1.

Homeostasis and Endocrine System

Homeostasis
 Homeostasis and fluid compartment
 ⅓: ECF
 ¼ intravascular
 ¾ interstitial
 ⅔: ICF
 Regulation of homeostasis
 Feed forward
 anticipate a change and start a reflex loop
 thought of food -> stomach (antrum) -> gastrin -> corpus / fundic stomach ->
HCl
 Negative feedback
 Simple VS complex
 Simple: paracrine VS autocrine VS gap junction(nexus)
 Macrophage -> pyrogen -> hypothalamus -> body temperature set point ↑
 Pancreas beta cell -> insulin -> skeletal muscles take up glucose from blood
 Body temperature ↓ -> hypothalamus -> thyroid releasing hormone -> pituitary ->
thyroid stimulating hormone -> thyroid hormone gland -> thyroid hormone ->
metabolism ↑
 Positive feedback
 Follicle stimulating hormone -> follicle stimulating hormone receptors ↑ -> follicle
stimulating hormone ↑
 Protease -> fibrin clot ↑ -> protease ↑
 Tonic control (Basal state, increased state, decreased state)
 contraction of smooth muscle
 sympathetic nervous system ↑ -> vasoconstriction
 sympathetic nervous system ↓ -> vasodilation
 Antagonistic control (different receptors but opposite control)
 parasympathetic ↓
 sympathetic ↑
 Circadian rhythm
 Early sleep: hypoglycemia (blood glucose ↓) -> ghrelin hormone -> pituitary gland
growth hormone -> blood glucose ↑ -> growth hormone ↓
 Before wake up: adrenal gland cortisol hormone ↑ blood glucose ↑ -> growth
hormone ↓
 Sleep wake, not light dark
 Transporters Pumps and Channels
 Fluid volume of body measured using isotope dilution
 intravascular: radiolabeled albumin
 extracellular: inulin
 whole body water volume is determined by infusing tritiated water
 Movement
 Flux = transfer rate
 Permeable solutes simple diffusion
 Urea soluble in lipid (hydrophobic)
 Non permeable solutes facilitated diffusion
 No energy
 Transporter & channel
 Basis of disease
 Defective transporter(integral membrane protein)
 Cystic fibrosis -> [Cl-] not moving correctly across membrane -> water no
moving correctly across membrane
 Defective channel
 Long QT syndrome -> beat prolong -> arrhythmia
 Basis of pharmacological therapy
 Hypertension: diuretic -> sodium transporter inhibited -> urine ↑
 Stomach ulcer: proton pump inhibitor
 Transporter (diffusion only)
 Glut / glucose transporter
 Co-transporter
 [Na+] + glucose
 Gastrointestinal epithelium & renal tubules epithelium
 Symporter same direction: sodium glucose
 Antiporter opposite direction: sodium proton, peptide proton (small
intestine)
 Channel / pore (diffusion only & bi-directional )
 Non gating / open at all times
 Aquaporin
 Gap junction (nexus) [Ca2+]
 Gating / open when triggered
 Ligand (chemically gated)
 unbind: close
 bind: open when chemical bind
 Eg skeletal muscle nicotinic receptor: acetylcholine
(parasympathetic neurotransmitter) open when bind, [Na+] enter
  Voltage (negatively charged protein inside cell -> inside - outside +)
 At certain voltage: close
 At certain voltage: open
 Eg neuron / cardiac myocyte voltage gated calcium channel
 Mechanical
 Unstretch: close
 Stretch / tension: open
 Eg smooth muscle contract after [Ca2+] enter
 Pump (against gradient) (enzyme) (primary active transport)
 Muscle cell calcium ATPase pump cleaves ATP -> [Ca2+] bind from inside ->
conformational change -> [Ca2+] extruded to outside -> muscle cell relax
 Sodium potassium ATPase: 3[Na+] out 2[K+] in
 Stomach cell proton potassium ATPase: acid
 Secondary active transport
 Apical surface: (in)
 sodium glucose cotransporter SGLT
 Basal surface: (out)
 Facilitated glucose transporter
 Sodium potassium ATPase pump
 Solute and water transport
 Osmotic pressure prevents the movement of water across a membrane
 Count all particles within solution
 Osmolarity: litre volume
 Osmolality: kg volume
 Molarity (Mol / L) x (number of particles) = Osmolarity (Osmol / L)
 Each cell ECF 300m OsM
 200m OsM < 300m OsM < 400m OsM
 Diluted < iso < concentrated
 Isosmotic / hypoosmotic / hyperosmotic
 Count non-penetrating particles (effective solutes) within solution
 Tonicity = effective osmolality and is equal to the sum of the concentrations of the
solutes which have the capacity to exert an osmotic force across the membrane.
 Isotonic / hypotonic / hypertonic
 Osmolarity or ion concentration controls the elimination of water in the urine.
 Changes in blood volume (or blood pressure) control sodium excretion-not osmolarity!

Endocrine system
 General concepts
 hormone ↓ -> high affinity receptor
  Concentration
 EU concentration (best)
 ↑ -> down-regulate receptor
 neurotransmitter ↑ -> low affinity receptor
 Ductless
 Fast neuron VS slow endocrine
 Mass action law: hormone from low affinity to high affinity
 degraded by the liver -> cleared by the kidney
 3 types hormone
 Peptide / protein
 RER synthesis / cleaved / packaged preprohormone (inactive)
 golgi cleaved preprohormone to be prohormone (inactive / active)
 Golgi packaged prohormone inside secretory vesicles
 Inside secretory vesicles, prohormone cleaved to be hormone (active)
 Secretory Vesicles sit in cytoplasm
 Secretagogue, [Ca2+] inside cell / cyclic AMP ↑, cell secret vesicles
 Soluble in plasma not lipid, no need carrier protein, prepackaged, short half
life, fast acting
 Examples:
 Insulin, inside vesicles, insulin cleaved, the cleaved section is c
peptide, the other is peptide, both released
 Steroid hormone (derivative of cholesterol)
 Made in
 Adrenal gland
 Gonad
 Placenta of pregnant female
 Cholesterol to pregnenolone
 formed on inner membrane of mitochondria
 shuttle between mitochondria and SER for further enzymatic
transformations
 testosterone
 Converted to more active species by enzyme
 Testosterone -> dihydrotestosterone DHT
 Testosterone -> estrogen
 Soluble in lipid not plasma, need carrier protein (made in liver), synthesis on
demand, long half life (60-90mins), slow acting
 Amino acid derivative
 Tyrosine derivatives
 Catecholamines
  Soluble in plasma not lipid, short half life (seconds-minutes)
 Adrenal gland -> epinephrine (hormone)
 Bind to adrenergic receptor (backup
sympathetic nervous system)
 norepinephrine (hormone & neurotransmitter)
 bind to adrenergic receptor (sympathetic
nervous system)
 thyroid hormone
 Soluble in lipid not plasma, need carrier protein, long half
life (7days), slow acting
 Thyroxine T4
 4 iodine
 Converted in target tissues into T3
 Triiodothyronine T3
 3 iodine
 Carrier protein
 Hormone concentration: active free hormone + carrier protein bound hormone
 3 types receptors
 On cell surface / integral membrane proteins
 Peptide derivatives hormone: hydrophilic (soluble in plasma)
 Type 1: enzyme linked eg tyrosine kinase: growth hormone binds to it
 Kinase: put a phosphate group on
 Phosphorylation cascade -> metabolism of cell changes
 Type 2: inherent enzyme activity eg tyrosine kinase: insulin binds to it
 Type 3: G protein coupled
 Adenylate cyclase
 Eg glucagon
 Inside cell / Cytosolic or Nuclear receptors
 Hormone soluble in lipid (steroid hormone & thyroid hormone) -> cross
plasma membrane -> bind to DNA -> activate gene transcription -> change
mRNA -> change protein
 Beta cells of the pancreas have different types of receptors
 On cell surface
 Epinephrine
 Acetylcholine
 Target cell sensitivity:
 Rebound: hormone ↓ -> receptor ↑
 Receptor affinity ↑
 Competition
 mineralcorticoid receptor can bind
  Cortisol
 Aldosterone
 Prevent cortisol from binding to mineralcorticoid receptor -> protective
mechanism to inactivate cortisol
 Saturation
 Regulatory stimuli types:
 Neuron control
 [Na+] ↑ -> Neuro endocrine cell eg posterior pituitary secretes antidiuretic
hormone -> kidney -> move water from presumptive urine to blood
 Hormonal control / Complex negative feedback fluke
 Hypoglycemia Glucose ↓ -> anterior pituitary hypothalamus secretes growth
hormone releasing hormone -> pituitary cell secretes growth hormone ->
liver / bone
 Substrate / Nutrient / ion control
 [Ca2+] ↓ -> parathyroid gland secretes parathyroid hormone -> bone releases
[Ca2+]
 Glucose ↑ -> pancreatic beta cell secretes insulin -> muscle / fat cells take
glucose back
 Regulation interactions:
 Synergy: net effect of several hormones acting on a target tissue causes a bigger
response than simple addition of each independent hormonal effect
 Re-enforcement: actions of a single hormone on multiple tissues converge to
regulate a process such as glucose production
 Permissiveness (or tropism)
 signal inactivation
 2 stages:
 Cellular inactivation
 Systemic inactivation
 Adaptation / Changing plasma hormone concentration
 Receptor desensitization, eg type II diabetic
 remove receptor
 uncouple receptor
 degradation
 Negative feedbacks
 Assessment and pathology
 Measuring hormone
 High sensitivity & high specificity
 Competitive binding assay using antibody
 Quantity: total hormone (carrier-bound + free)
 Radio-immune assay (RIA) and enzyme-linked immunosorbent (ELISA)
 assay measure the
 immuno-reactivity of the hormone
 Bioassay
 Functional or active?
 Stimulation / suppression tests
 measures the biological activity to hormone or substrate such as glucose
(glucose tolerance test)
 Eg hypoglycemia glucose ↓ -> hypothalamus secretes corticotrophin CRH ->
anterior pituitary secretes adrenocorticotrophin ACTH -> Adrenal gland secretes
cortisol
 Dexamethasone inhibits anterior pituitary from secreting ACTH
 Primary pathology:
 Last is faulty
 Secondary pathology
 Second last is faulty
 Tertiary pathology
 Third last is faulty