Physiology Flashcards
Mechanisms of hormone release
- humoral - respond to changing levels of ions or nutrients in the blood
- Neural - stimulation by nerves
- Hormonal - stimulation received from other hormones
Components of an endocrine axis
- Detection of homeostatic imbalance
- Ligand-Receptor activates secretory apparatus
- Release of hormone from cell
- Hormone in extracellular fluid – blood transport
- Target organ recognition of hormone - receptor
- End organ response to hormone
- Detector sense return to homeostasis – negative feedback
- Hormone cleared
- Synthesis of hormone reserves
3 types of hormones
- Hydrophilic = protein/peptide hormones
- Really small/variable = tyrosine derived hormones
- Hydrophobic = steroid hormones
Storage, release and inactivation of protein/peptide hormones
Storage: secretory granules or vesicles
Release/action: Hydrophilic bind cell surface receptors and activate intracellular signalling pathways
Rapid acting and short lived
Inactivation: internalised by receptor mediated endocytosis, sequestered by kidney –> excreted
Steroid hormones and inactivation
Lipids: derived from cholesterol. Include: cortisol, aldosterone, testosterone and progesterone.
Lipophilic:
- Require transport proteins - Bind intracellular receptors
Inactivation (Liver)
1. Cytochrome P450 oxidase 2. Conjugated
3. Excretion in bile
Examples of tyrosine-derived hormones and which bind extracellular and nuclear receptors
Catecholamines - adrenaline, and NA (extracellular)
Thyroid hormones - thyroxine (nuclear)
Dopamine (extracellular)
What determines how sensitive a receptor is to a hormone?
- number of receptors
- affinity of the receptor
- downstream signalling molecules
Capacity for maximal response is determined mainly by the number of functional cells
Overload desensitisation
Prolonged exposure to stimulus decreases cells response to the level of exposure.
Allows receptors to respond to changes in concentration of a signal rather than absolute concentration.
Biggest endocrine organ?
Most important endocrine organ?
Biggest - gut
Important - H-P-x axis
Hormones produced in the anterior pituitary
GH ACTH TSH LH PRL FSH
Hormones stored in the posterior pituitary
Oxytocin and vasopressin
Regulation of ACTH release
• Stimulation of release • CRH and ADH (hypothal.)
• Stress
• Hypoglycemia
• Circadian pattern of
release
• Highest levels early AM • Sleep-wake cycle (jet-
lag)
What is produced from pre-pro-opiomelanocortin?
- ACTH
- Endorphin
- Lipotrophin
- Melanocyte-stimulating hormone
Action of ACTH
• ACTH stimulates secretion of adrenal glucocorticoids
• Binds cell-surface melanocortin type II receptors (MC2R) • GPCR adenylyl cyclase cAMP protein kinase A
• Most dense in the zona fasciculata
• Regulates steroid hormone secretion (2 ways)
1. RAPID = stimulate lipoprotein uptake into cortical cells, cholesterol delivery
2. LONG TERM = stimulate transcription of steroidogenic enzyme genes
Adrenal gland hormones produced
Adrenal medulla - catecholamines
Zona reticularis - sex hormones
Zona fasciculata - glucocorticoids (cortisol)
Zona glomerulosa - mineralocorticoids (aldosterone)
**corticosteroids = glucocorticoids and mineralocorticoids
What mediates secretion of mineralocorticoids (aldosterone)?
- produced in zone glomerulosa
- mediated by mostly angiotensin II, and local increase in [K+]
Action of aldosterone in the kidney
- ↑ active K+, H+ secretion
- ↑ Na+/K+-ATPase
- active Na+ reabsorption (water follows) • ↑ increases of BP and blood volume
Action of glucocorticoids
- CHO metabolism – elevates blood [glucose]
- Stimulate gluconeogenesis (mobilises AAs, ↑ conversion anzymes) • ↓ cellular glucose use (oxidation of NADH)
- Lipid metabolism – elevates blood [fat] • Mobilises FAs from adipose tissue
- Also stimulates b-oxidation energy
- Protein metabolism – elevates blood [Protein, AA]
- Mobilises AAs from non-hepatic tissues (enhances liver protein synthesis)
- Anti-inflammatory
- Blocks early stage inflammatory inception
- Increases healing of inflammation
- Suppresses cellular immune response, stabilises lysosomes, reduces vessel permeability.
Production of cortical sex hormones
- Synthesised in the zona reticularis
- DHEA (dehydroepiandrosterone)
- Androstenedione
- Converted in peripheral tissues to testosterone, oestrogen
Secretions of the pancreatic islet of Langerhan cells
α-cells: secrete glucagon
β-cells: secrete insulin (+ amylin) ∆-cells: secrete somatostatin
Precursor thyroid hormone
Thyroglobulin
Thyroid hormones and what they are derived from
Derived from tyrosine
- thyroxine T4 (usually transformed into T3 within target cells, because T4 has low biological activity) - main one secreted and circulated in bloodstream
- Triiodothyronine T3 - binds to receptors, and has more biological potency than T4
2 major components of thyroid hormone synthesis
- Iodine
2. Thyroglobulin precursor
Function of iodine in thyroid hormone synthesis
Thyroidhormonesneedlargeamountsofiodine(I2). Scarce, low levels absorbed. (DRI 1mg/week)
Iodine is absorbed as iodide (I-) and converted to iodine.
Thyroidglandshavepowerfuliodidepumpstoconcentrateiodine
within the thyroid gland. ([I-] in follicular cells 20-50x > plasma)
Steps in thyroid hormone biosynthesis and secretion
- Iodine trapping
- Oxidation of iodide
- Synthesis of thyroglobulin
- Iodination of tyrosine residues
- Coupling of tyrosine residues
- DIT+DIT=T4
- MIT+DIT=T3
- Endocytosis and digestion of colloid
What is the consequence of a faulty iodide pump in the thyroid follicular cell?
Severe hypothyroidism
Importance of high concentration iodine storage
Allows storage of large amounts of TH precursor, so the body becomes somewhat independent of day to day Iodine availability.
Iodination of precursor to form mature thyroglobulin.
Function of thyroid binding globulin
Binds T3 and T4 and provides water solubility
Thyroid hormone binds intracellular nuclear receptors and regulate the activity of genes including:
- Na-K pump
- gluconeogenic enzymes
- respiratory enzymes
- Myosin heavy chain
- beta-adrenergic receptors
How can TSH increase thyroid activity?
- Increases hormone synthesis: Increases activity of NIS iodide pump Increases thyroglobulin production
2.Increases thyroid hormone secretion
• Vesicular reuptake
• Exocytosis
- Increases blood flow to the thyroid.
What is accelerated by TH?
- Oxidative metabolism
- CHO metabolism
- Lipid metabolism
- Nitrogen metabolism
What is hypothyroidism characterised by and what are some symptoms?
Low T3 + T4
High TRH + TSH
Signs: lack of energy, weight gain, poor tolerance of cold, enlarged thyroid gland (Hashimoto’s disease)
What is hyperthyroidism characterised by and what are some symptoms?
Causes?
High T3 + T4
Low TRH + TSH
Signs: poor heat tolerance, goiter, exophthalmos, muscle wasting and weakness, sweating, weight loss, fatigue
Cause: AI hyperthyroidism, thyroid tumours
Effects of hypercalcemia and hypocalcemia
Hypercalcemia – depresses neuromuscular activity (blocks Na+ channels raises AP threshold - bathmotropy), kidney stones
Hypocalcemia – Potentiates neuromuscular activity (positive
bathmotropy – lowers AP threshold), impairs clotting
SI enterocyte Ca2+ absorption
- TRPV6 is a Ca2+-specific channel (Ca2+-dependent fbk inhibition)
- Calbindin binds cytosolic Ca2+ - prevents free Ca2+ blocking TRPV6
Which part of the nephron is most important in retaining Calcium?
Proximal tubule - 70% of calcium retention
90% of calcium is ________ reabsorbed in the nephron
Passively
Function of osteoblasts and osteoclasts in calcium serum levels
Osteoblasts
– bone-forming cells: responsible for bone deposition – ↓serum [Ca2+]
Osteoclasts
– bone-eating cells: resorb the previously formed bone – ↑serum [Ca2+]
Actions of PTH on bone
Increases bone degradation (releases Ca2+).
Rapid action (minutes)
• ↑ osteocyte membrane permeability for Ca2+ →liquid Ca2+ of bone enters the cells→ Ca2+ pump transports Ca2+ to the extracellular fluid →↑ serum [Ca2+]
Delayed action (12~14h)
• ↑ osteoclast activity→↑ serum [Ca2+]
• ↑ production of osteoclast →↑ serum [Ca2+]
NET RESULT: increased release of Ca2+ from bone
Actions of PTH on kidney
• decreased renal Ca2+ excretion
Action
• Increases reabsorption of Ca2+ from thick ascending limb and distal tubule
• ↑ Ca2+ -ATPase and Na+-Ca2+ antiporter
• ALSO, Stimulates transcription of 1-alpha hydroxylase
Vitamin D activation in kidney
NET RESULT: increased plasma calcium levels
Function of calcitonin
- Major target cell – osteoclast
- Acts through calcitonin receptor (cAMP mechanism)
- Inhibits activity of osteoclasts→↓bone turn over
- Inhibits osteoclast formation
- Minor effect – decreases kidney Ca2+ reabsorption
Effects of growth hormone
GH directly activates growth of bone, soft tissue and viscera
• Metabolic switch (burn fat, store protein/CHO)
• Increased protein synthesis (↑ translation, transcription - new
muscle etc.)
• Increased amino acid transport (↑ tissue protein storage)
• Increased lipolysis (burn fat for fuel)
• Reduced glucose transport and metabolism
• Increased IGF production in liver (and other organs)
What is the starvation paradox?
• If nutrients are required for growth, why would starvation trigger GH release?
• GH helps us survive prolonged starvation by switching metabolism away from proteins as a fuel source (“protein-sparing”).
- allows body to switch from using proteins/glucose to sustain life, to storing glucose/proteins in tissues
- burn through fats first
Function of IFs
Regulate proliferation, differentiation and metabolism
- Resemble insulin in structure and function (i.e. regulates CHO metabolism)
- IGFs stimulate amino acid uptake and activate protein & DNA synthesis
- Strongly mitogenic and hypertrophic
- 2 Isoforms:
- IGF-1 = adult form, IGF-II = foetal form • autocrine and paracrine effects
Synergistic effects of signalling from insulin and IGF
- protein translation
- autophagy
- apoptosis
- oxidative stress
- gene transcription
- proliferation
Consequence of over secretion of GH before and after puberty
Before puberty - XS growth that continues throughout childhood and puberty, leading to extremely tall stature/gigantism
After puberty - thickening of bones in hands, feet and jaw causing a disease called acromegaly
Action of parathyroid hormone, vit D and calcitonin in calcium regulation?
¥ Parathyroid hormone – increases plasma [Ca2+]
¥ Vitamin Ds (1, 25, D) – increases plasma [Ca2+]
¥ Calcitonin – reduces plasma [Ca2+]
Action of PTH on bone
Rapid action (minutes) ¥ ↑ osteocyte membrane permeability for Ca2+ →liquid Ca2+ of bone enters the cells→ Ca2+ pump transports Ca2+ to the extracellular fluid →↑ serum [Ca2+] Delayed action (12~14h)
¥ ↑ osteoclast activity→↑ serum [Ca2+]
• ↑ production of osteoclast →↑ serum [Ca2+]
NET RESULT: increased release of Ca2+ from bone
Action of PTH on kidney
decreased renal Ca2+ excretion
Action
¥ Increases reabsorption of Ca2+ from thick ascending limb and distal tubule
¥ ↑ Ca2+ -ATPase and Na+-Ca2+ antiporter
¥ ALSO, Stimulates transcription of 1-alpha hydroxylase
Vitamin D activation in kidney
NET RESULT: increased plasma calcium levels
Consequences of vitamin D deficiency
Deficiency - “rickets” - low Ca2+ levels , which results in:
o soft and pliable bones (bending/distortion)
o impaired ossification of the newly created osteiod
Type I - Mainly due to Vit D deficiency (lack of sunlight, diet)
Type II - Vit D receptor (VDR) mutation
Normal ECF [H+] and normal variation/ pH
40nEq/L +-3-5
pH = 7.4
Acidosis and alkalosis pH levels
Acidosis: < 7.35
Alkalosis: >7.45
Venous blood has a lower pH to arterial blood due to:
Carbon dioxide levels being higher
How does pH effect metabolism and the neuromuscular system?
Metabolism: every step is pH dependent so altered pH reduces reaction efficiency due to enzymes
NM system: acidosis results in hypo excitability, alkalosis results in hyperexcitability
Due to acidosis increasing serum [K+] and alkalosis reducing it
Defense mechanisms to acid-base changes in the body
Chemical buffering (immediate but exhaustible)
• Solutions that resist change in pH
• Intracellular and extracellular buffers provide an immediate response to acid-base disturbances – bone also buffers
Pulmonary regulation (minutes/hours and limited capacity)
• PCO2 is regulated by changes in tidal volume and resp rate
• A decrease in pH increases in tidal volume or respiratory rate
• CO2 is exhaled blood pH increases
Renal regulation (hours-days and v powerful with infinite capacity)
• The kidneys control pH by adjusting the amount of HCO3- that is excreted or reabsorbed
•
Reabsorption of HCO3- is equivalent to removing free H+
Chemical buffer systems
Bicarbonate
Phosphate
Proteins - and Hb in RBCs
Ammonia
What speeds up the conversion of carbon dioxide and water into bicarbonate?
Carbonic anhydrase
Processes involved in renal control of pH
- Secretion of H+
- Reabsorption of filtered HCO3-
- Generation of new HCO3-
Mechanisms of hypokalaemia when plasma pH increases
- Na+/K+ ATPase: alkalosis causes a shift of K+ form the plasma ICF
- Electroneutrality is king: increase in plasma [HCO3-] will exceed renal PCT reabsorption capacity, and K+ will be excreted as an obligate cation partner to HCO3-
Difference between respiration and metabolic acidosis
Resp: ppCO2 increases massively
Metabolic: massive decrease in HCO3-
Types of nephrons
Cortical nephrons – 80% of nephrons
• Renal corpuscle in outer portion of cortex and short loops of Henle extend only into outer region of medulla –
Juxtamedullary nephrons – other 20% (important in water balance)
• Renal corpuscle deep in cortex and long loops of Henle extend deep into medulla
• Peritubular capillaries and vasa recta
- Ascending limb has defined thick and thin regions
- Enable kidney to secrete very dilute or very concentrated urine
Which part of the nephron contacts the glomerulus again and what is the purpose?
Purpose: feedback
Part: thick ascending loop of henle
What does glomerular filtration rate depend on?
- permeability of membrane
- surface area of membrane
- filtration pressure
Myogenic auto regulation of Glomerular filtration rate
¥ Automatic regulation of RBF + GFR
¥ In response to slight changes in BP
¥ Control at the local level (e.g. smooth
muscle cells)
(a) ↑ MAP automatically induces vasoconstriction of afferent arteriole↓ flow↓ GFR and bringing it back to normal
(b) ↓ MAP induces afferent arteriole vasodilation↑ flow and GFR, and bringing GFR back to normal levels.
Tubuloglomerular feedback regulation of glomerular filtration rate
Juxtaglomerular apparatus: macula densa
- alter glomerular resistance in response to changes in the flow rate through the distal nephrons
MD - monitors tubular fluid composition by the amount of sodium and chloride present
Hormones regulating GFR
Atrial natriuretic peptide (ANP):
- dilate Aff/ constrict Eff. = ↑↑ GFR (noΔRBF)
Angiotensin II: complex
- Constrict Aff / super constrict Eff = ↓RBF but ↓/noΔ GFR (GFR maintained due to greater efferent constriction)
What is taken out of blood to turn it into filtrate?
Cells, platelets or big proteins
What does filtrate contain?
Na Ca Mg K HCO3 PO4 glucose, AA, small proteins, urea
What proportion of glucose and salts are normally reabsorbed?
Glucose 100%
Salt 99.5%
The importance of sodium movement and active transport in the neprhon
Sodium is important for setting up concentration gradients to drag other ions - it drive a lot of secondary transport (very important in glucose and amino acid uptake)
Co or counter transport
Pinocytosis in the nephron
The cell forms a vesicle around the filtrate that touches the cell and reabsorbs it - passive and non specific but often collects proteins - hence we don’t have protein in urine normally
Is active transport saturable in the nephron?
Yes - in diabetes the glucose transport is saturated and hence there is glucose in the urine
What is passive transport rate in the nephron dictated by?
- electrochemical gradient
- permeability
- time
Water transport in the renal tubule
Through tight junctions and aquaporins
PCT: very leaky so water follows ions quickly
Ascending LOH: impermeable
DCT/CT/CD: varied permeability
Where is obligatory sodium reabsorption in the renal tubule?
67% in the proximal tubule and 25% in the loop of henle
Remainder is under hormonal control on the DCT
Where is the obligatory and hormonal control of water reabsorption in the renal tubule?
PCT - 65% obligatory
LOH - 15% oblig (but there is more sodium reabsorption hence it is semi impermeable to water)
DCT/CD - 20% under hormonal control
Reabsorption and secretion in PCT
Na+, Cl-, K+ (65%), glucose + AA (100%), water (65%)
ALSO most secretion: wastes and H+
Heterogeneity in the PCT
1ST HALF: majority of glucose and AA reabsorbed
2ND HALF: sodium reabsorbed with chloride
Difference between descending and ascending LOH in relation to water movement
Descending - thin and highly water permeable
Ascending - thick and impermeable to water (active reabsorption of sodium, chloride and potassium
–> osmolarity reduces as it goes through the ascending limb
Cells in the collecting tubule
Principle cells - reabsorb Na+ and secrete K+
Intercalated cells - secrete H+, reabsorb HCO3- K+
How is urine made more dilute through the renal tubule?
In the thick ascending LOH, salts are reabsorbed but water is not because it is impermeable and osmotic flood gates are not opened in the CD
Producing concentrated urine
Open up all the aquaporins so that water can follow salt movement
Leaky DCT/CT/CD - so h2o can be resorbed from the normally impermeable segments
Where do aldosterone and angiotensin II act?
Aldosterone - Collecting tubule and duct
Angiotensin II - PCT, thick ascending LOH, collecting tubule
How does ADH regulate osmolarity?
- An ↑ ECF osmolarity (ie - ↑ [Na+]) causes osmoreceptor cells to shrink.
- Osmoreceptor shrinkage AP relay post. Pit. release ADH
- ADH kidneys ↑ water permeability of DCT/CT/CDs ↑ resorption/Bvol
- H2O is conserved while Na+/solutes continue to be excreted dilution of ECF solutes
Where are the osmoreceptors found? and ADH production
Brain, ADH synthesis in supraoptic (most) and paraventricular (some) nuclei
Where does ADH act?
Increases water permeability of DCT/CT/CD
Usually aquaporin 2 channels are held in vesicles inside the cell, so ADH causes exocytosis of aquaporin vesicles to allow water transport
When is renin secreted?
From the granular cells of JGA - when there is low salt concentration in DCT(low BP)
What triggers renin secretion by the granular cells?
o ↑renin secretion due to
– ↓ [NaCl] in DCT macula densa cells (low GFR - JG fbk)
o ↓ stretch on afferent arterioles (low BP)
o ↑ sympathetic stimulation (baroreceptor reflex)
What regulates aldosterone secretion?
Angiotensin 2 and local potassium concentration
How does aldosterone activate signal transduction?
- gene transcription in hours
- non genomic activation in minutes
What is the action of aldosterone on the principle cells in the cortical CT?
o Stimulates basolateral Na/K+-ATPase (cortical CT)
o Also increase the Na+ permeability of the luminal membrane
o And Na+/K_ and Na+/H+ counter transporters
What is the potassium secretion rate from the renal tubule regulated by?
- Na+K+-ATPase activity
- K+ electrochemical gradient
- K+ permeability
Stimuli for thirst (4)
¥ Hypertonicity – hypothalamic osmoreceptors – NaCl accounts for 92% of ECF tonicity
¥ Hypovolaemia: low P baroreceptrs (great veins and right atrium)
¥ Hypotension: high P baroreceptors (carotid and aorta)
¥ Angiotensin II: V potent dipsogen (renal hypotension)
Two primary stimuli for hunger for salt
- Reduced ECF [Na+]
2. Reduced BP/Bvol
What receptors do glucocorticoids and mineralocorticoids bind?
GC - NR3C1
MC - NR3C2
What is glucagon secretion mediated by?
Stimulated: low plasma glucose, cortisol, adrenaline, CCK, gastrin
Inhibited: Glucose, insulin, SS
Action of somatostatin
Acts locally to inhibit BOTH insulin and glucagon secretion
How does thyroid hormone increase CHO metabolism
T3
- increases glucose absorption by intestine
- increase glucose oxidation in liver, fat, muscle
Thyroid hormone in lipid metabolism
TH determines rate of lipolysis and lipogenesis in liver
Stimulates mobilisation from fat cells - increasing free fatty acids and reducing plasma TG cholesterol
TH deficiency in children
Short stature, bony retardation, malformed facial structure, severe and irreversible mental and physical retardation
Action of PTH on kidney
Increases resorption of calcium from TAL and Distal tubule
Increases activity of Ca ATPase and Na+Ca2+ antiporter
Also stimulates transcription of 1 alpha hydroxyls to activate vitamin D which increases intestinal absorption
Calcitonin
Synthesised by parafollicular cells of the thyroid in response to increased plasma calcium concentration. Antagonises PTH in calcium regulation
Function of calcitonin
- acts through calcitonin receptor cAMP
- inhibits osteoclast activity
- inhibits osteoclast formation
- slightly decreases kidney Ca reabsorption
Excretory function of kidneys
- urea, uric acid, creatinine, bilirubin, foreign substances and XS substances
Pressure involved in net filtration in the glomerulus
- glomerular blood hydrostatic pressure
- capsular hydrostatic pressyre
- blood colloid osmotic pressure
What is the myogenic mechanism in regulating GFR?
Occurs when stretching triggers contraction of smooth muscle cells in the afferent arterioles and REDUCES GFR
What is the tubuloglomerular mechanism involved in regulating GFR?
Macula dense provides feedback to glomerulus, inhibiting release of NO and causing afferent arterioles to constrict = REDUCED GFR
How does the macula densa monitor and alter GFR?
Monitors tubular fluid.
If there is a high concentration of NaCl in DCT, then it inhibits the release of adenosine/NO = afferent arteriole constriction and reduced GFR
If there is a low concentration of NaCl in the DCT, then adenosine and NO result in afferent arteriole dilatation and increased GFR
Action of ANP on GFR and RBF
Dilate Aff, constrict Eff = increased GFR and no change to RBF
Action of angiotensin 2 on GFR and RBF
Constrict Aff, super constrict Off = reduced RBF, no change to GFR
What stimulates renin secretion from the granular cells of the JGA in the endothelial wall?
- low NaCl conc. detected by macula densa cells in DCT (low GFR)
- low stretch on afferent arterioles (low BP)
- sympathetic stimulation
