Cardio and renal L1

Question 1

end stage renal disease is a condition closely related to ..

Answer 1

end stage renal disease is a condition closely related to high blood pressure

Question 2

Label + 1-4?

Answer 2

0: Rapid depolarisation = NaV
1: Ca2+ current
2: prolongued plateu phase
3: K+ open - repolarisation
4: resting

Question 3

The fast depolarising phase of the cardiac action potential is due to the opening of ….

Answer 3

The fast depolarising phase of the cardiac action potential is due to the opening of sodium channels.

Question 4

describe what it meant by inactivated NaC cahnnels?

Answer 4

open transiently - and wont open again until the membrane as repolarisaed

Question 5

T or F

The difference is that in neurones and skeletal muscle the initial depolarisation needed to ‘gate’ the Na+ channels is produced by the action of a neurotransmitter, whereas in cardiac cells this depolarisation is provided by pacemaker cells

Answer 5

T

Question 6

Describe the structure of the voltage gated sodium cahnnel

Answer 6

large central alpha subunit - flanked by a1 and a2

Like most membrane proteins the subunits need some phosphorylation and glycosylation to function correctly

P is a phosphorylation site and trident thingy are glycosylation sites.

Question 7

T or f

In cardiac and skeletal muscle NaV channels have only b1 and a1 subunits

Answer 7

T

no B2 (previous card is NaV fromthe brain

Question 8

The structure of the alpha subunit of the cardiac voltage-gated Na+ channel

Answer 8

Question 9

what does the S4 segment fo the alpha NaV cahnnel do?

Answer 9

voltge sensor

Question 10

NaV chanel:

The regions between the __ and __ form the extracellular entrance to the channel, while the __ segments line the channel pore.

Answer 10

The regions between the S5 and S6 segments form the extracellular entrance to the channel, while the S6 segments line the channel pore.

Question 11

which domains in the alpha subunit of the NaV channel are important for producing inactivation?

Answer 11

cytoplasmic loop between domains III and IV is important in producing inactivation

Question 12

can local anaesthetics be used to control cardiac dysrhythmias?

how come?

Answer 12

yes.

they act on the intracellular surface of the voltage gated channel and block it

Question 13

what diameter aoxns are more sensitive to nerve blocks?

Answer 13

Broadly speaking, smaller diameter cells are more sensitive to the drugs than large diameter cells.

This means that the drugs will, at low concentrations, block nervous conduction while not affecting muscle action potentials.

Both sensory and motor fibres are affected by local anaesthetics.

In a mixed-fibre sensory nerve the sensation of pain is blocked first, followed sequentially by cold, warmth, touch and deep pressure.

This sequence corresponds to increasing diameters of nerve fibres.

Question 14

what effect does anaesthetic have on the NaV channel?

Answer 14

enhances inactivation

Question 15

why do local anaesthetics work best in smal diameter fibres?

Answer 15

because tey ajve a short space constnat

Question 16

the scientist Hille did some experiments:

what did he conclude about the action of local anaesthetics?

Answer 16

• The local anaesthetics act on the intracellular surface of the voltage-gated Na+ channel.
• The drugs need to be uncharged to pass across the cell membrane - the more hydrophobic the drug, the better it is at crossing the membrane.
• The charged form of the drug is the form that interacts with the channel to produce the anaesthesia.

Question 17

describe use dependance for local anaesthetics?

Answer 17

It is evidently necessary for the channel to be open for the majority of the anaesthetic effect to be initiated.

The more often the channel opens, the more likely it is that it will be blocked by the anaesthetic.

This phenomenon is known as ‘use- dependence’.

Question 18

picture for lidocaine use dependance:

Answer 18

higher rate of firing = more anaesthesia

Question 19

hwo does local anaesthetic gain access to the cell

Answer 19

diffuse across the cell membrane in their relatively hydrophobic, uncharged form.

Question 20

is it the uncharged or charged form of the local anaesthetic which interacts with the intracellular receptor?

Answer 20

charged with the NaV receptor

Question 21

whats going on here?

Answer 21

shows the effects of lidocaine

When some channels are left inactivated (in the right-hand panels) the inward currents are practically abolished by lidocaine, so it seems that the anaesthetic enhances the inactivation of the channels

Question 22

whats going on here?

Answer 22

This Figure gives a measure of the proportion of Na+ channels that can be activated at any given resting potential.

In the presence of lidocaine or benzocaine this inactivation curve is shifted to the left - more negative prepulse values. Thus, in the presence of lidocaine and benzocaine the proportion of channels that are in a state which cannot be activated is increased at any given membrane potential.

Question 23

describe tetrodotoxin

Answer 23

tetrodotoxin (or TTX) and saxitoxin (or STX)

They both are highly selective, reversible blockers of neuronal voltage-gated Na+channels

They do not affect voltage-dependence or inactivation.

Question 24

which NaV channels is TTx more effective on?

Answer 24

TTX is considerably less effective on cardiac Na+ channels.

It is blocked only by micromolar concentrations of the toxin whilst the neuronal and skeletal muscle channels require only nanomolar quantities.

Question 25

describe the Batrachotoxin

Answer 25

It acts on the intracellular portions of the channel to prevent inactivation and to move the activation potential to more negative potentials and so the channels open far more readily than in the absence of the toxin.

aconitine1 and veratridine act in similar ways and can provoke cardiac dysrhythmias.

Insect voltage-gated Na+ channels are similarly affected by the pyrethrin insecticides and DDT.

Question 26

describe scorpion toxins

Answer 26

á- scorpion toxin is a polypeptide that acts from the outside of the voltage-gated Na+ channel. It inhibits inactivation and acts cooperatively with batrachotoxin to open the channel almost permanently. Its binding is voltage-dependent and is enhanced by batrachotoxin (which shifts the activation potential in any case).

Question 27

do you know the strcutrue of the Ca2+ channel

Answer 27

Question 28

do different Ca2+ channels in differnet tissues behave differently?

Answer 28

yep

Question 29

The principal drugs acting on these channels are __________ (such as nifedipine), __________ (such as verapamil) and _____________ (such as diltiazem).

In current clinical practice, _______ and _______ are known as “non-dihydropyridines”.

Answer 29

The principal drugs acting on these channels are dihydropyridines (such as nifedipine), phenylalkylamines (such as verapamil) and benzothiazepines (such as diltiazem).

In current clinical practice, phenylalkylamines and benzothiazepines are known as “non-dihydropyridines”.

Question 30

describe L-type Ca2+ channels?

Answer 30

• important in cardio vascular system
• sensitive to dihydropyridines - bind inactived channels but show no use dependance
• need large depol (+30mv) to open
• open for long time and inactivate slowly
• responseible for plateu phase cardiac AP
• activity modulation alters strength adn rate of contraction of the heart
• lrage single channel conductance
• Adr and NA enhance channel activity (throguh phosphorylation)

Question 31

describe t-Ca2+ channels

Answer 31

• show rapid inactivation
• open transiently
• low single channel conductance
• not sensitive to dihydropyridines
• T-type channels occur together with L-type channels in nodal pacemaker tissues in the heart.
• Triggering of T-type channels can be sufficient to depolarise the cell sufficiently to activate L-type channels.

Question 32

divalent cations can block whcih channels?

Answer 32

eg, Ni2+

block nonspecifically all ca2+ channels

Question 33

describe photoaffinnity labelling?

Answer 33

very tough

Question 34

where do Phenylalkylamines bind to calcium channels

Answer 34

S5 to S6 loop

Question 35

where do Dihydropyridines bind to ca channels

Answer 35

• 2 binding sites
  
  • segment S6 and part of its associated S5-S6 loop in domain III
  • second is closely related to the phenylalkylamine binding site on the S5-S6 loop in domain IV

Question 36

where do Benzothiazepines bind ca channels?

Answer 36

• 1 major drug - diltiazem
• block form outside
• bind in differnet place to dihydropyridines but modulate dihydropyridine binding.
• specific location unknown

Question 37

If K+ channels open in a normal cell,… what happens?

Answer 37

If K+ channels open in a normal cell, current flows out of the cell, making the membrane potential more negative.

Question 38

how do potassium channels contribute to the repolarisation after an AP

Answer 38

cardiac cells (like other excitable cells) possess voltage-gated K+ channels which open slowly on depolarisation (actually they start to open at the same time as the voltage-gated Na+ and Ca2+ channels) and the current they carry leads to the restoration of the membrane potential to its normal resting leve

Question 39

T or F

K+ channels are ubiquitous, and do not only occur in excitable tissues

Answer 39

T

Question 40

Nerve and muscle cells contain what types of K+ channels?

Answer 40

Nerve and muscle cells contain both voltage-gated and non-voltage-gated

K+ channels

Question 41

T or f

K+ channels maintain the resting cell membrane potential in all animal cells

Answer 41

T

Question 42

what determines the resting membrane potenital is atrial and ventricular cells?

Answer 42

the resting membrane potential in atrial and ventricular cells are determined by the resting membrane having a high permeability to K+ ions (i.e. dependent on the activity of K+ channels).

Question 43

describe how the resting potential is set up?

Answer 43

the negative resting potential of atrial and ventricular cells is maintained by the Na+/K+ ATPase pump which exchanges three intracellular Na+ ions for two K+ ions.

The membrane at rest is highly permeable to K+ ions but to all intents and purposes impermeable to Na+ ions.

Due to the gradient of these two ions across the membrane, in combination with the different degree of permeability of the membrane to the two ions the resting potential (Vm . -80 mV) is close to the equilibrium potential for K+ (EK. -95 mV)

Question 44

dual role of K+ channels in the heart?

Answer 44

1. Repolarisation of the cell at the end of the action potential
2. Stabilisation and modification of the resting cell membrane potential in the atria and ventricles

Question 45

structural differnce between K+ and Na+ channels?

Answer 45

They have the six transmembrane segments familiar from Na+ channels, but only show a single group of the six segments, compared with the four of Na+ channels.

Question 46

where is the voltage sensor in the K+ cahnnel;?

Answer 46

As in the Na+ channel, every third residue in the S4 segment is positively charged and mutagenesis experiments suggest that this forms the voltage sensor.

Question 47

are all K+ channels voltage senssing?

Answer 47

no

Other K+ channels that do not display voltage-activation have a different structure

Question 48

how many Kv proteins aggregate together to form a pore?

Answer 48

4

Question 49

describe teh 2 types of inactivation of voltage gated K+ channels?

Answer 49

oltage-gated K+ channels show two types of inactivation.

1. ‘N-type’ inactivation or ‘ball and chain inactivation’ - the N-terminus of the protein forms a ball which is ‘sucked’ into the pore, occluding it, as the result of electrostatic changes associated with depolarisation.
2. ‘C-type’ inactivation, is slower and seems to be the result of movement of residues near the extracellular surface of the pore.

Question 50

‘I_K1 current’

what is this? - how does it affect cardio cells

Answer 50

the outeward K+ current flowing thorugh the largely open K+ channels maintaingin the resting potential.

usually doesnt really affect cells as theyre not depolarised for long enough for the cell to loose enough K+.

cardaic cells spend half their time depolarised, which leaves a large K+ gradient. so to stop K+ from flwoing out the cell in large quantities - theyre protected by the inward rectification current

Question 51

describe Inward rectifying K+ channels

Answer 51

• called Kir channels
• some dont show voltage gating
• wide range
• regulated by phosphorylation, intracellular Ca2+ levels or by intracellular ATP
• not confied to excitable tissues
• Some channels show both voltage-gating and inward rectification

Question 52

what causes the occulsion leading to rectification?

Answer 52

he rectification used to be thought to be due wholly to intracellular magnesium ions blocking outward current by lodging in the pore. However, it is now clear that besides magnesium, intracellular polyamines (especially the tetravalent polyamine spermine) are of great importance in accounting for the occlusion producing the rectification.

Question 53

label the Kir channel graph

Answer 53

Question 54

describe the I_K-ACh current

Answer 54

Muscarinic M2, via β/γ subunit of G protein direclty coupled to K+ channel

acti vates the K_GIRK1 channel

Leads to hyperpolarisation of cardiac cells = fewer APs

thast how Psympathetics slow HR

Question 55

describe the I_K-ATP current

Answer 55

• These channels (K_ATP Channels) open in the presence of low intracellular ATP, but close as intracellular ATP rises
• In the pancreatic ß cell their closure leads to insulin release
• In the heart they seem to be protective under conditions of hypoxia

Question 56

what drug opens K_ATP Cahnnels - whats it used to treat>

Answer 56

influenced by sulphonylurea drugs to stimulate insulin secretion in Type 2 (non-insulin-dependent) diabetes mellitus.

also targeted by some antihypertesive drugs

Question 57

describe how beta islets cells work - with glucose dependant insulin release

Answer 57

Glucose is metabolised

→ ATP is produced

→ ATP closes ATP-sensitive Kir channels

→ Cell depolarises

→ Voltage-activated Ca2+ channels open

→ Insulin is released

→ Ca2+-activated K+ channels open

→ Cell repolarises

Question 58

which APs are from which part of the ehart

Answer 58

Question 59

In the sinoatrial and atrioventricular nodes the membrane potential only reaches -__ mV (compared with -__ to -__ mV in the ventricles)

Answer 59

In the sinoatrial and atrioventricular nodes the membrane potential only reaches -60 mV (compared with -80 to -90 mV in the ventricles)

Question 60

tough label

Answer 60

Question 61

label the currents

Answer 61

Question 62

Answer 62

Question 63

Answer 63

Question 64

Answer 64

Question 65

Mutations in Voltage-gated K+ channels

what happens when the circles mutate?

what hapens when the squares and triangles mutate

A mutation in the loop connecting domains III and IV of the cardiac voltage-gated Na+ channel produces?

Answer 65

• Circles: episodic ataxia, characterised by attacks of imbalance, uncoordinated motor function, nausea and vertigo
• Squares and triangles: LQT1 and LQT2 - two types of ‘Long QT syndrome’
• loop connecting 3 and 4: LQT3

Question 66

Long QT syndrome is one of the causes of …..

Answer 66

Long QT syndrome is one of the causes of ‘Sudden Adult Death Syndrome’ (‘SADS’ also known as ‘Sudden Arrhythmic Death Syndrome).

Question 67

SADS can occur in individuals suffering from a range of different conditions. These include ……

Answer 67

SADS can occur in individuals suffering from a range of different conditions. These include hypertrophic cardiomyopathy and dilated cardiomyopathy as well as Long QT syndrome, where the heart may seem otherwise normal in routine tests.

Question 68

The QT interval can also be extended by a number of medicines, ……

Answer 68

The QT interval can also be extended by a number of medicines, notably some antibiotics and antipsychotics, with the same poor outcomes.

Question 69

In most cases of LQT syndrome: what drug? can be used prophylactically to prevent attacks

Answer 69

In most cases ß1-adrenergic antagonists can be used prophylactically to prevent attacks

Question 70

describe how teh pacemaker current produces APs?

Answer 70

• Nodal tissue - spontaneous APs are gnerated
• Nodal tissue doesnt have stable resting potential
• Potential gradually drifts towards the gating potential for Ca2+ channels
• Special current

Question 71

Parasympathetic and sympathetic nerves can ______ the production of action potentials, but the intrinsic rhythm of the heart is provided by the spontaneous action potentials generated by the nodal tissue, which are transmitted throughout the myocardium by the conductive system

Answer 71

Parasympathetic and sympathetic nerves can modulate the production of action potentials, but the intrinsic rhythm of the heart is provided by the spontaneous action potentials generated by the nodal tissue, which are transmitted throughout the myocardium by the conductive system

Question 72

describe the funny current

Answer 72

• HCN (hyperpolarization-activated and cyclic nucleotide-gated) channels open on hyperpolarisation and close on depolarisation (like inward- rectifying K+ channels)
• They are almost as permeable to Na+ as they are to K+
• On hyperpolarisation of the cell, Na+ begins to enter and this leads to a slow depolarisation and ultimately an action potential
• Sympathetic stimulation increases the rate of firing

Question 73

how are HCN channels modulated by the sympathetic nervous system

Answer 73

n important feature of these channels is that they are activated directly by cAMP, rather than through cAMP-mediated PKA phosphorylation

Question 74

…………….channels generate the peak of the nodal action potential and voltage-gated K+ channels result in repolarisation.

Answer 74

L and T-type Ca2+ channels generate the peak of the nodal action potential and voltage-gated K+ channels result in repolarisation.

Question 75

where does cAMP bind to hte HCN channels?

Answer 75

the C terminus binds cAMP as well as cyclic neucleotides

(since theyre cyclic nuceotide gated)

Question 76

HCN_, which is present not only in the heart, but also in the brain.

HCN_ and HCN_ are the types of HCN channel subunits that are most abundantly expressed in the heart, the former throughout the heart and the latter in the pacemaker regions and in Purkinje fibres

Answer 76

HCN1, which is present not only in the heart, but also in the brain. HCN2 and HCN4 are the types of HCN channel subunits that are most abundantly expressed in the heart, the former throughout the heart and the latter in the pacemaker regions and in Purkinje fibres

Question 77

Four HCN subunit types have been identified in vertebrates (HCN1-4). Other than in the heart they mostly appear in the ____

Answer 77

Four HCN subunit types have been identified in vertebrates (HCN1-4). Other than in the heart they mostly appear in the brain

Question 78

Sympathetic stimulation _____ the rate of contraction of the heart and parasympathetic stimulation ______ it.

Answer 78

Sympathetic stimulation increases the rate of contraction of the heart and parasympathetic stimulation slows it.

Question 79

t or F

Since the sinoatrial node provides the impulse for action potential propagation, any change in the heart rate must be mediated by the potentials produced by the sinoatrial node.

Answer 79

T

Question 80

label the Modulation of spontaneous action potentials in an isolated sinoatrial cell from a rabbit heart.

Answer 80

Question 81

Catecholamines effect on teh heat?

Answer 81

Catecholamines accelerate the heart and increase the strength of contraction (a positive chronotropic and inotropic effect)

Question 82

acetylecholine effect on the heart

Answer 82

Acetylcholine (negative chronotropic and inotropic effect)

Question 83

fat

Answer 83

mamba