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

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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

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