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5P&P > 5P&P > Flashcards

5P&P Flashcards

1
Q

how much filtrate is produced a day by the glomerulus?

A

180l/day

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2
Q

how many times is plasma filtered a day?

A

65 times/day

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3
Q

what is the filtration barrier of the glomerulus?

A

the glomerular capillary

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4
Q

what are the 3 components of the glomerulus?

A

epithelial cells
basement membrane
endothelial cells

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5
Q

describe the endothelial cells layer

A 
flat
large nuclei 
cells in contact with each other
circular fenestrations
filters blood and plasma
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6
Q

describe the basement cells layer

A

continuous
the main barrier
glycoproteins
fibronectins, collagen and laminin

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7
Q

describe the epithelial cells layer

A 
trabeculae - extensions from cell body
pedicels - extensions from trabeculae
interdigitate
slit pores
maintenance and phagocytosis - main roles
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8
Q

what 3 things determine whether or not something is filtered?

A

its molecular size, shape and charge

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9
Q

what happens if the F/P ratio is one and if it is less than 1?

A
  • if the F/P ratio is one, the molecules are free to cross the barrier. thesis because the concentration in the plasma and the filtrate is the same and so there is no resistance
  • if the F/P ratio is less than one, this means that there is resistance and so the molecule is less free to cross. there are more restrictions in what is filtered
  • shows that as mass/molecular weight increases, the likelihood of filtration decreases!
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10
Q

what is the charge of a natural dextran and it’s modified version?

A

a natural dextran is a negative charge

the uncharged dextran is the neural dextran manipulated to lose it’s charge

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11
Q

why must there be a consideration in the charge of the molecule trying to get across?

A

the basement membrane has a negative charge and so any molecule trying to get through will struggle if they have a negative charge due to the repellence of negative-negative charges.

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12
Q

what is the filtration coefficient kf?

A

a measure of the permeability of the filtration barrier

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13
Q

what are starlings forces?

A

the forces for and against the making up of the glomerular filtration rate
there are 4 forces, 2 hydrostatic and 2 oncotic
2 for: hydrostatic pressure in the capillaries and oncotic pressure in the bowman capsule
2 against: hydrostatic pressure in the bowman capsule
oncotic pressure in the capillaries

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14
Q

describe changes that may be seen in terms of the hydrostatic pressure in the capillaries, the hydrostatic pressure in the bowman capsule and the the oncotic pressure in the capillaries

A

as blood volume is lost in the capillaries, the hydrostatic pressure will also decrease
pbc is constant because as fluid comes in and fluid in is already on its way to the proximal tubule, this keeps a constant flow (open system)
the oncotic pressure increases as fluids being lost through filtration, proteins stay and the concentration increases.

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15
Q

what are the ideal numbers for the GFR equation? what is the resultant net filtration pressure?

A

GFR = forces for - forces against
GFR = (Pcap+oncBC) - (PBC+oncCAP)
GFR= (60+0) - (20+60)
net filtration pressure is 10mmHg

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16
Q

what is the ideal GFR and snGFR?

A 
GFR = 125ml
snGFR = 50nl/min
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17
Q

what is the afferent arteriole resistance?

A

the ability to constrict and change blood flow

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18
Q

describe the effect of auto regulation if the arteriole bp increased or the resistance in the afferent arteriole decreased

A

high arteriole blood pressure leads to an increase in renal blood flow then an increase in GFR and then auto regulation (vasodilation)
if there is an increase in the resistance of the afferent arteriole, there would be a decrease in renal blood flow, decrease in RBF and Pcap so a decrease in GFR (vasoconstriction)

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19
Q

describe the effect of auto regulation if the arteriole bp decreased or the resistance in the afferent arteriole increased

A

a decrease in arteriole blood pressure leads to a decrease in RBF and GFR so auto regulation (vasoconstriction)
an increase in resistance in the afferent arteriole, leads to an increase in RBF and Pcap so GFR increases (vasodilation)

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20
Q

what happens if there is any change in the arteriole blood pressure?

A

the kidney would detect this change and put in place autoregulatory mechanisms t counter act this changeably contracting/stretching the afferent arteriole

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21
Q

what are the 2 theories/mechanisms that have been put forward to explain the formation of the glomerular filtrate?

A

the myogenic theory and the juxtaglomerular feedback theory

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22
Q

explain the myogenic theory

A

the property afferent arteriole smooth muscle
if there is an increase in arteriole blood pressure, the afferent arteriole will stretch and then shortly afterward, will vasoconstrictor. this will lead to an increase in the afferent arteriole resistance therefore a decrease in GFR

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23
Q

explain the juxtaglomerular feedback theory

A

this uses juxtaglomerular apparatus
there is macula densa cells which checks the ate of flow in the glomerular capillary and releases chemicals to to act on these changes
if there is a change in the rate of fluid flow, there is a release of vasoconstrictors which would lead to afferent arteriole constriction

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24
Q

what theory out of the two that have been put forward to explain the formation of the filtration is right?

A

it is thought that they are both right and that a combination of these theres with their mechanisms are acting at the same time

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25
Q

what are the units for osmolality?

A

mOsmol/kgH20

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26
Q

what is the difference in osmolality between glucose and sodium chloride

A

glucose can only split into 1 molecule of [X]n would be [100]1=100 whereas sodium chloride can split into 2 molecules (Na and Cl) so [100]*2 = 200.

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27
Q

how many nephrons does the collecting duct drain?

A

6 nephrons

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28
Q

describe the process of Na, Cl and H2O handling in the kidneys

A

there is a loss of Na&Cl from the thin and thick LOH
so osmolality drops from 290-90mOsm (hypoosmolality)
this makes the ISF osmolality increase
provides a driving force for H2O movement
H20 loss from descending limb of LOH
tubular fluid osmolality increases which drives more Na and Cl loss
leads to huge multiplication

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29
Q

what allows the multiplication process to work?

A

the fact that in the ascending limb, it is very permeable to Na and Cl but NOT WATER
in the descending limb, it is very permeable to water but NOT NA & CL

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30
Q

why is there a high osmolality in the ISF?

A

as the fluid moves down the collecting duct, it leads to more H2O loss and so there is a maximum value of 1400 stored in the bladder to be excreted

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31
Q

what drives water reabsorption in the collecting duct?

A

the LOH maximises the osmolality around the kidney and this interstitial fluid osmolality is what drives water reabsorption in the collecting duct

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32
Q

what is the transverse and vertical gradient hypothesis?

A

loss of Na and Cl so osmolality decreases
loss of H20 so osmolality increases
overall, there is an increase in osmolality going down and a decrease in osmolality going up
the transverse gradient is at each level, comparing the ascending and descending limb

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33
Q

describe the thin descending limb

A

transports proteins
essentially impermeable to NaCl (less leaks)
H2O movement is mediated by AQUAPORIN 1

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34
Q

what occurred in the mice KO of aquaporin 1?

A

there were problems in its urine concentration

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35
Q

what is the purpose of aquaporin 1?

A

it allows water movement in the presence of an osmotic gradient

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36
Q

describe the thin ascending limb

A

it is H2O impermeable
very thin and narrow -difficult to dissect out of rats kidney
NaCl and urea permeable - passive
leak of urea through ISF into thin ascending limb

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37
Q

what is more important, the thinner thick ascending limb?

A

the thick ascending limb

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38
Q

describe the thick ascending limb

A

high electrochemical driving force
NKCC2 transorts Na, 2Cl and K into the cell
Cl builds up and is reabsorbed by CLCK
sodium out of the cell through Na/K ATPase
K reabsorbed through ROMK

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39
Q

what is the problem if K ions are not recycled across the apical membrane?

A

no Na/Cl- can be reabsorbed

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40
Q

describe Bartters syndrome

A 
genetic inheritance
salt wasting
hypokalaeimia 
polyuria
hypercalicuria
metabolic alkalosis
problem in concentrating their urine
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41
Q

do the principal cells play a direct role in counter-current multiplication?

A

no

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42
Q

what are the key proteins directly involved in CCM?

A

Aquaporins 2,3 and 4

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43
Q

describe aquaporin 2

A

regulated by vasopressin
increase in vasopressin so an increase in aquaporin so an increase n H2O reabsorption so an increase in concentrated urine

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44
Q

what channel is there a problem in during diabetes insipidus?

A

problem with the vasopressin system / AQP channels therefore impacts in the CCM system

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45
Q

what is urea permeability dependent on?

A

vasopressin

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46
Q

what are the two urea transport proteins?

A

UTA1 and UT-A3

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47
Q

what experiment was done to show the importance of UTA1 and 3?

A

there was a double knock out of UTA1 and 3 in mice
the osm of KO mice was half that of a wt mouse when there was free H2O availability
when there was no water, osm of KO mice was the same as when there was unlimited water but wt produced 4000osm when there was no H20
this is because when there is no water, there is less H2O in the urine and therefore the concentration of the urine increases
the KO mouse was unable to do this

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48
Q

what is vasa recta?

A

the specialised blood supply in the kidney

prevents washout due to it’s looping

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49
Q

why is there no washout though the vasa recta?

A

high permeability of H2O and solute
high ISF osmolality down the descending limb
as you go down, H2O out and solutes in
osmolality increases to the tip of the recta then goes round the ascending limb where everything happens in the opposite direction
tip of the top of the vasa recta is the same osmolality therefore no washout

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50
Q

discuss the importance of CCE and CCM in terms of UTB

A

as solutes move into the plasma, they move into RBCs
UTB mediates the loss of urea from RBC
some patients have lots of UTB
urea can’t easily leave their RBCs. this takes more time, the RBSs leave the vasa recta and they flush out the urea outside the kidneys
this shows the importance of counter-current exchange as well as CCM

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51
Q

what kind of scale is pH and what are the implications of this?

A

it is a log scale
a little change in pH has a massive impact on the [H+]
it is a reciprocal scale so if pH increases, [H+] decreases

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52
Q

what kind of physiological effects would a fluctuation in [H+] cause?

A

excitability of muscle/nerve
enzyme activities
K+ levels

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53
Q 
what are the pH values for:
gastric secretions
cerebrospinal fluid
pancreatic secretions
final urine
A

gastric secretion - 0.7
cerebrospinal fluid - 7.3
pancreatic secretions - 8.1
final urine - 5.4

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54
Q

how much acid is metabolised in the lungs and what is the net [H+]?

A

15 moles/day of CO2

40mmol/day net H+

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55
Q

what is the amount of H+ in a western diet?

A

alkali (fruit) and acid (food)
20mmol/day H+
loss base: 10mmol/day OH-
net excess = 70mmol/day H+

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56
Q

what are the systems involved in attempting to excrete the excess acid?

A

blood and tissue buffers -takes seconds
respiration - take minutes
renal - takes hours/days – most important mechanism for the direct loss of acid/base from the body

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57
Q

what is the only mechanism that can be used for the extrusion of acid/alkali?

A

the renal mechanism

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58
Q

where are buffers present in?

A

blood plasma & RBCs
extracellular fluid - ICF
intracellular fluid
urine (transcellular fluids)

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59
Q

what are some examples of buffers?

A

haemoglobin
HCO3-
in organic phosphate (kidney uses phosphate to excrete H+)
weak acids/bases on proteins - accept/donate H+

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60
Q

what is the henderson-hasselbach equation?

A

pH = pk+log[HCO3]/[H2CO3]

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61
Q

what is the normal value for [HCO3]/[CO2]? and for the pH or urine

A

20;1

so 6.1+log20=6.1+1.3=7.4

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62
Q

what causes metabolic acidosis and alkalosis. also respiratory acidosis and alkalosis?

A

low pH, [low bicarbonate] = metabolic acidosis
high pH, [high bicarbonate] = metabolic alkalosis
low pH, [high bicarbonate] = respiratory acidosis
high pH, [low bicarbonate] = respiratory alkalosis

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63
Q

what is the chemical control of ventilation?

A

controls blood gas composition - PO2, PCO2, pH - changes in creating have an impact on acid/base status
peripheral and central chemoreceptors
negative feedback system (firing, activity drops)

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64
Q

what do hypoxia, hypercapnia and acidosis cause?

A

increase in ventilation and so an increase in PO2, decrease in PCO2 and an increase in pH

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65
Q

what are the 2 types of bodies in the peripheral chemoreceptors?

A

carotid and aortic bodies?

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66
Q

what is the main stumbles of the peripheral chemoreceptors?

A

hypoxia - fall in PO2

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67
Q

what is the specialised cell in the peripheral chemoreceptors called?

A

glomus cells

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68
Q

how does a change in respiratory rate come about in peripheral chemoreceptors?

A

anoxia - membrane depolarises
fire AP when O2 is low
AP signal to nerves in the respiratory centre
changes respiratory rate

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69
Q

describe carotid bodies and glomus cells?

A 
small (around 2mg)
high blood flow - 40 x brain (/mass) - 40 times more blood going through PC then the brain
high metabolic rate
Glomus cells – neural phenotype
Type II – supporting
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70
Q

describe the mechanism of afferent nerve stimulation

A 
Inhibition BK K channels
Depolarisation
Action potential firing
Cav channels open
Increase Cai
Neurotransmitter release e.g. ACh, dopamine, NA etc
Afferent nerve fibre stimulation
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71
Q

describe the case of SIDs

A

sudden infant deaths
Some SIDS babies have higher concentrations of carotid body dopamine and NA
2-4 months old
stop breathing

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72
Q

what is the primary source of tonic drive to breathe?

A

Central chemoreceptor

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73
Q

what is the main activator of the central chemoreceptors?

A

hypercapnia (increased CO2 levels)

a 5mmhg increase in CO2 levels is enough to cause double the ventilation rate

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74
Q

what activates the central chemoreceptors? who identified this and what was done?

A

pH. was identified in the 1950s by isidore lessen who refused cereal ventricles with acidic solution then observed hyperventilation (exposed central chemoreceptors to acid which stimulated them)

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75
Q

what is the location of the central chemoreceptors?

A

within the brain parenchyma bathed in brain extracellular fluid (BECF)
separated from arterial blood by BBB - poor ion permeability

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76
Q

what does an increase in arterial PCO2 cause in terms of the BECF?

A

an increase in PCO2 leads to an increase in BECF PCO2 (acidosis) so pH falls therefore stimulation to signal to respiratory centre to change ventilation

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77
Q

why doesn’t BECF have many buffering capabilities?

A

CO2 easily gets into the BECF to cause this chain of events - doesn’t have any proteins so can’t bind/release H+ ions - there is a decrease in its buffering capabilities

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78
Q

what is the location 2?

A

less non-bicarb buffering power so larger fall in pH
some long term compensation
transports HCO3- from blood

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79
Q

what is the difference in pH change for metabolic disorders compared to respiratory disorders?

A

poor ion permeability so metabolic disorders changes pH of BECF by 10-35% of that observed with respiratory disorders for the same change in blood pH

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80
Q

what i the location of the peripheral chemoreceptors?

A

ventrolateral medulla and other brainstem nuclei

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81
Q

what are the 2 neurone populations that can fire AP depending on the conditions?

A

2 neuronal populations

  • acid activation - serotonin
  • acid inhibition - GABA
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82
Q

what do SID babies lack and what does this cause?

A

some SID babies lack serotonergic neurones - defect central chemoreceptor is possible. may have a defect in central chemoreceptors which impacts on the ability to breathe normally. an infant with hypoxia will have a worse impact i addition to this

83
Q

what are the differences in the response in the central and peripheral chemoreceptors?

A

physiologically, all change at the same time

integrated responses

84
Q

describe respiratory acidosis in the peripheral and central chemoreceptors

A

respiratory acidosis - both central and peripheral
normoxic-central 65-80%
peripheral = faster (1st to respond)
as PO2 falls, response to PCO2 is enhanced

85
Q

describe metabolic acidosis in the peripheral and central chemoreceptors

A

metabolic acidosis - severe hyperventilation
(kussmaul breathing)
decrease in PCO2 (acidosis)
peripheral acute response (more important)
central = longer term role

86
Q

what are the respiratory changes in acid base balance that we impose on ourselves?

A

breathe faster so O2 decreases, [H+] decreases and pH increases - mild respiratory alkalosis
breathe slower so O2 increases, [H+] increases and pH decreases - mild respiratory acidosis

87
Q

if the pH is higher or lower then usual, how can we get it back to normal?

A

low pH, increase rate of breathing, increase loss of CO2 - pH back to normal (increased)
high pH, decrease the rate of breathing, decrease loss of CO2, pH back to normal (decreased)

88
Q

what are the long term mechanisms of regulating levels of acid or alkali in the kidney?

A
  1. HCO3 handling
  2. Urine acidification
  3. Ammonia synthesis
89
Q

where does HCO3 handling occur?

A

90% in the proximal tubule

10% in the distal tubule

90
Q

what are the 2 processes of base conservation?

A

acidification - 25%

ammonia synthesis - 75%

91
Q

explain the process of urine acidification

A

alkaline salt to acid salt
alkaline phospate to acid phosphate
Na2HPO4 to NaH2PO4
(1 Na lost (excreted) and replaced with H)

92
Q

what are the 2 pH buffers found in urine?

A

Uric acid

Creatnine

93
Q

explain the process of ammonia synthesis

A

NH3 + H+ NH4+
ammonia ammonium
permeable impermeable (across cell membrane)

94
Q

what is NH3 formed by?

A

glutamate into alpha keta glutarate

95
Q

what is the renal response to respiratory acidosis/alkalosis?

A

change in CO2 levels
resp acidosis - increase in CO2
resp alkalosis - decrease in CO2

96
Q

what is the renal response to metabolic acidosis/alkalosis?

A

changes in levels of acid and base
metabolic acidosis - increases acid and decrease in base
metabolic alkalosis - decrease in acid and increase in base

97
Q

what is the renal compensation mechanism for respiratory acidosis?

A

the decrease in CO2 elimination leads to log disease and emphysema/chronic bronchitis.
the renal compensation mechanism for this would be an increase in the secretion of H+, more reabsorption go HCO3 so a rise in pH but further rise in HCO3

98
Q

what is the renal compensation mechanism for respiratory acidosis?

A

the decrease in CO2 elimination leads to log disease and emphysema/chronic bronchitis.
the renal compensation mechanism for this would be an increase in the secretion of H+, more reabsorption go HCO3 so a rise in pH but further rise in HCO3

99
Q

what is the renal compensation mechanism for respiratory alkalosis?

A

the increase in CO2 elimination leads to hyperventilation and fear,stress,pain. the renal compensation fro this is less secretion of +, less reabsorption of HCO3 which leads to a fall in pH but also a further drop by HCO3

100
Q

what is the respiratory compensation mechanism for metabolic acidosis?

A

metabolic acidosis leads to Ingestion acid, Loss of alkaline fluid, Diarrhoea, cholera and diabetic ketoacidosis.
the Respiratory compensation would be an increase in respiratory rate, a decreased arterial PCO2, a high pH and drop PCO2. the Renal correction would be more secretion of H+ and more reabsorption HCO-3

101
Q

what is the respiratory compensation mechanism for metabolic alkalosis?

A

Metabolic alkalosis leads to Ingestion of alkaline fluid, Loss of acid and Vomiting.
the Respiratory compensation increases respiratory rate, decreases Arterial PCO2 and leads to a fall in pH and rise PCO2
if you stop vomiting, everything else goes back to normal

102
Q

wha are mixed disorders?

A

when there is more than one primary disorder
eg respiratory acidosis - high PCO2
metabolic acidosis - low HCO3 bot be the same e.g. both acidosis/alkalosis

103
Q

what happens in the mixed disorders if they are both the same (both acidosis/both alkalosis)? and what about if they are opposite?

A

then the change in pH is additive -life threatening

change in pH is subtractive - mild

104
Q

what are some examples of mixed disorders?

A

alcoholic patients - met acidosis and met alkalosis
asthma - resp acidosis and lactic acidosis (big pH change)
COPD patients - treated with diuretics - rest acidosis and met alkalosis
salicylate poisoning - resp alkalosis (stimulates respiratory centre) and met acidosis

105
Q

give two examples of renal diseases

A

Lidless syndrome

diabetes insipidus

106
Q

when was Liddle’s syndrome first described?

A

1963

107
Q

what kind of disease is it? genetic or environmental?

A

it is an autosomal dominant inheritance (genetic)

108
Q

what are some of the symptoms that have been associated with Liddle’s syndrome?

A

sodium retention
fluid retention (due to h2o following sodium out)
therefore hypertension due to the increased volume of fluid so more blood therefore high blood pressure

109
Q

what are some of the secondary impacts of Liddle’s syndrome?

A

hypokalaemia, metabolic acidosis and low renin/ aldosterone levels

110
Q

what channel is affected by Liddle’s syndrome? and describe what happens to it?

A

epithelial sodium channel (ENaC). it has 3 subunits - alpha, beta and gamma (1:1:1)
Liddle’s causes a mutation in the COOH tail of the beta or gamma subunits.it causes a deletion in proline rich motifs which is a sequence in AA which has aloof proline that allows endocytosis of ubiquinone.

111
Q

what happens in a normal patient if they have high blood pressure and how is this different in Liddle’s patients?

A

normally, if there is a high blood pressure, ENaC is internalised from the apical membrane in response to low levels of renin and aldosterone. so, less channels means a decrease in sodium reabsorption so there is less h20 reabsorption therefore less fluid in the body so a low blood pressure
in Liddle’s patients, if they have a high blood pressure, there is low levels of renin and aldosterone still but now this is not enough to make ENaC be internalised from the apical membrane. so, there is no reduction in sodium reabsorption therefore hypertension persists

112
Q

what is the treatment for Liddle’s syndrome?

A

amiloride. this blocks the sodium channels and is a very effective treatment because it massively reduces the risk of heart disease and stroke

113
Q

why is spironolactone not an effective treatment for Liddle’s syndrome?

A

this is because it blocks aldosterone interactions with mineralocorticoids. but, the receptor isn’t activated by aldosterone anyway in Liddle’s patients, also, the problem is with the ENaC channels themselves - not alsoterone so it wouldn’t resolve anything
proof = treatment of an infant with amiloride and spironolactone. with amiloride the bp reduced from 121/67 to 98/45. but with treatment with spironolactone, it went from 119/65 to 122/64. this shows the lack of effect of this drug

114
Q

what are the symptoms of diabetes insipidus?

A

polyuria which is an increased blood flow with compensatory polydipsia (increased thirst)
dehydration could be a serious issue

115
Q

what is the occurrence of inheritance for diabetes insipidus?

A

1:25000-30000

116
Q

what are the types of diabetes insipidus?

A

central (congenital and acquired)
primary polydispia
gestational
nephrogenic (congenital and acquired)

117
Q

describe central diabetes insipidus

A

there is an impaired AVP production in the posterior pituitary

  1. acquired = infection, head trauma, surgery (brain)
  2. congenital = neurohypophyseal D1, 67 mutations on AVP gene, many mutations in the site important transport of AVP from hypothalamus to posterior pituitary
118
Q

describe primary polydipsia diabetes insipidus

A

suppressed AVP production - excessive H2O intake

119
Q

describe gestational diabetes insipidus

A

seen in pregnant ladies (have more enzymes)

metabolism by placental enzymes (of vasopressin)

120
Q

describe nephrogenic causes

A

produce normal AVP but can’t express it
impaired effect of AVP
1. acquired - more common, lithium (from bipolar disorder medication)- disrupts AVP-AQP2 system causing acquired diabetes insipidus, some antibiotics, antifungals, antineoplastic agents, hypokalemia & hypercalciuria , acute and chronic renal failure
2. congenital - mutations in AVPR2 receptor or AQP2 genes, AVP2 gene is X-linked, AQP2 gene: impact trafficking (dominant) or function (recessive) of proteins
symptoms appear in infants - hypernatimic dehydration, poor feeding, skin dryness and depressed anterior fontanel (helps identify if patient has diabetes insipidus)

121
Q

what are treatments of some cases of diabetes insipidus?

A

central: desmopressin - agonist at vasopressin receptor - nasal spray helps control H2O reabsorption - maintains H2O reabsorption in kidneys
nephrogenic: difficult to treat. possibilities:
modulator drugs - protein misfolded but still functional, drugs used to traffic misfolded protein to nucleus/membrane so that it can still work. pharmacological chaperones, cell permeable receptor agonists, cGMP and cAMP pathway agonists, statins, prostaglandins and heat shock protein 90

122
Q

what do sarcomeres contain?

A

proteins that mediate muscle contraction:

myosin: thick filament
actin: thin filament

123
Q

what is the cross bridge theory?

A

actin and myosin overlap. myosin head attached to actin and pulls so the sarcomere has a smaller diameter
depends on an increase in intracellular calcium which is mediated by muscle AP/ neuronal AP in nerve

124
Q

what is the sliding myofilament hypothesis?

A 
neuronal action potential
muscle action potential
increase in intracellular calcium
myofilaments slide
contraction
there is a transfer of electrical signal from nerve to muscle
125
Q

what is the moor unit?

A

the motor neurone and the muscle fibres it innervates. muscles have many motor neurones

126
Q

what does the number of muscle units influence?

A

the amount of grades the AP can move up e.g. 5 motor units = 5 grades

127
Q

what does Kv and Nav mediate? what is AChR?

A

Kv - mediates hyperpolaristaion
Nav - mediates depolarisation
AChR - cation non selective ion channel

128
Q

describe nicotinic AChR

A

a non selective ligand gated cation channel which opens when ACh binds to it
nernst potential around 0mv - which is the value between ENa and EK. leads to depolarisation

129
Q

describe the structure of nicotinic AChR

A 
complex structure
4 types subunits 
pentameric
2 binding sites for every 1 receptor
1. CHRNA1 - 9(diff aa)
-CHRNA1 - skeletal muscle
-2-8 neuronal tissues
2. CHRNB1-4
CHRNB1 - skeletal muscle 
2-4 neuronal tissue
130
Q

describe the gating process of nicotinic AChR

A

C (closed with no agonist) — A1C (closed. 1 agonist) — A2C (closed. 2 agonists) — A2O (open) — when AChR comes off, gets the conformation bad to C configuration

131
Q

how many vesicles are there in the NMJ and how many ACh molecules would be in there?

A

around 200 vesicles, 6000-10000 molecules of ACh

132
Q

what diseases are associated with problems with the NMJ? what is the incidence

A

myasthenia gravis - autoimmune disease (has misfunctional immune system) NMJ not working
2-7 in 10000 UK
30s females = at risk
60/70s male = at risk

133
Q

what is the action of antibiotics in AChR?

A

antibiotics (Abs) against AChR on post synaptic membrane ofNMJ. block and reduction in numbers: Abs ending to neurone is internalised and broken down. Abs bind to AChR so that ACh can’t bind to it.

134
Q

what are some effects of myasthenia graves on skeletal muscles?

A

weakness and tiredness in skeletal muscles - due to ack of contraction
can be fatal - respiratory failure

135
Q

what is evidence of the effects of antibody’s on MG patients?

A
  1. 87% of MG patients positive
    -individuals with myasthenia gravis have higher antibodies levels against AChR
  2. injection of mice with AB-AChR in experimental MG ;
    wt = normal mouse, no antibody.
    experimental MG = less action potential firing
    size of action potential affected
136
Q

what are some treatments for myasthenia gravis?

A

treatments amigo increase ACh levels and decrease AB levels.

  • acetylcholinesterase inhibitors - mild, eg pyridostigmine which enhances ACh levels.
  • corticosteroids - moderate-severe, eg prednisolone, immunosuppressant, reduces AB levels
  • immunosuppressants - eg cyclosporin, reduce AB leve;s
  • IV immunoglobins - severe, 400mg/kg for 5 days, mops up Abs so reduces levels
  • thymectany - tour removal/severe, mechanism no clear, removal of AChR AB secretary B cells

in life threatening symptoms ; PLASMAPHERESIS
when acute intervention needed, removal of Abs from the plasma e.g. filtration, immunoadsorption (as Abs bind to other molecules) reduces AB levels

137
Q

what are transverse tubules important for?

A

AP propagation into myofibrils

138
Q

explain the ‘triad’ of transverse tubules

A

Ryanodine receptor
Tetramer

L-type Ca2+ channel
Array of 4

Can have Ca2+ induced Ca2+ release
Skeletal not needed

Depolarisation

Activation L-type channels

139
Q

what is the mechanical aspect of the transfer tubules triad?

A

coupling ryanodine receptor
Release Ca2+ from SR
leads to:
Contraction

140
Q

what are the options for calcium reuptake?

A

calcium reuptake into sarcoplasmic reticulum / EC fluid compartment

141
Q

how does calcium re-uptake occur through the sarcoplasmic reticulum?

A

sarcoplasmic reticulum - Ca ATPase ; pumps calcium against the electrochemical gradient - calcium can bind to Calrectculin or Calsequestrin

142
Q

what are the 2 calcium transport proteins?

A
  • calcium ATPase

- sodium/Ca exchanger uses Na gradient set by Na/K gradient

143
Q

what is myotonia caused by and suggest variations of it

A

myotonia is the hyper excitability skeletal muscles. it can lead to muscle stiffness and is due to run of APs and a delayed relaxation. this causes myotonic seizures and affects 1;23000 - 1;50000 so is very rare
it has 2 types -
myotonia congenita - loss of function mutation in CLC1 chloride channel which is only found i skeletal muscle
paramyotonia (K+ aggravated myotonia), which is a gain function Nav1.4 mutation which causes sodium channels to open but don’t close when they should

144
Q

describe myotonia congenita

A
  • Thomsens autosomal dominant - symptoms less severe then Becker’s
  • Becker’s autosomal recessive - need 2 faulty copies to lead to the condition - more severe phenotype with earlier onset
145
Q

what are fainting goats and how do they relate to myotonia congenita

A

the fainting goats of
Tennessee were discovered in 1906 and were due to a CLC1 mutation - just like the human. it led to fainting due to stressful situations

146
Q

what other animal models were studied with myotonia congenita? describe what was found

A

moronic mice - late 70s. they had a mutation in the CLC-1 channel which turned Gly-Arg. this made the mutant channel have a lower open probability at negative membrane voltages but higher at positive voltages. e.g. at -70mV (Ecl), the wt had 0.5 Po but mutant had 0.08Po. eventually, it achieved 1Po but at more positive membrane potentials. this means that the expected contribution f CLCK1 to the negative Vm was decreased so it was driven to be more positive by potassium channels. so, less membrane potential was needed to reach the threshold therefore more APs are fired - leading to the over excitability of muscles – myotonia congenita.

147
Q

describe what happens when there is a CLC-1 mutation

A 
loss of Cl- contribution to Vm
depolarised
more excitability of muscle fibres
trains action potential
more contractions
148
Q

what is the treatment for myotonia congenita?

A

Inexilitene is the drug of choice. this inhibits sodium channels and so blocks some APs. too much can cause no APs to be released at all and so must find the lowest dosage to block certain APs so there is less AP frequency

149
Q

describe paramyotonia/K+ aggravated myotonia

A

issues with inactivation gate as there is a physical blocking of the inactivation gate so the Nav1.4 channels don’t close when they should. this means that they are open for longer then they should be so more sodium enters the membrane which prolongs the depolarisation. therefore, the cell struggles to repolarise

150
Q

what did studies on Nav1.4 mutations show?

A

they did an experiment to compare the affect of cold temperature on paramyotonia patients. there was a control condition which had normal and cold condition (trigger open) sodium levels checked and a paramyotonia patient who had their control and cold levels checked. this showed that the wild type had a small increase in muscle Na in the cold condition but the mutated channel had by far more sodium in the cell when it was cold. this sows that the channels didnt close right away- and stated open for longer and therefore had more sodium in the muscle

151
Q

describe malignant hyperthermia

A 
asymptomatic till they get general anaesthetic
1 in 10000 to 1 in 50000 individuals
autosomal dominant
abnormal response to halothane
death rate = 80%
treatment death rate = 10%
152
Q

what are the symptoms of malignant hypothermia?

A 
tachypnea (high respiratory rate - rapid breathing)
low plasma O2
high plasma CO2
Tachycardia
hypothermia 
rigidity (excessive body temperature)
sweating
shifts body pressure
153
Q

what is the biggest problem within all the symptoms of malignant hypothermia?

A

hypothermia as it is the first symptom and the patien overheats. this is more than 1 degree every 5 minutes. this is bad because proteins start to denature at 42 degrees so should be treated fast

154
Q

what happens if the patient with malignant hypothermia gets no treatment?

A

respiratory and lactic acidosis which has an additive effect
muscular rigidity
muscle breakdown - release K+ - severe hyperkalaemia - cardiac and neuronal excitability then death due to the severe acidosis and potassium in the plasma

155
Q

what are the reasons for the symptoms of malignant hyperthermia?

A

uncontrolled muscle contraction
excessive ATP hydrolysis
hypermetabolic state muscles

156
Q

what is the name of the skeletal muscle ryanodine receptor? and what kind of mutation happens to it?

A

RyR1. gain of function mutation

157
Q

describe one animal model which has a similar condition to malignant hyperthermia

A

the pig has a condition called Porcine Stress syndrome
it is an Arg 615 - Cysteine mutation and has the same symptoms as in the human MH. the trigger is physical stress and halothane.
MH pigs have more muscle mass then regular pigs so farmer selection happened in which these were chosen to be sold because of the ‘more meat’. this is decreasing however because the meat from these pigs is not as good

158
Q

describe an experiment on rabbit’s RyR1 614 gene that showed MH

A

INDO-1 fluorescence was used as the amount of light emitted was equal to the [Ca]. if [ca] changes, fluorescence emitted also changes.
wt put with halothane and showed no changes but with the mutant, more halothane was emitted
the wt had a response to 15mM of caffeine but not 3mM of caffeine where as the mutant showed a response to both.

159
Q

what happened to the rabbits that were exposed to more halothane?

A

there was an excess release of Ca from the SR
enhanced contraction rigidity
excess ATP hydrolysis
lactic acid production
increased use of O2 to make ATP so there ended up being little O2
increased production of CO2 - high plasma CO2
increased ventilation to try and remove CO2 (respiratory acidosis)
increase HR to supply O2

160
Q

what are the treatment options for MH?

A 
Dantrolene - inhibits RyR1
Diuretics - stops kidney damage from the muscle breakdown products (flushes out tissue fluid
IV hydration
NaHCO3 to counter acidosis
mechanical hyperventilation to remove O2
161
Q

how lethal is tetrodotoxin?

A

10-100 timesmore lethal than a black widow

10,000 timesmore lethal than cyanide

162
Q

how does tetrodotoxin get into the system?

A

it is ingested

163
Q

what is tetrodotoxin produced by?

A

marine bacteria

bacteria is in the puffer fish organs so if puffer fish isn’t prepared correctly when eating it - lethal

164
Q

what are the symptoms of tetrodotoxin ingestion?

A 
numbness of lips and tongue
facial paraesthesia 
headache
nausea
dizziness
diarrhoea
vomitting
increasing paralysis
respiratory paralysis
respiratory paralysis - leads to death
20mins - 8 hours from ingestion to death
165
Q

what is the time period from ingestion of tetrodotoxin to death?

A

20 minutes to 8 hours

166
Q

what are the symptoms of an envenoming bite?

A

depends on where you have been bitten but same as for tetrodotoxin ingestion but without the specific facial affects
has a faster time to death

167
Q

what is the treatment for both ingested an envenoming bites of tetrodotoxin ?

A

mechanical ventilation - because the cause of death is no more breathing and so a machine would keep the patent alive
no anti-venom as TTX

168
Q

why is anti-venom not a good source of treatment for tetrodotoxin?

A

this is because it is usually used to stop TTX from binding to its site but TTX binds too strongly to it’s site as it has an affinity too high for it so would not be useful

169
Q

what is the physiology of the tetrodotoxin affects on the body?

A

it inhibits sodium depolarisation
the site of action is the NMJ post synaptic membrane and sodium channel. they are both sensitive to TTX and are blocked by it. this is why were is muscle paralysis and numbness - as there are no APs so this events contraction

170
Q

how does TTX cause the inhibition of voltage gated Na channels?

A

failure neurotransmission
reduction neurotransmission release NMJ
loss sensation (1st) and muscle paralysis (sensory is on the outside which is why it is affected first)
respiratory paralysis and death

171
Q

what are the TTX sensitive and insensitive (need higher voltage) voltage gated sodium channels that seen in patients to be targets?

A 
sensitive = 
Nav1.4- skeletal
Nav1.6 - CNS and PNS
Nav1.7 - PNS
insensitive = 
Nav1.5 - heart
Nav1.8- sensory
Nav1.9 - PNS
172
Q

explain an experiment that shows the variable sensitivity to TTX

A
  1. rat Nav type 2
    E387Q - glutamate to glutamine - pore region
    wt = rat Nav channel to sensitive to TTX
    mutant = more sensitive to TTX
    shows that 1 aa change is enough induce a sensitivity to TTX when it wasn’t before
    can determine whether or not something is sensitive to TTX
  2. brain and muscle Nav 374 - tyrosine = TTX sensitive
    Heart Nav 374 - cysteine = TTX insensitive
    change heart 374to tyrosine = TTX sensitive
173
Q

explain the variable sensitivity in terms of how it could naturally be being selected for?

A

Garter snakes - there were 2 snake types with different geographical locations. they had different TTX sensitivities - due to their different Nav sequence domain
bear lake snakes were TTX sensitive and willow creak snakes are TTX insensitive
they both like to eat salamanders but if BLS eat them, they die but WCS are fine with them
theres a difference in the 4th/6 TM domain which gave them better food supply and an increased number that survived and therefore reproduced

174
Q

what is dendrotoxin and what does it do?

A

snake neurotoxin
mamba family
inhibits Kv channels
inhibition of depolarisation

175
Q

what are the symptoms dendrotoxin?

A 
early weakness/numbness 
30 mins to 1 hour after initial injection = systemic responses
Ptosis (eye droopiness)
ophthalmoplegia (paralysis eye muscles)
Disphagia (difficulty swallowing)
Paresis (mild paralysis)
respiratory failure leading to death
176
Q

what is the effect of dendrotoxin on Kv1.1?

A

add dendrotoxin, it blocks Kv channels (not completely)
inhibition of voltage gated K+ channels, excess release ACh from presynaptic membrane
ACh depletion (none left to be released)
failure of subsequent neurotransmission
problems in muscle control
respiratory paralysis and death

177
Q

what happens to Kv channels when they have been washed?

A

when washed off, the current starts to recover as the channel stops being blocked

178
Q

what is conotoxin?

A

its from a cone snail and there are >1000 different conotoxins
it has multiple targets with varying lethality’s

179
Q

what is the clinical relevance of conotoxins?

A

they are a new target for pain medication

180
Q

what are the symptoms associated with conotoxin?

A 
burning pain
swelling at site of toxin injection
numbness that spreads throughout the body
cardiac and respiratory distress
muscle weakness
loss of coordination
ptosis
headache
nausea
stomach cramps
lips become stiff (associated with lethal cases)
blurred vision
paralysis
coma
death
181
Q

how could conotoxins be used for pain therapy?

A

blocking Nav1, Cav2.2, Nav1.1 etc, if contain binds to these receptors, it would block them, stop sensory signalling and would therefore stop pain

182
Q

what is the occurrence of cystic fibrosis?

A

1 in 2500 births

1 in 20 carrier

183
Q

why are carriers of cystic fibrosis asymptomatic ?

A

this is because they have 50% of the normal protein to function and carriers have 15-20% of the normal gene due to the one faulty gene and so function properly.

184
Q

what tissue does the cystic fibrosis affect?

A

its an autosomal recessive disease of electrolyte transport that affects the epithelial tissue

185
Q

what are the main impacts of cystic fibrosis?

A

airways - clogging and infection
liver - blockage of small bile ducts and problems with liver function in 5%
pancreas - blockage of the ducts prevents secretion of digestive enzymes in 65%
small intestine
reproductive - absence/failure of development of vas deferens - making 95% infertile
skin - excess secretion of NaCl via sweat glands

186
Q

what are the clinal manifestations of cystic fibrosis?

A

meconium ileus - blockage in small intestine – must be picked up early (within 3 days) or death
pancreatic insufficiency -doesn’t put weight on
distal intestinal obstruction syndrome - obstruction in lower part of GI system
respiratory disease - appears within 1 month - increased rate of infection in lungs etc
liver disease - symptoms appear in around 2 years

187
Q

what protein is the mutation in to cause cystic fibrosis?

A

the cystic fibrosis transmembrane conductance regulator (CFTR)

188
Q

how many transmembrane domains are there in the CFTR protein? what kind protein is CFTR thought to be?

A

12 TMs. thought to be an ion channel

189
Q

what are the important parts of the CFTR protein that are used to regulate its function ?

A

there is a regulatory domain (R) which is a sequence of amino acids that regulates the opening/closing of the channel
there are NBD1 and NBD2 domains that are sequences of amino acids that combine nucleotides e.g. ATP which then regulates the opening/closing of the channels

190
Q

how many mutations of CFTR are there to cause CF? and which is the most common?

A

> 1900 mutations of CFTR causes CF

most common mutation = delta F508 in NBD1

191
Q

what could be the reason why patients of CF with the same mutation have different effects?

A

due to variable penetrance - environmental (biggest factor) and genetic (non-coding regions)
this causes a broad spread of symptoms
the treatment regime is very strenuous and so different individuals deal with it in different ways

192
Q

what are the 4 impacts that the CFTR mutations have on the channel?

A

conduction - impacts one ability to move through the pore
regulation - channel doesn’t open when it should
trafficking - prevents protein from getting to the membrane
processing - make truncated protein (not processed properly) / not enough mRNA or what is made is broken down as it is unstable
could be a combination of more than 1

193
Q

what are the most common mutations of CFTR and what are their allelic frequencies?

A

F508 - 90% allelic frequency
G551D - 1-3% allelic frequency
W1282X, G542X, N1303K - 0.1% or lower

194
Q

describe the full F508 lung pathology

A

viscous airway mucous
recurrent bacterial infectons - increased difficulty to treat sue to antibiotic resistance
antibiotic resistance - ability to that it decreases over time
inflammation - infection triggers an immune response - as a CF patient gets a much more hypersensitive immune response is there is more swelling
tissue degeneration - inflammation damages the tissue - lung tissue (once its gone), does not come back.lungs are no longer able to sustain life. 60-70% of CF patients die because of this. gets to a point where they breathe 100% oxygen to function but die by 40 years old

195
Q

what determines the height of the periciliary layer?

A

ENaC determines the height of the layer of liquid. depends on the balance of Na in and Cl out

196
Q

what is the optimal height of the periciliary layer

A

7um

197
Q

in CF patients, what does CFTR suppress?

A

ENaC

198
Q

what occurs in a CF patients airways?

A

there is no CFTR so there is nothing there to inhibit the ENaC. this means that the ENaC is hyperactive and so drives more H2O from apical to basolateral membrane therefore decreasing the size of the periciliary layer
the cilia is now bent over so they can’t beat proper. this means that it can’t move the liquid and the mucus properly so a virus is more likely

199
Q

what its the effect of the F508 station on cystic fibrosis

A 
it is a multi class mutation so both trafficking and processing is not working
the mutation leads to a misfolding of the CFTR protein and so is degraded by quality control cells. the CFTR would work well enough if it was to get to the membrane but the trafficking means that it is not able to make it to the membrane to be used
200
Q

what is the theory behind the reason that cystic fibrosis is so common?

A

a study done on rats (which have the same CFTR as us) showed that the crypt structure which is in contact with the lumen of the colon, has CFTR which has the same function as in the airways. the CFTR proteins are activated by enterotoxins (from cholera)
they secrete more chlorine and so H2O follows. this leads to diarrhoea which leads to dehydration and ultimately death.
a carrier of CF has half the number of channels available to secrete chlorine so they wouldn’t be able to secrete that much water anyway. this meant that overtime there was a cholera epidemic, CF patients would survive more likely then normal patients.

201
Q

what are the current treatments for CF?

A

physiotherapy - loosens mucus to be coughed up
bronchodilator drugs - dilate bronchioles to increase O2
antibiotics - not too much so hat they don’t get resistant
steroids - to decrease inflammation and damage
microlytics - eg Dnase - maes nucleus less thick and sick so can be coughed up during physio
gene therapy - delivery of CFTR DNA to the target cells in the lungs. inhaled to lungs
DNA transcribed to mRNA
protein produced and so normal lung function
but its challenging to work and has a poor success rae. this is because the epithelial cells are renewed constantly so must be corrected all the time
this makes this very expensive

202
Q

what are the current treatments for CF that treat the symptoms ?

A

physiotherapy - loosens mucus to be coughed up
bronchodilator drugs - dilate bronchioles to increase O2
antibiotics - not too much so hat they don’t get resistant
steroids - to decrease inflammation and damage
microlytics - eg Dnase - maes nucleus less thick and sick so can be coughed up during physio
gene therapy - delivery of CFTR DNA to the target cells in the lungs. inhaled to lungs
DNA transcribed to mRNA
protein produced and so normal lung function
but its challenging to work and has a poor success rae. this is because the epithelial cells are renewed constantly so must be corrected all the time
this makes this very expensive

203
Q

what are the treatments for CF that treat the cause?

A

read-through agents - force production of full length CFTR when premature stop/nonsence mutations. e.g. aminoglycoside antibiotics (gentamicin)
correctors - these force mutant protein to the cell membrane, if the mutant is functional then Cl secretion is restored (targets F508)
potentiators - these increase the Po of CFTR channels, which must be trafficked normally, the G55D mutation is the target for UX-770 (ivacafftor) so if they are trafficked normally, but don’t open very well and so this is good
combination of potentiators and correctors - undeyinvestigation in clinical studies

204
Q

what did a study of the effect of ivacafftor on placebo and CF patients show? use 4 experiment examples

A

it showed that the ivacafftor worked incredibly well in making a taller liquid layer and increased Cl and H2O secretion
clinical trial of ivacafftor in G551D mutated patients. a placebo group reported a 0% change in lug function meaning that there was no improvement
the ivacafftor group reported a 10% increases inland function which was sustained for 48 weeks. this shows that lung function increases with ivacafftor
in another study, with a placebo, 47% patients had no problems associated with the CF
in ivacafftor patients, 67% patients had no problems
this shows that ivacafftor decreases the likelihood ofhavin problems
another study checking the sweat chloride concentrations with the clinical threshold for CF diagnosis was 60mm and so placebo patents had 100mm of NaCl, this was sustained
in CF patients, they started at 100 NaCl but then dropped below the clinical threshold to around 50mm. this is because it opened CFTR channels and made them let out Cl
this shows that the sweat chloride concentration s decreased usingivacafftor

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