CELLULAR FUNCTION
CELLULAR FUNCTION
Fluid Compartments
Body weight: 18% protein, 7% mineral, 15% fat, 60% water
Water ingested (2100ml/day), synthesized via oxidation of carbohydrates (200ml/day)
700ml/day lost through insensible losses (300-400 from resp tract, 300-400 from skin); 100ml/day lost through sweating, 100ml/day in poo
42L
Decreases with age (indirectly proportion to fat), women have less water than men
|Extracellular Fluid |Intracellular Fluid |
|14L |28L |
|20% body weight |40% body weight |
|1/3 TBW |2/3 TBW |
|High in Na, Cl, HCO3, Ca |High in K, Mg, proteins, PO, organic anions |
|Low in protein |High in protein (4x more) |
A) Extracellular fluid:
Difficult to measure as few substances stay truly extracellular and takes a long time to equilibrate in jt spaces, aqueous humour, CT, cartilage, CSF
Cannot be separated from lymph (returns protein back to the circulation
|Interstitial fluid |Blood plasma |
|10.5L |3.5L |
|75% of ECF |25% of ECF |
|Outwith vascular system |In vascular system |
|Lower protein |Higher protein |
|Lower cations, higher anions |Higher cations, lower anions |
|15% body weight |5% body weight |
1) Interstitial fluid
Can’t be measured directly as difficult to sample fluid and drugs will spread to plasma
ECF/intracellular vol ratio is higher in children, so dehydration develops more rapidly in children
Interstital vol = ECF vol – plasma vol
2) Blood plasma
Total blood volume (5L, 7-8% body weight) = 60% plasma + 40% cells
Haematocrit (approx 0.36-0.4) = % of blood vol made up of cells
Plasma and interstitial fluid are constant mixing EXCEPT proteins which has a higher concentration in plasma as they can’t pass through capillary membrane, same ionic composition; because of Donnan effect conc of cations (+) is higher in plasma than interstitial fluid as protein is (-) binds cations, anions (-) higher in interstitial fluid
Total blood vol = plasma vol X (100 / 100 – haematocrit)
Red cell volume = total blood vol – plasma vol
Glandular secretions, synovial, peritoneal, pericardial, eye, and CSF are separate from rest ECF so are transcellular fluids, small vol (1-2L) – these are in potential spaces; have very permeable membranes with free exchange of fluid with interstitial fluid/capillaries
B) Intracellular fluid:
|Intracellular fluid |
|28L |
|40% body weight |
|2/3 TBW |
|High in K, Mg, PO, organic anions, protein |
|Decreases with age and women (indirectly proportional to fat) |
Can’t be measured directly: ICF vol = TBW – ECF vol
Measuring Volume of Fluid Compartments
Measure vol of comptmt by injecting substance that will stay in that comptmt and calculating its dilution
Must be amount injected / metabolized must be accurately measured
non-toxic
mix evenly through comptmt and not move to another comptmt
have no effect on distribution of fluids in body
Vol of distribution (eg. Sucrose space) = amount of drug injected – amount excreted or metabolized in mixing period / conc of injected drug (remember: vol of drug x conc of drug in solution = mass of drug)
To measure TBW: deuterium oxide, tritium oxide, aminopyrine/antipyrine
ECF vol: inulin, mannitol, sucrose, 22Na, 125I-iothalamate, thiosulfate, radioactive Cl
Interstitial fluid vol: can’t be measured directly
Plasma vol: Evans blue, 125I-albumin (labeled with iodine)
Blood vol: RBC’s labeled with 51Cr, 59Fe, 32P or antigens
ICF vol: can’t be measured directly
Measuring Solutes
Mole: molecular weight of substance in grams (eg. NaCl = 23 + 35.5g = 58.5g); 1 mole contains 6 x 1023 molecules
Millimole: 1/1000 of mole Micromole: 1/1,000,000 of mole
Molecular weight (in Daltons): mass of 1 molecule of substance : mass of 1/12 mass of atom of C-12
The Dalton: 1 Dalton = mass of 1/12 atom of C-12
Kilodalton: 1000th of Dalton, expressed as K, used as measure of mass of proteins
Equivalent: 1 eq = 1 mol of ionized substance / its valence (eg. NaCl divides into 1 eq Na and 1 eq Cl ( 1 eq Na = 23g, 1 eq Ca = 40g/2)
pH
Is negative logarithm of [H]; for each unit pH drops, [H] increased x10
pH of water is 7.0 ([H] = 10-7)
Need to maintain stable H; opposed by OH; should be 7.40
Maintained by buffering capacity – buffer can bind/release H (eg. Carbonic acid H2CO3 = H + HCO3 – if H added, equilibrium shifts to L, if OH added it will bind to H taking it out of the system and H2CO3 dissociates shifting eq to R; blood proteins)
Movement Across Cell Membranes
1) Diffusion
Gas/substance expands to fill all available volume - net flux from area of high concentration to low conc 2Y to continual random movement of substances
Time taken to equilibrium α square of diffusion distance
Magnitude of diffusing tendency α area diffusion taking place over (eg. Number of channels)
conc gradient (diff in conc / thickness of boundary = Fick’s law of
diffusion) (ie. Amount of substance)
elec gradient (Nernst potential) – remember elec and conc gradients
work together using Nernst equation
pressure difference across membrane (the sum of all forces of
molecules striking unit surface area)
velocity of kinetic motion
a) Simple diffusion: no interaction with carrier proteins; just through membrane/channel
b) Facilitated diffusion: involves interaction with carrier protein, including binding and conformational change but needs no energy; in simple diffusion rate of diffusion is α to conc gradient, in facilitated there is a max diffusion rate (ie. It plateaus)
Non-polar/lipid-soluble molecules (eg. O2, N2, CO2) can diffuse directly across lipid membranes of cells, but membranes have limited permeability to others therefore diffusion occurs through channels.
Filtration: occurs in capillaries; process by which fluid forced through a membrane due to difference in pressure on 2 sides; plasma proteins/colloids can’t pass through unless by vesicular transport ( osmotic pressure named oncotic pressure which opposes filtration out of capillaries
2) Osmosis
The net diffusion of water across a selectively permeable membrane from a region of high water conc to low water conc
High osmolality = concentrated solution = high osmotic pressure
Cell membranes are relatively impermeable to solutes
3) Intercellular Connections
a) Tight Junctions (zonula occludens): tie cells together, strength and stability (eg. In intestine, renal tubules, choroid plexus); interlocking ridges; permits passage of some ions and solute, prevent the movement of protein, maintaining different distribution of transporters in apical / basolateral membranes
b) Gap Junctions: narrow intercellular space (3nm as opposed to 25nm) at this point; units called connexons (made up of 6 connexins surrounding a channel 2nm wide) that connects to connexon in adjacent cell ( passage of substances (eg. Molecular weight 1 substance together (eg. Na and glu from intestinal lumen into mucosal
cells)
Antiports: exchange one substance for another (eg. Ca out, Na in in cardiac muscles)
NB. Patch clamping used to investigated transport proteins. Can be cell-attached / inside-out patch, or whole cell recording.
NB. Sometimes substances must pass through ‘cellular sheets’ using combination of transport.
Prinicples of Osmosis
Osmotic pressure: pressure necessary to prevent solute migration (α to no. particles in certain vol of soln)
higher osmotic pressure = higher solute concentration
related to temp and vol
dependent upon number rather than type of molecules
1mosm/L exerts 19.3mmHg of osmotic pressure so normal osmotic pressure of body
fluids is 19.3 x 300 = 5790mmHg (5500 since not an ideal soln)
Osmoles: express the conc of osmotically active particles
1 osmole = weight of substance / no. freely moving particles each molecule liberates in soln
= 1 mole of solute particles
= 1 gram molecular weight of osmotically active solute
Ions will partially dissociate to become separate osmoles
1mol of NaCl ( osmolar conc of 2osm/L
1 molecule of albumin exerts same effect as 1 molecule glucose
Osmole refers to NUMBER of osmotically active particles, not the molar
concentration nor the weight of the particle – all particles will exert roughly same
amount of pressure on membrane as small molecules move fast and large slow (
same kinetic energy
Ionic interactions prevent soln from being ideal soln and decrease its osmotic pressure
Use the osmotic co-efficient of a substance in calculations to allow for this
The more concentrated the solution the less it is an ideal soln
Osmolal conc: measured by extent to which it decreases freezing point of soln
1 mol of ideal soln decreases freezing point by 1.86˚C
expressed as osm/L of water
Osmolarity: no. osmoles per litre soln
affected by vol of solutes in soln and by temp
Osmolality: no osmoles per kg solvent;
Soln that has 1 osmole solute dissolved in kg water has osmolality of 1 osmole per kg
NOT affected by vol of solute / temp
Interstitial fluid and plasma: is 2Y to Na and Cl
Intracellular fluid: is 2Y to K
Plasma: Na, Cl, HCO3, plasma proteins, glucose, urea
Plasma has slightly higher osmolarity than ISF and ICF 2Y to plasma proteins; but all approx
300mOsm/L
Plasma osmolality = 2[Na] + [Glu x 0.055] + [BUN x 0.36]
If plasma osmolality > than formula expects, likely foreign substance (eg. Ethanol, mannitol)
Tonicity: osmolality of soln relative to plasma (eg. Isotonic, hypertonic)
cells can swell/shrink when exposed to changed tonicity so long as solute can’t permeate
membrane
Ion channels help maintain isotonicity (eg. Efflux of K + Cl if cell swells ( water follows)
N saline remains isotonic (mostly Na, Cl, HCO3) ( increased ECF vol, no movement of water
5% glu is initially isotonic but glu is metabolised to becomes hypotonic
0.45% NaCl is hypotonic ( water moves into cells ( increase ICF and ECF vol
Hypertonic (water moves out of cell ( increase ECF vol, decrease ICF vol, increase osmolarity
both compartments
Resting Membrane Potential
Non-ionic diffusion: when undissociated substance diffuses across membrane then dissociates therefore can’t cross membrane ( net movement in one direction (eg. In GI tract, kidneys)
Donnan effect: when an ion (eg. Prot-) can’t diffuse across membrane, affects diffusion of other ions
The diffusible ions distribute so concn ratios are equal
Gibbs-Donnan equation : (Ka/Kb = Clb/Cla) or (Ka x Cla = Kb x Clb)
( Intracellular protein concn is higher ( more osmotically active particles intracellularily than in
interstitial fluid ( cells would swell and rupture if not for Na-K ATPase. Since plasma protein
> interstitial fluid protein ( similar situation at capillary walls
( Concn of ions on either side of membrane is assymetrical ( electrical difference across
membrane which is exactly balanced by chemical gradient
eg. Chloride ions:
1) Cl conc higher in ECF than intracellular ( Cl diffuse INTO cell along concentration gradient
2) Intracellular charge (-) compared to extracellular ( Cl diffuse OUT along electrical gradient
3) Equilibrium established: efflux = influx ( membrane potential here is equilibrium potential of Cl (magnitute calculated by Nernst equation – the diffusion potential across membrane that is needed to prevent net diffusion of an ion, determined by ratio of conc of ion on either side of membrane)
a. Potential dependent upon electrical charge of ions, permeability of membrane, conc of ions on either side
b. Ion can only be involved in potential if membrane is permeable to it
c. At equilibrium there is excess cations (+) outside, excess anions (-) inside
|Ion |Conc in cell |Conc outside cell |Equilibrium potential |Conc Grad |Elec Grad |
|Na |15 |150 |+60 (+ ion coming in) |IN |IN |
|K |150 |5.5 |-90 (+ ion going out) |OUT |IN |
|Cl |9 |125 |-70 (- ion coming in) |IN |OUT |
Resting membrane potential is -70mV = ECl. Neither ENa or EK is at RMP ( you expect cell to gradually gain Na and lose K ( water to enter cell due to large Na in cell ( cell to burst. Prevented by Na-K ATPase (2K in, 3Na out) working against chemical and electrical gradients to maintain RMP. NA-K ATPase MAINTAINS MEMBRANE POTENTIAL.
Na-K ATPase
Electrogenic pump: catalyses hydrolysis of ATP ( ADP ( 3Na out, 2K in for each molecule ATP.
Hence internal of cell remains (-) compared to exterior.
• Extends through cell membrane
• Vital in controlling volume of cell
• Inhibited by ouabain and digitalis; separation of subunits eliminates action
• Accounts for 24% energy used by cells, 70% in neurons
• Pump is not saturated at normal conditions
• Activity affected by 2nd messengers (eg. cAMP, diacylglycerol); increased by thyroid, insulin and aldosterone (increase number of Na-K ATPase molecules); inhibited by dopamine (phosphorylates it)
• Heterodimer:
α subunit – spans membrane 10x; molecular weight 100,000
Na + K transport occurs through this
Binding sites: intracellular - 3 Na and 1 ATP binding sites and phosphorylation site
Extracellular – 2 K and ouabain
Na binds intracellularily, K binds extracellularily ( ATP binds ( phosphate transferred
to phosphorylation site ( change in configuration ( Na transferred out, K in
Can work in reverse with phosphorylated site donating P to ADP
α1 – found in all cells
α2 – found in muscle, heart, adipose tissue, brain
α3 – found in heart and brain
β subunit – spans membrane once; molecular weight 55,000; may act as an anchor
a glycoprotein with 3 extracellular glycosylation sites
β1 – absent in astrocytes, vestibular cells, fast-twitch muscle
β2 – found in fast-twitch muscle
β3
NB. There is a K-Na leak channel which allows K>Na leakage through which the initial equilibrium of ions is made to form RMP therefore K most important in determination of RMP.
Specific Ion Channels
1) K channels:
• Tetramers (4 subunits with a charged extension which surround a pore)
• When closed positive extensions are near negatively charged interior of cell ( membrane potential decreased ( paddles bend towards outside ( channel opens
• Channel has small diameter therefore selective for small K, Na can’t pass through
2) Ach channel and many other anion/cation channels: 5 subunits
3) Cl channel: many different types
• Dimer (2 subunits), but with a pore in each subunit
• Pentamers (5 subunits) (eg. GABA and glycine receptors)
4) Aquaporins: tetramers with water pore in each subunit; note, water can also travel by simple diffusion
5) Ca channel: many different types. Ca v low intracellularly as 1 pump pumps Ca into ECF, and another pumps Ca into vesicular organelles (eg. SR, mitochondria)
6) H channel: in parietal cells of gastric glands and intercalated cells of DCT and CD of kidneys
6) Na channel: many different types
• Can be blocked by tetrodotoxin and saxitoxin therefore can be tagged and investigated
• Inner surface is (-) to attract (+) Na ions
• Certain type = Epithelial sodium channels
In kidneys, colon, lungs, brain
Have 3 subunits: α: transports Na (inhibited by amiloride which binds it)
β and γ: aid transport
Span membrane twice
Play role in ECF vol via aldosterone
Intercellular Communication
Messengers: (eg. Amino acids, steroids, polypeptides, lipids, nucleotides)
can be measured by making ab’s and using radioimmunoassay – competes with endogenous
ligand for receptor
➢ Neural communication: NT’s released at synaptic junctions; local response
➢ Endocrine communication: hormones and GF’s by circulating in body fluid; general response
➢ Paracrine communication: diffuse to neighbouring cells in interstitial fluid; locally diffuse response
➢ Autocrine communication: messengers bind to own cell
➢ Juxtacrine communication: cells express GF’s (eg. Transforming GF α) extracellularily on transmembrane proteins, whereas other cells have TGF receptors ( 2 cells can bind
Also:
➢ Gap junctions: direct from cell to cell; local response
Receptors are active not static
Down-regulation occurs if XS of hormone/NT is present (eg. Via receptor-mediated endocytosis,
ligand-receptor complex is internalized; in desensitization receptors are chemically altered on binding)
Up-regulation in deficiency
First messengers: extracellular ligands
Often work via GTP-binding proteins
Can cause release of second messenger (intracellular ligands)
( Bring about short term changes in cells
( Can activate transcription factors ( induce transcription of immediate-early genes (
alter transcription of genes to produce products that cause longterm changes
( Often activate protein kinases ( catalyse phosphorylation of tyrosine/serine/threonine
( change of configuration ( alter function
Intracellular part of receptor may be protein kinase (eg. Insulin)
Phosphatases vital here
Eg. Of Protein Kinases
|Phosphorylate |Calmodulin-dependent |Myosin light-chain kinase |
|serine and/or | | |
|threonine residues | | |
| | |Phosphorylase kinase |
| | |Ca/calmodulin kinase I, II, III |
| |Ca-phospholipid dependent |Protein kinase C |
| |Cyclic nucleotide dependent |cAMP-dependent kinase (protein kinase A) |
| | |cGMP-dependent kinase |
|Phosphorylate | |Insulin receptor |
|tyrosine residues | | |
| | |EGF receptor |
| | |PDGF receptor |
| | |M-CSF receptor |
Effects of Messengers
1) Open/close ion channels
Change conductance
eg. Ach on nicotinic cholingergic receptor, noradrenaline on K channel in heart
2) Increase transcription of mRNA’s via cytoplasmic/nuclear receptors
Activated receptor has DNA-binding portion which is usually covered by heat shock protein
(Hsp90, amount increases in times of stress) ( Hsp90 release ( receptor-ligand complex binds to untranslated 5’-flanking portions of genes ( increased transcription of mRNA’s ( increase proteins
Ligand-binding portion of receptor is near carboxyl terminal
eg. Thyroid – receptor in nucleus
Steroid – receptor in nucleus for oestrogen, in cytoplasm for glucocorticoid; steroids also
have nongenomic actions via 2nd messengers which have faster action
1,25-dihydroxycholecalciferol, retinoids
3) Activate phospholipase C with intracellular production of DAG and IP3
Ligand binds receptor ( activation of phospholipase C on inner membrane via Gq protein or tyrosine kinase link ( catalyse hydrolysis of PIP2 (phosphatidylinositol 4,5-diphosphate) into IP3 (inositol 1,4,5-triphosphate) and DAG (diacylglycerol) ( IP3 triggers release of Ca from ER, DAG activates protein kinase C in cell membrane
eg. Angiotensin II, noradrenaline via α1-adrenergic receptor, vasopressin via V1 receptor
4) Activate/inhibit adenylyl cyclase ( inc/dec production cAMP (cyclic adenosine 3’,5’-monophosphate)
Adenyly cyclase: catalyst; transmembrane protein crossing membrane 12x
Activated by Gs α subunit when stimulatory receptor bound
( cAMP formed from ATP ( activates protein kinase A ( catalyses phosphorylation
of proteins including CREB (cAMP-responsive element-binding protein) ( altered
activity and transcription of genes
Deactivated by Gi α subunit when inhibitory receptor bound
Phosphodiesterase converts cAMP to inactive 5’-AMP (inhibited by caffeine and theophylline)
eg. Noradrenaline via α2 adrenergic receptor ( dec cAMP
Noradrenaline via β1-adrenergic receptor ( inc cAMP
Cholera toxin inhibits GTPase activity, prolonging stimulation of adenylyl cyclase
Pertussis toxin inhibits function of Gi
5) Increase cGMP (cyclic guanosine monophosphate) in cell
cGMP important in vision, helps regular ion channels
Guanylyl cyclase: catalyses formation of cGMP; 2 forms:
Transmembrane form: has extracellular, transmembrane and cytoplasmic portion
(eg. Receptor for ANP, receptor for E. coli enterotoxin)
Intracellular form: soluble, containing heme (eg. Activated by NO)
6) Increase tyrosine kinase activity of transmembrane receptors
Tyrosine kinases are closed associated with phosphatases, to remove phosphate groups from proteins
eg. Insulin, EGF, PDGF, M-CSF
7) Increase serine/threonine kinase activity
eg. TGF, MAPKs
G Proteins
Bind GDP/GTP
GTPase activity encouraged by RGS (regulators of G protein signaling) proteins
Many G proteins are lipidated
a) Small G proteins: eg. Rab (regulate vesicle traffic)
Rho/Rac (regulates interactions between cytoskeleton and cell membrane)
Ras (regulates growth)
b) Heterotrimeric G proteins:
• Couple receptors to catalysts for formation of 2nd messengers / ion channels
• 5 families (Gs, Gi, Gt, Gq, G13)
• Receptors coupled with G protein usually span cell membrane 7 times (serpentine receptors)
o G proteins interact with aa residues in 3rd cytoplasmic loop of receptor
o Small ligands bind to amino acid residues in membrane
o Large protein ligands bind to extracellular domains of receptor
• Made of α, β and γ subunits
o α bound to GDP ( ligand binds to G-coupled receptor ( GDP exchanged to GTP ( α separated from β and γ ( effect via α and βγ complexes (eg. Ion channels, enzymes) brought about ( GTPase activity of α converts GTP to GDP ( reassociation of all units ( termination of effect
Ligands for receptors coupled to heterotrimeric G proteins
|Neurotransmitters |Epinephrine, norepinephrine, dopamine, 5-hydroytryptamine, histamine, Ach, adenosine, opioids |
|Tachykinins |Substance P, neurokinin A, neuropeptide K |
|Other peptides |Angiotensin II, arginine vasopressin, oytocin, VIP, GRP, TRH, PTH |
|Glycoprotein hormones |TSH, FSH, LH, hCG |
|Arachidonic acid derivatives |Thrombozane A2 |
|Other |Odorants, tastants, endothelins, PAF, cannabinoids, light |
Intracellular Ca
At rest 100nmol/L
Multiple effects of Ca: changes may outlast high concentration of Ca intracellular; conc may oscillate; raised conc can spread from cell to cell in waves ( co-ordinated response
Extracellular: high concentration; chemical and electrical gradient inwards
Intracellular: Ca bound by ER and other organelles acting as a store
Intracellular Ca activated by 2nd messengers (eg. Release from ER and mitochondria mainly caused by IP3) ( may cause store-operated Ca channels in membrane to open ( Ca influx ( free Ca activates Ca-binding proteins ( activate protein kinases; free Ca also replenishes ER stores
Ca-binding proteins eg. Troponin in contraction of skeletal muscle
eg. Calmodulin which activates 5 different calmodulin-dependent kinases eg.
a) myosin light-chain kinase ( phosphorylates myosin ( contraction of smooth muscle
b) phosphorylase kinase ( activates phosphorylase; role in synaptic function and protein
synthesis
c) calcineurin ( inactivates Ca channels by dephosphorylating them; activates T cells,
inhibited by immunosuppressants
eg. Calbindin
Enters cell: through ligand gated channels
stretch gated channels
voltage gated channels (T transient or L longacting depending on whether deactivate
during prolonged depolarisation)
Exits cell: by Ca-H ATPase (2H in, 1Ca out)
antiport (3Na in, 1Ca out) – driven by Na gradient
Ca sparks is site of high concentration of Ca where it leaves cell
Growth Factors
Activate transcription factors which move to nucleus and alter gene transcription
4 main groups:
1) Agents which foster multiplication/development of various cells (eg. Nerve GF, ILGF, activins, inhibins, epidermal GF)
2) Cytokines – produced by macrophages and lymphocytes; regulate immune system
3) Colony stimulating factors – regulate proliferation and maturation of RBC and WBC’s
4) TGFβ and related polypeptides – receptors have serine-threonine kinase activity; effects mediated by SMAD’s ( bind DNA to initiate transcription of genes
In 1) receptor has membrane-spanning domain and intracellular tyrosine kinase domain
Ligand binds (tyrosine kinase domain autophosphorylates ( transcription factors and altered gene expression
In 2) and 3) most receptors don’t have tyrosine kinase domains, but use JAK-STAT pathway
Ligand binds transmembrane protein gp130 ( initiate tyrosine kinase activity in cytoplasm (eg.
JAKS (Janus tyrosine kinases)) ( phosphorylation of STAT (signal transducer and activator of
transcription) proteins ( act as transcription factors at nucleus.
Diseases
|Site |Type of Mutation |Disease |
|Receptor |
|Cone opsins |Loss |Color blindness |
|Rhodopsin |Loss |Congenital night blindness |
|V2 vasopressin |Loss |Nephrogenic diabetes insipidis |
|ACTH |Loss |Glucocorticoid deficiency |
|TSH |Loss |Hypothyroidism |
|Thromboxane A2 |Loss |Congenital bleeding |
|Endothelin B |Loss |Hirschsprung disease |
|LH |Gain |Male precocious puberty |
|TSH |Gain |Nonautoimmune hyperthyroidism |
|Ca |Gain |Hypercalciuric hypocalcaemia |
|G protein |
|Gs α |Loss |Pseudohypothyroidism |
|Gs α |Gain |Testotoxicosis |
| | |McCune-Albright Syndrome |
|Gi α |Gain |Ovarian and adrenocortical tumours |
Grave’s disease: ab against TSH receptor
Myaesthenia gravis: ab against nicotinic Ach receptors
NERVES
Nervous tissue made of neurons and glial cells
Nerve Cells
Dendrites: 5-7; extend from cell body; have knobbly projections called dendritic spines esp in brain; cell body may be at dendritic end, but may be anywhere within axon (eg. Auditory neurons) or to side of axon (eg. Cut neurons)
Axon: fibrous; poor passive conductor, conduction is active
originates from axon hillock on cell body
1st part is initial segment
terminal branches end in synaptic knobs (terminal buttons, axon telodendria) which contain granules containing NT’s
myelinated (protein-lipid complex wrapped around axon, no myelin at nodes of Ranvier)
produced by Schwann cells outside of brain which wrap membrane around 1 axon that it
sits on ( protein 0 (P0) locks to P0 of opposing membrane to compact myelin down)
produced by oligodendrogliocytes in CNS – send off multiple processes that form myelin on neighbouring axons
unmyelinated (surrounded by Schwann cells but no wrapping)
Epineurium: peripheral nerves made of multiple axons in fibrous envelope
4 important regions:
1) Receptor/dendritic zone: changes producted by synaptic connections are integrated
2) Site where AP’s are created: initial segment in spinal MN’s, initial node of Ranvier in cut SN’s
3) Axonal process: transmits impulses to nerve endings
4) Nerve endings: AP’s cause release of NT’s
Protein synthesis: occurs in cell body ( transported to axonal ending by axoplasmic flow; in some cases mRNA strands are transported from cell body to ribosomes and protein synthesis occurs locally
Anterograde transport: along microtubules (fast at 400mm/d, slow at 5-10mm/d)
Retrograde transport: along microtubules (200mm/d); some used synaptic vesicles and substances taken up by endocytosis (eg. Nerve GF) may be transported back to cell body
If axon cut, distal parts degenerated (Wallerian degeneration)
Excitation and Conduction
Measure electrical events with cathode ray oscilloscope – uses cathode which shoots electrons at glass tube coated with phosphors, +ive and –ive charged plate applied on either side of course of beam, when voltage applied across it beam pulled towards +ive plate, measure course of beam to work out voltage
May result in:
Local, nonpropogated potentials: synaptic/generator/electronic potentials
Propogated potentials: action potentials
Excitation
Low threshold
Resting membrane potential of nerve cells is -70mV (inside cell –ive compared to outside)
[pic]
Stimulus may be electrical, chemical, mechanical
Minimal intensity of stimulating current that acting at given duration will cause AP is threshold intensity – with weak stimuli this is long duration, with strong may be short ( strength-duration curve
Slowly rising currents fail to cause AP due to accommodation
Once threshold intensity reaches, AP will fire; increase in stimulation won’t cause increased AP – all-or-none law
Subthreshold stimuli will still have effect on membrane potential via local response even if don’t cause AP – electronic potentials (if produced by cathode – catelectronic, if anode – anelectronic); potential is proportionate to current
These will affect threshold – catelectronic are depolarizing ( lower threshold
Anelectronic are hyperpolarizing ( incr threshold
When stimulus applied stimulus artifact recorded by CRO due to current leakage from stimulating to recording electrodes
Followed by latent period – ends with start of AP; = time it takes impulse to travel along axon from site of stimulation to recording electrodes; duration proportionate to distance between stimulating and recording electrodes, inversely proportionate to speed of conduction – if you know distance you can work out speed of conduction
In peripheral nerves with multiple axons in epineurium some axons may be conducting and others not; stimulus that produces excitation of all axons is maximal stimulus
Action potentials due to changes in conduction of ions across membrane
After 15mV depolarization, rate of depolarization increases – this is firing level/threshold
Potential overshoots isopotential to +35mV
Spike potential occurs
Repolarisation – slows after 70% to perform after-depolarisation
Overshoot slightly to form after-hyperpolarisation – this is a small amplitude but long duration; it will increase if nerve has been conducting for a long time
Followed by refractory period
Absolute: time from firing level until repolarisation 1/3 complete; NO stimulus will excite nerve
Relative: from 1/3 complete til start of after-depolarisation; stronger stimuli can excite
During after-de and after-hyperpolarisation threshold is increased
Peripheral nerves will produce compound AP as there will be some fast and some slow conducting axons, some cell bodies may be further away
Ionic basis: remember Na diffuses in (along elec and conc grad)
K diffuses out (along conc grad only)
Na actively transported out
K actively transported in
Greater permeability to K so K determines resting membrane potential
When stimulus applied voltage-activated Na channels activated ( NA INFLUX ( firing level met ( Na effect overwhelms K effect for short time ( depolarization ( membrane potential moves towards +60mV ( spike potential ( doesn’t reach +60mV as Na channels only activated for short time ( Na channels close and Na influx prevented by membrane potential ( voltage-gated K channels open (longer time) ( K EFFLUX ( repolarisation followed by after-hyperpolarisation as K channels still open.
Decreasing extracellular [Na] ( decr AP, no effect on MP as Na not important there
Increasing extracellular [K] ( decr RMP
Decreasing extracellular [Ca] ( increases excitability as decr amount of depolarization needed to start changes in Na and K conductance
Accomodation: 2Y to slow opening of K channels; if Na channels stimulated over long time then K channels are still open so effect of Na channels decreased
Conduction
Occurs along axons; is active not passive; impulse moves at constant amplitude and velocity
At rest inside nerve is +ive, outside –ive (POLARISED) ( during AP polarity reversed, AP creates area of –ive charge and +ive charges from alongside (ahead and behind) move to this area – current sink ( decreases polarity of membrane ahead of AP ( local response until firing potential reached ( proprogated response.
Saltatory conduction: myelin is effective insulator; depolarization jumps from 1 node of Ranvier to next; myelinated conduction 50x faster than unmyelinated; Na channels concentrated in node and initial segment (where AP generated)
If AP initiated in middle of axon, impulse can travel either way
Orthodromic: when impulses travel in 1 direction only; in mammals
Antidromic: when impulses travel in opposite direction; since synapses are unidirectional, this impulse will die when it reaches one
Biphasic AP: when you measure AP with 2 electrodes on inside of membrane; electrode 1 –ive ( 2 electrodes same ( electrode 2 –ive
Volume conductor: conducting medium of body; complicates above processes somewhat
Nerve Fibre Types
|Fibre Type |Function |Diameter |Conduction Velocity |Spike duration |Absolute |
| | | | | |refractory period |
|A |
|α |Proprioception (Sensory to muscle spindle (Ia) and|12-20 (large) |70-120 (fast) |0.4-0.5 (short)|0.4-1 (short) |
| |golgi tendon organ (Ib)); somatic motor | | | | |
|β |Touch (II), pressure (II), motor |5-12 (mod) |30-70 (mod) | | |
|γ |Motor to muscle spindles |3-6 (small) |15-30 (mod) | | |
|δ |Pain, cold, touch (III) |2-5 (small) |12-30 (mod) | | |
|B |Preganglionic autonomic |1 knob; facilitate eachother to reach firing level
2) Temporal summation: repeated stimuli causes new EPSP before old EPSP finished
EPSP is not all-or-none, but proportionate to strength of stimulus
Inhibitory Postsynaptic Potential
Stimulation of some input may cause hyperpolarizing rather than depolarizing response via (eg. opening of Cl channels ( Cl enters postsynaptic cell along conc grad ( incr membrane potential ( closure of Na/Ca channels; opening of K channels allowing efflux) ( decr excitability due to movement of MP away from firing level; peak in 1-1.5ms then decrease over 3ms; decrease excitability; spatial and temporal summation can occur here also
Results in postsynaptic/direct inhibition
Slow Postsynaptic Potentials
Occur in autonomic ganglia, cardiac muscle, SM, cortical neurons; last several secs; EPSP due to decr K conductance, IPSP due to incr K conductance
Action Potentials
Initial segment has lowest threshold for generation of AP – once fired it goes down axon and retrogradely back into soma; constantly fluctuating MP 2Y to factors above, AP occurs when 10-15mV of depolarization to reach firing level occurs
Synaptic Delay
0.5ms delay between impulse reaching presynaptic terminal and response in postsynaptic neuron; due to time it takes for synaptic mediator to be released and cause effect; conduction along chain of neurons slowed by multiple synapses
Inhibition at Synapses
Post-synaptic inhibition: eg. Afferent nerves from muscle spindles ( EPSP and propagated AP in motor neurons supplying muscle, IPSP in antagonist muscles via inhibitory NT glycine
Pre-synaptic inhibition: mediated by neurons that end of excitatory endings forming axoaxonal synapses ( decr NT release; can occur in 3 different ways (eg. GABA) (eg. Used in gating pain transmission):
1) Activation of presynaptic receptor may incr Cl conductance ( decr size AP reaching excitatory ending ( decr Ca entry ( decr amount excitatory NT released
2) Activation ( open voltage gated K channels ( K efflux ( decr Ca influx ( decr NT released
3) Direct inhibition of NT release
Afferent inhibition: inhibition usually caused by stimulation of certain systems acting on one postsynaptic neuron
Negative feedback inhibition: when neuron may inhibit itself (eg. Occurs in spinal motor neurons via inhibitory interneuron, activated by AP in motor neuron, it releases inhibitory mediator to slow/stop discharge at motor neuron).
Feed-forward inhibition: when inhibitory cell and excitatory cell both stimulated by same stimulus; limits duration of excitation (eg. Purkinje cells)
Neuromodulation: non-synaptic action of substance on neurons which alters their sensitivity to synaptic stimulation/inhibition (eg. Steroids)
Facilitation at Synapses
Opposite to inhibition; eg. Serotonin causes incr intraneuronal cAMP levels ( phosphorylation of K channels ( closure of K channels ( slow repolarisation, prolonged AP
The Brain
Hierarchal systems:
All pathways involved in sensory perception and motor control; clearly delineated (made of large myelinated fibres); info processed sequentially at each relay nucleus on way to cortex;
Each nucleus contains:
Relay/projection neurons (excitatory; use glutatmate; large axons, many collaterals; transmit signals over long distances)
Local circuit neurons (inhibitory; use GABA or glycine; smaller; synapse with projection neurons, inhibiting them; some may from axoaxonic synapses on sensory axons)
3 types of pathways for inhibition: Recurrent feedback pathways
Feed-forward pathways
Axoaxonic interaction
Since only 3 main NT’s used, drugs can easily target these pathways (eg. GABAa antagonists ( convulsions)
Nonspecific/diffuse neuronal systems:
Involved in more global functions (eg. Sleeping, appetite, emotion)
Eg. Monoamines (NE, dopamine, 5-HT), peptide-containing pathways
Eg. Noradrenergic – axons fine and unmyelinated; slow
multiple branching, one neuron can go to many diff parts of CNS
fibres studded with varicosities containing vesicles
NT’s usually act on metabotropic receptors therefore have longer-lasting effects
Neurotransmitters
May be
Amines (eg. Dopamine, norepinephrine, epinephrine, serotonin, histamine)
Amino acids (eg. Glutamate, aspartate, glycine, GABA)
Polypeptides (eg. Substance P, vasopressin, oxytocin, CRH, TRH, GRH, somatostatin, GnRH, endothelins, enkaphalins etc…)
Purines (eg. Adenosine, ATP)
Gases (eg. NO, CO)
Excitatory Amino Acids
[pic]
|Gluta -mate |Relay neurons at all levels, some |NMDA |Excitatory: incr cation conductance esp Ca |NMDA |2-amino-5-phosphonovale|
| |interneurons | | | |rate, dizocilipine |
| | |AMPA |Excitatory: incr cation conductance |AMPA |CNQX |
| | |Kainate |Excitatory: incr cation conductance |Kainic acid, domoic | |
| | | | |acid | |
| | |Metabo – |Inhibitory (presynaptic): decr Ca conductance, decr cAMP |ACPD, quisqualate |MCPG |
| | |tropic |Excitatory: decr K conductance, incr IP3 and DAG | | |
Glutamate:
Responsible for 75% excitatory transmission of brain
Formation: reductive amination of α-ketoglutarate in cytoplasm ( glutamate becomes concentrated in synaptic vesicles by transporter BPN1
Cytoplasmic store kept high by transporters which import glutamate from interstitial fluid and reuptake it from synaptic clefts via Na-dependent uptake systems, if glutamate is allowed to accumulate ( excitotoxic damage and cell death
Mediates excitatory synaptic transmission by activation of ionotropic and metabotropic receptors:
1) Metabotropic: serpentine G protein linked receptors that act indirectly on ion channels; incr IP3 and DAG levels, or decr intracellular cAMP levels; widely distributed in brain; involved in production of synaptic plasticity; located just outside postsynaptic density
Can be pre-synaptic (group II and III, act as inhibitory autoreceptors via inhibition of Ca channels ( decr NT release)
Can be postsynaptic (group I, activate cation channel, activate PLc ( incr IP3 ( intracellular Ca release)
2) Ionotropic: ligand gated ion channels; 3 types
Kainite (KA) – simple ion channels; Na influx, K efflux; high levels in hippocampus, cerebellum
and SC may be pre- or post-synaptic
AMPA – present on all neurons; permeable to Na and K; activation results in channel opening at
RMP; located at periphery of postsynaptic density
NMDA – present on all neurons; highly permeable to Ca, Na and K ( rise in intracellular Ca (
long-lasting enhanced synaptic strength (long term potentiation, LTP) important in
learning and memory; only opens in concomitant glycine binding; channel will not open
at RMP due to block of channel by extracellular Mg which is expelled when neuron
depolarized (ie. By activation of other channels such as AMPA); located in centre of postsynaptic density
Clearance: glutamate transporters on surrounding glia ( converted to glutamine by glutamine synthetase ( released from glia ( taken up by nerve terminal ( converted to glutamate by enzyme glutaminase ( transported into vesicles by vesicular glutamate transporter (VGLUT)
Anaesthetics may inhibit NMDA and AMPA receptors
Inhibitory Amino Acids
Typically released from local interneurons
Anaesthetics are thought to work on GABAa and glycine receptors ( incr Cl conductance
GABA (gamma-aminobutyric acid):
|GABA |Supraspinal and spinal interneurons |GABAa |Inhibitory: incr Cl conductance |Muscimol |Biuculline, picrotoxin |
| | |GABAb |Inhibitory (presynaptic): decr Ca confuctance |Baclofen |2-OH saclofen |
| | | |Inhibitory (postsynaptic): incr K conductance | | |
Present in whole CNS; transmitter at 20% CNS synapses
Responsible for presynpatic inhibition
Formation: decarboxylation of glutamate catalysed by glutamate decarboxylase ( metabolized to succinic semialdehyde then succinate by GABA transaminase; cofactor for both these enzymes is pyridoxal phosphate
Effect = incr Cl influx, incr K efflux, decr Ca influx ( hyperpolarisation ( IPSP
Receptors:
GABAa – found in CNS; ionotropic receptors (Cl ion channel) made of 5 subunits; chronically
stimulated by GABA in interstitial fluid ( cuts down on ‘noise’ from incidental discharge of neurons; involved in fast component of IPSP’s; benzo’s bind this
GABAb – found in CNS; metabotropic (coupled to G protein) ( incr K efflux, inhibit adenylyl
cyclase, decr cAMP, inhibit Ca influx (so prevent NT release); involved in slow component (due to indirect coupling of G protein receptor) of IPSP’s; found in perisynaptic region
GABAc – found in retina; Cl ion channel made of 5 subunits
Clearance: GABA is reuptook via transporter
2) Glycine
|Glycine |Spinal and brainstem interneurons | |Inhibitory: incr Cl conductance |Taurine, β-alanine |Strychine |
Present in brainstem and SC
Inhibitory and excitatory
Bind receptors that are selectively permeable to Cl
NB. Activates NMDA receptors
Acetylcholine
|Ach |Cell bodies at all levels |M1 |Excitatory: decr K conductance, incr IP3 and DAG |Muscarine |Pirenzipine, atropine |
| | |M2 |Inhibitory: incr K conductance, decr cAMP |Muscarine, |Atropine, methoctramine|
| | | | |bethanechol | |
| |Motoneuron-Renshaw cell synapse |Nicotinic |Excitatory: incr cation conductance |Nicotine |Dihydro-β-erythroidine,|
| | | | | |α-bungarotoxin |
Important role in cognitive function and memory
Formation: made from choline (made in neurons and reuptook from synaptic cleft) and acetate (activated by combination with reduced coenzyme A) ( catalysed by choline acetyltransferase ( acetylcholine ( taken into synaptic vesicles by vesicular transporter VAChT ( released into synaptic cleft
Muscarinic receptors – in smooth muscle, brain and glands; M1-M4 are G protein-coupled receptors; affect adenylyl cyclase, K channels or phospholipase C
M1 – in brain; causes slow excitation
M2 – in heart; causes slow inhibition
M3+M4 – in smooth muscle
M4 – in pancreas ( increased secretion of pancreatic enzymes and insulin
Nicotinic receptors – in autonomic ganglia, CNS and NMJ; made of 5 subunits that form central channel; when activated α subunit binds Ach ( change in protein ( allows passage of Na and other cations ( depolarizing potential
Clearance: hydrolysed to choline and acetate by acetylcholinesterase in postsynaptic membrane (Pseudocholinesterase: found in plasma, hydrolyses other choline esters; under endocrine control)
Monoamines
Catecholamines: E, NE, dopamine
NB. Cocaine blocks reuptake of dopamine and NE
Amphetamines cause presynaptic terminals to release NT’s
[pic]
Formation: all made by hydroxylation and decarboxylation of amino acid tyrosine
1) Some tyrosine made from phenylalanine in liver, but most from dietary origin
2) Tyrosine transported into catecholamine-secreting (dopaminergic, adrenergic, noradrenergic) neurons or adrenal medulla
3) ( dopa ( dopamine in cytoplasm; TYROSINE ( DOPA is RATE-LIMITING PROCESS
4) Dopamine enters granulated vesicles ( converted to norepinephrine
5) ( transported into vesicles by vesicular transporters
6) NE leaves vesicles, is converted to E, then enters other storage vesicles
7) Released from neurons by exocytosis
Removed from synaptic cleft by:
1) Binding with postsynaptic receptor
2) Binding to presynaptic receptor
3) Re-uptake into presynaptic neurons: important for NE
4) Catabolism:
a. Oxidation catalysed by monoamine oxidase (MAO-A and MAO-B) on outer surface of mitochondria found esp in neurons; measure 3-methoxy-4-hydroxymandelic acid in urine
b. Methylation catalysed by catechol-O-methyl-transferase (esp in liver, kidneys, smooth muscle, glial cells); accounts for catabolism of extracellular E and NE; measure normetanephrine and meanephrine in urine
Receptors are metabotropic (serpentine with G proteins) - NE has higher affinity for α-receptors
E has higher affinity for β-receptors
Norepinephrine – made by noradrenergic neurons; at most sym postganglionic endings; noradrenergic neurons located in reticular formation, but most regions of CNS receive input; all receptors are metabotropic; stored in synaptic knobs in small granulated vesicles; NE and E bound to ATP and associated with protein called chromogranin A in vesicles; may also contain neuropeptide Y and dopamine beta-hydroxylase which get released with NE + E on exocytosis; can hyperpolarize neurons by increasing K conductance, or may enhance excitatory output via disinhibition or blockage of K channels
|NE |Cell bodies in pons and brainstem, project|α 1 |Excitatory: decr K conductance, incr IP3 and DAG |Phenylephrine |Prazosin |
| |to all levels | | | | |
| | |α 2 |Inhibitory (presynaptic): decr Ca conductance, incr K |Clonidine |Yohimbine |
| | | |conductance, decr cAMP | | |
| | |β 1 |Excitatory: decr K conductance, incr cAMP |Isoproterenol, |Atenolol, practolol |
| | | | |dobutamine | |
| | |β 2 |Inhibitory: incr Na conductance, incr cAMP |Albuterol |Butoxamine |
Dopamine – slow inhibitory effect on CNS neurons; mainly used in projection linking substantia nigra to neostriatum (function of antiparkinsonian drugs), and projection to limbal structures (function of antipsychotic drugs), and in hypothalamus; in small intensely fluorescent (SIF) cells; receptors are all metabotropic; reuptake via Na and Cl-dependent transporter; metabolized via MAO and COMT
D1-like receptors: D1, D5
D2-like receptors: D2, 3, 4
|Dopa -mine |Cell bodies at all levels |D1 |Inhibitory: incr cAMP | |Phenothiazines |
| | |D2 |Inhibitory (presynaptic): decr Ca |Bromocriptine |Phenothiazines, |
| | | |Inhibitory (postsynaptic): incr K conductance, decr cAMP | |butyrophenones |
Tyrosine hydroxylase gets negative feedback from dopamine and norepinephrine; tyrosine hydroxylase needs a co-factor named tetrahydrobiopterin
Phenylketonuria: build up of phenylalanine 2Y to mutation of gene for phenylalanine hydroxylase; NE and E can still be made from tyrosine; if caused by deficiency of tetrahydrobiopterin, since this is involved in many steps above as cofactor, will also get deficiency of NE and E
Serotonin (5-hydroxytryptamine)
|5-HT |Cell bodies in midbrain and pons; project |5-HT1A |Inhibitory: incr K conductance, decr cAMP |LSD |Metergoline, spiperone |
| |to all levels | | | | |
| | |5-HT2A |Excitatory: decr K conductance, inc IP3 and DAG |LSD |Ketanserin |
| | |5-HT3 |Excitatory: incr cation conductance |2-methyl-5-HT |Ondansetron |
| | |5-HT4 |Excitatory: decr K conductance | | |
[pic]
Found in enterochromaffin cells, myenteric plexus, brain (pons and upper brainstem), retina; found in unmyelinated neurons that innervate most regions of CNS
Inhibitory – usually via 5-HT1a (membrane hyperpolarisation via incr K conductance); 5-HT3 or 4 may be slow excitatory; may be excitatory and inhibitory on same neuron; involved in sleep, temp, appetitie, neuroendocrine control
Formation: hydroxylation and decarboxylation of aa tryptophan
Deactivated by: reuptake
Breakdown to 5-hydroxyindoleacetic acid by MAO
Converted to melatonin by pineal gland
Multiple receptors, all metabotropic (coupled to adenylyl cyclase or phospholipase C) except 5-HT3 which is ionotropic
5-HT2A – for platelet aggregation and SM contraction
5-HT2C – mediate food intake
5-HT3 – in GI tract, related to vomiting
5-HT4 – in GI tract, related to peristalsis and secretion
Histamine
Histaminergic neurons have cells bodies in tuberomammillary nucleus of post hypothalamus ( axons to all brain; also found in gastric mucosa and mast cells (in pituitary gland)
[pic]
Formed by decarboxylation of aa histidine; most histamine is converted to methylhistamine
H1-3 are known – found in peripheral tissues and brain; related to arousal and sexual behaviour, BP, pain threshold, itch
H1 – activate phospholipase
H2 – increase cAMP
H3 – mostly presynaptic, work in negative feedback
Tachykinins
Substance P: receptor is serpentine acting via G protein ( activation of phospholipase C, formation of IP3 and DAG ( slow EPSP in neurons transmitting noxious stimuli; involved in slow pain; also found in nigrostriatal system and hypothalamus, involved in peristalsis in intestine
Other tachykinins are neurokinin A, neuropeptide K, neurokinin B
Opioid Peptides
|Opioid |Cell bodies at all levels |Mu |Inhibitory (presynaptic): decr Ca conductance, decr cAMP |Bendorphin |Naloxone |
|peptides | | | | | |
| | |Delta |Inhibitory (postsynaptic): incr K conductance, decr cAMP |Enkephalin |Naloxone |
| | |Kappa |Inhibitory (postsynaptic): incr K conductance, decr cAMP |Dynorphin |Naloxone |
Enkephalins bind opioid receptors (eg. Met-enkephalin and leu-enkephalin); found in GI tract and brain; decr intestinal motility, pain relieving; they come from precursors from which the peptide is cleaved
Prokephalin ( met-enkephalin, leu-enkephalin, octapeptide, heptapeptide
Pro-opiomelamocortin ( beta-endorphin, other endorphins
Prodynorphin ( dynorphins, neoendorphins
Enkephalins are metabolized by enkephalinase A and B and aminopeptidase
3 receptors characterized, serpentine receptors coupled to Gq, inhibit adenylyl cyclase:
μ – analgesia, resp depression, constipation, euphoria, sedation, miosis, incr secretion GH and PL;
incr K conductance ( hyperpolarisation; bind endorphins
κ – analgesia, diuresis, sedation, miosis, dysphoria; close Ca channels
δ – analgesia; close Ca channels; bind enkephalins
Other Polypeptides
Somatostatin: sensory input, locomotor activity, cognitive function; inhibits insulin secretion from pancreas, inhibits GI hormones; 5 different G protein coupled receptors
Vasopressin, oxytocin, neurotensin, cholecystokinin, VIP, neuropeptide Y
Purine and Pyrimidine Transmitters
ATP: released with other NT’s during exocytosis; may act via G proteins or ligand-gated ion channels
Adenosine: general CNS depressant; vasodilator in heart; works via different serpentine G protein linked receptors changing cAMP concs
Gases
NO: made from arginine catalysed by NO synthase; activates guanylyl cyclase
Endocannabinoids
Triangle9-THC is psychoactive ingredient of cannabis; activates receptor CB1 (also activated by endogenous anandamide and 2-arachidonylglycerol) – can function as retrograde synaptic messengers (released from POSTsynaptic neurons ( activate CB1 on PREsynaptic neurons ( suppress NT release)
Cotransmitters
When NT released with eg. A polypeptide – one may potentiate the effect of another
Synaptic Plasticity and Learning
Posttetanic potentiation: enhanced postsynaptic potentials in response to stimulation; enhancement lasts up to 60secs; tetanising stimulation causes accumulation of Ca in presynaptic neuron until intracellular binding sites are saturated
Habituation: when benign stimulus is repeated, response to stimulus decreases; due to decr release of NT from presynaptic terminal 2Y to decr intracellular Ca due to gradual inactivation of Ca channels
Sensitisation: prolonged occurrence of augmented responses after a stimulus to which animal has been habituated is paired with noxious stimulus; may be transient/longer term; due to Ca-mediated change in adenylyl cyclase ( incr production cAMP
Long term potentiation: persistent enhancement of postsynaptic potential response to presynaptic stimulation after brief period of rapidly repeated stimulation; much more prolonged than posttetanic potentiation; due to accumulation of Ca in postsynaptic neuron
Long term depression: decreased synaptic strength
NEUROMUSCULAR TRANMISSION
NMJ
As axon approaches termination, loses myelin sheath and divides into terminal buttons/endfeet contains small clear vesicles containing Ach; endfeet fit into junctional folds (depressions in motor end plate – thickened part of muscle membrane, containing 15-40 million Ach receptors); 1 nerve fibre per end plate, no convergence of multiple inputs
1) Impulse arrives at end of motor neuron
2) Incr permeability to Ca ( Ca INFLUX
3) Incr exocytosis of Ach-containing vesicles (approx 60 per impulse, each vesicle containing 10,000 Ach molecules – 10x more than needed to depolarize)
4) Ach diffuses to nictonic receptors
5) Incr Na and K conductance of muscle membrane ( Na INFLUX ( depolarizing end plate potential
6) Adjacent muscle membrane depolarized to firing level ( AP conducted down fibre ( muscle contraction
7) Acetycholinesterase removes Ach from synaptic cleft
Drug curare competes with Ach at endplate; endplate potentials undergo temporal summation
At rest, small quanta of Ach (size proportional to Ca, inversely propotional to Mg at end plate) released randomly ( miniature end plate potential (0.5mV)
Myasthenia gravis: ab to nicotinic receptors ( destroy receptors or trigger removal by endocytosis
Lambert-Eaton syndrome: antibodies to Ca channels in nerve endings ( decr Ca influx ( prevents Ach release
Denervation hypersensitivity: when motor nerve to muscle cut, muscle becomes v sensitive to Ach, but muscle atrophies; this only affects the structure immediately innervated by neurons, not those further downstream; due to synthesis of more receptors; will result in wallerian degeneration with also retrograde degeneration up to site of nearest sustaining collateral; in cell body chromatolysis occurs (decr in Nissl substance); then regenerative sprouting with axon beginning to regrow – this can be helped by giving neurotrophins
Smooth and Cardiac Muscle
Postganglionic neurons branch extensively and have beads (varicosities) not covered by Schwann cells containing vesicles; may contain clear vesicles with Ach, or dense-core vesicles with NE; NO END PLATES – nerve fibres run membranes of muscles cells, so 1 neuron can innervate many effector cells (synapse en passant); fibres end on SAN, AVN, and Bundle of His (NE fibres also innervate ventricular muscle)
In smooth muscle NE ( partial depolarization called excitatory junction potentials (EJP’s); or partial hyperpolarisation called inhibitory junction potentials (IJP’s) depending on whether NE is excitatory or not to that tissue
Denervation hypersensitivity: when motor nerve to muscle cut, muscle becomes v sensitive to Ach; muscle DOES NOT atrophy
IMPULSES IN SENSE ORGANS
Sensory receptors transduce energy from environment (eg. Thermal, light, odour, taste) into AP’s in neurons; may be part of neuron or specialized cell that generates AP in neurons; receptor has much lower threshold to respond to adequate stimulus than other receptors (eg. For rods, this is light – will respond to pressure on eyeball however, but has to be higher stimulus); there are 11 conscious senses
Classification: special (smell, vision, hearing, rotational and linear acceleration, taste), cutaneous (touch-pressure, cold, warmth, pain – receptors for this likely on naked nerve endings, CMR-1 for mod cold, VR1 and VRL-1 for extreme heat, latter 2 are nociceptive), visceral. Or teleceptors (events at a distance), exteroceptors (external enviro near), interoceptors (internal enviro), proprioceptors (position)
Pacinian corpuscule: touch receptor; unmyelinated ending of sensory nerve fibre; large; surrounded by connective tissue; myelin sheath begins in corpuscule; responds only to transient touch; when small amount of pressure applied ( nonpropagated depolarizing potential occurs – generator/receptor potential ( generator potential proportionate to magnitude of stimuli ( at 10mV AP generated, fires repetitively if pressure further increased ( sensory nerve at 1st node of Ranvier depolarized ( propagated. Frequency of AP’s proportionate to magnitude of applied stimuli.
Adaptation/desensitisation: when maintained stimulus, frequency of AP’s decreases over time; this may be
Rapidly adapting: eg. Light touch
Slowly adapting: eg. Muscle spindles, nociceptive
Doctrine of specific nerve energies: sensation evoked by receptor is due to specific part of brain they ultimately activate (eg. Irritation from a tumour in armpit on sensory nerve from pacinian corpuscule in hand will cause sensation of touch)
Projection: no matter where in pathway is stimulated, sensation is referred to location of receptor (eg. Phantom limb)
Intensity discrimination: vary frequency of AP, or vary no. receptors stimulated
R (sensation felt) = K(constant) x S(intensity of stimulus)A(constant)
Sensory unit: single sensory axon and its many peripheral branches supply a receptive field; as strength of stimulus increases it activates sense organs immediately in contact with it and recruits those in surrounding area as receptive fields overlap; stronger stimuli will also stimulate receptors with higher thresholds ( increase intensity of sensation
REFLEXES
Reflex arc: sense organ
Needs adequate stimulus
Receptor potential proportional to strength of stimulus ( all-or-none potential in…
AFFERENT neuron
Enter via dorsal roots/CN; cell bodies in dorsal root ganglia/CN ganglia
No. potentials proportionate to size of generator potential
Synapses in central integrating system (eg. Brain/spinal cord)
EFFERENT neuron (the final common path)
Leave via ventral roots/motor CN
Receive multiple other inputs
Effector
In above, spatial and temporal facilitation, occlusion, subliminal fringe effects all occur
CNS can be in central excitatory/inhibitory state (eg. When excitatory, impulses radiate not only to somatic areas but also to autonomic areas (eg. Urination, sweating, - mass reflex)).
Habituation and sensitization can be applied to reflexes
Bell-Magendie law: dorsal roots sensory, ventral roots motor
Monosynaptic reflex: eg. Stretch reflex (muscle spindle ( fast sensory fibres ( NT at central synapse = glutamate ( motor neuron ( muscle)
Muscle spindle:
10 intrafusal muscle fibres enclosed in CT capsule, ends of which are contractile and attached to tendons at either end of muscle or to sides of extrafusal fibres.
2 types of intrafusal muscle fibre:
1) Nuclear bag fibre: many nuclei in central dilated area; 2 fibres per spindle, 1 with high and 1 with low ATP-ase activity
2) Nuclear chain fibre: thinner, shorter, no central bag; 4+ per spindle; attached to 1)
Respond to changes in length and changes in rate of stretch:
Stimulation of NBF’s ( dynamic fusiform response (ie. Discharge most rapidly when muscle being stretched, less rapidly during sustained stretch) – physiologic tremor would be worse if it wasn’t for NBF’s being sensitive to rate of stretch
Stimulation of NCF’s ( static fusiform response (ie. Discharges rapidly so long as muscle is stretched
Motor nerve supply
1) Exclusive motor nerve supply (γ efferents of Leksell / small motor nerve system) – 3-6um
diameter, 30% fibres in ventral roots, group A γ; have motor end plates (plate endings) on NBF’s
and trailing endings on NCF’s
Stimulation causes contractile ends of intrafusal fibres to shorten (become shorter than
extrafusal fibres) ( stretches NBF’s ( stimulates Ia sensory fibres ( may cause reflex
contraction of muscle (via α motor neurons); as there is α-γ linkage, spindle shortens with
muscle during contraction, so spindle discharge may continue throughout contraction, so
spindle remains capable of responding to stretch; regulated by descending tracts from
brain, regulating sensitivity for posture etc… (discharge incr by anxiety, unexpected mvmt, Jendrassik’s manouvre, noxious stimulus to skin)
INCR DISCHARGE INCREASES SPINDLE SENSITIVITY
3) β motor neurons – have motor end plates (plate endings)
There are also γ and β dynamic and static efferents – stimulation of dynamic efferents increases spindle sensitivity to rate of stretch; stimulation of static efferents increases sensitivity to steady, maintained stretch
Sensory nerve supply
1) Primary (annulospiral) ending: the terminations of rapid Ia sensory afferent fibres; 1 branch
innervates NBF 1 and another NBF 2 and NCF’s; nerve endings wrap around centre of fibres
and go to motor neurons supplying extrafusal fibres of same muscle
2) Secondary (flowerspray) ending: the terminations of II sensory fibres; near ends of intrafusal
fibres on NCF only
Stimulation caused by stretching of muscle spindle ( receptor potential ( AP in Ia fibres at f proportionate to degree of stretching ( spinal cord ( motor neuron to extrafusal fibres (monosynaptic)
Reaction time: time between application of stimulus and response (eg. 19-24ms for knee jerk)
Central delay = reaction time – time taken for impulse to travel to and from spinal cord = time
taken for reflex activity to traverse spinal cord (0.6-0.9ms)
II sensory fires may be involved in polysynaptic mechanisms.
Feedback device that maintains muscle length – if stretched, reflex contraction; if shortened, reflex relaxation
Reciprocal innervation: Ia fibres cause postsynaptic inhibition of motor neurons to antagonists via inhibitory interneron (Golgi bottle neuron) – BISYNAPTIC
Inverse stretch reflex/autogenic inhibition: when tension becomes so great that there is no longer reflex contraction ( muscle relaxes; note, elastic muscle fibres take up much of stretch so takes strong stretch to cause relaxation; receptor is in Golgi tendon organ (net-like knobbly nerve endings along fasiscles of tendon; 3-25 muscle fibres per organ, Ib myelinated rapidly-conducting sensory nerve fibres; stimulated by both passive stretch and active contraction of muscle – acts as feedback circuit to regulate muscle force; low threshold)
Stimulation ( spinal cord ( inhibitory interneuron ( generation of IPSP’s on motor neuron that
supply that muscle, excitatory connections to motor neurons supplying antagonist muscle
Tone: flaccid is α neurons cuts
hypotonic if γ efferent discharge low
hypertonic if high (if you lengthen muscle passively, it wants to contract, so high tone ( further
stretch causes inverse stretch reflex, sudden loss of resistence – clasp-knife effect/lengthening
reaction); clonus – regular rhythmic contractions in muscle exposed to sudden sustained stretch (spindle hyperactive so bursts of impulses discharge motor neurons all simultaneously ( muscle contraction stops spindle discharge ( we keep pushing and cause passive stretch again…)
ALL THE ABOVE DETERMINE RATE OF DISCHARGE OF α MOTOR NEURONS
- SPINDLES FEEDBACK TO REGULATE MUSCLE LENGTH
- GOLGIS FEEDBACK TO REGULATE MUSCLE FORCE
Polysynaptic Reflexes
Synaptic delay = approx 0.5ms, so the more synapses the slower the response’
Reverberating response: some pathways may turn back on self, activity reverberates until unable to cause propagated reponse ( dies out
Withdrawal reflex: nociceptive stimulus ( flexion of agonist, inhibition of antagonist; it is prepotent (ie. Take priority over any other reflex activity occurring in spinal cord at that moment)
Crossed extensor response: with withdrawal reflex, also get extension of contralateral limb
Irradiation of the stimulus: when spinal cat’s paw pinched, limb withdrawn, contralateral hindlimb extended, ipsilateral forelimb extended, contralateral forelimb flexed – spread of excitatory impulses up and down spinal cord causing recruitment of motor units
Local sign: if noxious stimulus is medial aspect leg, also get some abduction of leg
Fractionation: each input only goes to part of motor neuron pool for the flexors so doesn’t produce maximal response
Occlusion: various afferent inputs share some motor neurons ( submaximal response
Stronger stimulus causes larger and more prolonged response due to repeated firing of motor neurons (after-discharge – due to continuing stimulation of motor neurons along a polysynaptic path, many impulses arriving at different times). Stronger stimulus causes faster response due to temporal and spatial summation in polysynaptic pathway.
SENSATION
Cell bodies in dorsal root ganglia
Dorsal horns arranged into laminas I-VII (I most superficial)
I-VI: unilateral input
II, III: substantia gelatinosa
VII: bilateral input
3 types of sensory fibres:
1) Aα and Aβ fibres: large, myelinated; mechanical stimuli; ( III-VI
2) Aδ fibres: small, myelinated; mechanoreceptors (III + IV), cold, fast nociceptors (I + V)
3) C fibres: small, unmyelinated; pain, temperature, mechanoreceptors (I + II)
Pathways
Dorsal column / lemniscal system (fine touch (localization, spatial form, temporal pattern) and proprioception)
Travel up dorsal column
( synapse in MEDULLA (gracile and cuneate nuclei)
( cross midline IN MEDIAL LEMNISCUS
( ventral posterior nucleus in thalamus
Damage ( loss of vibratory sensation and proprioception, loss of localization of touch sensation, incr touch threshold, decr no touch-sensitive areas in skin
Some collaterals synapse in dorsal horn, may modify input into other cutaneous sensory systems
Dorsal horn acts as a ‘gate’ allowing certain pain impulses through depending on impulses from descending tracts from brain and nature of input
Lower axons more medial
Anterolateral system / spinothalamic (touch (gross), pain, cold, warmth):
Synapse in dorsal horn
( cross midline IN SPINAL CORD locally
( ascend in anterior spinal cord (touch)
lateral spinal cord (pain and temp)
( relay nuclei in thalamus, projection nuclei near midline, reticular activating system
Damage ( incr touch threshold, decr no touch-sensitive areas; touch localization normal; deficit less profound than dorsal columns
Lower axons more lateral
From thalamus sensory info goes to cortex:
Somatic sensory area I (Brodmann’s area 1, 2 and 3): in postcentral gyrus; legs at top and head at
Bottom; hand and mouth have large amounts; cells organized in vertical columns, each column
responds to a certain sensory modality
Ablation ( deficits in position sense, discrimination of size and shape; also effects SII
(hence SI processes stuff then projects it on to SII)
Somatic sensory area II: in superior wall of sylvian fissure (separated temporal from frontal and
parietal lobes); head at inf end of postcentral gyrus, feet at bottom of sylvian fissure
Ablation ( deficits in tactile discrimination; has no effect on SI
Cortical plasticity: above mapping can change rapidly to reflect use of represented area; cortical connections of sensory units to cortex have convergence and divergence, connections can become weak/strong with disuse/use; this doesn’t only occur with touch
Cortical lesions mainly effect proprioception and fine touch, affect temp and pain to lesser extent.
Touch
Not necessarily visible specialized receptors; numerous in fingers and lips, around hair follicles
Receptor: associated with BNC1 Na channel (a degenerin – when hyperexpressed, cause neurons they are in to degenerate)
Nerve: Aβ (5-12um diameter, conduction velocity 30-70m/s) and C fibres
Pathway: transmitted in dorsal (more important) and spinothalamic columns, so rare to get complete loss
Proprioception
Nerve: Aα
Pathway: dorsal
Central: cerebellum, medial lemniscus, thalamus
NB. ‘Spray’ endings, touch receptors in skin, muscle spindles all convey info along antlat column to cortex for conscious awareness of position of body
Temperature
More cold sensitive (10-38deg) than heat sensitive (30-45deg) spots
Receptor: from the TRP family of cation channels
Moderate cold – cold- and menthol-sensitive receptor 1 (CMR1)
Severe heat – VR1 and VRL-1 (both nociceptors)
Nerve: Aδ + C for cold, C for hot
Pathway: spinothalamic column
Central: postcentral gyrus, insular cortex
Pain
Sense organ: naked nerve endings; vanilloid receptor-1 (VR1) and VRL-1 discovered which respond to pain, protons, harmful temps
Nociceptive substances: P factor (?may be K) causes pain in muscles not receiving enough blood supply, washed away when blood returned
Nerve: Aδ (small myelinated, 2-5um diameter, 12-30m/s) ( terminate in dorsal horn on lamina I + V; fast
Pain (sharp); deficiency in deep structures
Dorsal root C fibres (large unmyelinated, 0.4-1.2um diameter, 0.5-2m/s) ( terminate in dorsal horn
lamina I + II; slow pain (dull)
Neurotransmitter: mild pain = glutamate, severe pain = substance P - from 1Y afferent to dorsal cord
Pathway: some in dorsal, some in lat spinothalamic
Central: to ventral post nuclei in thalamus ( cortex (areas SI, SII, cingulates gyrus, mediofrontal cortex, insular cortex, cerebellum)
Visceral pain: no proprioceptors, few temp or touch, sparse pain receptors (sensitive to distension and chemical irritation); afferent fibres reach CNS via paraS and sym fibres (splanchnic, pelvic, phrenic, intercostal, facial, GP, vagus, trigeminal) ( cell bodies in dorsal roots and CN ganglia ( travel in spinothalamic tracts, or may make connections with collaterals to postganglionic sym neurons for reflex control ( reflex contraction of nearby skeletal muscle
Referred pain: visceral / deep somatic to somatic structure; may appear to radiate; referred to structure developed from same embryological segment / dermatome (dermatomal rule); due to plasticity of CNS and convergence of pain fibres on same 2nd order neurons (lamina 1-VI ipsilateral, lamina VII bilateral, hence can be referred to opp side of body) – peri neurons don’t usually fire the 2nd order neuron, but if visceral stimulation prolonged facilitation occurs at peri endings
Central inhibition: inhibition of pain pathways in dorsal horn gate due to stimulation of large-diameter touch-p afferents
Inflammatory pain: exaggerated response (hyperalgesia) and pain on normally non-painful stimuli (allodynia); due to release of cytokines and GF’s facilitating perception and transmission in cut areas and dorsal horn
Neuropathic pain: causalgia – burning pain after trivial injury; reflex sympathetic dystrophy – skin thin, shiny, incr hair growth; nerve inj causes growth of sym nerve fibres into dorsal root ganglia of sensory nerves from injured area ( sym discharge causes pain
Analgesics: opiates can work peripherally in tissue, in dorsal horn where 1Y afferent synapses, in brainstem (activate inhibitory descending pathways that decr transmission of pain impulses); placebo can cause release of endogenous opioids
Itch and Tickle
Pathway: spinothalamic
Relieved by scratching as activates large, fast-conducting neurons that gate transmission at dorsal horn
Synthetic Senses
Touch, warmth, cold, pain ( cortex makes vibratory sensation, 2-point discrimination, stereognosis
Vibration: pacinian corpuscules ( dorsal column
2-point discrimination: smallest where touch receptors most numerous; back = 65mm, fingers = 3mm
Stereognosis: ability to identify objects by handling them; also dorsal column
VISION
Anatomy
Sclera: protective outer covering
Cornea: transparent
Choroid: BV’s
Retina: lining post 2/3 of choroid, neural tissue, extends almost to ciliary body (containing circular and longitudinal muscle fibres; makes aqueous humour that nourishes cornea and lens ( enters ant chamber ( through canal of Schlemm at iridocorneal angle
Accomodation: must contract ( relax lens ligaments if object >6m away
Near point of vision is closest object can be focused – 9cm aged 10, 83cm aged 60 (presbyopia) due to hardness of lens
Near response: accommodation + convergence of visual axes + papillary constriction
Lens: held in place by lens ligament (zonule) attached to thickened choroid (ciliary body)
Parallel (ie. >6m away) light rays strike biconvex lens are refracted (at cornea, ant lens and post
lens) to point (principle focus) which is on line passing through centres of curvature of lens
(principal axis); distance between lens and PF is principal focal distance (will be longer if object
37 ( receptors indicate temp is 41 can cause brain damage, >43 causes heat stroke)
Malignant hyperthermia: mutations in gene coding for ryanodine receptor ( XS Ca release during muscle contraction during stress ( contractures, incr metabolism ( incr heat
Hypothermia: slow HR, slow RR, decr BP, decr LOC; ability to spontaneously return to temp to N lost 230bpm; in AF, due to circulating reentrant excitation waves in both atria, AVN discharges at irregular intervals ( V beat at irregular rate (80-160)
Ventricular ectopics: bizarre QRS due to slow spread of impulse from focus through V muscle; can’t excite BOH so retrograde conduction of A doesn’t occur; normal SAN depolarizes atria but P wave hidden in QRS, if it reaches V they will still be in repolarisation phase; however next SAN impulse produces normal beat after compensatory pause (longer than pause from atrial ectopic)
Ventricular tachycardia: due to circus movement in V’s
VF: rapid discharge from multiple V ectopic foci / circus movement; can be produced by electric shock / extrasystole during vulnerable period (midportion of T wave, when some of V myocardium depolarized and some incompletely repolarised, some completely repolarised)
Accelerated AV conduction (WPW syndrome): bundle of Kent is aberrant muscular/nodal tissue connection between A+V which conducts more rapidly than AVN ( 1V excited early ( short PR and slurred QRS deflection, with normal PJ interval; tachycardias often follow atrial premature beat which conducts down AVN then sprads to aberrant bundle and back up to A ( circus movement (or vice versa less often)
Lown-Ganong-Levine syndrome: short PR but normal QRS; depolarization down aberrant pathway but enter IV conducting system distal to node
Other ECG Changes
MI:
MP of infarcted area greater than in normal area ( current flows from +ive infarct into -ive normal area ( flows toward electrodes over injured area ( ST elevation
ST elevation 1) MP of infarcted area greater than in normal area ( current flows from infarct into normal
area ( flows toward electrodes over injured area ( ST elevation
2) Rapid repolarisation due accelerated opening of K channels ( ST segment elevation,
within secs, lasting few mins
3) Decr RMP due to K loss ( current flow into infarct during V diastole ( TQ segment
depression (looks like ST elevation); within mins
4) Delayed depolarization ( again infracted area +ive comparied to normal ( ST segment
elevation; within 30mins
Normalisation of ST segment over days/weeks
Dead muscle becomes electrically silent so becomes –ive relative to normal myocardium during systole and doesn’t contribute to positivity of complexes ( Q wave development, incr size of Q wave; failure of progression of R wave; may get BBB if septum involved
Ventricular arrhythmias occur during 1st 30 mins (due to reentry) ( after 12hrs (due to incr automaticity) ( after 3/7 to several wks (due to reentry)
Infarcts affecting epicardium interrupt sym nerve fibres ( dennervation supersensitivity to NE+E in area beyond infarct; endocardial infarct lesions affect vagal fibres
Hyponatraemia: low voltage complexes
Hyperkalaemia: peaked T waves (altered repolarisation) ( prolonged QRS, paralysis of atria ( V arrhythmia; decr RMP ( fibres become unexcitable ( heart stops in diastole
Hypokalaemia: prolonged PR, prominent U waves, late T wave inversion; if T and U waves merge, apparent prolonged QT
Hypercalcaemia: stops in systole (Ca rigor)
Hypocalcaemia: prolonged ST
Phenothiazines, tricyclic antidepressants: prolonged ST
The Heart As A Pump
Pericardial sac contains 5-30ml clear fluid
Cardiac muscle contracts faster when incr HR; duration of systole fomr 0.16-0.27s; duration of diastole from 0.14-0.62; cannot be tetanised as will not contrat until near end of another contraction due to prolonged refractory period (theoretical max HR 400; AVN will not conduct faster than 230 so higher HR only seen in V tachy
Contraction starts just after depolarization and lasts until 50ms ater repolarisation is completed; atrial systole starts after P wave; V systole starts near end of R wave and ends just after T wave
[pic]
Jugular Venous Pulse: shows atrial p changes; decr during inspiration due to –ive intrathoracic p
a wave: atrial systole due to regurg of blood into veins and stopping of venous inflow; in CHB will be asynchronous a waves with giant a waves (cannon wave) when A contract against close TV
c wave: rise in Ap due to bulging of TV into A during isovolumetric V contraction; giant c wave in tricuspid insufficiency
v wave: incr Ap before TV opens during diastole
z: drop in Ap during ejection phase of V as MV and TV pulled downward
Heart Sounds:
S1: lub; closure of MV and TV at start of V systole; 0.15s long, low f
S2: dup; closure of AV and PV after end of V systole; 0.12s long, higher f; loud and sharp when incr diastolic p in aorta/pul art
S3: 1/3 way through diastole due to rapid V filling and inrush of blood; 0.1s long
S4: just before S1; if high Ap or stiff V (eg. LVH)
Arterial pulse:
Rate at which wave travels is independent of and greater than velocity of blood flow (4m/s in aorta, 8m/s in large arteries, 16m/s in small arteries – moves faster in older people); pulse in radial artery felt 0.1s after peak systolic ejection
Strength of pulse: determined by pulse pressure; not affected by MAP
STRONG: large SV
incompetent AV (may be so strong than head nods with heartbeat; collapsing /
Corrigan / water-hammer pulse)
WEAK: shock
Dicrotic notch: oscillation in falling phase of pulse wave when aortic valve shuts; not palpable
Cardiac Output
SV: amount of blood pumped by each V in 1 HB = 70ml
CO: output per unit time; ave 5L/min; controlled by SV (inotropic) and HR (chonotropic)
Cardiac index: output per min per square metre body surface; ave 3.2L
Preload: degree to which myocardium is stretched before it contracts
Afterload: resistance against which blood is expelled
Measure with:
Doppler and echo
Direct Fick Method: only applies when arterial blood is only source of substance being taken up; measure amount of O2 used by body in period and divide by AV difference across lungs; use ABG and pul art blood from cardiac catheter
Fick principle: Amount of substance taken up by organ per unit time
= (arterial level of substance – venous level (A-V difference)) X blood flow
CO = O2 consumption (mL/min) / [AO2] – [VO2]
Indicator dilution method: dye/radioactive isotope (which must stay in blood stream; can use cold saline injected into RA and measure temp change in pul art - thermodilution technique) injected into vein and conc in arterial blood determined serially
CO = amount injected / av. arterial conc after single circ through heart
Starling’s Law of Heart
[pic]
Energy of contraction proportional to initial length of cardiac muscle fibre (in heart, this is proportionate to end-diastolic vol – SV/EDV = Frank-Starling curve): when stretched tension incr to max then declines
Heterometric regulation: change in CO due to muscle fibre length
Homometric regulation: change in CO due to contractility
EDV: affected by intrapericardial p (incr ( V cannot fill)
V stiffness (incr by eg. MI)
VR (incr by incr blood vol, venoconstriction, decr intrathoracic p, muscular activity,
lying down)
Contractility: SNS shifts length-tension curve up and left; NE+E work on β1 receptors and Gs ( adenylyl
cyclase, incr cAMP
Small incr contractility with incr HR
Postextrasystolic potentiation – V extrasystole makes succeeding contraction stronger due to
incr availability of intracellular Ca
Depressed by incr CO2, decr O2, acidosis, quinidine, procainamide, barbs
Intrinsic depression in CCF, ? cause
NB. Athletes have lower HR, greater end-systolic V vol, greater SV @ rest
O2 Consumption of Heart
Determined by: intramyocardial tension, contractile state, HR; correlates with V work (= SV x MAP in pul art or aorta; approx 7x higher for LV as aortic p higher) – for unknown reason incr MAP has bigger effect in workload than incr vol (ie. afterload has bigger effect than preload; ie. AS will be greater problem than regurg)
Basal: 2ml/100g/min (higher than resting skeletal muscle)
Beating: 9ml/100g/min
Extracts most O2 from blood so incr O2 must be provided by incr coronary blood flow
NB. Law of Laplace: tension of wall of hollow viscus proportionate to radius of viscus ( stretch myocardial fibres ( incr SV
NB. Incr HR ( incr velocity and strength of contraction BUT decr end-systolic vol and hence radius of heart
Dynamics of Blood and Lymph Flow
Move blood forward: heart pump, diastolic recoil of arteries, compression of veins by skeletal muscle, negative pressure of thorax
Blood Vessels
In vessels: SM innervated by noradrenegeric fibres ( constriction, cholinergic fibres ( dilation
Artery ( arteriole ( metarterioles (may be connected to venule via thoroughfare vessel) ( capillaries (openings surrounded on upstream side by precapillary sphincters (not innervated, but respond to local vasoconstrictors; when dilated RBC can pass in single file in thimble shape)
Arteries: 0.4cm diameter, 1mm wall thickness, 20cm2 cross-sectional area, 8% blood
Outer layer adventitia (CT), middle layer media (SM), inner layer intima (endothelium – secretes
growth regulators, vasoactive substances - and CT)
Large amount elastic tissue in inner and outer layers ( recoil during diastole
Resistance vessels: principle site of PVR
Arterioles: 30μm diameter, 20μm wall thickness, 400cm2 cross-sectional area, 1% blood
Less elastic tissue, more SM
Major site of PVR
2% blood in aorta
Capillaries: 5μm diameter at arterial end, 9μm diameter at venous end, 1μm wall thickness (single layer of
endothelial cells); 4500m2 cross-sectional area, 5% blood; typical p is 32mmHg at arteriolar
end, 15mmHg at venous end; pulse p 5mmHg at arteriolar end, 0 at venous end; blood travels
at 0.07cm/s; transit time is 1-2secs; 24L fluid filtered per day
Junctions between cells permit passage of molecules oncotic p), into capillary at venous end
(oncotic p > filtration)
If fluid reaches equilibrium in tissue diffn can be increased by incr flow (flow-limited)
If doesn’t, diffn is diffusion-limited
Pericytes: outside endothelial cells; long contractile processes wrap around vessels and react to
local vasoactive agents to regulate flow esp in inflamm
In resting tissues, most capillaries collapsed and bypassed via thoroughfare vessels; in active
tissues metarterioles and precapillary sphincters dilate
Noxious stimulus ( release of substance P, bradykinin and histamine ( incr cap permeability
AV anastomoses (shunts): in fingers, palms, earlobes; have thick, muscular walls; abundant innervation
Venules: 20μm diameter; 2μm wall thickness; 4000cm2 cross sectional area
Veins: 0.5cm diameter; 0.5mm wall thickness (thin and easily distended); 40cm2 cross sectional area;
pressure 12-18mmHg (5mmHg in gt veins; 4.6mmHg is CVP as enters RA); affected by gravity;
velocity incr as blood enters larger veins
Little SM but capable of much venoconstriction from noradrenergic nerves and circulating vasoC
Intima folded to form venous valves (not in small veins, great veins, brain, viscera)
Capacitance vessels: can ake large amount of blood before incr venous p
Flow encouraged by negative intrathoracic p on inspiration (falls to -6 from -2.5mmHg ( decr CVP
to 2 from 6mmHg ( aids VR; also diaphragm produces +ive intraabdo p ( pushes blood into
thorax) and muscle pump
Muscle pump, also pulsations of arteries near veins
Gravity causes pooling ( decr CO
Veins above heart collapse, but dural sinuses don’t as rigid walls so have p that is subatmospheric
Veins and venules contain 54% blood
12% blood in heart cavities
Veins + pul circ + RA, LA, RV = low pressure system
LV + arterial system = high pressure system
Smooth muscle: contains Ca, K and Cl channels; contraction by myosin light-chain and latch-bridge mechanism
Influx of Ca through voltage-gated channels
( incr cytosolic Ca ( contraction
( Ca release from SR via ryanodine receptors ( Ca sparks ( incr activity of Ca-activated K
channels (big K/BK channels) ( incr K effluex ( incr MP ( closed voltage gated Ca
channels ( relaxation; important in control of vascular tone
Angiogenesis: in embryo development network of leaky capillaries formed from angioblasts (vasculogenesis) ( vessels hook up with capillaries which give then SM ( maturation; vascular endothelial GF (VEGF) important, also involved in lymphangiogenesis
Blood Flow
Flow = Effective perfusion pressure / Resistance
Flow = vol per unit time (cm3/s)
Flow and resistance markedly affected by small changes in caliber of vessels
Flow x2 by 19% incr radius
Laminar flow: infinitely thin layer of blood in contact with wall doesn’t move
next layer has low velocity
flow fastest in centre of stream
Occurs up to critical velocity – higher than this causes turbulent flow; probability of this related to diameter of vessel (more turbulent with smaller diameter) and viscosity of blood (more turbulent with decr viscosity eg. anaemia)
Measuring blood flow: electromagnetic flow metres, Doppler flow metres, adaptations of Fick and indicator dilution techniques, plethysmography
Shear Stress: flow blood creates force on endothelium that is parallel to long axis of vessel; change in shear stress ( change in genes in endothelial cells related to CV function ( produce integrins, GF’s etc…
Shear stress (γ) = viscosity (η) X shear rate (rate at which velocity increases from vessel wall
toward lumen)
Windkessel effect: recoil during diastole of stretched vessels during systole (ie. elastic) ( forward flow
Air embolism: forward movement of blood depends on blood being incompressible; air compressible so if enters heart can stop heart; bubbles lodge in small vessels and markedly incr resistance to flow
Effective perfusion p = mean intraluminal p @ arterial end – mean p @ venous end
Pulse pressure = systolic – diastolic p = normal is 50mmHg; incr with incr age
Mean pressure = diastolic p + 1/3 pulse pressure; av p throughout cardiac cycle; systole shorter than diastole so slightly less
Critical closing pressure: when p in small BV decreased to < tissue p ( no blood flows and vessel collapses (even tho p is not 0)
Pressure falls rapidly in small arteries/arterioles as high resistance to flow; p at arterioles 30-38mmHg (pulse p 5mmHg)
Pressure incr below heart level, decr above heart level
Resistance (in R units) = pressure (mmHg) / flow (ml/s)
Also determined by radius of BV’s (vascular hindrance), viscosity of blood (plasma 1.8x more viscous than water, blood 3-4x more viscous than water depending on hematocrit; hematocrit has greater effect on viscosity in larger vessels due to difference of nature of flow in small vessels; must be v large incr viscosity to have effevt on PVR; decr viscosity incr blood flow)
Velocity = displacement per unit time (cm/s)
= flow / area of conduit
Average velocity: incr area ( incr velocity; high in aorta, decr in arteries, incr in veins, high in IVC (but lower than aorta); measure by injecting bile salt in arm and measuring time til bitter taste; ave arm-to-tongue circulation time = 15secs
Mean velocity in prox portion of aorta = 40cm/s (from –ive value in diastole to 120 during systole)
Law of Laplace: tension in wall = (transmural p x radius of vessel) / wall thickness
Transmural p = pressure inside – pressure outside
Protects small diameter vessels from rupture – the smaller then vessel the lower the tension needed to balance transmural p; in dilated heart large radius, so greater tension must be developed to produce any given pressure ( dilated heart must do more work
Measuring BP
Auscultatory method: using Riva-Rocci cuff attached to sphygmomanometer; use sounds of Korotkoff; in hyperthyroidism, children, aortic insufficiency and after exercise diastolic is sound when muffles, not disappears; constriction causes critical velocity to be exceeded; tapping due to turbulent flow at peak of systole which is staccato; then as approached diastolic turbulent flow becomes more continuous so becomes muffled; artificially high in fat people as some cuff pressure dissipated so use wider cuff; if left inflated too long reflex vasoC falsly incr BP; auscultatory gap when sound disappear above diastolic then return, may accidentally get low BP
Palpation method: 2-5mmHg lower than auscultatory method
Lymphatics Normal flow in 24hrs = 2-4L; return protein to blood
Capillary efflux > influx ( extra fluid enters lymphatics (prevents incr IFp) ( enter R and L subclavian veins at junction with IJV; contain valves; regular LN’s; no fenestrations, little basal lamina, open junction between endothelial cells with no tight intercellular connections
2 types: initial lymphatics: no valves or SM; found in intestine and skeletal muscle; fluid enters through
loose junctions between endothelial cells. Drain into…
collecting lymphatics: have valves and SM which have peristalsis, aided by skeletal muscle pump,
negative intrathoracic p during insp, high velocity blood flow in veins in which lymph terminates
Lymphagogues: incr lymph flow
Incr interstitial fluid vol and oedema:
Incr filtration p – arteriolar dilatation
venular constriction
incr venous p (CCF, incompetent valves, venous obstruction, incr total ECF vol
due to salt and water retention (eg. cirrhosis, nephrosis), gravity)
Decr osmotic p gradient across capillary – decr plasma protein level (eg. cirrhosis, nephrosis)
accum of osmotically active substance in interstitial
space
Incr cap permeability – substance O, histamine, kinins etc…
Also depends on: capillary p, IFp, capillary filtration coefficient, no. active capillaries, lymph flow, ratio of precap to postcp venular resistance (precap constriction lower filtration p, postcap incr)
In active tissues ( incr cap pressure ( osmotically active particles can’t enter capillaries as osmotic p overcome ( accumulation ( affect osmotic gradient so fluid leaves capillaries ( incr lymph flow, but still incr vol in muscles
Lymphoedema: high protein content lymph fluid accumulates ( chronic inflamm condition ( fibrosis of interstitial tissue ( elephantitis
Cardiovascular Regulatory Mechanisms
Central Control
BP controlled by vasomotor centre in MO
Excitatory: CO2, hypoxia
cortex via hypoT (emotion, sexual excitement)
pain pathways via reticular formation and exercising muscles (pressor response to stim of
somatic afferent nerves is somtatosympathetic reflex)
carotid and aortic (in carotid and aortic bodies) chemoreceptors – discharge causes production
of Mayer waves (slow regular oscillations in arterial p); carotid body ( glossopharyngeal,
aortic body ( vagus
stimulation ( vasoC and bradycardia
however hypoxia ( inc RR, incr E+NE release from adrenal medulla ( incr HR, BP,
CO
hypercapnia ( stimulates vasomotor area but CO2 is vasoD so no vasoC
incr ICP ( compromised blood supply to vasomotor centre ( local hypoxia and
hypercapnia ( incr discharge ( Cushing reflex ( incr BP, decr HR (due to
baroreceptor reflex)
Inhibitory: cortex via hypoT
inflation of lungs
carotid (small dilation of ICA just above bifurcation of CCA, in carotid sinus) + aortic (in wall
of AoA in aortic arch, monitor arterial circ) and cardiopul (in walls of atria – type A discharges
mainly during A systole, type B mainly late in diastole during peak A filling; type B discharge
incr when VR incr) baroreceptors resembling Golgi tendon organs located in adventitia of
vessels – stimulated by distension ( incr discharge r ( afferent fibres via glossophargyngeal
(for carotid) and vagus (for aortic) nerves (buffer nerves) to MO ( nucleus of tractus
solitarius ( secrete glutamate to stimulated GABA-secreting inhibitory neurons and vagal
motor neurons
( incr PNS, decr SNS ( vasoD, decr BP, decr HR, decr CO, incr renin (retain H20); reach max discharge at 150mmHg but linear increase with BP til then; respond to sustained p, change in p and pulse p
( incr release of vasopressin
In chronic incr BP ‘reset’ to maintain incr BP
Bainbridge reflex: rapid infusion of blood/saline ( incr HR if initial HR slow
Coronary chemoreflex / Bezold-Jarisch reflex: injections of serotonin/veratridine/capsaicin into CA supplying LV cause apnea followed by rapid breathing, hypotension and bradycardia
Pulmonary chemoreflex: injections of drugs into PA cause same effect
Valsalva manouvre: incr BP due to incr intrathoracic p added to p of blood in aorta ( decr BP as incr intrathoracic p causes decr VR and CO ( decr pp and MAP ( inhibit baroreceptors ( incr HR and PVR ( stop manouvre ( CO restored but still incr PVR so incr BP ( stimulate baroreceptors ( decr HR; will fail to show these responses in autonomic insufficiency; still have responses in sympathectomy as still have vagal tone intact
LV stretch receptors may play a role in vagal tone
SNS ( cell bodies in rostral ventrolateral medulla ( sym preganglionic neurons in interomediolateral gray column of SC ( secrete excitatory NT glutamate
PNS ( dorsal motor nucleus of vagus and nucleus ambiguous
Mechanisms for Regulation
1) Alter output of heart
SNS ( +ive chonotropic effect and inotropic effect; inhibit vagal stimulation; mod sym tone (tonic discharge)
PNS ( -ive chonotropic effect; high vagal tone (tonic discharge)
2) Change diameter of resistance vessels:
1) Autoregulation: compensate for changes in perfusion pressure; esp good in kidneys
Intrinsic contractile response of SM to stretch (myogenic theory of autoregulation)
Law of Laplace: wall tension proportionate to distending p X radius of vessel
2) Locally produced vasoD metabolites – accumulate in active tissues (metabolic theory of autoreg); decr blood flow (decr O2 tension, decr pH, incr CO2 – esp important in skin and brain, incr osmolality) causes accum ( relaxation of arterioles and precapillary sphincters
eg. K (important in skeletal muscle); lactate; adenosine (in cardiac muscle)
3) Substances secretes by endothelium
Serotonin released from platelets in injured arteries ( sticks to vessel wall ( vasoC
Prostacyclin from endothelial cells: inhibits plt aggregation and causes vasoD
Thromboxane A2 from plts: promotes plt aggregation and vasoC
( together localize plt aggregation and clot formation; shifted towards prostacyclin by
aspirin (inhibits COX ( decr TA2 and prostacyclin, but endothelial cells can create new
TA2 in hours but new plts need to be formed in 4 days)
NO (endothelium-derived relaxing factor, EDRF): made from arginine, catalysed by NO synthase
(NOS1 in NS, NOS2 in macrophages and other immune cells, NOS3 in endothelial cells; 1+3
activated by agents that incr intracellular Ca inc Ach and bradykinin; 2 activated by cytokines);
when flow to tissue incr by arteriolar dilation, large arteries to tissue also dilate – mediated by
NO; products of plt aggregation cause NO release to keep blood flow patent; tonic release of
NO needed for normal BP; involved in angiogenesis
( activates guanylyl cyclase ( cGMP ( vasoD
Endothelin-1: made from prohormone big endothelin-1 ( endothelin via endothelin- converting
enzyme; secreted into media of BV’s, act in paracrine fashion; stimulators (AII, NE+E, GF’s,
hypoxia, insulin, HDL, shear stress, thrombin), inhibitors (NO, ANP, PGE2, prostacyclin); incr
circulating conc in CCF and after MI; endothelin-1 in brain, kidneys and endothelial cells;
endothelin-2 in kidneys and intestine; endothelin-3 in blood, brain, kidneys, GI tract; play role in
regulating passage across BBB, decr GFR in kidneys
( G protein coupled receptor ( phospholipase C ( vasoC
Kinins – bradykinin (precursor high-molecular-weight kininogen)
lysylbradykinin (kallidin, can be converted to bradykinin; precursor low-molecular-weight
kininogen)
Act on B1 (pain producing effects) and B2 receptors
Proteases (kallikreins – plasma kallikrein circulates in inactive form, tissue kallikrein located
on apical membranes of cells) release BK and LBK)
Inactive kallikrein (prekallikrein) converted to active form by active factor XII (CF XII and
kallikrein exert +ive feedback; HMWK activates CF XII) both metabolized to inactive
fragments by kininase I and II (which is same as ACE)
( contraction of visceral SM; relax vascular SM via NO; incr capillary
permeability, chemotaxis; responsible for incr blood flow when glands are
secreting products
CO produces by heme, catalysed by HO2 ( vasoD
4) Circulating vasoactive substances:
VasoD: Adrenomedullin (AM) – inhibits aldosterone secretion, incr production NO, inhibit peri SNS
action; found in plasma, tissues, adrenal medulla, kidney, brain
ANP – secreted by heart; antagonizes vasoC substances
VIP, histamine, substance P, E in skeletal muscle and liver
VasoC: vasopressin – causes little change in BP
NE – generalized effect; circulating levels unimportant, more effecting when released from nerves
E – other than skeletal muscle and liver
AII – generalized effect; also causes incr H20 intake and stimulates aldosterone secretion
Urotensin-II – in cardiac and vascular tissue, very potent
AVP, Na-K ATPase inhibitor, neuropeptide Y
5) Nerves: resistance vessels more densely innervated than capacitance (except splanchnic)
Noradrenergic ( vasoC (resistance and capacitance not necessarily the same), all over body; have tonic activity (lack of activity ( vasoD); may also contain neuropeptide Y
Sympathetic vasodilator system: cholinergic sym vasoD fibres of which postganglionic neurons to BV’s in skeletal muscle secrete Ach ( vasoD in skeletal muscle to run through thoroughfare channels
Cholingergic ( vasoD; in skeletal muscel, heart, lungs, kidneys, uterus; travel with sym fibres; no tonic activity; may also contain VIP
Form plexus on adventitia of arterioles ( fibres extend to media and end on outer surface of SM ( transmitters diffuse into media and current spreads through gap junctions
NB. Afferent impulses from sensory nerves in skin relayed down branches to blood vessels ( release substance P ( vasoD and incr cap permeability (axon reflex)
6) Incr temp in active tissues ( vasoD
3) Alter amount of blood pooled in capacitance vessels: circulating vasoactive substances, nerves
Venocontriction ( incr VR ( shift blood to arterial side of circulation
Circulation Through Special Regions
Fick principle: blood flow of organ = amount of substance removed from blood stream by organ in unit time / (conc of substance in arterial blood) – (conc substance in venous blood)
Cerebral Circulation Ave blood flow is 54ml/100g/min
(756ml/min to brain; 69ml/100g/min to gray matter, 28 to white matter)
In carotids more important than vertebrals; little crossing over from contralateral side, anastomotic channels don’t permit much flow and insufficient to prevent infarction; capillaries surrounded by endfeet of astrocytes close to basal lamina with gaps of 20nm between endfeet; total blood flow remains relatively constant – autoregulation important and keeps arterial p at 65-140mmHg
Kety method: uses Fick principle using inhaled N2O; measures flow to perfused areas of brain only, gives ave blood flow to brain
Measuring blood flow to specific parts of brain: use position emission tomography (2-deoxyglucose uptake is good indication of blood flow; can measure concs of dopamine etc…); MRI can image amount of blood in area
Awake: blood in premotor and frontal regions
Sequential movements: blood in supplementary motor area
Creative speech: Broca’s and Wernicke’s area
Problem solving, reasoning, motor ideation without movement: premotor and frontal cortex
R handed – verbal task ( L hemisphere, spatial task ( R hemisphere
Alzheimers: decr blood to sup parietal cortex, then temporal then frontal
Huntington’s: decr blood to caudate nucleus
Manic depression: decr blood to cortex when depressed
Schizophrenia: decr blood to frontal and temporal lobes and basal ganlgia
Innervation: postganglionic sym neurons (cell bodies in sup cervical ganglia) ( NE, neuropeptide Y; end
on large arteries
cholinergic neurons (from sphenopalatine ganglia) ( Ach, VIP; end on large arteries
sensory nerves (cell bodies in trigeminal ganglia) ( substance P, neurokinin A, CGRP; end
on more distal arteries
Incr BP ( incr noradrenergic discharge ( decr the incr in blood flow and protects BBB; so has
effect on autoregulation and p-flow curve shifted to R (greater incr p can occur without incr
flow)
Choroid plexus: choroid epithelial cells connected by tight junctions
CSF: CSF vol 150ml, produce 550ml/day, turnover 3.7x per day; lumbar CSFp 70-180mm (112 ave); formation independent of IVp, but absorption is proportionate to IVp (and stops aortic p
@ birth: incr PVR, gasps causing negative intrathoracic p causing expansion of lungs ( aortic p > pul art p (decr to 20% of in utero p) ( incr p in LA ( PFO closes ( PDA constricts within hours thought to be due to arterial O2 tension
Fetal respiration: fetal cells have greater affinity for O2 (HbF) than maternal cells (HbA); fetus has good resistance to hypoxia
Cardiovascular Homeostasis in Health and Disease
Gravity Effects greater when decr blood vol
Postural hypotension in sympatholytic drugs, diabetes/syphilis damaging SNS, 1Y autonomic failure, abnormal baroreceptor reflexes in 1Y hyperaldosteronism
In feet: MAP = 180-200mmHg, venous p = 85-90mmHg; if don’t move 300-500ml pool in capacitance vessels of legs ( oedema, decr SV
In head: MAP = 60-75mmHg, venous p = 0
Stand up ( decr BP in baroreceptors ( incr HR, maintain CO; incr renin and aldosterone;
arteriole constrict
( MAP in head drops by 20-40mmHg, JVP drops 5-8mmHg so less drop in perfusion p
(MAP-VP); ICp decr so less vascular resistance as less p on cerebral vessels
( more O2 taken from each unit of blood
( muscle pump needed on prolonged standing to maintain VR
Blood flow decr by only 20% on standing; effects multiplied by acceleration
0 gravity ( atrophy of mechanisms that usually maintain normal CO ( postural hypotension
Space motion sickness: headward shift of body fluids ( loss of plasma vol, diuresis; loss of muscle mass and bone minerals (incr Ca excretion), loss of red cell mass, altered plasma lymphocytes
Exercise Resting skeletal muscle blood flow = 2-4ml/100g/min
Contraction ( compression of blood vessels if >10% tension; total stop of blood flow if >70% tension; however between contraction massive incr blood flow so overall 30x more; impulses in sym vasoD system and decr SNS tonicity may be involved
Local mechanisms:
Hypoxia, hypercapnia, accum of K (esp important in early exercise) and vasoD metabolites, incr T ( dilation of arterioles and precapillary sphincters (10-100x incr in open capillaries)
( incr area of vascular bed, decr velocity of flow, incr cap p > oncotic p, accum of osmotically
active metabolites faster than can be taken away decr osmotic grad across cap walls ( fluid
transudation into ISF and incr lymph flow
Decr pH and incr T ( shift dissociation curve of Hb to R ( more O2 given up from blood
Incr 2,3-DPG ( decr affinity of Hb for O2
Anaerobic metabolism: uses glu; muscle incurs O2 debt
Systemic mechanisms:
Isometric muscle contraction ( incr HR and BP due to decr vagal tone (little change in SV); likely due to psychic stimuli acting on MO; decr blood flow to muscles due to compression of BV’s
Isotonic muscle contraction ( incr HR (max HR decr with age, in adults rarely >195) and SV and CO, decr PVR due to vasoD in exercising muscles; only mod incr in SBP, unchanged or decr DBP; incr VR due to muscle and thoracic pump, mobilization of blood from viscera (may incr arterial blood by 30%), incr p from dilated arterioles on veins, venoconstriction; after exercise BP may become subnormal due to continued local vasoD
Temp regulation: lost through skin, resp, vaporization of sweat, dilation of cut vessels (inhibition of SNS tone)
Trained athletes: decr HR, incr SV, incr max O2 consumption possible (related to max CO and max O2 extraction by tissues), incr mitochondria, enzymes, capillaries in skeletal muscle ( less lactate production; improved production of NO and prostracyclin by CA’s
Inflamm
Inflammation: localized response to foreign substances; involves cytokines, neutrophils, adhesion molecules, complement, IgG, PAF, monocytes, lymphocytes; arterioles dilate, cap incr permeability; nuclear factor-κB plays important role (cytokines/viruses/oxidants activate it ( binds DNA ( icnr production and secretion of inflammatory mediators; activation inhibited by glucocorticoids)
Systemic response: cytokines ( acute phase proteins (proteins in which levels change by 25% following injury) eg. CRP, serum amyloid A, haptoglobin, fibrinogen, albumin, transferring
Wound healing
Tissue damage ( plts adhere to exposed matrix via integrins that bind collagen and laminin
( plt aggregation and granule release encouraged by thrombin
( granules ( inflamm response
( selectins attract WBC
( bind to integrins on endothelial cells ( extravasation through BV walls
( WCC and plt release cytokines
( up-regulate intergrins on macrophages ( migrate to injury
fibroblasts and epithelial cells ( mediate wound healing
and scar formation
( plasmin removes excess fibrin
( aids migration of keratinocytes into wound to restore epithelium under scab
( collagen proliferation ( scar
Shock Inadequate tissue perfusion and CO
Hypovolaemic shock: inadequate fluid; haemorrhage, trauma (may get rhabdo, accum of myoglobin in kidneys clogging tubules), surgery, burns (more plasma loss so haemoconcentration; haemolytic anaemia, inc BMR), vomiting, diarrhoea
Effects: Decr VR ( decr CO (if mod pp decr but MAP normal) and inadequate perfusion (
anaerobic metabolism ( lactic acidosis ( depress myocardium and peri vascular responsiveness
to NE+E
Loss of RBC ( decr O2 carrying capacity
( low BP, incr HR, thready pulse, cold pale clammy skin, thirst, incr RR
Compensatory mechanisms:
1) Baroreceptors less stretched ( incr SNS
( incr HR
vasoC (spare brain and heart; marked in skin, kidneys (afferent leaving lung as more O2 enters than CO2 leaves
Can’t measure with spirometer:
Total lung capacity =
Residual vol (gas still in lung after max expiration)
Functional residual vol (gas still in lung after normal expiration)
1) Gas dilution technique: breath helium (due to low solubility in blood) from spirometer which equilibrates in lungs without any lost; measures only communicating gas
1 = in machine; 2 = in lung
Amount before equilibration of helium = C1 x V1 Amount helium after equilibration = C2 x (V1 +V2)
Amount of helium is unchanged so C1 x V1 = C2 x (V1 + V2)
( V2 = V1 x (C1 – C2)
C2
2) Body plethysmograph: sit in box; breath out ( shutter closes ( try to breath in by increasing vol of lung ( incr p in box; measures all gas in lung inc that in closed airways that doesn’t communicate with mouth; in diseased lungs there is big difference
Boyles law: PV=K at constant pressure
P 1 and 2 = pressure in box before and after insp effort; V = vol in box
P3 and 4 = pressure in mouth before and after insp effort; V2 = FRC
P1 x V1 = P2 x (V1 – ΔV)
P3 x V2 = P4 x (V2 – ΔV)
Blood vessels:
R heart ( pul art ( capillaries ( pul vein; low resistance; initially art, vein and bronchus run together but in periphery veins pass between lobules, but bronchi and art travel together down centre of lobules ( dense capillary network (diameter 10μm) in walls of alveoli; each RBC spends 3-4secs in cap network transversing 2-3 alveoli – complete equilibrium occurs in this time; capillaries easily damaged (eg. high cap p, high lung vol) ( leak plasma and RBC into alveolar spaces
Conducting system blood supply comes from bronchial circ; v small blood flow compared to above
Pul cap blood = 70ml
Pul blood flow = 5000ml/min
Diffusion
Diffusion determined by Fick’s law:
Rate of diffusion through tissue slice proportional to area (50-100m2)
inversely proportional to thickness (0.3μm in places)
Diffusion rate proportional to partial pressure difference between 2 sides
proportional to solubility of gas in blood-gas barrier
inversely proportional to square root of molecular weight
Diffusion limited (eg. CO): RBC enters capillary ( CO moves from alveolar gas into RBC rapidly ( CO binds with Hb so little incr in partial pressure so CO can continue to enter RBC’s; not limited by amount of blood available but diffusion properties of blood-gas barrier
Diffusing capacity CO depends on area and thickness of blood-gas barrier
vol of blood in pul capillaries
alveolar vol
Reaction rate of CO can be altered by high alveolar pO2 as they compete for Hb
Perfusion limited (eg. NO): no combination with Hb ( incr pp after RBC has travelled only 1/10 along capillary so no further NO transferred; depends on blood flow and not properties of blood-gas barrier
For O2: pO2 in RBC entering capillary = 40mmHg
pO2 in alveoli = 100mmHg so passes into RBC; capillary pO2 reaches alveolar pO2 1/3
of way along capillary then transfer becomes PERFUSION LIMITED ( little diff between alveolar gas and end-capillary blood
O2 combines with Hb in 0.2s (less avidily than CO) ( some raise in pp, delaying loading of O2 into RBC so increasing ‘overall diffusion distance’
Resistance of uptake of O2 due to reaction rate = resistance due to blood-gas barrier
For CO2: diffusion 20x faster than O2 as has higher solubility, but can still be diff between end-capillary blood and alveolar gas in diseased lung
DM = diffusion membrane
θ = rate of reaction of Hb with O2 (in ml per minute of O2 = diffusion capacity of 1ml of blood
VC = vol of capillary blood
1/DL = 1/DM (resistance of blood-gas barrier) + 1/(θ x VC = effective ‘diffusing capacity’ of rate of reaction of Hb with O2
Challenges:
Exercise ( incr pul blood flow ( RBC usually spends 0.75s in capillary, but decr to 0.25s ( less time available for oxygenation, but no fall in end-capillary pO2 in normal people
If tissue slice thickened ( poor diffusion ( doesn’t equilibrate fully even by end of capillary (diffusion limited) ( diff between alveolar gas and end-capillary blood
Lower alvolar pO2 (eg. high altitude) ( decr pp diff so O2 moves more slowly ( fails to reach alveolar pO2
Measuring diffusing capacity: Normal = 25ml/min-1/mmHg-1
ie. vol CO transferred per min per mmHg of alveolar pp
CO used as uptake is diffusion-limited; note as p capillary blood slow low, can usually be ignored
Vgas (amount gas transferred) = DL (diffusing capacity of lung) x (p alveolar gas – p capillary blood)
Single breath of CO ( rate of disappearance of CO from alveolar gas during 10sec breathhold calculated by measuring expired CO; incr by 2-3x on exercise
Blood Flow and Metabolism
RV ( main PA (walls thin with little SM so work of R heart as small as possible)
( branches accompany airways as far as terminal bronchioles
( capillary bed around alveolar wall (variable pressure, most p drop occurs here)
( pul veins running between lobules
( 4 large pul veins
( LA
Pul capillaries (alveolar vessels): surrounded by gas in alveoli so collapse/distend depending on alvolear p; pressure around caps decr by surface tension of surfactant; diff between p inside and outside capillaries = transmural p
Pul arts and veins (extraalveolar vessels): less p surrounding them; as lung expands, pulled open by parenchyma – dependent on lung vol
V large vessels are outside lung substance and dependent on intrapleural p
Pul Vascular Resistance
Vascular resistance = input p – output p
blood flow
Main PA = 15mmHg LA = 5mmHg Difference = 10mmHg (Pul circ)
Pul blood flow = 6L/min
Vascular resistance = (15-5)/6 = 1.7mmHg/L-1/min (low as just for distribution)
Any incr pul art/venous p ( pul vascular resistance falls (ie. on exercise)
Due to recruitment: spare capillaries which under normal conditions are closed/open with
no flow, as p rises they begin to conduct; important when high arterial p
distension: widening of capillary segments; important when high vascular p
Inc resistance at low vol (Extra-alveolar vessels have high resistance when lung vol low causing
high critical opening pressure for pul art ( regional change in blood
flow starting at base where parenchyma less expanded)
high vol (Alveolar vessels – if alveolar p incr compared to capillary p ( incr
resistance (eg. on deep inspiration; calibre of capillaries decr at large
lung vol due to stretching of alveolar walls ( incr resistance)
Incr resistance if hypoxia as causes constriction of small pul arteries
Drugs that cause incr resistance = serotonin, histamine, NE; esp effective when decr lung vol as
affect extra-alveolar vessels
Drugs that decr resistance = Ach, isoproterenol
Aorta = 100mmHg RA = 2mmHg Difference = 98mmHg (Systemic circ)
Higher resistance due to muscular arterioles
Measuring Pul Blood Flow
Using Fick Principle: O2 consumption per minute = amount of O2 taken up by blood in lungs per minute
VO2 = O2 consumption per minute (collect expired gas in spirometer)
Q = vol of blood passing through lungs each minute
CaO2 = O2 content in blood leaving lungs (arterial, via ABG)
CVO2 = O2 content in blood entering lungs (pul art, via catheter)
VO2 = Q (CaO2 – CVO2) ( Q = VO2
CaO2 – CVO2
Passive Distribution of Blood Flow
In human upright lung blood flow lower at apices – in zone 1 alveolar p > cap p ( no flow if decr arterial p (eg. severe haemorrhage) or incr alveolar p (eg. PPV). Becomes alveolar dead space as is ventilated but not perfused.
Zone 2: below apices; sufficient arterial p but low venous p; blood flow determined by diff between arterial and alveolar p as opposed to the normal arterial/venous p difference (Starling resistor / waterfall effect – when chamber p greater than downstream p, downstream p has no effect on flow so venous p has no effect here)
Zone 3: venous p > alveolar p so flow determined by arterial/venous p difference; incr blood flow in this region of lung due to distension of capillaries; transmural p difference increases the further down lung you go as cap p incr but alveolar p is same throughout lung
Zone 4: region where get decr blood flow at low lung vols due to narrowing of extra-alveolar vessels
Affected by posture (lying increases flow to apices, but doesn’t affect basal flow; incr post flow, decr ant flow) and exercise (upper and lower blood flow increases)
Active Control of Circulation
Decr pO2 alveolar gas ( hypoxic pulmonary vasoconstriction (contraction in hypoxic region; doesn’t need CNS ?due to release of vasoC substance by perivascular tissue ?due to inhibitors of NO ?causes inhibition fo voltage-gated K channels ( membrane depolarisation ( incr Ca channels in cytoplasm ( SM contraction; changes more marked when alveolar pO2 2000 (wide tube, high velocity) (less likely if low-density gas (eg. helium))
Re = 2rvd (radius, velocity, density)
n (viscosity)
Entrance conditions to tube important: if eddy formation occurs at branch point, disturbance will be carried downstream; laminar flow likely to only occur in small terminal bronchioles; in most of tree, flow is transitional; turbulence occurs in trachea
Low flow rate: laminar flow; driving p is proportionate to flow rate (P=KV); Note that radius is more important to resistance than length
In circular tubes: vol flow rate (V) = driving p (P) x π x r4
8 x viscosity (n) x length (l)
Flow resistance = driving p / flow
…so R = 8nl
πr4
High flow rate: formation of eddies, or even turbulence; has different properties as driving p is proportionate to square of flow r (P=KV2); viscosity of gas less important, but density more important
Pressures During Breathing Cycle
[pic]
Airway Resistance
Major site of resistance is medium-sized bronchi; 8nm size; decr for anionic substances, incr for cationic substances; albumin is negatively charged (anion), albuminuria due to nephritis due to loss of negative charges in glomerular wall which usually decreases filtration of albumin
Hydrostatic and osmotic p gradients across capillary wall – high p in glomerular capillaries as efferent vessels have high resistance; osmotic p gradient is usually negligible; net filtration p is 15mmg at afferent end ( drops to 0 at efferent end as equilibrium reached (uncertain whether this is reached in humans); exchange across capillaries is flow-limited rather than diffusion limited, some portions of capillaries don’t participate
Kf = glomerular ultrafiltration coefficient (product of glomerular capillary wall permeability and filtration surface area)
Pgc = mean hydrostatic p in glomerular capillaries
Pt = mean hydrostatic p in tubule
Ogc = osmotic pressure of plasma in glomerular capillaries
Ot = osmotic pressure of plasma in tubule
GFR = Kf [(Pgc - Pt) – (Ogc – Ot)]
Filtration fraction: ratio of GFR to renal plasma flow; normally 0.16-0.2; when decr systemic BP ( GFR falls less than RPF ( incr filtration fraction
Tubular Function:
Amount excreted per unit time = amount filtered + net amount transferred by tubules
Clearance = GFR if no net tubular secretion/reabsorption
> GFR if net secretion
< GFR if net reabsorption
Reabsorption/secretion may occur by:
Endocytosis
Paracellular diffusion: through tight junctions
Passive diffusion, facilitated diffusion, ion channels, exchangers, cotransporters, pumps
AT systems have a transport maximum (max rate) at which they can transport solute – at higher concs becomes saturated
Lymphatics: abundant supply ( thoracic duct
Renal capsule: thin but tough; limits swelling ( incr renal interstitial pressure ( decr glomerular filtration
Arterioles and glomeruli secrete PGI2 (prostacyclin)
In interstitium in medulla are type I medullary interstitial cells – secrete PGE2
Reabsorption in Specific Areas
PCT: AT of solutes (60-70%)
H20 passively out (60-70%) along osmotic gradient via aquaporin-1 ( isotonicity maintained
Na reabsorption (60%): Na-H exchange in PCT ( AT into interstitial space or lateral intercellular
spaces via Na-K ATPase (3Na, 2K)
Glu reabsorption: mostly reabsorbed in PCT; glu and Na bind carrier SGLT2 in luminal
membrane (Na moves down gradient taking glu with it) ( Na pumped into interstitium,
glu via GLUT2 (usually binds d isomer)
aa reabsorption: Cotransport with Na in luminal membrane ( Na pumped out by Na-K ATPase,
aa via passive/facilitated diffusion
NB. Glu reabsorption: amount reabsorbed proportionate to (plasma glu level x GFR) up to transport maximum; filtered at approx 100mg/min; Renal threshold is level at which glu first appears in urine = 180mg/dl venous level (this is lower than expected as reabsorption splays from ideal curve as renal threshold not same in all tubules)
LOH: fluid in ding LOH becomes hypertonic as H20 passes out ( becomes more dilute as moves up
aing LOH as H20 trapped ( hypotonic to plasma at top; Bartter’s syndrome due to defective transport in aing LOH ( Na loss ( hypovolaemia ( stimulation of RAA ( hypertension, hyperkalaemia, alkalosis
H20 reabsorption: 15% filtered water reabsorbed; ding limb permeable to H20; aing limb
impermeable to H20
Na reabsorption (30%): Na-2Cl-K cotransporter in thick aing LOH ( AT into interstitium by Na-
K ATPase
K reabsoprtion: Na-2Cl-K cotransporter in thick aing LOH ( K diffuses back into tubular lumen
or back into interstitium via ROMK
Cl reabsorption: Na-2Cl-K cotransporter in thick aing LOH ( Cl enters interstitium via CIC-Kb
channels
Diuretics: loop (eg. frusemide, ethacrynic acid, bumetanide) inhibit Na-K-2Cl cotransporter (
natiuresis and kaliuresis
DCT: relatively impermeable to H20; continued removal of solutes further dilutes urine
H20 reabsorption: 5% filtered water reabsorbed
Na (7%) and Cl reabsorption: Na-Cl cotransporter in DCT
Diuretics: metolazone, thiazides (eg. chlorothiazide) inhibit Na-Cl cotransporter
CD’s: Na reabsorption (3%): ENaC channels in CD (regulated by aldosterone)
H20 reabsorption (10% in cortex, 4.7% in medulla): depends on vasopressin (ADH from PPG
which acts on V2 receptor ( cAMP and PKA ( incr permeability to H20 due to
insertion of aquaporin-2 into apical membranes of cells from vesicles stored in cytoplasm of principal cells) ( H20 moves out of hypotonic CD ( cortical interstitium
When ADH absent, CD relatively impermeable to H20 so urine stays hypotonic – but 2% H20 can be reabsorbed in absence of ADH
Diuretics: H20 inhibits ADH secretion
ETOH inhibits ADH secretion
V2 antagonists inhibits action of ADH on CD
K-sparing (eg. spironolactone, triamterene, amiloride) inhibit Na-K exchange but
inhibiting aldosterone (spironolactone) or ENaCs (amiloride)
Conc mechanism dependent of maintenance of gradient of incr osmolality along medullary pyramids ( maintained by countercurrent mechanism of LOH and vasa recta (dependent on AT of Na and Cl out of aing limb and high permeability of ding limb to H20, inflow through PCT and outflow through DCT) – see pics; this is greater in longer (JM) nephrons; osmotic gradient and hypertonicity of interstitium maintained by vasa recta countercurrent mechanism (solutes move out of vessels going towards cortex and into vessel descending into pyramid, H20 into descending vessels and out of ascending vessels ( solutes recirculate in medulla but H20 bypasses it; removes H20 from CD’s
Urea contributes to osmotic gradient in medullary pyramids; urea transporters are facilitated diffusion (UT-A1 – 4)
Magnitude of osmotic gradient increased when decr r of flow in LOH ( urine becomes more concentrated
H20 excretion: 180L filtered/day, at least 87% is reabsorbed; absorption of H20 can be altered without changing solute excretion; aquaporins 1,2,5,9 have been found in humans (9 in WBC, liver, lung spleen; 5 in lacrimal glands
H20 diuresis: normal reabsorption of H20; begins 15mins, peaks 40mins post ingestion; max urine flow is 16ml/min
H20 intoxication: swelling of cells when max urine flow reached
Osmotic diuresis: decr reabsorption of H20; due to unreabsorbed solutes (eg. mannitol; glu when capacity exceeded) in tubules; note that conc grad against which Na can be pumped out of PCT is limited, usually maintained by H20 reabsorption in PCT but this is decreased if there are unreabsorbable solutes in PCT ( decr reabsorption of H20 and Na in LOH (mainly due to decr action of Na-K-2Cl cotransporter in aing LOH ) and CD due to decr medullary hypertonicity
Free water clearance: CH20 is negative when urine is hypertonic, +ive when hypotonic
CH20 = urine flow rate - (urine osmolality) x (urine flow rate)
(plasma osmolality)
Tubuloglomerular feedback: as rate of flow increases through aing LOH and DCT, filtration decreases so constant load delivered to distal tubule; sensor is macula densa (amount of fluid is related to amount of Na and Cl ( Na and Cl enter macula densa cells via Na-K-2Cl cotransporter in apical membranes ( incr Na causes incr Na-K ATPase activity ( incr ATP hydrolysis ( incr adenosine formed ( works via A1 receptors on macula densa cells to incr release of Ca to vascular SM in afferent arterioles ( afferent vasoC ( decr GFR
Glomerulotubular balance: incr GFR causes incr reabsorption of solutes and water in PCT; occurs within seconds; thought to be due to oncotic p of capillaries
Other diuretics: xanthines (eg. theophylline, caffeine) decr tubular reabsorption of Na, incr GFR
acidifying salts (eg. CaCl2, NH4Cl) supply H ( H buffered and Na is replaced with H (
an anion is excreted with Na when this ability is exceeded
CA inhibitors (eg. acetazolamide) decr H secretion ( incr Na and K excretion, depressed
HCO3 reabsorption
NB. Both thiazide and loops cause incr delivery of Na to Na-K exchange area if CD (
incr K excretion
H Secretion in PCT, DCT, CD
PCT: H comes from intracellular dissociation of H2CO3 (formation of this cataylsed by carbonic
anhydrase – drugs that inhibit this enzyme decr secretion of acid in PCT)
1 H secreted via Na-H exchanger (1H out, 1Na in - gradient for Na maintained by Na-K
ATPase)
1 HCO3 reabsorbed via diffusion into interstitial fluid
Buffer: H reacts with HCO3 ( H2CO3 ( CO2 and H20; CA in brush border facilitates this
( CO2 re-enters tubular cells to form more H2CO3
For each mol HCO3 removed from urine in this reaction, 1mol HCO3 enters blood and
hence is reabsorbed
Most H has no effect on pH of urine due to formation of CO2 and H20
DCT H secretion independent of Na
and CD: ATP-driven H pump in intercalated cells (in acidosis, action increased by deposition of
more of these pumps in membranes); increased activity by aldosterone
Also a H-K ATPase
Cl-HCO3 exchanger transports HCO3 into interstitial fluid
Buffer (PCT and DCT): NH3 is lipid soluble and diffuses down conc gradient into interstitial fluid and
urine via nonionic diffusion ( reacts with H ( NH4 which remains in urine
Priniciple reaction producing NH4 in cells is glutamine ( glutamate + NH4 (enzyme
glutaminase); glutamate may ( α-ketoglutarate + NH4 (enzyme glutamic dehydrogenase); α
ketoglutarate metabolized using 2H and freeing 2HCO3
Incr secretion of NH3 and excretion via NH4 in chronic acidosis (adaptation)
Buffer (DCT and CD): H reacts with HPO4 ( H2PO4 as PO4 is highly concentrated here due to
reabsorption of H20
DCT has less ability to secrete H than PCT, but secretion has more effect on pH
Limiting pH of urine is 4.5 (can go from 4.5 – 8.0) – below this secretion stops (ie. in CD’s); buffers important; H cause urinary titratable acidity (amount of alkali that must be added to urine to return pH to 7.4 – this doesn’t account for H2CO3 which has been converted to H20 and CO2)
Secretion limited by changes in:
Intracellular pCO2 (incr pCO2 ( incr H2CO3 available to buffer, H secretion enhanced)
K (decr K ( enhanced H secretion)
CA (CA inhibition ( decr H secretion as less formation of H2CO3)
Aldosterone (incr aldosterone ( incr transport of Na ( incr secretion of H and K)
HCO3 Excretion
HCO3 reabsorption is proportionate to amount filtered over wide range
When high plasma HCO3 ( HCO3 appears in urine, urine becomes alkaline
When low plasma HCO3 ( secreted H no longer used to reabsorb HCO3 ( H must combine with buffers ( acidic urine, with higher NH4 content
Na Excretion
Normally 96-99% filtered Na is reabsorbed; urinary Na output can change a lot depending of diet. Determined by:
1) GFR: affected by tubuloglomerular feedback etc…
2) Reabsorption: governed by
a. Aldosterone (adrenal mineralocorticoid): incr reabsorption Na acting primarily on CD’s by incr number of active ENaC’s; also incr Cl reabsorption and incr K and H secretion; eventually kidneys escape effect of steroid (escape phenomenon) preventing oedema, this phenomenon is absent in nephrosis, cirrhosis, heart failure
b. PGE2: inhibits Na-K ATPase and ENaCs ( excretion of Na
c. Endothelin and IL-1 incr formation of PGE2 ( excretion of Na
d. Ouabain ( inhibits Na-K ATPase ( excretion of Na
e. Angiotensin II ( action of PCT ( incr reabsorption of Na and HCO3
K Excretion
Much is reabsorbed in PCT THEN secreted by DCT and CD (much of K movement is passive, so rate of secretion proportionate to rate of flow); amount secreted equal to K intake; secretion of K in CD related to reabsorption of Na (which is related to excretion of H), so decr K excretion when decr Na reaching distal tubule or when incr H secretion
Renal Disease
( proteinuria – usually albuminaemia ( hypoproteinaemia ( decr oncotic p, decr plasma vol, oedema
( loss of conc and diluting ability ( polyuria/nocturia; in advanced renal disease loss of countercurrent mechanism and loss of functioning nephrons ( nephrons compensate by producing osmotic diuresis ( damages nephron ( oliguria and anuria
( uraemia
( anaemia
( 2Y hyperparathyroidism (due to 1,25-dihydroxycholecalciferol)
( acidosis – urine is maximally acidified and decr renal tubular production of NH4 so decr H secretion
( abnormal Na metabolism – Na retention due to decr filtration (GN) / incr aldosterone (nephrotic syndrome, due to decr plasma proteins ( decr plasma vol due to interstitial oedema ( trigger RAA) / heart failure
The Bladder
Filling: walls of ureters contain SM in spiral, longitudinal and circular bundles; regular peristalsis; oblique passage through bladder wall prevents reflux
Emptying: also spiral, longitudinal and circular (detrusor) muscle; internal urethral sphincter doesn’t encircle; external urethral sphincter is skeletal muscle; intravesical p not raised until bladder well filled (as radius increases; law of Laplace – pressure = 2x wall tension / radius); plasticity – when bladder stretched, tension initially produced not maintained; sharp rise in p as micturition reflex produced – first urge to void felt at 150ml, marked sense of fullness at 400ml
Micturition: contraction of detrusor ( emptying; micturition is sacral spinal reflex (initiated by stretch receptors in bladder wall) initiated at 300-400ml facilitated and inhibited by higher brain centres which alter threshold for voiding reflex; afferent limb of reflex travels in pelvic nerves, paraS efferent limb also travel in pelvic nerves
Facilitatory area – in pontine region
Inhibitory area – in midbrain
Transection above pons ( threshold for voiding lowered
Transection at top of midbrain ( reflex normal
Effect of deafferentation – all reflex contractions stop; bladder becomes distended and hypotonic;
some contraction maintained due to intrinsic response of SM to stretch
Effect of deafferent- and deefferentation – flaccid and distended, but later becomes shrunken with
hypertrophied wall and many contractions due to denervation hypersensitisation
Effect of SC transaction – during spinal shock flaccid and unresponsive ( overfilled with
overflow incontinence ( voiding reflex returns but without voluntary control; voiding reflex
may become hyperactive
Regulation of ECF Volume and Composition
Tonicity Plasma osmolality 280-295mosm/kg
Total blood osmolality α total body Na + total body K / total body H20 ( changes occur when disproportion between amount of electrolytes and amound of H20
Incr osmolalilty ( release of vasopressin and stimulation of thirst
Volume
Determined by amount of osmotically active solute in ECF; Na most important factor
Decr vol ( incr aldosterone, vasopressin, AII (also causes thirst and constricts BV’s); incr vol ( incr ANP and BNP from heart ( natiuresis and diuresis; volume overrides osmotic regulation
Buffers (Henderson-Hasselbach Equation) NB. ANION (-)
If acid is added: eq shifts to L ( levels of ‘buffer anions’ (A-) drop as they react with added H ( less effect on pH
Anions of added acid excreted by renal tubules with a ‘covering’ cation (usually Na) to maintain electrochemical neutrality
2NaHCO3 + H2SO4 ( Na2SO4 + 2H2CO3
Kidney then replaces Na with by H, so reabsorbing Na and HCO3 (effectively reversing the
above)
Na2SO4 + 2H2CO3 ( 2NaHCO3 + 2H+ + SO42-
H+ and SO4 excreted
If base added: eq shifts to R; H ions bind OH, but more H ions released so less effect on pH
Buffering capacity greatest when amount of free anion = amount of undissociated acid (when A/HA = 1 ( log[A][HA] = 0 ( pH = pK); K applies to infinitely diluate solutions in which interionic forces are negligible
HA ( H+ + A- ( [H+] x [A-] = K ( pH = pK + log [A-]
HA [HA]
Regulation of H Conc
Note a decr in pH by 1 unit is a 10-fold incr in H conc; pH of blood is pH of true plasma that has been in equilibrium with RBC (as RBC contain Hb which is an important buffer); normal arterial pH is 7.4 (venous slightly lower; acidosis 7.4)
H load comes from:
Aa metabolism: H load of 50meq/day
Aa in liver for gluconeogenesis ( NH4 + HCO3 ( NH4 incorporated into urea and
protons produced bufferered by HCO3, so little NH4/HCO3 enter circulation
Metabolism of other aa ( H2SO4, H3PO4 (strong acids) ( major H load
CO2 metabolism: usually hydrated to H2CO3 and excreted by lungs/kidneys; H load of 12,500meq/day
Exercise ( lactic acid
Diabetic ketosis ( acetoacetic acid and β-hydroxybutyric acid
Renal failure
Buffers in blood:
Plasma proteins: free carboxyl and amino groups dissociate
HProt ( Prot- + H+
eg. RCOOH ( RCOO- + H+ ( pH = pK(RCOOH) + log [RCOO-]
[RCOOH]
eg. RNH3+ ( RNH2 + H+ ( pH = pK(RNH3+) + log [RNH2]
[RNH3+]
Haemoglobin: dissociation of imidazole groups of histadine residues; also has free carboxyl and amino groups; present in large amounts so 6x buffering capacity of p proteins
HHb ( H+ + Hb –
Carbonic acid – bicarbonate system: first system is difficult to measure as low H2CO3 and low pH; however H2CO3 is in equilibrium with CO2 ( 2nd system (in clinical practice, [CO2] is x by 0.301 as this is solubility coefficient) – this system still has low pK, but is most effective buffer system as amount of dissolved CO2 can be controlled by respiration and HCO3 can be controlled by kidneys
When H added: H2CO3 formed, HCO3 declines; extra H2CO3 converted to CO2 (excreted by lungs effectively as incr H causes incr RR) and H2O so H2CO3 conc doesn’t rise and pH isn’t altered much
NB. CA inhibited by cyanide, azide, sulfide, sulfonamides
1) H2CO3 ( H+ + HCO3- ( pH = pK (3) + log [HCO3]
[H2CO3]
2) H2CO3 ( CO2 + H20 (CA catalyst) ( pH = pK (6.1) + log [HCO3-]
[CO2]
Buffers in interstitial fluid: carbonic acid – bicarbonate system as abov
Buffers in intracellular fluid: proteins as shown above
Also H2PO4 ( H+ + HPO42-
Buffers in CSF and urine: bicarbonate and phosphate systems
Acidotic/Alkalotic States
Resp acidosis: retained CO2 is in equilibrium with H2CO3, which is in equilibrium with HCO3- ( incr HCO3-; most buffering is intracellular; renal compensation
Resp alkalosis: decr pCO2; most buffering is intracellular; renal compensation
Metabolic acidosis: when acids stronger than buffers are added to blood; only 15-20% acid load will be buffered in ECF, the rest dealt with intracellularily; incr H ( incr RR (resp compensation), renal compensation causes excretion of H
Metabolic alkalosis: when alkali added to blood; incr plasma HCO3 and pH; 30-35% OH load buffered intracellularily; resp compensation with decr RR; renal compensation as below
Renal compensation:
HCO3 reabsorption depends on filtered load of HCO3 (affected by GFR and plasma HCO3 level)
rate of H secretion by renal tubular cells (as HCO3 is reabsorbed in
exchange for H) which is α pCO2
In resp acidosis ( incr renal tubular H secretion, incr HCO3 reabsorption ( incr plasma HCO3 ( incr pH
In resp alkalosis ( decr renal H secretion, decr HCO3 reabsorption ( decr plasma HCO3 ( decr pH
In metabolic acidosis ( anions(-) are filtered (each with a cation, Na) in renal tubules ( tubules then secrete H in exchange for 1Na and 1HCO3 ( urinary buffers then tie up H so this can continue; when acid load v large, cations are lost with anions ( diuresis; glutamine synthesis by kidneys increased ( incr supply of NH4 to kidney, can also be converted to α-ketoglutarate which produces HCO3 to help buffer
In metabolic alkalosis (
ABG’s
Can measured pCO2 and pH then calculate HCO3
Venous gas: has pCO2 7-8mmHg higher, pH 0.03-0.04 unit lower, HCO3 2mmol/L lower
Anion gap: difference between conc of cations (+) other than Na and conc of anions (-) other than Cl and HCO3 in plasma. Consists mainly of proteins in anionic form and organic acids
Increased (eg. ketoacidosis, lactic acidosis)
decr plasma conc of K, Ca, Mg
incr conc/charge of/on plasma proteins
incr organic anions in blood (eg. lactate, aspirin)
Decreased: incr cations (+)
decr plasma albumin
Normal (eg. hyperchloraemic acidosis – eg. due to CA inhibitors)
DO LAST BIT WITH SIGGAARD-ANDERSON CURVE NOMOGRAM
METABOLISM
Metabolism: chemical and E transformations occurring in body ( produce CO2 and H20
Catabolism: oxidation liberating small amounts of E
Anabolism: formation of substances taking UP energy
Energy Metabolism
Metabolic Rate: Amount of E liberated per unit time
Amount of energy liberated by catabolism of food in body = amount liberated when food burned outside of body
Energy output = external work + E storage (0 or –ive if fasting) + heat
Efficiency = work done / total E expended (eg. 50% for isotonic muscle contractions)
Factors:
1) Muscular exertion: O2 consumption incr for long time afterwards 2Y to O2 debt
2) Recently ingested food: assimilation of food into body produces specific dynamic action (SDA)
3) Environmental temp: U-shaped; when lower than body, shivering etc…; when higher metabolic processes elevate 14% for every degree elevation; MR @ rest in comfy temp 12-14hrs after last meal = BMR (decr by 10% during sleep, by 40% with prolonged starvation) = 2000kcal/day in normal man
4) Others: height, weight (BMR = 3.52W0.75), sex, age, growth, reproduction, lactation, emotional state, thyroid hormones, E and NE
Calories (gram/small/standard): Amount of heat E needed to raise temp of 1g H20 by 1 degree
1kcal = 1000cal
Calorimetry – burn foodstuffs outside body and measure heat produced
Indirect calorimetry – measure O2 consumption per unit time (as O2 isn’t stored) which is α metabolism
Carbohydrate = 4.1 kcal/g Fat = 9.3 kcal/g Protein = 5.3 kcal/g (in body, incomplete so 4.1)
Respiratory Quotient (RQ): SS vol of C02 produced : vol O2 consumed per unit time
Work out O2 consumed = blood flow per unit time x AV difference between O2 concs
Respiratory Exchange Ratio (R): CO2 : O2 at any given time whether or not equilibrium reached
RQ carbohydrate = 1 (as H and O present in same amount as H20) (RQ brain 0.97-0.99 so primary E source is carbohydrate)
RQ fat = 0.7 (as extra O2 needed for formation of H20)
RQ protein = 0.82
During exercise: incr R as lactic acid converted to C02 during anaerobic glycolysis
Metabolic acidosis: incr R as incr CO2 being expired
Metabolic alkalosis: decr R
Intermediary Metabolism
E stored in high/low-energy phosphate compounds which have bonds between phosphoric acid residues and organic compounds ( released when bond hydrolysed
Eg. ATP (( ADP releasing E, AMP releasing E) – formed by oxidative phosphorylation which
takes up 80% basal E consumption; 27% used for protein synthesis, 24% Na-K ATPase, 9%
gluconeogenesis, 6% Ca ATPase, 5% myosin ATPase, 3% ureagenesis
Eg. Creatine phosphate (phosphorylcreatine, CrP) – found in muscle
Eg. Thioesters (eg. Coenzyme A)
Digestion ( aa, fat derivatives, fructose, galactose, glucose ( absorbed ( metabolized to short-chain fragments (common metabolic pool, intermediates ie. High/low E phosphate compounds)
( carbohydrates, proteins and fats made
( enter citric acid cycle ( hydrolysis ( E and H and CO2 ( H20
Oxidation: combination of a substance with O2 / loss of H / loss of electrons
Catalysed by co-enzymes (organic, non-protein) and co-factors (simple ions) which act as carriers for products of reaction (eg. Accept H)
Eg. Nicotinamide adenine dinucleotide (NAD) ( NADH
Eg. Dihydronicotinamide adenine dinucleotide (NADP) ( NADPH
Eg. Flavin adenine dinucleotide (FAD) ( FADH)
H from NADH and NADPH then transferred to…
Flavo-protein- cytochrome system (in mitochondria) – a chain of enzymes which are reduced then reoxidised ( final enzyme cytochrome c oxidase which transfers H to O2 ( H20
Reduction: reverse of above
Carbohydrate Metabolism
Made up of glucose, galactose and fructose; principle product of carbohydrate digestion is glucose
Fasting plasma glu = 70-110 mg/dL (3.9-6.1mmol/L); 15-30mg/dL higher in arterial blood
Normal 70kg man has 2500kcal stored in 400g muscle glycogen, 100g liver glycogen, 20g glu; 112,00kcal stored in fat (80%)
Glu load: 50% ( CO2 and H20
5% ( glycogen
30-40% ( fat
Factors affecting glu level:
1) Dietary intake
2) Rate of entry of glu into cells
3) Glucostatic activity of liver – 5% converted into glycogen, 30-40% converted into fat
Renal handling of glucose: renal threshold is 180mg/dL ( glycosuria
Exercise: during exercise plasma glu raised by hepatic glycogenolysis; muscles use glycogenolysis with incr uptake glu; incr gluconeogenesis; decr insulin; incr glucagon and E
@ rest: brain uses 70-80% glu, rest by RBC; muscles use fa’s for metabolism
1) Glucose ( enters cells ( phosphorylated to glucose 6-phosphate
Catalysed by hexokinase; in liver catalysed by glucokinase which has greater affinity for glu and incr by insulin, decr by diabetes/starvation
1 mol ATP used for conversion of glu to G6P
2) ( G6P ( polymerized to glycogen (glycogenesis; G6P ( G1P ( uridine diphosphoglucose (UDPG)
( glycogen catalysed by glycogen synthase (dephosphorylated form active, phosphorylated
form inactive); a protein primer named glycogenin is required, and its availability limits
reaction) ( stored in liver and skeletal muscle
or ( catabolised (glycolysis) ( pyruvate and lactate via 2 pathways
1) Embden-Meyerhof pathway: via cleavage through fructose to triose
a. 1 mol ATP used for converstion of fructose 6-phosphate to fructose 1,6-diphosphate
2) Direct oxidative pathway (hexose monophosphate shunt): oxidation and decarboxylation to pentoses
3) ( phosphoglyceraldehyde ( phosphoglycerate (this reaction ANAEROBICALLY releases 1 mol ATP; requires NAD+ and produces NADH)
4) ( phosphoglycerate ( phosphoenolpyruvate
5) ( phosphoenolpyruvate ( pyruvate (this reaction ANAEROBICALLY releases 1 mol ATP)
NB. Via EM pathway, 2 phosphoglyceraldehyde produced, so 4 ATP produced ANAEROBICALLY per mol glu, but 1 mol ATP used ( net production of 3 ATP per mol G6P (this figure is 2 ATP if made from glu))
6) ( pyruvate
( lactate (in this reaction pyruvate accepts H from NADH (when needed under anaerobic
conditions) produced in 3) thereby reforming NAD+ needed for above reaction; lactate produced
converted back to pyruvate when O2 restored as H then accepted by flavoprotein-cytochrome
chain)
( proteins (gluconeogenesis – regulated by PGC-1, a transcriptional coactivator, induced by
fasting)
( acetyl-CoA (this is IRREVERSIBLE; this reaction requires NAD+ and produces NADH)
7) Acetyl-CoA enters citric acid/Krebs/tricarboxylic acid cycle with oxidation of carbohydrate/fat/protein to CO2 and H20; AEROBIC)
( joins oxaloacetate ( forms citrate ( 7 subsequent reactions
( release 2 CO2
( 4 H transferred to flavoprotein-cytochrome chain (2 from NADH from step 3, 2 from
NADH from step 6)
( overall producing 12 ATP and 4 H20 (2 H20 used in cycle)
( 24 ATP formed by subsequenct 2 turns of cycle
So, net production by EM pathway and CA cycle = 38 ATP
If hexose monophosphate shunt used, amount ATP released depends on amount of NADPH convered to NADH then oxidized.
Aa’s ( intermediates in reactions; hence non-glucose protein molecules converted to glu
NB. Glu makes fat through acetyl-CoA but since this is a one-way reaction there is very little conversion of fat to carbohydrate, but there can be conversion of glycerol (from fat) ( dihydroxyacetone phosphate (muscle uses fa’s for metabolism)
Directional flow valves: when enzymes can make reactions unidirectional hence effect metabolism
Glycogenolysis: catalysed by phosphorylase which is activated by:
1) E working on beta-2 receptors in liver (incr cAMP ( activation of PKA ( phosphorylase kinase activated ( phosphorylates phosphorylase activating it – phosphorylated form active (a), dephosphorylated inactive (b))
2) E working on alpha-1 receptors in liver ( intracellular Ca ( activation of phosphoylase kinase independent of cAMP
Glycogen ( G6P ( glucose (via glucose-6-phosphatase which is present in liver; other tissues don’t have this enzyme to G6P follows route above ( incr lactate)
Glucagon: only stimulates phosphorylase in liver so will cause incr plasma glu
E: stimulates phosphorylase in liver and skeletal muscle, so will cause incr plasma glu and lactate
McArdle’s syndrome: deficiency of muscle phosphorylase
Other hexoses:
1) Galactose ( phosphorylated ( reacts with UDPG to form uridine diphosphogalactose (can be used for formation of glycolipids and mucoproteins) ( converted to UDPG ( glycogen synthesis; utilization of galactose requires insulin
2) Fructose ( F6P (catalysed by hexokinase or fructokinase) ( F1,6P ( split into dihydroxyacetone phosphate (which enters pathway for glu metabolism) and glyceraldehydes (which is phosphorylated); these reactions are independent of insulin; F6P can also form F2,6DP (regulates gluconeogenesis; high F2,6DP level ( incr breakdown of F6P to F1,6P ( so incr pyruvate; low F2,6DP level ( incr gluconeogenesis; glucagons ( decr F2,6DP)
Protein Metabolism 2-10 aa = peptides; 10-100 aa = polypeptides; >100 aa = proteins
1g/kg body weight / day desirable for needs
Supplies 9.3 kcal/g
Essential aa = must be obtained from diet; Aa pool = supplies needs of body; hormones made from aa’s
Protein Formation:
Proteins made of aa’s linked by peptide bonds joining amino to carboxyl group; aa’s are acidic/neutral/basic in reaction; Glycoproteins contain carbs, lipoproteins contain lipids; Body’s own proteins being constantly broken down and reformed; turnover rate 80-100g/day; during growth synthesis > breakdown
Order of aa in peptide chain = 1Y structure; twisting and folding = 2Y structure (eg. α-helix; β-sheet); arrangement of twisted chains into layers, crystals or fibres = 3Y structure; arrangement of subunits = 4Y structure
Use of protein:
1) Formation of hormones (eg. Thyroid, catecholamines, histamine, serotonin, melatonin
2) Formation of urinary sulfates: via oxidation of cysteine; SO4 will be excreted accompanied by Na/K/NH4/H; ethereal sulfates are fromed in liver from oestrogens, steroids, indoles and drugs
3) Interconversions
a. Transamination (an interconversion): conversion of aa ( keto acid with simultaneous conversion of another keto acid ( aa; catalysed by transaminases; occurs in many tissues
Eg. Alanine + alpha-ketoglutarate ( pyruvate + glutamate
b. Oxidative deamination (an interconversion): aa undergo dehydrogenation ( imino acid ( hydrolysed to keto acid with production of NH4; occurs in liver
Eg. Aa + NAD+ ( imino acid + NADH + H
Imino acid + H20 ( Keto acid + NH4
c. Ketogenic: leucine, isoleucine, phenylalanine, tyrosine; converted to ketone body acetoacetate
d. Glucogenic: alanine and other aa’s; converted to compounds that can form glucose
4) Urea cycle: much NH4 produced by deamination in liver enters urea cycle ( carbamoyl phosphate ( citrulline in mitochondria ( arginine ( urea (formed in liver; so in liver disease decr BUN and incr NH3) ( excreted in urine
a. NB. Aa can also react with NH4 ( amide; or can convert NH4 ( NH3 (eg. In urine, NH3 reacts with H permitting it to be secreted)
5) Formation of creatine: made in liver from methionine, glycine and arginine; in skeletal muscle creatine reacts with ATP formed by glycolysis and oxidative phosphorylation ( ADP and phosphorylcreatine (which is important store of ATP, reversed during exercise); creatine shouldn’t be excreted in urine in normal men – marker of extensive muscle breakdown
6) Formation of creatinine: formed from phosphorylcreatine
7) Formation of purines and pyrimidines: made in liver; combine with ribose to form nucleosides; found in co-enzymes, DNA, RNA
Protein loss:
1) Proteins lost: hair, menstruation, urine, stools
2) Protein degradation: removal of abnormal/old protein
a. Conjugation of protein to ubiquitin tickets them for degradation (ubiquinitination) ( degraded in proteasomes / lysosomes; or tickets them for various destinations in cell
b. Uric acid formed by breakdown of purines ( excreted in urine via filtration ( 98% reabsorbed ( 80% secreted
Starvation:
Low protein / normal calorie diet ( decr excretion urea and sulfates
( normal excretion creatine (wear-and-tear, not affected by diet)
Low protein / low calorie diet ( insulin ( glucose attempts to spare protein (enough glycogen stores for
1/7 starvation; ie. 0.1kg in liver, 0.4kg in muscles)
( fats ( ketoacids attempt to spare protein ( ketosis (12kg fat)
( protein catabolism (from liver, spleen, muscles) ( incr urea nitrogen excretion (urea and
nitrogen formed)
Fat Metabolism
Fa’s (can be saturated – have double bonds; unsaturated – no double bonds), triglyceraides (3x fa’s bound to glycerol), phospholipids, sterols
Essential fa’s: linolenic, linoleic and arachidonic acids; polyunsaturated; arachidonic acid formed from tissue phospholipids by phospholipase A2
These are precursors of eicosanoids (PG’s, prostacyclin, TX, lipoxins, leukotrienes); formation inhibited by glucocorticoids which inhibit phospholipase A2, NSAID’s which inhibit COX’s; have short HL’s made via enzymes
COX: makes PG, prostacyclin, TX
LOX: makes 5-HETE, 12-HETE, 15-HETE, lipoxins, LT
CYP monooxygenases: make 12-HETE, EETs, DHTs
PG: PGH2 is precursor for PG’s, TXs and prostacyclin (converted by tissue isomerases); made
from arachidonic acid by prostaglandin G/H synthases 1 and 2 (COX 1 and 2); COX1
constitutive, COX2 induced by GF’s, cytokines and tumour promoters; work via G
proteins
TX: TXA2 made by plts ( promotes vasoC and plt aggregation
Prostacyclin: produced in endothelium ( promotes vasoD
Leukotrienes: arachidonic acid converted to 5-hydroperoxyeicosatertraenoic acid (5-HPETE) by
5-lipoygenase ( leukotrienes (eg. Aminolipids – LTC4, LTD4, LTE4, LTF4); ( bronchoC, arterioC, incr vasc perm, chemotaxis; work via CysLT1 receptor ( broncoC, chemotaxis, incr vasc perm, CysLT2 ( pul vasc SM constriction; BLT ( chemotaxis
Lipoxin: A dilates microvasculature, B inhibits cytotoxic effects of NKC’s
Cellular lipids:
1) Structural lipids – part of membranes
2) Neutral fat – stored in adipose cells; mobilized during starvation; make up 15% body weight in men, 21% in women; adenylyl cyclase in adipose tissue activated by glucagons, NE + E via beta-3 receptor
3) Brown fat – more in infants; between scapulas, at nape of neck, along gt vessels; extensive SNS supply (( release of NE ( beta3-adrenergic receptors ( incr lipolysis, fa oxidation ( varies efficiency with which E produced and food utilized; incr nerve output when eating ( heat production); contain many droplets of fat and many mitochondria; normal oxidative phosphorylation occurs but also uncoupling of metabolism and generation of ATP so more heat produced (via uncoupling protein UCP1)
Plasma lipids: major lipids are insoluble in aqueous solutions hence aren’t free
1) Free fatty acids: bound to albumin
2) Lipoprotein complexes: cholesterol, triglycerides, phospholipids; complexes incr solubility of lipids; generally contain hydrophobic core of triglycerides surrounded by phospholipids and protein (apoproteins – APO E,C,B)
Exogenous pathway: transports lipids from intestine to liver
1) Chylomicrons: formed in intestinal mucosa during absorption of products of fat digestion; very large lipoprotein complexes containing APO C; enter circ via lymphatics; cleared from circ by lipoprotein lipase in capillary endothelium (catalysed breakdown of triglyceride ( fa and glycerol (enter adipose cells or enter circ bound to albumin) ( become chylomicron remnants which go to liver ( internalized by receptor-mediated endocytosis ( degraded in lysosomes
Endogenous pathway: transports lipids to and from tissues
1) Very low density lipoproteins (VLDL): contain APO C; formed in liver; transport triG formed in liver to other tissues
2) Intermediate density lipoprotein (IDL): lipoprotein lipase removes triG from VLDL ( IDL; give up phospholipids; pick up cholesteryl esters via lecithin-cholesterol acyltransferase
3) Low density lipoprotein (LDL): when more triG lost; provide cholesterol to tissues (LDL taken up by receptor-mediated endocytosis in clathrin coated pits ( endosome ( proton pumps in endosome decr pH inside endosome ( LDL receptor released and recycled ( endosome fuses with lysosome ( cholesterol made available ( inhibits production of intracellular chol by HMG-CoA reductase, stimulates esterification of XS chol, inhibits synthesis of new LDL receptors); LDL also taken up by macrophages (via scavenger receptor) esp LDL that has been modified by oxidation ( when become overloaded become foam cells
4) High density lipoprotein (HDL): take up chol from cells; made in liver and intestinal cells; transfer chol to liver where is excreted into bile
Metabolism
TriG broken down by lipoprotein lipase as shown above (feeding INCREASES activity, fasting DECREASES activity), or hormone-sensitive lipase found intracellularily in adipose tissue (activity slowly INCREASED by GH, steroids and thyroid hormones and starvation via incr activity of cAMP; DECREASED activity by insulin and PGE and feeding by inhibiting formation of cAMP) ( fa ( enter cell or mobilize bound to albumin (provided to cell by chylomicrons and VLDL (used extensively in heart), or synthesized in depots) ( acetyl-CoA ( citric acid cycle (in mitochondria by beta-oxidation – serial removal of 2 C from fa with high yield of ATP compared to glu; medium and short chain fa can enter mitochondria easily, long-chain must be bound to carnithine to cross inner mitochondrial membrane – the linked pair then moved into matrix space by a translocase ( ester hydrolyse and carnithine recycled)
Formation
Acetyl-CoA ( fa occurs in many tissues; occurs principally outside mitochondria
Ketone Body Formation Normal level 1mg/dL
Acetyl-CoA ( acetoacetyl-CoA in many tissues ( acetoacetate in liver (a β-keto acid, a ketone body) ( β-hydroxybutyrate and acetone (ketone bodies; anions) ( enter circulation.
Ketones normally metabolized as fast as formed: acetoacetate metabolized with CoA (from succinyl-CoA; and via other pathways) ( form CO2 and H20 via citric acid cycle (occurs in tissues other than liver)
If incr acetyl-CoA or decr supply of products of glu metabolism (eg. Starvation, DM, high-fat low
carb diet, less can enter citric acid cycle ( acetoacetate accumulates ( ability of tissues to
oxidize ketones exceeded ( ketosis ( anions so metabolic acidosis ( abolished by giving glu
(hence carbs are antiketogenic)
Cholesterol Metabolism Normal level 120-200mg/dL
Precursor of steroid hormones and bile acids, important in cell membranes
Chol synthesis: shown in diagram; negative feedback by inhibiting HMG-CoA reductase; so when dietary intake high, hepatic synthesis inhibited
Chol absorption: absorbed via chylomicrons ( after chylomicrons give up triG in adipose tissue ( chylomicron remnants bring chol to liver ( most incorporated in VLDL ( circulates
Chol excretion: excreted in bile in free form and as bile acids ( some reabsorbed from intestine
Decr chol: thyroid hormones, oestrogens ( incr LDL receptors in liver, incr HDL levels
Incr chol: biliary obstruction, untreated DM
Trace Elements: essential for life; arsenic, chromium, cobalt, copper, fluorine, iodine, iron, manganese, molybdenum, nickel, selenium, silicon, vanadium, zinc
Vitamin: organic dietary constituent necessary for life, health and growth that doesn’t supply E; vit E is bound to chylomicrons ( transferred to VLDL in liver
B1 (thiamine, B complex) ( beriberi, neuritis
B2 (riboflavin) ( glossitis, cheilosis
Niacin ( pellagra
Pyridoxine ( convulsions, hyperirritability
Pantothenic acid ( dermatitis, enteritis, alopecia, adrenal insufficiency
Biotin ( dermatitis, enteritis
Folates ( sprue, anaemia, NTD
B12 (cycobalamin) ( pernicious anaemia
C ( scurvy
D ( rickets
E ( ataxia
K ( haemorrhagic phenomena
ENDOCRINOLOGY
Thyroid Gland
Effect ( stimulates O2 consumption; regulate lipid and carbohydrate metabolism
XS ( body wasting, nervousness, incr HR, tremor, XS heat production
Lack ( mental and physical slowing, poor cold resistance
T3 = triiodothyronine; 25mcg daily production; 60% turnover per day; HL 1/7; 4x more potent; VOD 40L
T4 = tetraiodothyronine / thyroxine; 75mcg/day daily production; 10% turnover per day; HL 7/7; VOD 10L
Anatomy: comes from evagination of floor of pharynx; 2 lobes connected by thyroid isthmus, occasional pyramidal lobe; high rate blood flow; made of multiple acini; follicles filled with colloid
Iodine: Normal plasma level 0.3μg/dL
Ingested iodine (500μg; min 150 needed; def when sex hormones
Inner zona reticularis (7%) – continuous with inner ZF; secrete corticosterone, cortisol < sex
Hormones
Catecholamines
Synthesis:
NE: formed by hydroxylation and decarboxylation of tyrosine
E: formed by methylation of NE (catalysed by phenylethanolamine-N-methyltransferase (PNMT), induced by glucocorticoids which are in high conc in adrenal vein)
D: 50% comes from medulla, 50% from ANS
Stored in granules with ATP and chromogranin A
Also made in adrenal medulla: metenkephalin, adrenomedullin
Regulation of secretion:
Ach from preganglionic neurons ( opens cation channels ( Ca influx from ECF ( exocytosis of granules
Incr release: incr SNS; familiar stree ( incr NE, unexpected stress ( incr E
Decr release: sleep
Metabolism:
( enter plasma ( 95% dopamine, 70% E and NE conjugated to sulphate (inactive) ( HL 2mins ( methoxylated ( 50% occurs in urine as free/conjugated metanephrine and normetanephrine
( 35% occur in urine as 3-methoxy-5-hydroxymandelic (vanillymandelic) acid (VMA) (700
μg/day)
( small amount of free E (6 μg/day) or NE (30 μg/day)
Mechanism of Action: work of alpha and beta receptors
Effects: Mostly mediated through E in physiological circumstances
Most of effects of NE are through local release from postganglionic sym neurons
Metabolic: glycogenolysis in liver and skeletal muscle (via beta-receptor ( cAMP and phosphorylase)
(via alpha-receptor ( Ca)
Incr secretion isulin and glucagons (via beta-receptor; decr secretion via alpha-receptor)
Lipolysis ( fa
Incr plasma lactate
Incr BMR (may be due to cut vasoC ( incr temp; incr muscle activity; oxidation of lactate in
liver)
Cardiac: positive inotrope and chonotrope (via beta1-receptor)
Incr myocardial excitability
NE ( VasoC in most organs (via alpha1-receptor)
E ( vasoD in skeletal muscle and liver (via beta-2 receptor) ( net decr PVR
NE alone ( incr BP but reflex bradycardia with decr CO
E alone ( widened PP, incr HR and incr CO (due to insufficient reflex)
CNS: incr alertness; anxiety and fear
Other: incr K due to release from liver ( then prolonged decr K due to incr entry into skeletal muscle
Dopamine: ( renal vasoD; vasoD in mesentry; vasoC elsewere via release of NE; +ive inotrope via beta1-receptors; natiuresis by inhibition of renal Na-K ATPase; net incr SBP
Cortical Hormones
Made from chol
C19 steroids: androgenic – dehydroepiandrosterone (DHEA), androstenedione (most oestrogens made from
this)
C21 steroids: mineralocorticoids – aldosterone, deoxycorticosterone (on 3% activity of aldosterone); 9α-
fluorocortisol has mineralocorticoid activity
Glucocorticoids – cortisol (10-20mg/day in normal adult), corticosterone (7:1 ratio);
prednisone and dexamethasone have glucocorticoid activity
Synthesis:
1) Acetate / uptake from LDL in body ( cholesterol ( esterified and stored in lipid droplets ( transported to mitochondria by sterol carrier protein
2) In mitochondria converted to pregnenolone (catalysed by cholesterol desmolase / side-chain cleavage enzyme / P450scc / CYP11A1 – CP450 member)
( Pregnenolone ( 17α-hydroxypregnenolone (catalysed by 17α-hydroxylase / p450c17 /
CYP17– CP450 member)
3) Pregnenolone ( moves to SER ( dehydrogenated to progesterone (catalysed by 3β-hydroxysteroid dehydrogenase – NOT a CP450 member; this enzyme more active in ZF)
( Progesterone ( 17α-hydroxyprogesterone (catalysed by 17α-hydroxylase)
NB. 17α-hydroxypregnenolone can be converted to 17α-hydroxyprogesterone (catalysed by 3β-
hydroxysteroid dehydrogenase)
4) In SER: Progesterone ( hydroxylated to 11-deoxycorticosterone (catalysed by 21β-hydroxylase /
P450c21 / CYP21A2 – a CP450)
17α-hydroxyprogesterone ( hydroxylated to 11-deoxycortisol (catalysed by 21β-hydroxylase)
5) 11-deoxycorticosterone and 11-deoxycortisol move back to mitochondria
IN ZONA FASCICULATA/RETICULARIS ( hydroxylated to corticosterone and cortisol (catalysed by 11β-hydroxylase / P450c11 / CYP11B1 – a CP450)
IN ZONA GLOMERULOSA ( catalyst aldosterone synthase / p450c11AS / CYP11B2 is present ( aldosterone formed (no 11β-hydroxylase or 17α-hydroxylase in ZG)
NB. 17α-pregnenolone and 17α-progesterone ( C19 steroids dehydroepiandrosterone and androstenedione (catalysed by 17,20-lyase; this enzyme more active in ZR therefore makes more androgens)
( androstenedione converted to testosterone and oestrogens in fat and other peri tissues
(important in postmenopausal women)
Deficiencies: 17α-hydroxylase – rare; no sex hormones produced so female genitalia; can still make
mineralocorticoids so get hyperT and hypoK; def cortisol but can still make corticosterone and aldosterone
21β-hydroxylase – common; decr production cortisol and aldosterone ( incr ACTH; steroids
converted to androgens ( virilisation; def in aldosterone ( hypoNa and hypoV
11β-hydroxylase – virilisation, but hyperT
Regulation of release:
Glucocorticoid:
ACTH (HL 10mins) binds to receptors on adrenocortical cells ( Gs ( adenylyl cyclase ( incr formation pregnenolone and derivatives ( release of hormones (inc androgens); ACTH increases sensitivity of adrenal to further release of ACTH
ACTH released in circadian rhythm (peak in morning); governed by biologic clock in suprachiasmatic nuclei of hypothalamus
Decr ACTH release: free GC’s (also decr adrenal responsiveness to ACTH) – inhibition at pituitary and hypothalamic level
Incr ACTH release: stress (there is a ceiling at which incr ACTH no longer incr release of GC); incr due to incr CRH from paraventricular nuclei in hypothalamus ( transported through portal-hypophysial vessels to APG; multiple inputs to hypothalamus from emotional stress / pain etc…
Mineralocorticoid:
ACTH can stimulate MC release, but effect is transient
Renin (from JG cells surrounding renal afferent arterioles which notes drop in ECF vol) ( activates angiotensinogen ( conversion of angiotensin I to II ( AII binds to AT1 receptors in ZG ( G protein ( activation of PLC ( incr PKC
( incr chol converted to pregnenolone
( incr conversion of corticosterone to aldosterone (helps action of aldosterone synthase)
K ( stimulates conversion of chol to pregnenolone, and of deoxycorticosterone to aldosterone
Works via depolarizing cell ( opens voltage-gated Ca channel ( incr intracellular Ca
Hence low K diet decr sensitivity of ZG to AII
ANP inhibits renin secretion ( decr responsiveness of ZG to AII
Conc of dehydroepiandrosterone sulphate higher in young men than old, due to altered activity of lyase activity
Incr release GC and MC: surgery, anxiety, physical trauma, haemorrhage
Incr release MC only: hyperK (small incr needed), hypoNa (large drop needed), constriction of IVC in thorax (decr intrarenal p), standing
Plasma Binding: bound steroids are inactive; bound acts as reservoir
Cortisol: 90% bound to transcortin / corticosteroid-binding globulin (CBG) (synthesized in liver;
production increased by oestrogen – incr in pregnancy and hyperthyroidism; decr in
cirrhosis, nephrosis; if incr ( more cortisol incr ACTH ( incr cortisol secretion until
normal free level, so high total level without symptoms of XS)
Albumin (minor; 5%; large capacity but low affinity); 5% free
Stronger bound than corticosterone so longer HL (60-90mins); very little free; binding saturated at
20μg/dL; total amount 13.5μg/dL
Corticosterone: similar to above, but lesser extent
HL 50mins
Aldosterone: slight protein binding; HL 20mins (short); total level 0.006μg/dL
Metabolism:
Cortisol: in liver (similar for cortisone except not step 3); rate decreased in liver disease and stress
1) Cortisol reduced ( dihydrocortisol ( tetrahydrocortisol ( conjugated to glucuronic acid
2) 20% Cortisol ( cortisone (catalysed by 11β-hydroxysteroid dehydrogenase type 1 and 2) ( this is active but promptly reduced and conjugated to tetrahydrocortisone glucuronide
3) 1/3 Cortisol ( 17-ketosteroid version ( conjugated to sulphate
( conjugates freely soluble ( enter circ and bind to p proteins
( excreted in urine, by tubular secretion (only 1% excreted unchanged)
( 15% excreted in stool (may under enterohepatic circ)
Aldosterone:
1) Converted in liver to tetrehydroglucuronide derivative
2) Converted in liver and kidneys to 18-glucornide derivative (will be converted to free aldosterone in v acidic pH)
( excreted in urine 1% free form, 5% form 2, 40% form 3
Mechanism of action:
Glucocorticoids: bind to glucocorticoid receptors (which when not bound are complexed with Hsp90 ( binding causes dissociation of Hsp) ( AT to nucleus ( complexes act as transcription factors (binds to GC receptors elements (GRE) in genes) ( synthesis of enzymes which alter cell function; hGRα is active receptor; hGRβ is inactive form capable of inhibiting GC’s; proteins called coregulators / corepressors help/inhibit interaction of GRE’s with receptor
Mineralocorticoids: bind to cytoplasm receptor (eg. Principle cell in renal tubules) ( complex moves to nucleus ( altered transcription of mRNA’s ( incr protein production
( incr activity of epithelial Na channel (ENaC) via incr insertion of channel in cell membranes, incr
synthesis of channel, incr serum and glucocorticoid-regulated kinase
( incr activity of Na-K ATPase
NB. GC’s can bind to MC’s receptors; hence MC-sensitive tissues contain enzyme 11β-hydroxysteroid dehydrogenase type 2 which converts cortisol ( cortisone ( 11-oxy derivative which is not active at receptor; if this enzyme is absent, GC have MC effects
Effects:
Androgens: adrenal androgens only have 20% effect of testosterone
( masculinising effects (little effect unless in XS amount)
( promote protein anabolism and growth
Glucocorticoids: overall catabolic
incr protein catabolism ( incr aa
Incr hepatic glycogenesis and gluconeogenesis
Incr G6Pase activity
Incr plasma glu level ( incr insulin release (which stimulates lipogenesis, so net
deposition of fat with incr fa and glycerol in circ)
Incr lipid levels (lipolysis) and ketone body formation
Permissive action: small amounts vital for certain reactions to occur (ie. Needed for
metabolic action of glucagon and NE+E, vascular reactions of NE+E
Needed for effective H20 excretion
Encourage sequestration of eosinophils in spleen and lungs; decr basophils; incr
neutrophils, plts and RBC’s; decr lymphocyte count; decr secretion of cytokines; inhibit
inflamm response; inhibit macrophages and APC’s; decr PG, LT and PAF synthesis,
and COX2; suppress mast cell degranulation; decr histamine release from basophils and
mast cells ( decr cap permeability; no effect on ab’s at mod doses
Deficiency ( altered H20, carb, protein, and fat metabolism; fasting ( hypoG
XS ( Cushing’s syndrome; will be protein depleted; thin skin, poor muscles, poor wound healing, easy bruising, thin hair, central fat distribution, buffalo hump, striae, hyperG, hyperlipidasemia, ketosis; may get mineralocorticoid action from v high GC ( salt and H20 retention ( moon face, K depletion, weakness; may get hyperT; bone dissolution ( OP; incr appetite, insomnia, psychosis; chronic XS ( decr ACTH, GH, TSH, LH; antagonize effect of Vit D on Ca absorption
NB. Corticosterone exerts minor MC effect
Mineralocorticoids: incr reabsorption of Na from urine (via action on principal cells in CD ( K diuresis), sweat, saliva, colon ( Na retention (takes 10-30min to develop); Na exchanged for K and H
Deficiency ( hypoNa, hypoV, hyperK
XS (eg. Conn’s; 2Y due to cirrhosis, heat failure, nephrosis) ( hyperNa but also hyperH20 so Na level normal, hyperV ( incr BP, hypoK; H lost in urine; weakness, tetany, polyuria, hypokalaemic alkalosis
Escape phenomenon: still get urinary loss of Na due to incr secretion of ANP; this prevents
Oedema
NB. Deoxycorticosterone is precursor of aldosterone; HL 70mins; control of secretion related to ACTH
Calcium Metabolism
Calcium Normal plasma level 10mg/dL; 2.5mmol/L
Normally ingest 600-1000mg/day (absorb 100-250mg/day)
Absorption: Active tranposrt out of SI via Ca-dependent ATPase (increased by
1,25dihydroxycholecalciferol; incr Ca ( decr 1,25DHCC so absorption indirectly
proportionate to dietary intake
Some passive diffusion
Distribution
99% Ca sequestered in skeleton
Readily exchangeable reservoir – small; 500mmol/day moves in and out
Slowly exchangeable reservoir – large; involves bone resorption and deposition; only
7.5mmol/day moves in and out
1% Ca free – important for 2nd messenger, coagulation, muscle contraction, nerve function
some bound to p protein (proportionate to p protein level; incr binding at high pH)
is filtered by kidneys but 98-99% reabsorbed (60% in PCT, rest in aLOH and DCT; DCT
regulated by PTH)
Deficiency: ( hypocalcaemic tetany via excitatory effect on nerve and muscle cells; may cause fatal laryngospasm
\98% filtered Ca reabsorbed by kidney
Phosphate Normal plasma level 12mg/dL
Found in ATP, 2,3-DPG, proteins
Absorption: absorbed in duodenum and SI by AT and passive diffusion; absorption proportionate to dietary intake; incr absorption by 1,25dihydroxycholecalciferol
Distribution
85-90% in skeleton
Rest free – is filtered in glomeruli ( 85-90% reabsorbed (2Y to AT in PCT; this AT is inhibited by PTH)
2/3 is in organic compounds; 1/3 in PO4, HPO4, H2PO4
85% filtered phosphate reabsorbed by kidney
Vitamin D Are secosteroids
Synthesis:
7-dehydrocholesterol ( sun ( previtamin D3 (rapid) ( slow development of Vit D3 (cholecalciferol) (can also be ingested in diet)( transported in plasma bound to vitamin D-binding protein (DBP) (has lower affinity for 1,25 (hence more rapid clearance) than for 25, and 24,25
Metabolism:
In liver, cholecalciferol converted to 25-hydroxycholecalciferol (calcidiol, 25-OHD3) (normal level 30ng/mL)
( in PCT of kidneys converted to 1,25-dihydroxycholecalciferol (calcitriol, 1,25-(OH)2D3 (catalysed by 1α-hydroxylase; normal level 0.03ng/mL; also made in keratinocytes in skin, placenta, macrophages)
( in kidneys 24,25-dihydroxycholecalciferol also formed
Regulation of synthesis: of 1,25-dihydroxycholecalciferol
Incr formation: caused by PTH (low Ca ( incr PTH); low PO4
Decr formation: decr PTH (high Ca ( negative feedback on PTH); high PO4 (inhibits 1α-hydroxylase); 1,25-dihydroxycholecalciferol (which also inhibits 1α-hydroxylase, encourages formation of 24,25-dihydroxycholecalciferol, inhibits formation of PTH)
( 24,25-dihydroxycholecalciferol formed instead
Mechanism of Action:
1,25-dihydroxycholecalciferol ( binds receptor ( exposes DNA-binding region ( altered transcription
( formation of calbindin-D proteins (calbindin-D9k and D28k) ( incr Ca transport
( incr no Ca-H ATPase molecules in intestinal cells ( incr Ca transport
Effects: of 1,25-dihydroxycholecalciferol Incr Ca and phos for formation of bone
( incr Ca absorption in SI
( incr reabsorption of Ca in kidneys (25 more potent)
( incr synthetic activity of osteoblasts (with 2Y incr activity of osteoclasts)
( regulates PTH release, insulin release, cytokine production by macrophages and T cells
Deficiency: rickets / osteomalacia; bowed bones, dental defects, hypoCa
PTH Normal plasma level 10-55pg/mL
HL 10mins
Anatomy: 4 glands embedded in thyroid; chief cells make and secrete PTH; also contain oxyphil cells function of which unknown
Synthesis: preproPTH made ( enters ER ( aa removed ( proPTH ( removal of more aa in Golgi apparatus ( PTH ( packaged into secretory granules and released from chief cells
Metabolism: rapidly cleaved by Kupffer cells in liver into biologically inactive fragments ( cleared by kidney; HL few mins
Mechanism of action:
1) hPTH/PTHrP receptor: binds PTH and PTH-related protein (PTHrP; marked effect on growth and development of cartilage in utero; involved in Ca transport in placenta); serpentine receptor coupled to Gs ( adenylyl cyclase ( incr cAMP; also activated PLC via Gq ( incr intracellular Ca ( PKC
2) PTH2 receptor: in brain, placenta and pancreas; binds PTH; serpentine receptor coupled to Gs ( adenylyl cyclase ( incr cAMP
3) CPTH receptor: binds PTH
Regulation of Secretion:
Ca binds calcium sensing receptor (CaR); incr phos ( binds free Ca ( decr level of free Ca ( incr PTH
Incr secretion: low Ca; incr phosphate (which causes low Ca and inhibits formation of 1,25DHCC)
Decr secretion: incr Ca (cell membrane serpentine Ca receptor coupled via G protein to phosphoinositide turnover ( inhibits PTH secretion); 1,25DHCC decreases preproPTH via decr gene transcription; ow Mg; low PTH ( Ca deposited in bones
Effects: Incr Ca level by bone resorption
Decr plasma phosphate
( incr bone resorption (incr activity and no of osteoclasts)
( incr phosphate excretion in urine (decr reabsorption phosphate at PCT)
( incr Ca reabsorption in DCT (decr reabsoprtion of phos, aa, HCO3, Na, Cl, SO4)
( incr formation of 1,25DHCC ( incr absorption Ca at SI
( stimulates osteoclasts and osteoblasts in longterm
( suppresses further formation of PTH
Deficiency: low Ca ( NM hyperexcitability ( hypoCa tetany (Chvostek’s sign, Trousseau’s sign); high phosphate
XS: hyperCa, hypophosphataemia; may get kidney stones
Calcitonin
Secreted from parafollicular cells of thyroid; HL 10mins
Regulation of secretion: incr release by beta-agonists, dopamine, oestrogens, gastrin, CCK, glucagons, secretin
Mechanism of action: serpentine receptors in bone and kidney
Effect Decr Ca and phos as all entering bone:
( Inhibits bone resorption (inhibits activity of osteoclasts) ( decr Ca and decr phos
( increases Ca and phos (and Na, K, Mg) excretion by kidney
( incr secretion of Na, K, Cl and H20 into gut; decr release of gastrin
May protect pregnant bone, prevent postprandial hyperCa, have role in skeletal maturation
Others
Oestrogen: inhibit secretion of cytokines (eg. IL-1, IL-6, TNFα) which aid development of osteoclasts ( decr breakdown of bone; inhibit bone resorbing effects of PTH
GC’s: lower Ca by inhibiting osteoclast formation and activity, but cause OP over longterm (decr bone formation by inhibiting osteoblasts, incr bone resorption); decr absorption of Ca and phos from SI; incr renal excretion of Ca and phos
GH: incr Ca ecretion in urine; incr intestinal absorption of Ca; resultant incr Ca
IGF-1: incr protein synthesis in bone
Thyroid: incr Ca
Insulin: incr bone formation
Pituitary Gland
Anatomy
PPG: endings of axons from supraoptic and paraventricular nuclei of hypothalamus on BV’s; contains pituicytes
APG: connected to brain via portal hypophysial vessels; made up of interlacing cells (containing granules of stored hormone) and network of sinusoidal fenestrated capillaries
Contain chromophilic cells – can be acidophils / basophils; secretory
1) Somatotropes – secrete GH
2) Lactotropes – secrete prolactin
3) Corticotropes – secrete ACTH; POMC is hydrolysed in there cells for from ACTH and β-LPH and β-endorphin which are secreted
4) Thyrotropes – secrete TSH
5) Gonadotropes – secrete FSH and LH
chromophobic cells – secretory; inactive with few granules
IPG: proopiomelanocortin (POMC) further hydrolysed to corticotropin-like intermediate-lobe peptide (CLIP; function unknown), γ-LPH (function unknown) and β-endorphin
Deficiency: decr adrenal GC’s and sex hormones (still some secretion); decr stress-induced incr aldosterone, but still some secretion so no H20 retention; decr growth; decr thyroid function; decr 2Y sex characteristics; tendancy to hypoG when fasted; decr ACTH ( decr protein catabolism ( decr osmotically active substrate in urine ( decr urine production (despite decr ADH);
GH 0.2-1.0mg/day output; basal level 0-3ng/mL in adults
Distribution: bound to p protein which is produced by cleavage of GH receptors; 50% bound
Metabolism: rapid, partly in liver; HL 6-20mins
Mechanism of action: large receptor has 2 binding sites for receptors (JAK/STAT cytokine receptor)– binds 1 subunit, attracts another subunit ( homodimer ( receptor activation ( activates intracellular enzyme cascades (eg. JAK2-STAT pathway); possibly acts on cartilage to make stem cells that respond to IGF-I
Regulation of secretion: feedback control
Incr release: GHRH from hypothalamus; ghrelin from hypothalamus
Def of E substrate (eg. hypoG, exercise, fasting), incr aa (eg. Protein meal), glucagon, stress, goint
to sleep, L-dopa, apomorphine, oestrogens and androgens (peak at puberty has protein anabolic effect ( growth; cause incr size of spikes of GH ( incr release IGF-I ( growth); thyroid hormones needed for proper release of GH
Decr release: somatostatin (GH release-inhibiting factor; inhibits release of GH, glucagons, insulin, and gastrin); IGF-I (via direct negative feedback on APG and incr relase of somatostatin)
REM sleep, hyperG, cortisol, fa, GH
Effects:
( stimulate growth (eg. Incr chondrogenesis ( giganticism if growth plates not fused; if GP’s fused ( acromegaly – incr size organs, incr protein content, decr fat content); higher spikes during puberty with higher mean plasma level over 24hrs
Works via incr secretion of somatomedins (eg. IGF-I (somatomedin C), IGF-II) synthesized in
liver, cartilage and other tissues
IGF-I – secretion independent of GH in utero, but after birth dependent on GH; peaks at puberty
then decr thereafter
IGF-II – secretion independent of GH; role in growth of fetus; constant level
( incr plasma phosporus
( decr plasma urea nitrogen and aa
( incr lean body mass
( decr body fat and chol
( incr fa (ketogenic, catabolic)
( incr BMR
( incr GI absorption of Ca
( decr renal excretion of Na and K (probably cos redirected to growing tissues)
( incr GFR and renal blood flow
( incr hepatic glu output (def causes hypoG)
( incr ability of B cells to respond to insulinogenic stimuli
FSH
Made of α and β subunits which must be combined for max physiologic activity; act via GPCR
LH
Made of α and β subunits which must be combined for max physiologic activity; act via GPCR
TSH
Made of α and β subunits which must be combined for max physiologic activity
Renal Endocrine Function
Renin-Angiotensin System
Renin: acid aspartyl protease; made as preprorenin ( converted to prorenin
( some secreted (very little converted in circulation)
( some converted to renin in kidneys (in secretory granules of JG cells located in media of
afferent arterioles)
HL 80mins
Angiotensinogen: made in liver; incr lvel by GC, thyroid, oestrogens, cytokines, AII
ACE: form AII from AI; inactivates bradykinin (hence cough on ACEi); found in endothelial cells; conversion of AI ( AII occurs in lungs
Angiotensin: AI (no physiological activity) ( AII (physiological activity) metabolized rapidly by peptidases (in RBC’s, and many tissues for local effect – uterus, placenta, eyes, pancreas, heart, fat, adrenal cortex, testis, ovary, pituitary, brain) ( AIII (has 40% pressor activity, 100% aldosterone-stimulating activity) ( further metabolism to AIV (also has some physiogical activity); also removed from circ by trapping mechanism in vascular beds of various tissues; HL 1-2mins
Mechanism of action of AII:
AT1 receptors: serpentine; coupled to Gq ( PLC ( incr cytosolic free Ca level; responsible for most effects of AII – found in arterioles and adrenal cortex; XS AII downregulates receptors in arterioles, but upregulates receptors in cortex
AT2 receptors: via G protein ( activate phosphatases ( antagonize growth effects, open K channels
( incr production of NO ( incr cGMP
Regulation of secretion of renin:
Incr release: incr SNS; incr NE+E (act on beta1-receptors on JG cells); PG’s; Na depletion; diuretics; hypotension; haemorrhage; upright posture; dehydration; heart failure; cirrhosis; RAS (( decr afferent arteriole p)
Decr release: incr Na and Cl reabsorption across macula densa (renin release inversely proportional to amount of Na and Cl entering DCT from LOH; Na and Cl enter macula densa cells cia Na-K-2Cl transporter); incr afferent arteriolar p; AII (negative feedback); ADH
Na-depleted people and cirrhosis circulating AII increased ( downregulation of receptors in vascular SM ( decr response
Effects of AII:
( arteriolar constriction ( incr SBP and DBP
( incr aldosterone secretion from adrenal cortex
( helps release of NE from postganglionic sym neurons
( contraction of mesangial cells ( decr GFR
( incr Na reabsorption in renal tubules
( decr sensitivity of baroreflex in brain (helps pressor effect) via action on circumventricular organs (area postrema)
( incr H20 intake via action of circumventricular organs (subfornical organ and organum vasculosum of lamina terminalis)
( incr secretion of ADH and ACTH via action on circumventricular organs
Erythropoietin
Synthesis: 85% from kidneys (produced by interstitial cells in peritubular capillary bed), 15% from liver (produced by perivenous hepatocytes)
Metabolism: metabolized in liver; HL 5hrs
Mechanism of action: receptor has tyrosine kinase activity ( inhibits apoptosis of RBC’s and incr growth
Effect: Incr no of erthyropoietin-sensitive committed stem cells in BM ( converted to RBC precursors ( erthyrocytes; takes 2-3days for incr RBC’s
Regulation of release: incr release: hypoxia, androgens, helped by E+NE
GI Physiology
Carbohydrates
Polysaccharides (eg. Starches - glycogen, amylopectin, amylose), disaccharides (eg. Lactose, sucrose), monosaccharides (eg. Fructose, glucose)
Digestion
Mouth: salivary α-amylase digests starch ( α-dextrins, maltotriose and maltose
Stomach: α-amylase inhibited by acidic gastric juice
SI: salivary and pancreatic α-amylase active as above
Oligosaccharidases present in brush border
\ α-dextrinase – breaks down α-dextrins, maltotriose and maltose
Maltase – breaks down α-dextrins, maltotriose and maltose
Sucrase – breaks down sucrose, maltotriose and maltose
Disaccharidases present in BB
Lactase – breaks down lactose
Trehalase – breaks down trehalose
Sucrase ( 1 glu + 1 fru Lactose ( glu and galactose Trehalose ( 2 glu
Def in enzymes ( osmotic diarrhoea, bloating + flatulence (due to production of CO2 and H2 from disaccharies in lower SI and LI)
Def lactase ( lactose intolerance
Absorption
Glucose: rapid absorption in all SI (no absorption in LI) – via Na-dependent glu transporter (SGLUT) a Na-glu cotransporter (incr absorption if incr Na conc on mucosal surface of cells); same mechanism for galactose
1) Na moves along conc gradient
2) Na undergoes AT into lateral intercellular spaces (maintaining conc grad)
3) Glu transported by GLUT2 into interstitum and capillaries
Fructose: facilitated diffusion by GLUT5 in enterocytes, then via GLUT2 into intersitium; independent of Na
Pentoses: simple diffusion
Proteins
Digestion
Endopeptidases (eg. Trypsin, chymotrypsin, elastase) - digest interior peptide bonds
Exopeptidases (eg. Carboxypeptidase A and B) - digest aa at carboxyl ends
Stomach: pepsinogen I (in acid secreting regions) and pepsinogen II (in pyloric region) activated by HCl ( pepsin ( digest proteins and polypeptides (cleave peptide linkages)
Work in acidic enviro so decr activity when gastric contents mixed with alkaline pancreatic juice in duodenum and jejunum
SI: occurs in 3 sites
1) Enzymes from pancreas – act in lumen
Enteropeptidase stimulates trypsin (endo) ( digests proteins and polypeptides
Trypsin stimulates Chymotrypsin (endo) digests proteins and polypeptides
Elastase (endo) digests elastin and other protesin
Carboxypeptidase A and B (exo) digest proteins and polypeptides
Nucleases digest nucleic acids ( nucleotides
2) Enzymes from SI mucosa – act in brush border
Enteropeptidase: digests trypsinogen ( trypsin
Aminopeptidase digests polypeptides
Carboxypeptidase digests polypeptides
Endopeptidases digests polypeptides
Dipeptidase digests dipeptides ( 2aa
Enzymes split nucleotides ( nucleosides and phosphoric acid ( sugars and purine and pyrimidine bases
3) Intracellular mucosal enzymes:
Peptidases digest di- and tripeptides which are AT into intestinal cells
Absorption
Rapid in duodenum and jejunum, slow in ileum, none in LI; 50% from food, 25% from digestive juices, 25% from desquamated cells
Multiple systems – into enterocytes: 3 systems require Na, 2 require Na and Cl, 2 don’t need Na
Into blood: 3 system require Na, 2 don’t need Na
2-5% not absorbed ( digested by bacteria in LI ( excreted
Protein absorption indicated in food allergies; absorption of protein Ag’s occurs in microfold cells overlying Peyer’s patches ( Ag presented to lymphoid cells
Lipids
Digestion
Mouth: lingual lipase from Ebner’s glands on dorsal surface of tongue digests up to 30% triG’s ( fa + 1,2-diacylglycerols; still active in stomach
SI: most occurs in duodenum; emulsified by bile salts, lecithin and monoglycerides ( form micelles which contain fa, monoglycerides and chol in hydrophobic centres ( these can pass to BB for digestion
Pancreatic lipase digests triG’s ( 2 monoglycerides and fa; action inhibited by acid, but OK as pancreatic juice is alkaline
Colipase binds to pancreatic lipase, increasing action; released in prohormone form which is
activated by trypsin
Bile salt-acid lipase (lipase activated by bile salt) digests cholesteryl esters ( chol; also digests esters of fat-soluble vitamins and phospholipids
Cholesteryl ester hydrolase digests cholesteryl esters ( chol
Absorption – mostly in upper SI; 95% absorbed
Passive diffusion / carriers into enterocytes ( rapidly esterified in enterocytes so conc grad maintained
( small fa’s are H20-soluble so can be ATed into blood and circulate as free fa’s
( larger fa’s are reeesterfied to triG in SER
( chol is esterified
( esters coated in protein, cholesterol and phospholipid ( chylomicron ( enter
lymphatics via exocytosis
NB. Colonic bacteria ( short-chain fa’s via action on carbs and fibre ( absorbed and metabolized, have trophic effect on colonic epithelial cells, combat inflamm, help maintain acid-base equilibrium, promote absorption of Na
H20 and Electrolytes
2000ml ingested + 7000ml secreted ( 98% reabsorbed, 200ml lost in stools
Na: Na moves either way depending on conc grad
Na-K ATPase in BL membrane ( some Na active absorbed in SI and esp in LI
2Y AT of Na with glu and aa
Cl: from IF ( enterocyte via N-K-2Cl cotransporter ( Cl secreted into lumen via channels (activated by incr cAMP)
H20: move according to osmotic p – usually equals out at the jejunum then maintained thereafter; much absorption in LI 2Y to AT of Na
K: some secreted into lumen (eg. As part of mucus) and some passively enters lumen down conc grad
H-K-ATPase in distal LI causes AT of K into enterocytes
Vitamins and Minerals
Vitamins: ADEK fat soluble; mostly in upper SI; B12 in ileum (bound to intrinsic factor from stomach); B12 and folate Na-independent, but others co-transported with Na
Ca: 30-80% absorbed; incr absorption is defiency, decr if XS
Fe: Fe3+ ingested ( Fe3+ reductase in BB converts to Fe2+ (aided by gastric secretions which dissolve Fe3+ making reduction easier) ( Fe2+ absorbed in duodenum via DMT1
( stored as ferritin in enterocytes; may aggregate as haemosiderin
( transported into IF via ferroportin 1 (facilitated by hephaestin)
( Fe2+ converted back to Fe3+ in plasma ( bound to transport protein transferrin (has 2 binding sites; usually 35% saturated)
70% Fe in Hb, 3% in myoglobin, 27% in ferritin; XS Fe ( accum of haemosiderin which causes damaged ( haemachromatosis
Regulation of GI function
Layers:
1) Muscosa
2) Submucosa: contains SM fibres (circular)
3) Muscularis: contains 2 layers of SM (inner circular, outer longitudinal)
4) Serosa: continues on to mesentery
Nervous Supply:
1) Myenteric (Auerbach’s) plexus: between 2 muscle layers in muscularis; innervates these muscles, involved in motor control
2) Submucous (Meissner’s) plexus: between mucosa and submucosa; innervates glands, endocrine cells and BV’s
PNS: preganglionic paraS efferents end on cholinergic nerve cells in plexuses ( incr Ach secretion
SNS: postganglionic sym efferents end on cholinergic nerve cells in plexuses ( NE inhibits Ach secretion via alpha-2 receptors; some end directly on SM cells or on BV’s
Basic electrical activity: (not in oesophagus and prox stomach) SM has spontaneous rhythmic fluctuations in membrane potential (-65 - -45mV); initiated by interstitial cells of Cajal located near myenteric plexus in stomach and SI, near submucous plexus in colon; rarely causes contraction but cause muscle tension; depolarization due to Ca influx, repolarisation due to K efflux; Ach incr tension, E decr; co-ordinates motor activity – contraction only occurs during depolarizing part of wave
Migrating motor complex: quiescent period (I) ( irregular electrical and mechanical activity (II) ( bursts of regular activity (III); occur every 90mins with cycles migrating from stomach to distal ileum; stopped by ingestion of food, only during fasting state
Peristalsis: reflex response inititated when wall stretched ( release of 5-HT ( activates sensory neurons ( activates myenteric plexus
( release of substance P and Ach ( SM contraction behind bolus
( release of NO, VIP and ATP ( SM relaxation ahead of bolus
Moves at 2-25cm/sec; occurs intrinsically, but influenced by extrinsic input
GI hormones:
Enteroendocrine cells: are hormone secreting; called enterochromaffin cells if also secreted 5-HT; called APUD/neuroendocrine cells if also secrete amines
Gastrin:
Synthesis: Preprogastrin processed into multiple gastrins of multiple lengths (G17 is principle form causing gastrin secretion); produced by G cells antral portion of gastric mucosa; contain many gastrin granules; some gastrin also found in pancreas, APG, IPG, hypothalamus, medulla, vagus and sciatic nerves
Regulation of secretion: G cells have microvilli at luminal border ( detect changes in gastric contents
Incr secretion: luminal peptides and aa; luminal distension; incr vagal discharge (release gastrin-releasing polypeptide (GRP) at G cells); Ca and E in blood
Decr secretion: luminal acid and somatostatin; secretin, GIP, VIP, glucagons and caltinonin in blood
Metabolism: HL 2-3mins for principle form; inactivated in kidney and SI
Effects: stimulation of gastric acid and pepsin secretion
trophic action of mucosa of SI, LI and stomach
stimulates gastric motility
stimulates insulin secretion (after protein meal)
incr glucagons secretion
Cholecystokinin-Pancreozymin (CCK-PZ / CCK)
Sythesis: secreted by I cells in mucosa of upper SI, nerves in distal SI and LI (also found in brain); preproCCK processed into many fragments; CCK 8 and 12 are most active
Metabolism: 5mins
Regulation of secretion:
Incr secretion: contact of intestinal mucosa with products of digestion (peptides and aa and fa); digestion caused by release of pancreatic juice causes +ve feedback loop
Decr secretion:
Mechanism of action: CCK receptors activate PLC ( incr production IP3 and DAG
Effects: contraction of GB
Secretion of pancreatic juice
Helps action of secretin in causing secretion of pancreatic juice
Inhibits gastric emptying (augments contraction of pyloric sphincter)
Trophic effect on pancreas
Incr secretion of enterokinase
Incr motility of SI and LI
Incr glucagon secretion
Stimulates insulin secretion
Secretin
Synthesis: secreted by S cells in mucosa of upper SI
Metabolism: HL 5mins
Regulation of secretion:
Incr secretion: products of protein digestion; acidic contents of SI
Decr secretion:
Mechanism of action: works via cAMP
Effects: incr secretion of HCO3 by duct cells of pancrease and biliary tract ( secretion of waterly,
alkaline pancreas juice
augments actions of CCK in causing secretion of pancreatic juice
decr gastric acid secretion
contraction of pyloric sphincter
stimulates insulin secretion
GIP
Synthesis: made by K cells in muscosa of duodenum and jejunum
Regulation of secretion: inc by glu and fat in duodenum
Effects: inhibits gastric secretion and motility in high doses; stimulates insulin secretion
VIP
Synthesis: preproVIP
Metabolism: HL 2mins
Effects: stimulates intestinal secretion of electrolytes and H20; relaxation of intestinal SM; dilation of peri BV’s; inhibition of gastric acid secretion; potentiates action of Ach at salivary glands
Peptide YY
Inhibits gastric acid secretion and motility; release from jejunum stimulated by fat
Ghrelin
Secreted in stomach; stimulates GH secretion; central control of food intake
Motiliin
Secreted by enterochromaffin cells and Mo cells in stomach, SI and colon; acts on GPCR’s in duodenum and colon ( contraction of SM in stomach, SI and LI; regulator of MIC’s
Somatostatin
Secreted by D cells in pancreatic islets and GI mucosa; inhibits secretion of gastrin, VIP, GIP, secretin and motilin, pancreatic exocrine secretion, gastric acid secretion, gastric motility, GB contraction, absorption of glu, aa and triG’s; stimulates acid in lumen
Neurotensin: from mucosa of ileum; stimulate by fa; inhibits GI motility and incr ileal blood flow
Substance P: incr motility
GRP: in vagal nerve ending terminating on G cells; incr gastric secretion
Guanylin: from intestinal mucosa; ( incr conc of intracellular cGMP ( incr secretion of Cl into lumen
Mouth
Mastication: wet, smaller particles
Saliva: 1500ml/day; helps swallowing, keeps moist, solvent for molecules, neutralize gastric acid when regurgitated into oesophagus; hypotonic, slightly acidic, rich in K, low in Na and Cl (when salivary flow rapid, less time for removal of Na and Cl and addition of K and HCO3 in ducts ( saliva more isotonic)
Glands: Parotid: ( serous, watery; 20%
Submandibular: ( mixed, moderately viscous; 70%
Sublingual: ( mucous, viscous; 5%
Salivary glands contain zymogen granules containing salivary enzymes ( discharged from acinar cells into ducts; contains:
Lingual lipase: by glands on tongue
α-amylase: by salivary glands
Mucins: glycoproteins that lubricate food, bind bacteria, protect oral mucosa
Immune globulin IgA\
Lysozyme: attacks walls of bacteria
Lactoferrin: binds Fe, bacteriostatic
Proline-rich proteins: protect tooth enamel, bind toxic tannins
Regulation of secretion: PNS ( incr secretion of watery saliva, vasoD in gland due to VIP
Atropine and anticholingergics ( decr saliva
SNS ( vasoC in gland, decr saliva
Swallowing: afferent impulse: trigeminal, GP and vagus nerves
( nucleus of tractus solitarius and nucleus ambiguous
efferent impulse: trigeminal, facial and hypoglossal nerves
Voluntary stage: tongue pushes backwards
Involuntary stage: contraction of pharyngeal muscles, inhibition of resp and glottic closure, peristalsis at 4cm/sec
Oesophagus
Lower oesophageal sphincter: tonically active (prevents reflux) but relaxes on swallowing; vagal input causes contraction; release of NO and VIP from interneurons causes relaxation; achalasia due to incr tone due to deficiency of myenteric plexus ( decr release NO and VIP
1) Intrinsic sphincter: more prominent SM
2) Extrinsic sphincter: fibres of diaphragm surrounding oesophagus
3) Oblique fibres of stomach wall create flap valve that helps prevent regurg when intraG p rises
Stomach
Secrete gastric juice (2500ml)
Cardia and pyloric region: neck cells of gastric glands and mucosa secrete mucus (with HCO3, made of glycoproteins called mucins) ( alkaline pH at luminal surface; incr by PG
Body: several glands open onto gastric pit
Contains parietal (oxyntic) cells: secrete HCl and IF
HCl: kills bacteria, necessary pH for digestion, stimulates flow of bile
stimulated by histamine via H2 (( incr cAMP via Gs), Ach via M3 (( incr intracellular
Ca), gastrin (incr intracellular Ca)) and IF
Inhibited by PG but activating Gi
H-K ATPase pumps H (from CO2 + H20 ( H2CO3 (catalysed by CA) ( H + HCO3)
against conc grad and IF; at rest cell contains tubulovesicular structures in walls ( on
activation, structures move to apical membrane inserting more H-K ATPase into it
Cl channels activated by cAMP transport Cl down electrochemical grad into lumen; Cl \
enters parietal cell from blood via countertransport with HCO3 from above (after meal,
may get postprandial alkaline tide as blood becomes alkaline)
IF: binds to cyanocobalamin (B12) ( complex taken up by cubilin in receptors in distal ileum
( absorption of complex by endocytosis ( B12 transferred to transcobalamin II which
transports B12 in plasma
Chief (zymogen / peptic) cells: contain zymogen granules ( secrete pepsinogens
Enterochromaffin-like (ECL) cells: secrete histamine; stimulated by gastrin; inhibited by
Somtostatin
Dumping syndrome: in gastrectomised pt; rapidly absorption of glu ( incr insulin ( hypoG ( weakness, dizziness, sweating; hypertonic meals rapidly entering intestine ( movement of H20 into gut ( hypoV
Gastric Motility
Mechanism: food enters stomach ( upper part relaxes (receptive relaxation; vagal; triggered by mvmt of oesophagus) ( peristalsis in lower, mixing (contraction in distal part is antral systole; 3-4 waves/min) ( contraction of pyloric region and duodenum; liquid food enters duodenum (pyloric contraction prevents regurg due to CCK and secretin
Regulation: cephalic (CNS; presence of food in mouth incr vagus output ( incr gastrin via GRP, incr Ach
to incr acid and pepsin; incr by anger, decr by fear and depression)
gastric (local reflex responses to gastrin; stretch and chemical stimuli esp aa; receptors (
submucosal plexus synapsing on postganglionic paraS neurons ( parietal cells ( gastrin)
intestinal (reflex and hormonal feedback; fats, carbs and acid in duodenum inhibit gastric aicd
and pepsin secretion and gastric motility via peptide YY)
alcohol and caffeine act directly on mucosa
Osmolarity of contents: duodenal osmoreceptors sense hyperosmolarity ( decr gastric emptying
Empting fastest for carbs > protein > fat
Pancreas
Zymogen granules contain digestive enzymes ( exocytosis into lumens of pancreatic ducts ( pancreatic duct of Wirsung joins CBD ( ampulla of Vater opening in duodenal papilla, encircled by sphincter of Oddi
Pancreatic juice: 1500ml/day
high HC03 ( neutralize gastric acid
also contain Na, K, Ca, Mg, Cl, SO4, HPO4
enzymes – secreted as proenzymes
Trypsinogen ( converted to trypsin by enteropeptidase (from BB; NOT activated in
pancreas as this would cause autodigestion), also activated by trypsin itself (+ive
feedback loop; pancreas contains a trypsin inhibitor)
Trypsin: converts chymotrypsinogens ( chymotrypsin
Proenzymes ( active enzymes
Regulation of secretion: secretin acts on ducts ( juice rich in alkaline (high HCO3, low Cl), low in
enzymes (due to incr cAMP)
( incr bile secretion
CCK acts on acinar cells ( juice high in enzymes, low in volume (via PLC)
Ach acts on acinar cells ( jucie high in enzymes, low in volume (via PLC)
Liver and Biliary System
Blood extensively modified on passage through liver (portal vein ( sinusoids ( central veins ( hepatic veins ( IVC) – acini, at one side portal vein, hepatic artery, bile duct, this area has best oxygenation
Bile formation: intralobular BD ( interlobular BD ( R+L hepatic ducts ( CHD ( unites with CD ( CBD
Functions: formation and secretion of bile
Metabolism of glu, aa, lipids, fat and water soluble vits
Inactivation of toxins, steroids and other hormones
Synthesis of acute phase proteins, albumin, CF’s, steroid and hormone-binding proteins
Kuppfer cells for immunity
Bile: Alkaline; 500ml/day
Made of bile salts (Na and K salts of bile acids; conjugated to glycine and taurine; made from chol)
Cholic and chenodeoxycholic acid formed in liver
2Y bile acids: Cholic ( deoxycholic acid by bacteria in LI
Chenodeoxycholic ( lithocholic acid by bacteria in LI
Reduce surface tension; emulsification of fat (amphipathic so can form micelles –
hydrophilic out, hydrophobic in)
90-95% absorbed from SI via Na-bile salt cotransporter powered by basolateral Na-K
ATPase ( portal vein ( reexcreted in bile
5-10% enter colon ( converted as above ( lithocholic acid excreted, deoxycholic acid
absorbed and H20 soluble
bile pigments (glucuronides are bilirubin and bilverdin – breakdown products of heme)
Bilirubin: formed by breakdown of Hb ( bound to albumin ( enters liver cells (
bound to cytoplasmic proteins ( conjugated to glucuronic acid by glucuronyl
transferase (activity incr by barbs, antihistamines, anticonvulsants) in SER ( bilirubin
diglucuronide (more H20 soluble)
( AT into bile canaliculi ( SI which is impermeable to conjugated bilirubin,
most of which excreted but colon bacteria can form urobilinogen which can be
reabsorbed into general circ or enterohepatic circ ( excreted in urine
( small (conjugated) amount enters blood ( excreted in urine
Jaundice can be due to XS production of bilirubun, decr uptake of bilirubin into hepatic
cells, disturbed intracellular protein binding/conjugation ( incr
free bilirubin
disturbed secretion of conjugated bilirubin, intr/extrahepatic bile
duct obstruction ( incr conjugated bilirubin
If bile doesn’t enter faeces ( white acholic stools
Also secreted in bile: chol (supersaturation ( gallstones; not able to form micelles if too much), ALP
Gallbladder: absorption of water in stored bile
Cholagogues: cause contraction of GB; CCK
Choleretics: cause incr secretion of bile; vagus nerve, secretin
Small Intestine
Duodenum becomes jejunum at ligament of Treitz ( upper 40% jejunum, lower 60% ileum ( ends at ileocaecal valve
Contains solitary lymphatic nodules
aggregated lymphatic nodules (Peyer’s patches)
intestinal glands (crypts of Lueberkuhn) throughout - enterocytes formed from undifferentiated
cells here which migrate to tips of villi; ave lifespan 2-5/7 as rapidly sloughed; secrete isotonic
fluid; contain Paneth cells in bottom which secrete defensins – natural AB’s
duodenal (Brunner’s glands) – secrete mucus
various enteroendocrine cells
valvulae conniventes
m membrane covered in villi covered by single layer of columnar epithelium containing network
of capillaries and lymphatic vessel (lacteal), with submucosa running to tip of villus; free edges
of cells in villi form microvilli covered in glycocalyx (layer rich in amino sugars) which make up
brush border
epithelial cells – secrete mucus
goblet cells – secrete mucus in SI and LI
Cells connected by tight junctions
Mucus secretion incr by cholinergic stimulation, chemical and physical irritation
Motility: MMCs present; replaced by peristalsis controlled by BER; 12 BER cycles/min in prox jejunum ( 8 in distal ileum; Peristaltic rushes are intense waves occurring when obstruction present; mvmt below slow transit time
Segmental contractions move chime to and fro, incr exposure to mucosal surface, initiated by
focal incr Ca influx
Tonic contractions prolonged contractions which separate regions of SI from eachother
Intestinal adaption: when some bowel removed, hyperplasia and hypertrophy of remaining bowel; still malabsorption if >50% bowel removed (decr enterohepatic circ ( decr fa absorption, osmotic effect of unabsorbed bile salts ( enter colon where incr intestinal secretion; jejunum worse at adapting so worse if distal ileum removed
Paralytic ileus: due to activation of opioid receptors / incr discharge from NA fibres in splanchnic nerves; lasts 6-8hrs in intestine, 2-3/7 in colon
Colon 4hrs to get to cecum, 6 hrs to hepatic flexure, 9hrs to splenic flexure, 12hr to pelvis
For absorption of H20, Na and minerals; external muscle layer collected into 3 longitudinal bands (teniae coli) ( haustra; no villi; short glands; solitary lymph follicles; ileum progects into cecum so incr colonic p closes ileocaecal valve, but incr ileal p opens it; gastroileal reflex causes relaxation of cecum, SNS causes contraction of valve
Na AT out, H20 along osmotic grad; net secretion of HCO3 and K
Segmentation contraction and peristalsis in colon, also mass action contraction with large contraction of SM ( move material ( defecation reflex; BER 2/min at ileocaecal valve, 6/min at sigmoid
Intestinal bacteria: eg. E coli, enterobacter aerogenes, bacteroides fragilis; may use nutrients (eg. Aa’s), but also make nutrients (eg. Folic acid, B vits, vit K, fas); role in cholesterol metabolism; 3 types:
1) Pathogens: cause disease
2) Symbionts: benefit host
3) Commensals: no effect on host or vice versa
Dietary fibre: cellulose, hemicellulose, lignin, gums, algal polysaccharides, pectic substances; poorly digested; forms bulk
Defecation: a spinal reflex that can be inhibited or facilitated voluntarily
SNS to internal anal sphincter ( contraction (involuntary); relaxes on distension with reflex
muscular contractions
external anal sphincter nerve supply from pudendal nerve; tonic contraction ( relaxes when p
55mmHg in rectum / voluntary defecation due to straining (abdo muscles contract, pelvic
floor lower 1-3cm, relaxation of puborectalis, decr anorectal angle to 15 deg
Gastrocolic reflex: distension of stomach ( contractions in rectum
BLOOD
Plasma Composition
Circulating Body Fluids
[pic]
Blood: normal circulating vol is 8% body weight, 5600mL; 55% of vol is plasma
Bone marrow: extramedullary haematopoiesis occurs BM disease; in children occurs in all bones, by 20yrs only in long bones; active cellular marrow is red marrow, inactive is infiltrated with fat yellow marrow; 75% is WBC, 25% is RBC as average life span of WBC is short; HSC’s best derived from blasocytes of embryos in umbilical cord blood
Granuloctye and Macrophage Colony-Stimulating Factors: stimulate growth of certain cell lines; also sustain mature cells; some crossing-over of action of factors; usually acting locally in BM; Stem cell factor – needed from prolif and maturation of HSC’s
|Cytokine |Source |Cell Line Stimulated |
|IL-1 |Multiple cell types |Erythrocyte, granulocyte, megakaryocyte, monocyte |
|IL-3 |T cells |Erythrocyte, granulocyte, megakaryocyte, monocyte |
|IL-4 |T cells |Basophil |
|IL-5 |T cells |Eosinophil |
|IL-6 |Endothelial cells, fibroblasts, macrophages |Erythrocyte, granulocyte, megakaryocyte, monocyte |
|IL-11 |Fibroblasts, osteoblasts |Erythrocyte, granulocyte, megakaryocyte |
|Erythropoietin |Kidney, Kupffer cells |Erythrocyte |
|SCF |Multiple cell types |Erythrocyte, granulocyte, megakaryocyte, monocyte |
|G-CSF (granulocyte) |Endothelial cells, fibroblasts, monocytes |Granulocyte |
|GM-CSF (granulocyte-macrophage) |Endothelial cells, fibroblasts, monocytes, T cells |Erythrocyte, granulocyte, megakaryocyte |
|M-CSF (macrophage) |Endothelial cells, fibroblasts, monocytes |Monocyte |
|Thrombopoietin |Liver, kidney |Megakaryocyte |
WBC’s: 4000-11000cells/ μL
Granulocytes/polymorphonuclear leukocytes: horseshoe nuclei, become lobed as older; contain
cytoplasmic granules that contain substances involved in inflamm/allergic reactions
Neutrophils: 3000-6000cells/μL; 50-70% of WBC; halflife 6hrs; attracted to endothelial
cell surfaces by selectins ( roll along it ( bind to neutrophil adhesion molecules of
integrin family ( pass through wall of capillaries between endothelial cells by
diapedesis
Eosinophils: 150-300cells/ μL; 1-4% of WBC; halflife short; also undergo diapedesis;
maturation and activation induced by IL3 and 5, GM-CSF
Basophils: 0-100cells/ μL; 0.4% of WBC
Lymphocytes: large round nuclei and scanty cytoplasm; 1500-4000cells/ μL; 20-40% of WBC
Monocytes: much agranular cytoplasm and kidney-shaped nucleus; 300-600cells/ μL; 2-8% of
WBC
Mast cells: heavily granulated wandering cells found in areas rich in CT; contain heparin, histamine and proteases; have IgE receptors and degranulate when IgE coated antigens bind them
Monocytes: circulate for 72hrs then enter tissues and become tissue macrophages (eg. Kupffer cells in liver, pul alveolar macrophages, microglia in brain) where they persist for 3/12
Lymphocytes: enter blood stream via lymphatics; only 2% usually found in blood, rest in lymphoid organs
Lymphocyte precursors come from BM
( thymus to be transformed into T cells ( to LN’s ( to body
T cells ( cytotoxic (CD8) – destroy foreign cells; development aided by helper T cells;
divided into αβ and γδ types
( helper 1 (CD4) – secrete IL-2 and γIF, important in cellular immunity
( helper 2 (CD4) – secrete IL-4 and 5, interact with B cells for humoral
immunity
( memory T cells
( bursal equivalents (eg. fetal liver, BM, spleen) to be transformed into B cells ( to LN’s ( to
body
B cells ( plasma cells – secrete Ig from Ag-binding receptors
( memory B cells
Antibodies:
1) Bind and neutralize protein toxins
2) Block attachment of viruses and bacteria to cells
3) Osponise bacteria
4) Activate complement
Natural Killer Cells: are cytotoxic lymphocytes, but are not T cells
Cytokines: hormone-like molecules that act in paracrine fashion to regulate immune responses; a superfamily are chemokines which attract WBC’s to areas (receptors are G proteins)
|Cytokine |Source |Activity |Relevance |
|IL-1 |Macrophages |Activate T cells and macrophages; causes fever; incr slow |Septic shock, RA, atherosclerosis |
| | |wave sleep and decr appetite | |
|IL-2 |TH1 cells |Activate lymphocytes, NKC’s and macrophages |Trt of metastatic RCC, melanoma, tumours |
|IL-4 |TH2 cells, mast cells, |Activate lymphocytes (esp TH2), monocytes, IgE class |Allergy |
| |basophils, eosinophils |switching | |
|IL-5 |TH2 cells, mast cells, |Differentiation of eosinophils |Allergy |
| |eosinophils | | |
|IL-6 |TH2 cells, macrophages |Activation of lymphocytes, differentiation of B cells, |Acts as GF in myeloma |
| | |stimulate production of acute-phase proteins; causes fever| |
|IL-8 |T cells and macrophages |Chemotaxis of neutrophils, basophils, T cells |Marker of disease activity |
|IL-11 |BM stromal cells |Simulate production of acute-phase proteins |Decr chemotherapy-induced thrombocytopaenia |
|IL-12 |Macrophages and B cells |Stimulate production of IFγ by TH1 cells and NKC’s; induce|Vaccines |
| | |TH1 cells | |
|TNFα |Macrophages, NKC’s, T and B |Inflammation; causes fever |RA |
| |cells, mast cells | | |
|Lymphotoxin (TNFβ)|TH1 cells and B cells |Inflammation |MS and IDDM |
|TGFβ |T cells, B cells, mast cells |Immunosuppression |MS and MG |
| |and macrophages | | |
|GM-CSF |T cells, B cells, NKC’s and |Promote growth of granulocytes and monocytes |Decr neutropenia after chemo; stimulate cell |
| |macrophages | |production after BM transplant |
|IFα |Virally infected cells |Induce resistence of cells to viral infection |AIDS, melanoma, chronic hepatitis B and C |
|IFβ |Virally infected cells |Induce resistence of cells to viral infection |Decr relapse of MS |
|IFγ |TH1 cells and NKCs |Activate macrophages, inhibit TH2 cells |Help chronic granulomatous disease |
Complement system: 3 pathways activate system
1) Classic pathway: triggered by immune complexes
2) Mannose-binding lectin pathway: triggered when lectin binds mannose groups in bacteria
3) Alternative/properdin pathway: triggered by contact with pathogen
Pathways work in various manners;
1) Opsonisation ( chemotaxis ( lysis by inserting perforins into cell membranes ( disrupt
membrane polarity
2) Activate B cells and aid immune memory
3) Dispose of waste products after apoptosis
Inflamm response: may kill bacteria / damage host tissue (eg. RA)
1) Incr production of neutrophils
a. Bacteria interacts with factors and cells to cause chemotaxis of neutrophils to infected area via chemokines (C5a, leukotrienes, mast cells, basophils); this movement + phagocytosis require microfilaments and microtubules, interaction of actin and myosin-I
b. Plasma factors cause opsonisation of bacteria – usually IgG and complement proteins added so can bind easily to neutrophil ( G-protein mediated response
( incr motor activity of cell ( ingestion of bacteria by phagocytosis
(exocytosis (neutrophil granules discharge contents into phagocytic vacuoles, and into
interstitial space – degranulation)
Granules contain defensins (antimicrobial proteins)
proteases
elastases
metalloproteinases (attack collagen)
c. Respiratory burst: cell membrane enzyme NADPH oxidase activated ( toxic oxygen metabolites to help kill; this requires incr O2 uptake and metabolism of neutrophil
NADPH + H+ + 2O2 ( NADP + 2H+ + 2O2- (free radical)
O2- + O2- + H+ + H+ ( H2O2 + O2 (catalysed by superoxide dismutase) (both are
bactericidal)
H2O2 ( H2O + O2 (catalysed by catalase)
d. Myeloperoxidase: released by neutrophils, catalyses conversion of Cl, Br, I, and SCN to acids (HOCl, HOBr etc…) which are oxidants
2) Incr activity of eosinophils
a. Release proteins, cytokines and chemokines that produce inflammation; esp abundant in GI, RS and GU tract mucosa; incr in allergic disorders and other RS/GI diseases; more selective than neutrophils
3) Incr activity of basophils
a. Release proteins and cytokines; contain histamine and heparin which are all released when activated by histamine-releasing factor secreted by T cells; for immediate hypersensitivity
4) Incr activity of mast cells
a. Involved in inflamm reactions initiated by IgE and IgG; release TNF-α by ab-independent mechanism ( non-specific natural immunity; involved in allergic reactions
5) Incr activity of macrophages
a. Activated by lymphokines from T cells ( migrate via chemotaxis ( phagocytosis similar to neutrophils; secrete substances that affect lymphocytes, PGE and CF’s
Phagocytic disorders:
Neutrophil hypomotility: poorly polymerized actin ( slow neutrophils
Chronic granulomatous disease: failure to make O2 in neutrophils and monocytes
G6PD def: failure to make NADPH and hence decr O2 production
Immunity:
Innate immunity: found in invertebrates and 1st line defense in vertebrates
Receptors bind sequences of sugars/fats/aa found in common bacteria / urate crystals secreted by bacteria activate immune response ( defense mechanisms via NKC’s, neutrophils, macrophages
( release of IF’s, phagocytosis, antibacterial peptides, complement system, proteolysis
( activate acquired immune system
Eg. TLR4 (toll receptor) binds bacterial lipopolysaccharide protein CD14 (important in production of septic shock in G-ive bacteria) ( cascade of immune events
Eg. TLR2 for microbial lipoproteins, TLR6 for peptidoglycans, TLR9 for DNA
Acquired immunity: specific Ag’s activate T and B cells ( production of ab’s
1) Humoral immunity: mediated by ab’s (in γ globulin fraction of plasma proteins) produced by B cells ( activate complement system and neutralize ag’s; important in bacterial infection
2) Cellular immunity: mediated by T cells ( insert perforins; important in viral/fungal infections, delayed allergy, rejection of transplants, fighting tumours
Antigens:
Ag taken up by APC – can be dendritic cells in LN’s, spleen and skin
macrophages
B cells
Ag partially digested in APC ( peptide fragment coupled to HLA (human leukocyte Ag’s) - protein products of MHC (major histocompatibility complex) genes on C6
Class I – heavy chain assoc noncovalently with β2-microglobulin; found on all nucleated
cells; mainly coupled to peptide fragments generated from proteins (in proteasomes)
from WITHIN cells
Class II – lighter chain assoc noncovalently with lighter β chain; present in APC’s (inc B cells and
activated T cells); mainly couped to peptide fragments from EXTRACELLULAR
proteins that enter cell by endocytosis (eg. bacteria)
HLA-Ag complex put on cell surface ( presented to αβ T cell receptors (made up of α and β units)
Cytotoxic (CD8) T cells bind MHC-I ( kill target directly
Helper (CD4) T cells bind MHC-II ( T cells secretes cytokines that activate other lymphocytes
For T cell activation 2 signals needed - there is also binding of adhesion molecules to complementary proteins in APC
B cells can binds Ag’s directly ( contact TH2 cell for activation and ab formation ( memory B and plasma cells (secrete ab’s)
Immunoglobulins
Bind and neutralize protein toxins; block attachment of viruses and bacteria to cells; opsonise bacteria; activate complement
Made of 4 polypeptide chains – 2 heavy chains, 2 light chains – joined by disulphide bridges that permit mobility; heavy chains flexible at hinge; contain C constant segment, and variable segments (J joining, D diversity, V variable); V are Ag binding sites; Fc portion is effector portion
IgG: complement activation
IgA: localized protection in external secretions (secretory immunoglobulins)
IgM: complement activation
IgD: Ag recognition by B cells
IgE: reagin activity; releases histamine from basophils and mast cells
Platelets:
Small granulated bodies that accumulate at sites of vascular injury; no nuclei; HL 4/7; formed from megakaryocytes in BM by pinching off bits of cytoplasm; 60-75% in blood, rest in spleen; membranes have receptors for collagen, ADP, vWF and fibrinogen
Cytoplasm contains dense granules (containing substances secreted on plt activations – 5-HT, ADP,
adenine nucleotides)
α-granules (contains proteins in lysosome – CF’s, PDGF (stimulates wound healing,
mitogen for vascular SM))
Production regulated by CSF’s from megakaryocytes and thrombopoietin (from liver and kidneys)
BV wall injury ( exposed collagen and von Willebrand factor in wall ( plts adhere via receptors ( plt activation ( release contents of granules
( ADP stimulates more plt aggregation (aided by platelet activating factor from neutrophils and
monocytes which acts via GPCR ( incr arachidonic acid derivatives (eg. TXA2))
Red Blood Cells:
Biconcave discs made in BM; no nuclei; last 120days; shrink/swell depending on osmotic p (haemolyse in hypotonic saline); spleen removes abnormal RBC’s
Hb: O2 carrying pigment; globular molecule made of 4 subunits each containing heme (Fe containing porphyrin derivative) and polypeptides (2 pairs per Hb molecule) which form globin portion; binds O2 ( oxyHb (O2 attaches to Fe in heme; H and 2,3BPG compete with O2 ( decr affinity of Hb for O2); drugs may cause Fe2+ to be converted to Fe3+ ( methemoglobin; CO reacts with Hb ( COHb (has much higher affinity for Hb than O2)
HbA: α2β2; normal adult Hb
HbA2 (2.5%): α2δ2
HbF: α2γ2; bind less avidly to 2,3-BPG so higher affinity for O2
Gower 1 Hb: ζ2ε2 (in embryo)
Gower 2 Hb: α2ε2 (in embryo)
Catabolism: RBC’s destroyed in tissue macrophage system ( heme converted to bilverdin (CO formed in process) ( converted to bilirubin and excreted in bile
Plasma:
Normal plasma vol is 5% body weight (3500ml); contains CF’s
If whole blood allowed to clot, and clot removed ( remaining is serum (same as plasma but minus fibrinogen, CF II, V, VIII)
Plasma proteins: albumin, globulin, fibrinogen, CF’s, ab’s; capillary walls impermeable to these ( exert 25mmHg oncotic pressure across capillary wall pulling H20 into blood; also responsible for 15% buffering capacity of blood; mostly anionic; most made in liver except ab’s
Low in liver disease, starvation, malabsorption
Lymph:
Tissue fluid that enter lymphatic vessels ( enters venous blood via thoracic and R lymphatic ducts; contains CF’s; lower protein content than plasma; involved in absorption of H20-insoluble fats; lymphocytes enter blood through lymph
Haemostasis:
Damage to blood vessel wall ( constriction (due to 5-HT) and formation of haemostatic plug of plts as they bind to collagen and aggregate ( bound together by insoluble fibrin as fibrin monomer polymerises and has covalent cross-linkages, catalysed by XIII and requiring Ca (formed from soluble fibrinogen in clotting cascade) ( definitive clot
Thrombin: activates plts, endothelial cells, leukocytes
SEE DIAGRAMS
03 3263242
-----------------------
A = when AVN activated
H = transmission through His bundle
V = V depol
PA interval = time from 1st appearance of atrial depolarization to A wave = conduction time from SAN to AVN
AH interval = AVN conduction time
HV interval = from start of H to start of QRS = conduction in BOH and BB’s
Late diastole: MV and TV open; AV and PV closed; MV and TV drift closed towards end
blood flows into A and V (70% of V filling); r of filling decr as V’s become
distended
End-diastolic V vol = 130ml
Atrial systole: R systole occurs before L
MV and TV open
propels more blood (30%) into V via incr Ap
contraction of atrial muscle around IVC, SVC and pul veins but still some regurg
into veins ( a wave in JVP
Ventricular systole: L systole occurs before R (but ejection in R occurs 1st as pul art p p in aorta (80mmHg) and pul art (10mmHg))
( AV and PV open; AV valves bulge into atria causing small rise in IAp
( c wave in JVP
ventricular ejection (rapid then slow ejection; IVp (L @ 120mmHg, R @
25mmHg) reaches max then decr so late in systole Ap > Vp but momentum
keeps blood going; contraction causes MV and TV to be pulled down
causing decr Ap; 70-90ml ejected per V overall)
End-systolic V vol = 50ml
EF (% end-diastolic vol ejected per stroke) = 65%; reflects V function
Early diastole: protodiastole (when V muscle fully contracted and Vp drops; 0.04s)
Ends when momentum of blood overcome
( AV and PV close (during expiration occurs @ same time, during
inspiration AV closes before PV due to lower impedance of pul vasc
tree)
isovolumetric ventricular relaxation (IVp drops rapidly; blood enters A causing
incr Ap ( v wave on JVP)
Ends when Vp < Ap
( MV and TV open
V’s fill rapidly then slower, causing decr Ap
O2 + Hb ( HbO2 (oxyhaemoglobin)
Amount of O2 bound to Hb increases rapidly until 500mmHg then levels out thereafter
Max amount O2 that can bind Hb is O2 capacity – when all available binding sites occupied – expose blood to v high pO2 and subtract dissolved O2
1g Hb can bind 1.39ml O2
Normal blood has 15g Hb/100ml so capacity 20.8ml/100ml
O2 saturation: % of available binding sites that have O2 attached; 97.5% if 100mmHg O2 (arterial), 75% if 40mmHg (venous)
O2 combined with Hb X 100
O2 capacity
Normal value of pO2 at 50% sat is 27mmHg which is P50
More linear than O2 dissociation curve
The lower the sat of Hb with O2, the larger the CO2 conc for given pCO2 (Haldane effect – better ability of reduced Hb to mop up H+ produced when carbonic acid dissociates, greater ability of reduced Hb to form carbaminohaemoglobin
More steep than O2 dissociation curve
Between 40-50mmHg CO2 conc changes more that O2 – so pO2 diff between arterial and venous blood is large, but pCO2 diff is small
~¯¯›¯œ¯¤¯×¯¿°Ç°Ò°ð°ñ°ú°±/±:±E±^±µ±¶±Ê±Ù±Ú±â±(²)²Ù²õ²ö²÷²û²³9³Q³q³y³Ï³Ó³Ý³è³ó³ý³´Ç´Ò´(µ0µ~µ‡µöµ÷µ4¶òêßÖÎêÆêÆê½´ê´ê´êß´êß´êòêÆ©¡½´ê´ê˜Æ?˜Æ˜Æ˜Æ?Æ?Æ?Æ?ÆCO2 curve shifted to R by incr SO2
As long as ratio of HCO3 : pCO2 x 0.03 remains 20, pH will remain same; HCO3 detemined by kidney, pCO2 by lung
Davenport diagram: shows relationship between HCO3, pCO2 and pH; A is normal plasma; line CAB (buffer line) is effect as carbonic acid is added to whole blood – presence of Hb makes line steeper, displaced upwards if more HCO3 from kidneys (incr base excess defined by distance between new buffer line and old), vice versa
Respiratory Acidosis
Incr pCO2 ( decr HCO2/pCO2 ratio ( decr pH ( move towards B as HCO3 must incr due to dissociation of carbonic acid, but ratio of HCO3:pCO2 decr; if persists, kidney conserves HCO3 and secretes H+ as H2PO4 and NH4 so ratio HCO3:pCO2 returns to normal (moves from B to D ( compensated resp acidosis which is usually not complete so pH not completely normalized, amount detemined by base XS (vertical difference between BA and DE)
Resp alkalosis
Decr pCO2 ( incr HCO3:pCO2 ratio ( incr pH (A(C); renal compensation excretes HCO3 ( return ratio to normal (C(F) which may be nearly complete ( base deficit
Metabolic acidosis
Decr ratio HCO3:pCO2 ( decr pH (A(G); resp compensation lowering pCO2 ( incr HCO3:pCO2 due to H+ ions detected by chemoreceptors (G(F) ( base defecit
P-V curve is non-linear; becomes stiffer at high vols
Hysteresis: lung vol at any p during deflation is larger than during inflation
Note lung without any expanding p still has air inside it; even if p is above atmospheric p (0 on horizontal axis) airways will collapse trapping air inside (this occurs at higher vols in lung disease)
p in airways and alveoli = atmospheric; change in pressure occurs outside lung ( transpulmonary pressure (p outside lung is subatmospheric due to elastic recoil of lung
Compliance = slope of p-v curve (ie. vol change per unit p change); compliance is 200ml/cm water; at higher expanding pressures
Decr compliance (slope of curve flattens): lung disease, alveolar oedema, incr pul venous p and if lung unventilated for long period due to atelectasis and incr surface tension
Incr compliance: pul emphysema, normal aging lung, asthma attack
Elasticity: tendancy of lung to return to resting vol after distension due tp fibres of elastic and collagen in alveolar walls and around vessels and bronchi
Shape of intrapleural p curve different to vol curve due to changes in lung compliance
Before inspiration:
Intrapleural p = -5cm due to elastic recoil of lung
Alveolar p = 0cm (atmospheric); with no airflow there is no p difference along airways
On inspiration:
Lung expands ( elastic recoil increases ( intrapleural p drops from A(B on black line; intrapleural p decreased even more by airway resistance (80%) (hatched area, A(B on blue line)
Part of hatched area is due to tissue resistance (20%) – p required to overcome viscous forces of tissue as they slide over eachother
Tissue + airway resistance = pulmonary resistance
On expiration:
Note airway resistance causes intrapleural p to be LESS negative (follow blue line)
Inspiration: intrapleural p A(B(C
Work done = 0ABCD0
Work done to overcome elastic forces = 0AECD0
Work to overcome airway+tissue resistance = ABCEA; the more airway resistance, the more negative intrapleural p needs to become
The faster RR, faster flow rate, larger this area ABCEA is, but also 0AECD0
Expiration: intrapleural p C(F(A
Work done = 0AECD0
Work to overcome airway+tissue resistance = AECFA (this lies within 0AECD0 so is done by energy stored in elastic structures (ie. passive)
( O2 consumption incr linearly; above certain limit VO2 becomes constant (VO2max) – incr work above here needs anaerobic glycolysis
( Ventilation incr linearly ( at high VO2 values, due to lactic acid release, more incr ventilation due to ventilatory stimulus; change occurs at anaerobic threshold
( incr diffusing capacity of lung (incr diffusing capacity of membrane and vol of blood in pul capillaries due to recruitment and distension of capillaries due to incr CO and hence high pul art and venous p)
( incr CO linearly with work level due to incr HR and SV; change in CO is only ¼ that of change in ventilation
( decr ventilation-perfusion inequality due to more uniform distribution of blood flow
( O2 dissociation curve moves to R due to incr pCO2, H+ and temp ( easier O2 unloading
( decr PVR as caps open ( decr diffusion distance to tissues
Flow-volume curve: remember after small amount gas exhaled, flow limited by airway compression and determined by elastic recoil force of lung and resistance of airways upstream of collapse point
Restrictive: max flow rate decreased, total vol exhaled decreased; flow rate unnaturally high during latter part of expiration due to incr lung recoil
Obstructive: max flow rate decreased, total vol exhaled decreased; low flow rate in relation to lung vol throughout
................
................
In order to avoid copyright disputes, this page is only a partial summary.
To fulfill the demand for quickly locating and searching documents.
It is intelligent file search solution for home and business.
Related download
- 5 dextrose injection usp
- osmolality as a valuable tool in formulation studies for
- bio416k practice osmolarity problems key answer the
- the implications of osmolality osmolarity and ph in
- commack high school hl biology
- جامعة نزوى
- cellular function
- osmosis plant phys
- fluid electrolyte
- pharmacology—iv solutions parenteral and enteral nutrition
Related searches
- function and function notation problems
- function and function notation
- function keys function windows 10
- function of a function math
- function of a function calculator
- function inside a function python
- function not a function worksheet
- the function of cellular respiration
- main function of cellular respiration
- linear function using function notation
- is locomotion a function of cellular membranes
- function or not a function worksheet answers