Na+ reabsorption in the kidney tubules.

Reabsorption of H2O

• H2O is reabsorbed by osmosis.
  • Osmosis: a process by which molecules of a solvent tend to pass through a semipermeable membrane from a less concentrated solution into a more concentrated one.
• 80% H2O is obligatorily reabsorbed in the proximal tubules and descending limb of loop of Henle; water channels in  these segments are always open.
• The remaining 20% H2O is absorbed in the distal tubules and collecting ducts depending on the insertion of aquaporin  2 under the regulation of vasopressin  (ADH).

Water channel Aquaporin was first discovered  as a 28 kDa membrane protein

• Contains Six transmembrane domains
• Exists as a tetramer with each subunit containing its own water pore
• Loops B and E are juxtaposed to form the water channel
• HgCl (mercury) binds to Cysteine residue in E loop to close  the channel

Vasopressin stimulates the insertion of  aquaporin 2 in  apical membrane of distal tubule and collecting duct

Glucose reabsorption

Kidneys do not regulate plasma [Glucose]

• Glucose is reabsorbed by Na+-dependent secondary active transport using Na-glucose co-transporter.
• It’s called secondary active transport because for Na+ to get into the cell it requires energy, thus it’s active.
• The absorption of glucose exhibits a tubulamaximum (Tm) (limited total absorption) due to the limited number of carrier  protein available in the cells.
• Tm is the maximal quantity of a substance that can be reabsorbed per minute (375 mg/min for  glucose).
• Does this have implications to ingesting high amounts of glucose in short periods of time? E.G. 100g of glucose in 10min?
• Yes, but we don’t know how much you need to intake for it to enter your urine. If you get a high amount of glucose flooding your body, if it doesn’t get synthesised into glycogen in time then it will get passed through to urine.

Glucose is excreted when filtered load is greater than Tm

To determine whether glucose will be excreted into the urine you need to consider the filtered load, which is the amount of glucose passing through the tubular cells per unit of time using the equation below. If the filtered load exceeds the tubular maximum then the glucose will be excreted into the urine.

• Filtered load (mg/min) = plasma concentration of the substance x GFR
  • When filtered load is greater than Tm, glucose is excreted into the urine.
• Renal threshold = the plasma concentration at which the Tm (tubular maximum) of a substance is reached
  • >=300 mg/100 ml for glucose.
• In theory, glucose appears in urine in diabetic patient when plasma concentration is 3 times the normal; in reality, glucose may start to spill into the urine at 180 mg/100ml so urine glucose concentrations are not accurate for detecting diabetes
• So how do you figure out if you’re getting glucose in you’re urine? How much glucose do you need to consume for that to occur?
  • Pharmacies have tests you can check if you have glucose in your urine.

Glucose is excreted when filtered load  exceeds its Tm

You only see glucose in urine when filtered load exceeds Tm (tubular maximum).

Reabsorption of Urea

• Urea is the by product of protein metabolism.
• Why would we want to reabsorb urea? Urea is three times more concentrated at the end of proximal tubule compared to that at the beginning. So if you do not reabsorb urea gradually you will actually draw the water into the tubule and in the end lose much more water therefore it’s necessary to reabsorb uera.
• Does not exhibit Tubular maximum.
• The concentration gradient enable urea to passively diffuse from tubular lumen into the peritubular capillary plasma.
• About 50% of the filtered urea is passively reabsorbed (50% is eliminated).

Reabsorption of other filtered solutes

• Amino acids is also reabsorbed by Na+-dependent secondary active transport.
• Renal threshold for PO4 – and Ca++ equals to their normal plasma concentration; Reabsorption of PO4 and Ca++ by the kidney is subject to the control of  parathyroid hormone.

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Lecture 11 Renal system II

Three basic renal processes

Filtration, reabsorption and secretion

This lecture will focus on SECRETION

• Urinary excretion and plasma Clearance
• Fluid balance
• Renal failure
• Regulation of kidney function

Secretion

• Secretion is the transfer of substances from the peritubular capillaries (blood) into lumen of tubules, and into the urine.

• Concept of renal secretion
• K+ Secretion
• H+ secretion and renal regulation of acid- base balance
• Urinary buffers

• Substances are transferred from the peritubular capillaries into lumen of tubules, and into the urine.
• Regulates the plasma concentrations of K+ and H+
• Secretes organic anions and cations.

Maintenance of Blood [K+] is crucial for the  function of excitable tissues

Change in K+ concentration can have significant effects on the resting membrane potential.

So raising the K+ can raise the AP rate by raising the resting state closer to the threshold potential. Does that mean ingesting supplemental K+ can aid exercise performance?

No. After the initial stage of increased AP rate some of Na+ channels are then inactivated, therefore they will have a SLOWER repolarisation so then you will have eventually a slower AP.

K+ Secretion (II)

• Most filtered K+ is reabsorbed in proximal tubules.
• Secretion of K+ occurs in distal and collecting tubule by baselateral Na/K pump.
• Controlled by aldosterone: when aldosterone is absent, no K+ is excreted in the  urine.
• If you have increase K+ in the blood it will stimulate adrenal cortex to stimulate aldosterone which will increase K+ secretion in order to maintain k+ homeostasis.

Mechanism of K+ Secretion (III)

Na+/K+ ATPase in the basolateral membrane of the collecting duct transfer Na+ to the interstitial space (reabsorbed), and K+  into tubular cell and then secreted.

H+ secretion and renal regulation of acid-  base balance

• Control of Renal excretion of H+
  • Depend on plasma H+ concentration
  • No neural or hormonal control
• HCO3 conservation and excretion
• Urinary buffers

Acid-Base balance is essential for  survival (pH)

Sources of H+

• H+ is continuously added to plasma from ongoing metabolic activity.
• Major source of H+ is from CO2.

 

• Other sources include production of inorganic and organic acids by metabolism.

Defense against changes in ECF [H+]

• Chemical buffer systems
  • Mainly HCO3– (bicarbonate)
• Respiratory control of pH
  • The brain triggers an increased respiratory rate in response decreased in pH (higher acidity)
• Renal control of pH

Renal secretion of H+ is associated with K+  retention

• The distal and collecting tubules secrete either H+ or K+ in exchange for Na+  reabsorption.
• An increased rate of secretion of either K+ or H+ is accompanied by a  decreased secretion of the  other.
• In severe acidosis, H+ is secreted at the expense of K+, which may cause  hyperkalemia.

+ secretion is coupled with reabsorption and addition of bicarbonate to the plasma

The filtered H+ can help return the bicarbonate back to the blood.

HPO4-2 and NH3 are Urinary Buffers

• Nephron cannot produce a urine pH < 4.5 (normal 4.6 – 8).
• Filtered phosphate buffer and secreted ammonia provide buffering mechanism for the tubular fluid.

Na2HPO4 + H+  →  NaH2PO4 + Na+

NH3 + H+  →  NH + (lost in urine)

• Ammonium is a more important urinary buffer
  • The amount of phosphate secretion is not subject to control. Parathyroid hormone controls reabsorption, it doesn’t control secretion, therefor ammonium buffer is more important because it can be resynthesized.
  • NH3 is synthesized from glutamine in the tubular cells in response to excess H+. Therefore, Ammonium is a more important urinary buffer

Fluid balance, urinary excretion and  plasma clearance

• The kidneys can produce urine of varying solute concentrations (100 – 1200 mOsm/l).
• Typically, 124 of 125 ml/min filtrate is reabsorbed, producing 1.5 L urine per day.
• A small reduction in filtrate reabsorption can have large influence on urine volume: 1% reduction in  reabsorption (e.g. from 124 mil/min to 123 mi/min)  can double the urine volume.

Body fluid distribution

Ionic composition of the major fluid  compartments.

Fluid balance is achieved by regulation  of ECF volume and osmolarity.

• ECF volume is important for blood pressure.
• Imbalance in ECF osmolarity influences ICF volume.
• Hypertonic ECF (dehydration) causes cells to shrink.
  • disturbs brain function.
  • Justification to keep hydrated
• Hypotonic ECF causes cell to swell
  • Leads to neural dysfunction, muscle weakness, hypertension and edema.

Hypertonicity

Hypertonicity or spastic dystonia is a continual increase in the muscle tension compared to normal resting tension, regardless of movement. Hypertonicity is muscle tightness (increased tone), which makes moving body parts more difficult (resistance to movement). It is caused when parts of the brain find it hard to send the right signals to muscles. For example, the brain may not be able to ‘turn on’ a muscle or may ‘turn on’ a muscle too much.

Causes of Hypertonicity

• Insufficient H2O intake.
• Excessive H2O loss in heavy sweating, vomiting, or diarrhea.
• Diabetes insipidus, a disease characterized by a deficiency of vasopressin (ADH) which causes you to pass excess urine.
• Patients with renal failure who cannot excrete a dilute urine.
• Rapid excess H2O ingestion so that the kidneys cannot respond quickly enough to eliminate the extra  H2O intake (Water toxicity)
• Occurs as result of the syndrome of inappropriate hypersecretion of vasopressin which can cause a large amount of water that is reabsorbed into the body

Vertical osmotic gradient in medullary fluid enables  excretion of urine of 100 – 1200 mOsm/L

• Vertical osmotic gradient is established by means of countercurrent multiplication.
• This vertical osmotic gradient is essential for regulating urine volume.

Properties of Jaxtamedullary nephrons for  generating vertical osmotic gradient

Long Loop of Henle

• Dip deep in medulla near renal pelvis.
• Descending limb is permeable to water but not to NaCl
• Ascending limb is impermeable to  water but actively transports NaCl.
• Vasa recta (peritubular capillaries in renal medulla) also dip deep in hairpin loop next to loop of Henle.
• Flow in both long Loop of Henle and vasa recta run in opposite direction  (countercurrent) in close proximity.

Generation of vertical osmotic gradient in renal  medulla by means of countercurrent multiplication

 

• Along the medulla is a increasing concentration of solutes from low to high (300,700,1000,1200). How is this established?
• The tubular cells will be able to reabsorb Na+ across the cell via a pump
• It can pump against a gradient of 200.

Summary of water excretion by means  of countercurrent multiplication

• The long loops of Henle from juxtamedullary nephron establish vertical osmotic gradient by means of counter current multiplication.
• The vasa vecta preserve this gradient while providing blood to medulla by means of countercurrent exchange.
• The collecting duct from all nephrons use this gradient in conjunction with ADH to produce urine of various concentrations.
• The primary driving force for countercurrent multiplication is the reabsorption of Na+ in the long ascending limb of Henle.

Plasma Clearance

• The volume of plasma completely cleared of a particular substance by the kidneys per minute.
• An indication of renal efficiency.
• How well the kidneys clear plasma is a indication of kidney function.

Commonly used substances for  plasma clearance test

• Inulin: a natural polysaccharide from plants (garlic, onion, banana) substance that is freely filtered, not reabsorbed and not secreted, the plasma clearance of Inulin is equal to GFR. (We can’t digest inulin)
• Creatinine: Derived from creation phosphate located in the muscle. An endogenous substance used that is freely filtered, not reabsorption and slightly secreted.
  • A good indication of GFR and clearance
  • Widely used for renal function test.
• Para-aminohippuric acid (PAH): a synthetic substance that is freely filtered, not reabsorbed and completely secreted.
  • All the blood through the kidney is completely cleared of PAH.
  • Plasma clearance for PAH is a good estimater of renal plasma flow.

Kidney/Renal failure

Definition: Occurs if the kidneys fail to perform the regulatory function to maintain homeostasis

Causes:

• Most Common: High blood pressure and diabetes.
• Infection, toxic substances, autoimmune response etc.
• Urinary tract obstruction: stone, tumor, enlarged prostate
• Insufficient renal blood supply
  • E.G. renal stenosis: the narrowing of major renal blood vessels therefore you have a decreased blood flow to kidney nephrons and a cascade of hormonal and mineral affects that can cause secondary hypertension.

Types

• Acute renal failure: rapid loss of renal function; condition may be reversible
• Chronic renal failure: progression in disease of the kidneys; gradual loss of renal function; condition is not  reversible only treatment is renal dialysis.

Major consequences of Renal failure

• Uremia: accumulation of waste products
• Metabolic acidosis
• Salt and water retention
  • K+ retention
  • Na+ imbalance
• Anemia
• Endocrine disorder
• Disorder of mineral metabolism

Dialysis separates molecules on the basis of the ability  to diffuse through selectively permeable membrane.

 

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Digestive System

W11 L11

Function: The function of the GI tract is to process ingested food by mechanical and chemical means, extract nutrients and excrete waste products.

The small intestine has three parts.

1. The first part is called the duodenum. The duodenum has the greatest amount of digestive enzymes.
2. The jejunum is in the middle and the ileum is at the end.

Jejunum: Most of the water in the GI tract is absorbed from the jejunum

 

CHO are broken to simple sugars glucose (monosaccharide), galactose and fructose.

PRO are broken down into amino acids.

FAT is broken down in the gut into it’s components free fatty acids, monoglycerides. However, there is catch that separates them from the rest, they are taken back into the cells that line the upper SI, the catch here is that fatty acids are synthesised back into fats again – fatty acids and monoglyceridescombine to form triglycerides. Because the molecules are very big they don’t get absorbed into the portal vain. The fat goes into the lymphatic system.

CHO and PRO go to the liver and the systemic circulation and then rebuild. But fat is different. Fat is broken down, resynthesized and sent out.

GI PHYSIOLOGY

There is a chemical (enzyme) and mechanical (churning) digestive process that takes place. It gets broken down into it’s component parts and then it is absorbed.

Sugar & PRO Absorption: Need help from a transporter molecule to bring the components in.

FAT: Because fats are already back into the components of free fatty acids (monoglycerides) – because they are very big molceules they have to go through a process through the endoplasmic reticulum and into small vesicles called chylomicrons and the move out.

Fat goes through the lymphastic system and sugar and PRO go through the portal circulation.

As it goes through things are absorbed and it goes into the LI.

We used to think the LI wasn’t that important – just to absorb water and store faeces. But the bacteria inside the LI plays a very important immunoregulatory functions.

Regulation of Gastrointestinal Processes

• Control mechanisms of the gastrointestinal system are governed by the volume and composition of the luminal contents, rather than by the nutritional state of the body
• This means that the body is designed to absorb all the nutrients that are ingested, whether or not the body really needs them to function

Negative and Positive Feedback

When the pH drops in the stomach messages will be sent to stop stomach acid from continually being secreted.

Summary of Pathways Controlling Digestive System Activities

2 categories of importance: one the hormones and one the nerves.

The nerves have two sets: the intrinsic nerves are found within the gut itself and react to local factors such as distension (intrinsic control).

The external nerves (cranial nerve #10 – vegas nerve which innervates the GI up to mid colon. They get the message from the brain.

LAYERS OF THE DIGESTIVE TRACT

Mucosa: Slipery moist mucos layer

Muscularis Mucosa: Thin layer of muscle

Submucosa: Where nerves and blood vessels are contained

Submucosal Plexus:

Circular & Longitudinal Muscles are striated so they perform different functions to the smooth muscle of the anal sphincter.

 

LAYERS OF THE DIGESTIVE TRACT

Peristalsis, involuntary movements of the longitudinal and circular muscles, primarily in the digestive tract but occasionally in other hollow tubes of the body, that occur in progressive wavelike contractions. Peristaltic waves occur in the esophagus, stomach, and intestines.

Neural Control of GI Motility

Enteric Nervous System (ENS) – consists of two networks:

(1) submucosal plexus (Meissner’s plexus) – lies between submucosa and muscularis externa

(2) myenteric plexus (Auerbach’s plexus) – linear sheath within muscularis externa (between circular and longitudinal)

Vagus nerve innervates tract from esophagus to transverse colon, pelvic nerve from descending colon to anus

Intestinal Motility

2 main movements of the intestine:

Peristalsis: Is to move things forward – proulsion

Segmentation: Kneading and mixing of enzymes into food to ensure digestion

Peristalsis

Behind the bolus of food you get the contraction of circular muscles and relaxation of longitudinal muscles and then the opposite occurs – this back and forth contraction helps push the bolus of food for peristaltic population.

In the upper segment is food but in the colon it will be feces.

GASTRIC MOTILITY

Contractions of gastric smooth muscle serves two basic functions:

• ingested food is crushed, ground and mixed with digestive enzymes liquefying it to form what is called chyme.
• chyme is forced through the pyloric canal into the small intestine, a process called gastric emptying.
• The stomach can be divided into two regions on the basis of motility pattern
• The upper stomach, composed of the fundus and upper body, shows low frequency, sustained contractions and makes digestive enzymes
• The lower stomach, composed of the lower body and antrum, develops strong peristaltic waves of contraction that increase in amplitude as they propagate toward the pylorus. These powerful contractions constitute a very effective gastric grinder (crush food); chyme is thus delivered to the small intestine in spurts.

Absorption in the Small Intestine

• The small intestine is anatomically arranged for a large surface area, which enhances nutrient absorption
• Villi increase surface area and contain blood vessels and lacteal (lymphatic vessel of the SI that helps absorb fat), which play a role in the absorption of nutrients.
• Microvilli increase surface area and form the brush border

MOTILITY OF SMALL INTESTINE

The small intestine is more than 5 m long, and makes up 75% the length of the GI tract

Segmentation – dominant form of motility – different regions contract differently to mix contents without net movement

Peristalsis – short (5-10 cm) waves triggered by local stimulus – called myenteric or peristaltic reflex

• a bolus in the lumen produces a peristaltic wave behind it – this is the “Law of the Intestine”

Reflexes – occur over considerable distances

• (1) intestinointestinal – overdistention in one segment causes relaxation in other
• (2) ileogastric – distention of ileum decreases gastric motility. When the food goes into the ileum and is distended it will send a message to the stomach to slow down gastric motility.
• (3) gastroileal – gastric motility stimulates movement through ileocecal sphincter

What happens when you need to go perform a bowel movement quickly after eating?

Because they have very sensitive and enhanced gastrocolic reflex. It signals your colon to empty food once it gets to your stomach in order to make room for more food to increase peristalsis to trigger you to go to the toilet. This is often seen in people who are anxious or nervous where this gastrcolic reflex is enhanced. This reflex is natural but is abnormally strong in those with IBS, and it has been implicated as playing a part in some of the symptoms of the condition. Symptoms of an abnormally strong gastrocolic reflex may include cramping, a sudden urge to move your bowels, and in some people, diarrhea.

This reactivity appears to be the result, at least in part, to abnormal levels of the hormones cholecystokinin (CCK) and motilin, both of which are responsible for regulating the motility of the digestive system.

From the oesophagus to the stomach there is a esophageal gastric sphincter.

From the stomach to the dudenem is the pyloric sphincter.

From intestine into the colon and into the ilium into the cecum there is another sphincter.

All these sphincters are to stop movement.

Imagine if we didn’t have any sphincters, once the stomach is full and starts churning the food could go backwards. Sphincters prevent backwards flow (reflex) in a similar way valves in the heart prevent blood backflow.

The Large Intestine

• Much smaller surface area than small intestine and lacks villi
• Sphincter at the ileum prevents ‘backflow’ of bowel contents
• Primary function to store and concentrate faecal material
• Bacterial fermentation a major event producing short-chain fatty acids

Colon

We have 2 sphincters in the colon.

The internal sphincter which is under intrinsic nerve control.

The external sphincter which is under the brains control. This is what we can contract consciously to stop ourselves from a bowel movement. People with spinal injuries often lose the control of the external sphincter.

Motility of the colon

The colon absorbs water and electrolytes , stores fecal matter, and eliminates waste

• two anal sphincters – internal consists of smooth muscle and external of striated muscle which is under extrinsic nerves and can be taught and conditioned from childhood

Innervation – vagus nerve above transverse colon and from the pelvic nerve below

• sympathetic decreases motility, parasympathetic – increases segmental movements and sustained contractions
• longitundinal muscle is gathered into three narrow bands (teniae coli)
• external anal sphincter is innervated by somatic motor fibers – both voluntary and reflex control

Haustration – segments (haustra) mix and knead contents

Mass Bowel Movements – periodic (1-3 per day) sustained contractions that move material forward triggered by your first meal of the day, exercise or drinking a glass of warm water

• can be triggered by gastrocolic reflex or duodenalcolic reflex
• Defecation – mass movement of feces into rectum causes internal sphincter relaxation and external sphincter contraction
• voluntary relaxation of external sphincter initiates defecation – control of muscle is learned behavior
• if no motor nerves to external sphincter (babies or lower spinal damage), defecation is automatic upon filling of rectum
• Cramping feelings from not letting a bowel movement pass can occur from the internal sphincter relaxing while the external sphincter is still consciously being contracted. It’s important to not suppress the external sphincter otherwise it may contribute to constipation later in life.

Anatomy and Function

SALIVARY GLANDS

Main enzyme is salivary amylase. Amalase breaks down the bonds of alpha 1,4 – amalase is only effective against alpha 1,4 linkeges of glucose, galactose and fructose. The amalase reaction with the bonds in CHO change the chemical structure enough to chance the flavour profile as CHO often taste sweeter after chewing.

Lingual lipase digestive enzyme is especially important for infants where the diet is mainly breast milk.

The moment food enters the mouth the stomach begins to change to a very acidic environment (decrease pH)

Resting pH is 4-5. After a meal the stomachs pH drops to 1-2~. Water is 7.~. Hence you can see why consuming water pre, intra or post meal can disturb the stomach’s pH and ability to digest. #Post

FUNCTIONS OF SALIVA

• Moistening dry foods to aid swallowing
• Providing a medium for dissolved food materials that chemically stimulate taste buds
• Buffering of the contents of the oral cavity through its high concentration of bicarbonate ion
• Digestion of carbohydrates by the digestive enzyme alpha-amylase
• Controlling the bacterial flora because of the presence of the antibacterial enzyme lysozyme
• People with nasopharyngeal cancer get their salivary glands destroyed by radiation therapy and they suffer from a situation where they have no saliva.

Anatomy of the Stomach

The top part of the stomach is the thin part of the stomach which is mucus is secreted and endocrine hormones.

The lower part of the stomach is the part that does the crushing and combining of food.

FUNCTION OF THE STOMACH

1. Store food and empty into duodenum
2. Secrete HCL (hydrochloric acid) and Pepsin
3. Mixing and pulverized food into chyme
4. Stomach produces a substance called ‘Intrinsic factor’ which is necessary for the absorption of Vit B12. If you have an ulcer or stomach cancer you have to watch for Vit B12 deficiency.

Gastrointestinal Hormones

MAJOR COMPONENTS OF GASTRIC JUICE:

• Hydrochloric acid
• Pepsinogen (converted to pepsin which breaks down proteins)
• Intrinsic factor (Vit B12 binding protein)
• Mucus (protect mucosa from acid, pepsin and mechanical trauma).

EXAM: REMEMBER THE TABLE BELOW. WHAT COMPOUND COMES FROM WHAT CELL

Other secretory cells are –

• Enterochromafin like cells – dispersed among the parietal and chief cells secrete Histamine which act on parietal cells to release HCL and potentiate Ach and Gastrin
• D cells – scattered among gastric glands in pylorus and Duodenum, secrete Somatostatin which inhibit gastric acid secretion by parietal cells

Digestive Enzymes:

Enzymes are biological catalysts that enhance the rate of a chemical reactions that otherwise would occur slowy, if at all.

Pepsin: an endopeptidase digestive enzyme produced in the stomach; breaks down protein into smaller peptides (that is, a protease).

Trypsin → a protease produced by the small intestine. An enzyme which breaks down proteins and peptides.

Peptidase → proteases; can be found in the stomach and small intestine

Sucrase → Breaks down sucrose into fit’s subunits fructose and glucose.

Maltase → catalyzes the hydrolysis of maltose to glucose; located in the brush border of the small intestine

Amylase → catalyzes the hydrolysis of starch into glucose; synthesized by the pancreas and glands in mouth and throat

Lipase → catalyzes the hydrolysis of fat into fatty acids and glycerol.

Bromelain → is a digestive enzyme derived from the stem and fruit of pineapples. It’s used to help reduce swelling after surgery or injur y.*

Supplemental bromelain can help you in several ways:

• Promotes healing after trauma or surgery*

• Reduces bruising*

• Decreases swelling after injury*

• Reduces tenderness after acute injury*

Cullulase an enzyme that converts cellulose into glucose or a disaccharide. An insoluble substance which is the main constituent of plant cell walls and of vegetable fibers such as cotton. It is a polysaccharide consisting of chains of glucose monomers.

Pancreatin is a combination of digestive enzymes (proteins). These enzymes are normally produced by the pancreas and are important for digesting fats, proteins, and sugars. Pancreatin is used to replace digestive enzymes when the body does not have enough of its own

Regulation of Gastric Acid Secretion

 

Gastric Acid secretion goes through 3 phases.

1. Cephalic Phase: When we see, taste or smell food nerve impulses are sent to the medulla oblongata. These impulses cause parasynpathic neurons via the vagus nerve to stimulaute secretion of HCL and pepsin in the stomach (feedforard mechanism). The PNS stimulation also triggers the release of gastrin in the stomach which travels through the bloodstream and further stimulautes HCL and pepsin.
2. Gastric Phase: Food distends the stomach which activates a parasymapthic reflex via the medulla oblogonato resulting in contiunued secretion of HCL and pepsin.
3. Intestinal Phase: Chyme enters the duodenum. When pH drops <2 gastric secretion is inhibited.

When food enters the stomach then internal factors activate the G cells to secrete hormones and acid.

Gastrin secretion stops when stomach pH reaches 1.5-2~: When stomach acid reaches pH 2~ it sends an inhibition signal to the gastric cells so you stop producing more and more stomach acid (negative feedback loop) because you obviously don’t want to keep producing stomach acid otherwise it will get too acidic.

Gastric Acid Secretion Regulation

Control of Gastric Emptying

Parietal cell and acid regulation

Parietal cells (also known as oxyntic or delomorphous cells) are the epithelial cells that secrete hydrochloric acid (HCl) and intrinsic factor. … They contain an extensive secretory network (called canaliculi) from which the HCl is secreted by active transport into the stomach.

ECL cells secrete Histamine – histamine will stimulate a secretion of HCL.

Gastrin from the G cells secrete into the blood and is a positive influence in HCL secretion.

D cells slow down G cell production.

Histamine is an organic nitrogenous compound involved in local immune responses, as well as regulating physiological function in the gut and acting as a neurotransmitter for the brain, spinal cord, and uterus. Histamine is involved in the inflammatory response and has a central role as a mediator of itching.

We have 4 Histamine receptors H1, H2, H3, H4.

H2 stimulates HCL secretion.

Regulation of Gastric Acid Secretion by Parietal Cell

Histamine, Ach and Gastrin will activate the proton pump. They all have ‘anti’ versions of themselves to stop acid production.

PGE2 (prostaglandin) which is effective and directly inhibitory but it has many side effects. It can induce abortion and cause diarrhea so medical practioners opt for a proton pump inhibitor.

Mucosa protective factors

With so much acid being created you need protective factors for the stomach to stop it being digested.

Prostaglandin is protective.

Painkillers/NSAIDs (ibuprofen) which are non-specific will block these protective factors which is how painkillers is one of the common causes of stomach ulcers. They inhibit COX1 and COX2 pathways. Which is why we should pay a little more for higher quality medication and buy the COX2 inhibitor painkiller that allows the COX1 function (the protective function) to remain.

First that inhibit COX-2 inhibit the production of a molecule called prostacyclin which is produced by cox 2 and relaxes blood vessels and sort of “unglues” platelets. Second, they inhibit the production of nitric oxide (which is also regulated by cox 2 to some degree) and needed for proper vascular function. Finally, one more mechanism by which chronic NSAIDs use may increase heart attack risk is through a disruption mitochondrial function in heart cells. Knowing these risks sort of motivated me to put avoiding the use of NSAIDs such as ibuprofen, alieve, and naproxen, just to name a few, at a generally higher priority than it may have been previously for me on a personal level.

GASTRIC ACID RELATED PROBLEMS

• Reflux esophagitis
• Gastric and Duodenal ulcers
  Nsaids/Aspirin induced ulcers
• Helicobacter pylori is the most important cause of gastric acid problems via inflammation of the stomach and is correlated to stomach cancer due to it’s inflammatory nature.

Gastrinoma:

• Summary: Cancer of the gastrin secreting cells where HCL pours into duodenum and ulcers form. The pancreatic bicarbonate cannot overcome it then your pancreatic enzymes cannot work because the pH is wrong thus fat is not absorped.
• Gastrin: a peptide hormone that stimulates the release of hydrochloric acid (HCl) by the parietal cells of the stomach and aids in gastric motility.
• With an increase in the amount of hydrochloric acid secreted due to increased stimulation by gastrin, the pH level of the stomach decreases and becomes acidic. As a result, the acid starts to digest the tissue lining in the gastrointestinal tract causing gastric ulcers to form. The prominent gastric folds are formed due to the corrosive effects of the gastric acid to the stomach. The formation of ulcers cause a stimulation of the proliferation of the mucosa cells lining the stomach. The mucosa cells secrete mucus that traps HNO3-(nitric acid) so there is a gradient in pH from acidic in the lumen, to near neutral pH adjacent to the cells that are covered with mucus, protecting the stomach lining. Thus, a proliferation of the mucosa cells in response to the damaged lining can cause a thickening of the stomach lining resulting in prominent gastric folds.

How is fat digestion and absorption affected?

Due to the hypersecretion of HCl, the pancreatic enzymes are unable to reach their optimal pH level. As a result, the pancreatic enzymes are unable to stimulate the proper secretion of bile to allow for the emulsification of fat. This causes fat to be digested more slowly and hence, the fat to be absorbed less efficiently in the small intestine as well.

GERD WITH BARRETTS ESOPHAGUS

Gastroesophageal reflux disease

The lining of the esophagus is striated and does not produce mucous, thus it has no defence against HCL. When there is erosion of the esophagus lining caused by GERD, it is replaced by intestinal lining, because of this it becomes like the stomach thus increases the chances of cancer.

CANCER OF LOWER ESOPHAGUS

Cancer of the esophagus. Treated via proton pump inhibitors.

PATHOGENESIS (CAUSES) OF GERD

1. Reflux of gastric content into lower esophagus
2. “Incompetent” (loose) lower esophageal sphincter
3. Impaired clearance of ‘refluxate’
4. Failure of esophageal mucosal defence

Acute duodenal ulcer

Young people commonly get duodenal ulcers compared to older people.

3 causes:

• helicobacter pylori
• NSAIDs
• Gastrinoma

HELICOBACTER PYLORI

HP is a bacteria that lives in the stomach that can survive an acidic stomach environment around 1-2.

HP will cause inflammation

Gastric acid plays a secondary role to sterilise food if you eat contaminated food the bacteria will be killed by it, yet HP survives in it.

Why can HP survive? HP uses urea (a waste product protein metabolism). HP breaks down urea into ammonia and CO2. Ammonia is alkaline, so it surrounds itself with an alkaline layer so it survives the acidic environment.

How do they measure you have HP?

Put a scope in and take a piece of the stomach tissue.

OR

Can do a breath test where you drink a solution of radioactive urea  (C14 isotype) – then breath out into a tube and they measure the CO2 in your breath and indirectly tell if you have HP. Then they give antibiotics to kill it and re-test

NSAID INDUCED GASTRIC ULCERS

Because NSAID’s are non-specific they can induce ulcers.

Cyclo-oxygenase Pathway – COX 1 & COX 2

The enzymes that produce prostaglandins are called cyclooxygenase (COX). There are two types of COX enzymes, COX-1 and COX-2. Both enzymes produce prostaglandins that promote inflammation, pain, and fever; however, only COX-1 produces prostaglandins that activate platelets and protect the stomach and intestinal lining.

It is COX2 that we want to supress. That’s we take COX2 inhibitors.

PRACTICAL: When you have pain from injuries ask your Doctor for a COX-2 inhibitor instead of NSAIDs.

Plain Xray Abdomen – Calcified Pancreas

Drinking a lot of alcohol you can get chronic pancreatitis as the pancreas becomes calcified.

Anatomy of the Pancreas

The pancreas is a gland which secretes endocrine (insulin) and exocrine (glucagon) functions.

Exocrine: secretion of a substance through a duct. The exocrine portion produces “pancreatic juice” rich in bicarbonate as well as digesting enzymes

Endocrine: Chemical messengers comprising of feedback loops of hormones released by internal glands directly into circulatory system.

Acinar cells secrete digestive enzymes which are stimulated by cholecystokinin produced by the I cells in the duodenum.

Cholecystokinin:

• Stimulates the release of bile into the intestine by the contraction of the gallbladder 
• Stimulates the secretion of enzymes by the pancreas.
• But Cholecystokininis is stimulated to release BY lipids

S cells secrete the hormone secretin. Secretin is secreted in response to acidity by making bicarbonate in order to neutralize acid. We need bicarbonate to maintain the optimal pH.

Stimulation of the vegus nerve increases pancreative HCO3 and enxzyme secretion.

When food enters the duodenum the acinar cells and s cells are stimulated.

When you have acid and chyme inside the stomach the gallbladder produces bile. The bile will emulsify the fat to break it into smaller component parts. The bile duct drains into the second part of the duodenum, similarly, the pancreas also drains into the duodenum.

Control of Pancreatic Secretion

PANCREATIC ENZYMES

The enzymes break down the peptide bonds.

Proteolytic – Trypsinogen, chymotrypsinogen, procarboxypeptidase (They are stored in an ‘inactive’ form to prevent autodigestion of the pancreas which is what happens in pancreatitis).Ttrypsin is secreted by the small intestine but the active form trypsinogen is secreted by the pancreas

Pancreatic amylase: only breaks down alpha 1,4 bonds (CHO). Pancreatic amylase completes digestion of carbohydrate, producing glucose, a small molecule that is absorbed into your blood and carried throughout your body

Pancreatic lipase: Pancreatic lipase is the main enzyme that converts triglycerides to monoglycerides and fatty acids.

Villus – Microscopic

Villi of the SI all to enhance absorption.

Villus Structure

Brush border enzymes help break down and finish off the work. E.G. When starch is broken down into disaccharides, sucrose, maltose, lactose – we need to break it down into a single unit and the brush border enzymes help do that.

Inside we have blood vessels that will carry away protein and sugar digested. The lymphatics will deal with the fats.

Transport Across the Intestinal Epithelium

The cells are joined to each other by a tight junction that stops compounds passing through.

So you need to go through the cells instead, you need a protein molecule to carry across – this is the transporter protein.

Active (SGLT) and Passive (GLUT) Sodium and Glucose Transport

When NA+ is brought in you will drag in the sugar, making it a co-transporter.

If you block Sodium-glucose link transport protein 2 (SGLT2) then sugar will not be absorbed and it will be excreted in the urine. SGLT2 inhibitors are becoming popular in treating diabetes and aiding weight loss.

GLUT2 is for the glucose to cross the cellular membrane to get into the blood stream.

Carbohydrate Digestion

• Most carbohydrates in the diet are consumed as disaccharides or polysaccharides
• Only monosaccharides are absorbed by the intestinal cells for use in the body
• Disaccharides and
  polysaccharides must be digested to monosaccharides beforthey can be absorbed for use in the body.
• Dextrose monohydrate is a monosaccharide.

Polysaccharides are complex carbohydrates composed of numerous monosaccharides.

Disaccharides aren’t just broken down into glucose monosaccharides. They can be broken down into fructose, galactose and other compounds.

Foods High in Fructose/Fructans

Problem foods include:

• Those with high fructose to glucose ratio (glucose assists absorption of fructose) e.g. apples, pears, melons, mango, honey
• Foods with high total sugar load (overwhelms absorptive capacity) e.g. dried fruit, juice, confectionary, sweet drinks
• Foods high in fructans/inulins (long-chain fructose) e.g. wheat, onion, leek, asparagus, artichokes
• Fructose malabsorption → gas, pain, osmotic diarrhoea (possibly also fatigue and effects on mood)
• Quite common cause of IBS

Protein Digestion

• Proteins are broken down to peptide fragments in the stomach by pepsin, and in the small intestine by trypsin and chymotrypsin, the major proteases secreted by the pancreas
• These fragments are further digested to free amino acids by carboxypeptidase from the pancreas and aminopeptidase, located on the luminal membranes of the small intestine epithelial cells
• The free amino acids then enter the epithelial cells by secondary active transport coupled to Na+
• Short chains of two or three amino acids are also absorbed by a secondary active transport coupled to the hydrogen ion gradient.

Protein is broken down into small peptides.

Aminopeptidases cleave the peptide bonds.

Antrum grinds food into chyme so that it can pass through to the duodenum. Undergoes mechanical digestion, but protein digestion mainly occurs due to enzymes.

Fat Digestion

Main dietary and storage form of lipid is as a triglyceride = three fatty acid chains attached to a glycerol backbone

Fat digestion and absorption take place soley in the small intestine.

Absorption of Lipids 

95%~ of the fat we consume are triglycerides made up of free fatty acids.

Bile salts help emulsify the fat then pancreatic lipase will act to break it down into monoglycerides and free fatty acids.

Micelle Formation

Fat and water don’t mix so you need an interface. The bile salts will emulsify will break the fat into small parts.

A co-enzyme called colipase will help lipase. You need the presence of colipase for the action of lipase, because bile acid

can inhibit lipase.

Vit A, D, E, K are fat soluble (dissolved and stored in fat) vitamins.

Micelle

An aggregate of molecules in a colloidal solution, such as those formed by detergents.

Fat Absorption

When fatty acids pass through they have to be resynthesized in the endoplasmic reticulum.

Because they are heavy large molecules they have to be cleaved off into small vesicles so they can fit to circulate through the blood.

Lacteals are a lymphatic capillary that are essential for the absorption of fat in the villi of the SI.

STEATORRHOEA

Diarrhoea due to excessive fat (undigested, malabsorption ) in faeces

Causes:

• Pancreatic insufficiency
• Medication for losing weight (Xenical) which block the lipases so the fat is not digested
• Zollinger Ellison Syndrome (high amounts of gastric acid which the bicarbonate cannot overcome)
• Short bowel (resection) we the intestines are cut and shorterened &
• Bacterial overgrowth
• Treated via getting enzymes from animals and giving it to the patient

Enterohepatic Circulation of Bile Salts

Bile salts are produced from the liver from CHOL. Bile salts are important in solubilizing dietary fats in the watery environment of the small intestine.

Bile salts are secreted by the liver enters the terminal ileum > 95% of bile salts are reabsorbed by the liver.

• Bile salts are re-absorbed via active transport by in the terminal ileum before being transported to the liver via the hepatic portal vein to the recycled

Bile also serves as the route of excretion for bilirubin, a byproduct of red blood cells recycled by the liver. Bilirubin derives from haemoglobin by glucuronidation.

Most substances absorbed by the small intestine are carried to the liver by the hepatic portal vein

EnteroHepatic Circulation of Bile Acids

Primary Bile acids. Cholic and chenodeoxycholic acid

Secondary Bile acids. Deoxycholic and lithocholic acid

Total bile acid pool is 4 gm. 50 mg synthesized by liver daily. Conjugated to taurine or glycine. Absorbed by active Na+ dependent process in terminal ileum. Transported back to liver via portal vein to be re-secreted.

BILE SALT DIARRHOEA

If the bile salts are not absorped because something happens to your terminal ileum you get bile salt diarrhoea.

• Terminal Ileum –Resection or Chronic Infection/Inflammation resulting in loss of Bile salts – Interruption of Enterohepatic Circulation of Bile salts.
• Bile salts in Colon – stimulate active chloride secretion – diarrhoea
• If the bile salts are not absorped because something happens to your terminal ileum you get bile salt diarrhoea.

Vitamins and Minerals

• Fat-soluble vitamins (A, D, E, and K) are absorbed like other lipids
• Water-soluble vitamins are absorbed by diffusion or mediated transport, except for vitamin B12, which must first bind to a transport protein known as intrinsic factor
• Water and minerals are absorbed by diffusion primarily within the small intestines
• The absorption of Na+, Cl-, and K+ as well as Ca2+ and iron are important to maintain physiological processes

Abnormalities in Digestion and Absorption

VITAMIN B12 ABSORPTION

The intrinsic factors combines in the duodenum.

Theoretically if the pancreas is not healthy it can affect the absorption of Vit B12.

VITAMIN B12 MALABSORPTION

• Megaloblastic Anaemia
• Stomach – Resection/chronic gastritis
• Terminal ileum – Resection/Crohn’s/TB
• Long term Metformin treatment can result in B12 deficiency nebcause metformin blocks the absorption of B12. But this can be mediated by giving CA+.

SHORT BOWEL SYNDROME

Cause: When the SI are operated upon due to accident or disease”

1. Loss of intestinal absorptive surface area – you must have 100-150 cm of the proximal jejunum adequate. Otherwise you lose the ability to produce certain hormones and regulate acid.
2. Irreplaceable loss of enteric hormones (Upper segment)
3. Malabsorption of water, electrolytes, macronutrients (proteins, carbohydrates, fats), and micronutrients (vitamins, minerals, trace elements).
4. Loss of acid control
5. Retention of the terminal ileum is important & of Ileo-caecal valve (Bacterial overgrowth)
6. Residual intestine adaptation

Short

Ferritin is iron in storage. This iron can only be used when the cells die.

Fe+ = serum circulating iron.

Ferroportin is a iron transporter.

Transferrin will carry will carry the iron to the marrow or other sites it needs to be transported to.

Hepcidin controls the amount of iron being absorbed

However iron is carcinogenic. Hemochromatosis is a disorder where too much iron builds up in your body. Sometimes it’s called “iron overload.” Normally, your intestines absorb just the right amount of iron from the foods you eat. But in hemochromatosis, your body absorbs too much, and it has no way to get rid of it.

syndrome Symptoms

• Diarrhoea & Steatorrhoea
• Fluid depletion
• Weight loss, Anaemia, Malnutrition (calories, vitamins, minerals)
• Fatigue

Lactose Intolerance

Lactose Intolerance

• Lactose is a disaccharide of glucose and galactose find in milk
• Associated with a deficiency of the intestinal lactase (b-galactosidase)
• Prevalence up 60-90% in some ethnic groups
• Symptoms from malabsorption and fermentation: abdominal pain, flatulence, and frothy diarrhoea

 

IRON ABSORPTION

Ferritin is iron in storage. This iron can only be used when the cells die.

Fe+ = serum circulating iron.

Ferroportin is a iron transporter.

Transferrin will carry will carry the iron to the marrow or other sites it needs to be transported to.

Hepcidin controls the amount of iron being absorbed

However iron is carcinogenic. Hemochromatosis is a disorder where too much iron builds up in your body. Sometimes it’s called “iron overload.” Normally, your intestines absorb just the right amount of iron from the foods you eat. But in hemochromatosis, your body absorbs too much, and it has no way to get rid of it.

CALCIUM ABSORPTION

Active Transcellular & Passive Paracellular

CA+ binds to albumin in the blood and carries it away.

Calbindin is a vitamin D–responsive gene in many tissues, in particular the chick intestine, where it has a clear function in mediating calcium absorption. In the brain, its synthesis is independent of vitamin-D

Vid D will enhance the synthesis of calbindin which will therefore enhance the absorption of Vit D.

COLON

Function

1. Store waste (faeces)
2. Absorb water
3. Bacterial fermentation
4. Vitamin K synthesis
5. Undigested Polysaccharides (fiber) are metabolized to short-chain fatty acids by bacteria

On the left ascending colon the faeces is still soft, once it reaches the descending colon and water is removed the faeces forms. So much so that the faeces we pass has only 50-100ml of water.

CONSTIPATION

Common causes of constipation

Something wrong with the gut Motility and Motor disorders.

Gut motility is the stretching and contractions of the muscles in the gastrointestinal (GI) tract, and it controls movement of food throughout the digestive tract.

• Symptoms of headache, abdominal distension, loss of appetite and nausea – caused by distension of rectum
• Longer the period in large intestine = more water absorbed from fecal mass, making it harder to move the bolus
• Primary cause in decreased motility (common with ageing)
• Fibre increases motility

1. Obstruction (cancer)
2. Medication – Painkillers, Opiates
3. Severe inflammation
4. Endocrine problems – Hypothyroid, High serum Calcium

DIARRHOEA

• Defined as having at least 3 loose or liquid bowel movements each day
• Result from ↓ fluid absorption and/or ↑fluid secretion
• Symptoms include cramps and abdominal pain, nausea and vomiting

Common causes of Diarrhoea

Caused by Motility issues with too much movement, too much water inside and Secretions

1. Infection – bacteria and toxins

• Cholera is an infectious disease that causes severe watery diarrhea, which can lead to dehydration and even death if untreated. It is caused by eating food or drinking water contaminated with a bacterium called Vibrio cholerae. The bacteria produces a toxin that paralyses your ‘sg’.

2. Inflammation
3. Malabsorption: Food intolerance (e.g. lactose)
4. Medications

Treat diarrhea: Boil water, rice and salt together and drink the liquid.

Abnormalities in Digestion and Absorption

Inflammatory Bowel Disease

• Includes ulcerative colitis and Crohn’s disease, which cause chronic inflammation of the intestinal tract
• Abdominal pain, vomiting, diarrhoea, rectal bleeding, severe internal cramps/muscle spasms, weight loss, and anaemia
• Environment, genes and gut bacteria all linked to cause

The Liver

Functions of the Liver

• Production and storage of bile
• Production of certain proteins for blood plasma (albumin, globulin, clotting factors)
• Central role in glucose regulation: Stores (glycogen) and release glucose
• Stores iron and vitamins
• Clearance of bilirubin: Serves as a filter and functions in the removal of old red blood cells which leads to hemoglobin processing and the generation of bilirubin
  • Bilirubin occurs in the normal catabolic pathway that breaks down heme. This catabolism is a necessary process in the body’s clearance of waste products that arise from the destruction of aged or abnormal red blood cells.
• Clearance and activation of Drugs to a more benign form
• Conversion of harmful ammonia to urea. It is the only organ that acts on ammonia and converts it to urea.
• When people have liver failure they get very confused because a lot of ammonia is being secreted and crosses into the brain.
• Gluconeogenesis, lipid synthesis, and ketogenesis
• Production of albumin, macroglobulins, lipoproteins, transport proteins, and clotting factors
• Excretion of cholesterol, steroid hormones, bile salts, drugs, toxins
• Storage of glycogen, vitamins A, D, and B12, Cu and Fe

GallBladder

The gallbladder is a pear-shaped, hollow structure located under the liver and on the right side of the abdomen.  Its primary function is to store and concentrate bile, a yellow-brown digestive fluid produced by the liver.

Gallstone – Ultrasound Picture

Ultrasounds are the best way to observe gallstones as of right now.

Function of Bile

Greenish/yellowish brown fluid produced by the liver, stored in the gallbladder, contains bile salts.

• Emulsify fat ( formation of micelles )
• Absorption of Vitamins A, D, E ,K ( fat soluble )
• Alkaline (pH 7.05 – 805 ) – helps neutralise gastric acid in duodenum
• Bile salt is made from CHOL so it is also how the body excretes excessive CHOL
• Elimination – bilirubin, cholesterol
• Bactericides – prevents putrefaction of food

Causes of Jaundice

• Blockage of Common Bile duct – stones, worms (ascaris), cancer
• Inflammation of the Liver – Alcohol, Drugs
• Viral infection – Hepatitis
• Hemolysis (excessive RBC destruction)

Mechanisms Involved in Appetite Control

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