8. Electrical and Molecular Events

Question 1

How does permeability to K+ set up the resting membrane potential?

Answer 1

• The resting membrane potential of a cell is based on the permeability of the membrane to certain ions and thus the activity of protein ion channels in the membrane.
• Overall the membrane is very permeable to potassium and not very permeable to other membrane ions.
• Cardiac myocytes are permeable to K+ions at rest.
• K+ ions move out of the cell - down their concentration gradient. Use Na/K ATPase.
• SMALL movement of ions makes the inside negative with respect to the outside
• As charge builds up an electrical gradient is established. Net outflow of K+ until Ek reached (ie no net movement at Ek).

Question 2

Why doesn’t the resting membrane potential not equate to the equilibrium potential of K+

Answer 2

The potential of K+ isn’t reached even though the membrane is permeable to it
There is a small permeability to other ionic species at rest, stopping this

Question 3

What is Ek?

Answer 3

-95mV

Question 4

What is RMP of ventricular myocytes?

Answer 4

-90 to -85 mV

Question 5

What is the difference in length of action potentials in axons, skeletal muscle, SA node and cardiac ventricle?

Answer 5

axons and skeletal muscle have the shortest action potential and SA node and cardiac ventricle have the longest

Question 6

Explain the process involved in a ventricular cardiac action potential

Answer 6

The resting membrane potential is due to background (non-voltage K+ channels)
1. Voltage gated sodium ion channels are opened due to the arrival of an action potential, this causes an influx of Na+ ions
2. This causes depolarisation as a result of local currents (Upstroke) causing even more VGSIC to open.
This explains the fast and steep depolarisation.
The Na+ channels become inactivated almost as soon as they open.
3. There’s a transient outward current of potassium ions (through voltage gated K+ channels) out of the cell resulting in a small decrease in membrane potential (initial repolarisation).
4. There’s a plateau due to the opening of voltage-gated Ca2+ channels (L-type), there’s an influx of Ca2+ but this is balanced with K+ efflux.
5. The calcium ion channels will inactivate and then voltage gated potassium ion channels(and other potassium channels) open to repolarise the cell membrane, efflux of potassium ions.

NA+ INFLUX -> CA2+ INFLUX and K+ EFFLUX -> K+ EFFLUX

Question 7

Are all K+ channels in cardiac myocytes the same?

Answer 7

• Cardiac myocytes have lots of different types of K+ channels
• Each behaves in a different way and contributes differently to the electrical properties of the cells.

Question 8

What are pacemaker cells?

Answer 8

Pacemaker cells are specialized myocytes that generate an electrical event at regular intervals.
This initiates the cardiac action potential which spreads over the myocardium.

Question 9

Describe the pacemaker/ SA node action potential

Answer 9

> Initial Depolarisation/Pacemaker potential - Funny current (If). funny current because behaves unusually, channels open when hyperpolarised, not depolarised. Influx of Na+ through HCN channels (Hyperpolarisation-activated, Cyclic Nucleotide-gated channels ) result in long slow depolarisation .

> Depolarisation - due to opening of V-gated Ca2+ channels - Once the HCN has channels have brought the membrane potential to around -40mV = UPSTROKE. NO PLATEAU.

> Repolarisation- opening V-gated K+ channels=DOWNSTROKE. Eflux.

> Depolarise again slowly

1 SAN AP = 1 HEARTBEAT

Question 10

What are HCN channels sensitive to?

Answer 10

CAMP

Question 11

Describe the conducting fibres within the body and the speed of activity of each
E.g SA node, AV node

Answer 11

Once generated an action potential will pass through the conducting fibres of the heart.
The SA node is the fastest to depolarise, it acts as the pacemaker and works to set the rhythm of the heart.
Within the AV node you also have cells that are capable of pacemaker activity however their natural rate is a lot slower than that of the SA node so they’re often overlooked.
But they can be useful if something goes wrong in the SAN.

Question 12

Why does SAN AP have natural automaticity?

Answer 12

Because of unstable membrane potential due to pacemaker potential (slow depolarisation to theshold) and funny current. They can depolarise themselves and fire action potentials. Therefore does not need nervous input, but there is nervous input to modulate rate and force of contraction

Question 13

What is the potential difference in a cardiac myocytes cell at rest

Answer 13

-80mv

Question 14

Give the basis of the RMP in cardiac myocytes

Answer 14

The basis for this resting membrane potential is to allow interaction to occur between different concentrations of ions inside and outside of the cell, and selective permeability of the cell membrane to potassium ions.

Question 15

What initiates action potentials in the cardiac myocytes cells?

Answer 15

They’re initiated by the action of voltage gated ion channels which causes depolarisation in the cell.
This allows a spread of activity from adjacent cells. For all cells, except pacemaker, the small depolarisation comes about by spread of activity from adjacent cells, taking the membrane potential beyond the ‘threshold’ for opening the fast Na+ channels. That is to say a single action potential will propagate throughout the heart muscle, aided by conducting fibres.

Question 16

What is responsible for contraction in the heart

Answer 16

The triggering of a single action potential spreading through myocardium

Question 17

Compare the length of a cardiac action potential to the length of an action potential in a nerve or striated muscle

Answer 17

A cardiac action potential is a lot longer (around 280ms) than the action potential in other muscle cells. This is due to the plateau sustained mainly by calcium channels.
The length of this action potential is very important this is because it ensures that once the action potential has begun in any part of the heart, it is long enough for the cell to still be depolarised when the last cell in the myocardium starts its action potential.

Question 18

What structure in the heart initiates action potential and describe the effect pathology can gave on this function.

Answer 18

Pacemaker cells In the SAN are used to initate action potentials in the heart and set the rhythm of the heartbeat. They are the fastest to depolarise

Question 19

Difference between cardiac AP and SAN AP?

Answer 19

• SAN AP triangular shaped bcs no plateau.
• SAN AP involves pacemaker cells which don’t have a constant membrane potential during diastole (bcs slowly depolarise).
• SAN has HCN Na+ channels which activated slower and by hyperpolarisation.
• SAN doesn’t need NT. myogenic.

Question 20

How do APs spread btwn cardiomyocytes?

Answer 20

Gap junctions are regulated pores found between cardiac myocytes. They form a channel that allows the cytosol of two adjacent cells to mix, this means that ions can easily pass from cell to cell.
This means that ions that cause an action potential in one cell can spread to its adjacent cell to initiate an action potential there.

Question 21

What are the functions of SAN?

Answer 21

Sets rhythm
Pacemaker
Fastest to depolarise.

Question 22

Function of purkinje fibres?

Answer 22

Conduct excitation through ventricular myocardium

Question 23

Why are cardiac myocytes so sensitive to changes in [K+]?

Answer 23

Establish RMP
K+ permeability dominates the resting membrane potential
The heart has many different kinds of K+ channels

Question 24

What happens if APs fire too slowly?

Answer 24

Bradycardia

Question 25

What happens if APs fail?

Answer 25

Asystole

Question 26

What happens if APs fire too quickly?

Answer 26

Tachycardia

Question 27

What happens if electrical activity (ie APs) becomes random?

Answer 27

Fibrillation

Question 28

What do you call it when plasma K+ conc is too high? What value is this?

Answer 28

Hyperkalaemia - above 5.5mmol/L

Question 29

What do you call it when plasma K+ conc is too low? What value is this?

Answer 29

Hypokalaemia - below 3.5mmol/L

Question 30

Describe the pacemaker potential

Answer 30

• Initial slope to threshold - If (funny current)
• Activated at membrane potentials that are more negative than -50mV
• The more negative, the more it activates

Question 31

Compare the action potential in the SAN to that in the ventricular myocytes

Answer 31

Unlike the ventricular action potential, the opening of Ca2+ channels is not sustained, and there is no ‘plateau’ stage, hence the action potential is triangular in shape.

Question 32

What is the normal Plasma K+ concentration ?

Answer 32

3.5 – 5.5 mmol/L-1

Question 33

What is the effect of hyperkalaemia ?

Answer 33

In hyperkalaemia, initially the raised extracellular K+ makes the environment outside the cell more positive. This increases the driving force for Na+ entry during fast depolarisation as it is repelled by the positive charges on K+. The extra K+ outside also increases the driving force for K+ entry during repolarisation. This makes repolarisation happen quicker. This may cause tachycardia in the short term.

Eventually the cell will re-equilibrate moving closer to the new EK. As hyperkalaemia makes EK less negative, this moves the membrane potential closer to threshold.so the membrane potential depolarises a bit

At these depolarised potentials voltage gated Na+ channels become inactive. This means fewer Na+ channels are available to participate in action potential generation. Action potentials are less likely to occur under these conditions causing bradycardia in the long term.

Overall hyperkalemia will slow the upstroke of of the action potential

Question 34

How can hyperkalaemia result in asystole of the heart?

Answer 34

An increase in potassium levels can disrupt electrical conduction in the heart due to a chemical imbalance.
There’s a suppression of electrical activity in the Heart which can cause It to stop beating.

Question 35

. Values for mild, moderate and severe hyperkalaemia

Answer 35

Mild: 5.5-5.9 mmol/L
Moderate 6.0-6.4 mmol/L
Severe >6.5 mmol/L

Question 36

Treatment of hyperkalaemia

Answer 36

Calcium gluconate can be used it shields the membrane of the cell and makes it less excitable.
Insulin and glucose can also be used as it drives potassium into cells and lowers extracellular potassium levels.
However it’s important that these things are all done before the heart stops.

Question 37

Explain the effect of hypokalemia on the heart

Answer 37

• Delays repolarisation (reduced rate of repolarisation)
• Lengthens the action potential

Due to types of potassium ion channels in the heart, and how they behave if extracellular potassium is reduced
- some don’t function as well

Question 38

What are the problems with hyperkalaemia?

Answer 38

• Longer action potential can lead to early
after depolarisations (EADs)
• This can lead to oscillations in membrane
potential
• Can result in ventricular fibrillation (VF)

Question 39

Give the step by step process involved in contraction in the cardiac myocytes

Answer 39

1. Depolarisation cause the opening of L-type Ca2+ channels in the T-tubule system.
2. There’s localised calcium ion entry which triggers CICR from inside the SR via ryanodine receptors.
3. The released calcium ions will bind to troponin C triggering a confidence actionable change to shift tropomyosin and reveal the myosin binding site in the action filament.
4. Myosin heads are able to bind to sites on the actin filament to cause contraction to occur
5. To relax the cardiac myocytes the calcium ion levels have to return to resting levels.
6. Intracellular Ca2+ is pumped back into the SR via SERCA.
7. Extracellular calcium ions are pumped back across the membrane by Ca2+ ATPase and Na+/Ca2+ exchanger

Question 40

Smooth muscle is a very important component of vascular vessels.

1. Where can it be found in the structure of blood vessels?
2. In which blood vessels can smooth muscle be found ?

Answer 40

1. Where can it be found in the structure of blood vessels?
   It’s located in the tunica media.
2. In which blood vessels can smooth muscle be found ?
   In arteries, arterioles, veins but not capillaries.

Question 41

Describe Excitation contraction coupling

Answer 41

It essentially shows that there 2 mechanisms that can be used to increase intracellular calcium.

Option 1 involves the depolarisation of the membrane causing voltage gated calcium ion channnels to open. This causes an influx of calcium ions.

Option 2 involves circulating noradrnaline binding and activating an a1 receptor. This triggers the breakdown of PIP2 into IP3 and DAG.
IP3 binds onto IP3 receptors on the surface of the SR causing calcium release.

4 calcium ions will bind onto a calmodulin molecule activating it. This activated CaM molecule will then activate Myosin Light Chain Kinase (MLCK). MLCK will then phosphorylate myosin light head to activate it. This will allow myosin to bind into sites in actin allowing contraction to occur.

This will continue till Myosin light chain phosphatase (MLCP) dephosphorylates myosin light head deactivating it

DAG produced from PIP2 can also be used to encourage contraction as it inhibits the action of MLCP. This means that the myosin light head can’t be deactivated meaning contraction will continue longer than normal.

Question 42

What effect does phosphorylation if MLCK have?

Answer 42

Phosphorylation of MLCK by PKA inhibits the action of MLCK

This therefore inhibits phosphorylation of the myosin light chain and inhibits contraction

Question 43

Describe the shape of the pacemaker action potential.

Answer 43

• slow depolarisation from -60mV
• upstroke to +30mV
• repolarisation back to -60mV

Question 44

What is different about resting potential in pacemaker cells compared to other cells?

Answer 44

Don’t have a stable resting membrane potential

• In diastole the membrane potential of pacemaker cells is not stable. It depolarises steadily from its most negative value of around -60mV.

Question 45

What is different about ventricular repolarisation compared to repolarisation in other cells?

Answer 45

There is no hyperpolarisation.

Question 46

Describe the shape of ventricular action potential.

Answer 46

• resting membrane potential at -80mV
• rapid depolarisation (upstroke) to +30mV
• transient repolarisation
• plateau
• repolarisation to resting membrane potential