Electrical And Molecular Mechanisms In The Heart & Vasculature

Question 1

What is responsible for setting the resting membrane potential in excitable cells?

Answer 1

The cells K+ permeability

ATPase sets up the difference in concentration of the ions either side

If membrane is permeable to sodium, then the RMP would be closer to ENa+

Question 2

What is the cardiac output of an average 70kg man?

Answer 2

5 litres per minute

Question 3

What channel type is responsible for the upstroke of the action potential in pacemaker cells?

Answer 3

L-type Calcium channels

Question 4

Why do you see different absolute values of ion concentrations?

Answer 4

May be looking at different cell types

Question 5

How does K+ permeability set the RMP?

Answer 5

• Cardiac myocytes are permeable to K+ions at rest
• K+ ions move out of the cell – down their concentration gradient
• Small movement of ions makes the inside negative with respect to the outside
• As charge builds up an electrical gradient is established

At equilibrium of ion, the concentration gradient and electrical gradient will be equal

Question 6

Why is it that the RMP is not exactly equal to Ek?

Answer 6

Not solely permeable to K+

Very small permeability to other ion species at rest

Question 7

What is the point of electrical excitation of the heart?

How does it carry out this role?

Answer 7

To allow cardiac contraction

Cardiac myocytes are electrically active
– Fire action potentials

Action potential triggers increase in cytosolic [Ca2+]

A rise in calcium is required to allow actin and myosin interaction
– Generates tension (contraction)

Question 8

What is the difference between AP in heart, neurone and sketelal muscle?

Answer 8

Length of AP is longer in cardiac ventricle and SAN (heart in general

Skeletal muscle and neuron - 0.5ms

In heart - 100ms

Question 9

Describe the phases of the ventricular (cardiac) action potential.

Answer 9

• The upstroke is caused by opening of V-gated NA+ channels, with depolarisation - THEN INACTIVATE!!
• An initial fast repolarisation caused by transient outwards K+ current
• Then a plateau caused by opening of V-gated L-type Ca2+ channels (some K+ channels also open too because the membrane is not only permeable to Ca2+ otherwise the membrane potential will be very positive. This balances it.)
• This is a long duration is very important. It allows for Ca2+ to enter the cell. This is important for Excitation-Contraction Coupling
• Eventually, the Ca2+ channels inactivate and even more V-gated K+ channels open causing repolarisation, and coming back to rest
• Longer period where cell is not excitable

Question 10

Which is longer, diastole or systole?

Answer 10

Diastole is 2/3rds the cycle

It is 2/3rds longer than the duration of systole

Systole is 1/3rd

Question 11

In the graph of the cardiac AP, how would you label the graph? How long would the AP be? How long would the resting phase (diastole) be?

Answer 11

X axis = Time (ms)

Y axis = Membrane potential (mV)

AP - 200ms

Resting (diastole) - 400ms

Question 12

What are the phases of the cardiac AP?

Answer 12

0 - NA+ influx

1 - Transient K+

2 - Ca2+ influx and K+ efflux

3 - Ca2+ channel inactivation and K+ efflux

4 - rest

Question 13

Briefly talk about the different types of K+ channels

Answer 13

• 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 14

What are pacemaker cells?

Answer 14

Specialised myocytes that do not need any nerve impulse or depolarisation from neighbouring cell to activate them

Question 15

Outline the process of SA node action potential generation

Answer 15

Pacemakers spontaneously depolarise, most negative = -60mV.

They have a long slow depolarisation to threshold.

This is called the pacemaker potential, caused by the funny current.

The funny current is made by HCN channels, they are permeable to NA and K and you get influx of NA ions. Can be seen as slow NA channels.

Called HCN because they are activated by hyperoplarisation. The more negative a cell gets, the more likely they are to open.

Pacemaker potential different to AP, caused by funny current because it behaves in a funny way , made by HCN channels, similar to NA channels but they are slow NA+ channels.

Called HCN because they are activated by negative current

Activated by voltage and also inactivated by voltage

Once threshold is reached, the upstroke is caused by opening of V-gated L-type Ca2+ channels. this is because NA+ channels become inactivated. The depolarisation also inactivates them.

The opening of V-gated K+ channels caused repolarisation

Question 16

What is the initial slope of the pacemaker potential caused by?

What is it activated by?

Answer 16

I f - funny current

Activated at membrane potentials that are more negative than -50mV

The more negative, the more it activates

Question 17

What is the funny current due to?

Answer 17

HCN channels
– Hyperpolarisation- activated, Cyclic Nucleotide-gated channels

They allow influx of Na+ ions which depolarises the cells

Question 18

What is the difference between the SAN and AVN?

Answer 18

SA node is fastest to depolarise and so sets the rhythm of the heart

• It’s the pacemaker

AVN has delay, conducts slower, allows for atria to contract before ventricles do, and allows time for filling

Question 19

Describe the differences seen in the AP through the the heart.

1) SAN
2) AVN
3) Atrial muscle
4) Ventricular muscle
5) Purkinje fibres

Answer 19

1) Fastest
2) Fast, but not as fast as SAN and there’s a delay
3) AP doesn’t last as long

5) Fast NA+ helps it conduct quickly. It has an unstable membrane potential but slower than SAN. Could set rhythm is something stops conduction getting to the ventricles

Question 20

What is responsible for heart muscle contraction?

Answer 20

The triggering of a single action potential which spreads throughout the heart is responsible for contraction

Question 21

What happens if the AP is:

1) Too slow
2) Fails
3) Too quick
4) Random

Answer 21

• If action potentials fire too slowly → bradycardia
• If action potentials fail → asystole
• If action potentials fire too quickly → tachycardia
• If electrical activity becomes random → fibrillation

Question 22

What is hyperkalaemia and hypokalaemia?

Answer 22

• Hyperkalaemia – Plasma K+ concentration is too high > 5.5 mmol.L -1
• Hypokalaemia – Plasma K+ concentration is too low < 3.5 mmol.L -1

Question 23

What is the normal range for plasma K+?

Answer 23

• Plasma K+ concentration must be controlled within a tight range
– 3.5 – 5.5 mmol/L-1

Question 24

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

Answer 24

They have a very negative resting membrane potential is very close to Ek, moreso than any other cell

Have loads of important K+ channels

All the K+channels present behave in different ways and behave weirdly when K+ conc is changed

Question 25

What are the effects of hyperkalaemia?

Answer 25

If you raise plasma K+ extracellularly then Ek gets less negative so the membrane potential depolarises a bit

This decreases the driving force of K+ and that depolarises the cells

This is turn inactivates some of the voltage-gated Na+ channels – Slows the upstroke

It also narrows the AP - black box

In summary…Hyperkalaemia depolarises the myocytes and slows down the upstroke of the action potential

Question 26

What are the risks with hyperkalaemia?

Answer 26

Asystole - The heart can stop

Slowing contraction down, if you slow it enough and inactive enough NA+ channels, you will eventually stop heart. Depends on severity of hyperkalaemia and how quickly it develops too.

More dangerous if it develops more quickly.

Question 27

What are the severity ranges of hyperkalaemia?

Answer 27

• Mild 5.5 – 5.9 mmol/L
• Moderate 6.0 – 6.4 mmol/L
• Severe > 6.5 mmol/L

Question 28

What are the treatment options available for hyperkalaemia?

Answer 28

– Calcium gluconate

Because it makes heart less excitable. Calcium is the important substance so could be CaCl. Divalent cations tend to make electrical excitable membranes less excitable.

– Insulin + glucose
Insulin helps promotes K+ moving into the cells and the glucose prevents the patient from getting a hypo.

These won’t work if heart already stopped because if heart cannot pump the drugs around the body, it’s too late.

Question 29

What are the effects of hypokalaemia?

Answer 29

Makes the AP last longer

Delays repolarisation

K+ conductances involved in repolarisation have an allosteric effect if K+ is lowered too much and so it reduces the K+ current

Question 30

Why is hypokalaemia a problem?

Answer 30

• Longer action potential can lead to early after depolarisations (EADs)
• This can lead to oscillations in membrane potential
• this is probably due to reactivation of some Ca2+ channels that have been active in this time
• this can result in ventricular fibrillation and so you don’t have an cardiac output

Question 31

In what cases is hypokalaemia most dangerous?

Answer 31

Hypokalaemia is not dangerous in all patients

More dangerous to those already on arrthymic drugs or if they have heart failures

Question 32

Briefly explain the excitation-contraction coupling process in cardio myocytes

Answer 32

Depolarisation spreads from neighbouring myocytes becasue they are all connected by gap junctions

AP occurs

Depolarisation opens L-type Ca2+ channels in T-tubule system

Localised Ca2+ entry opens Calcium-
Induced Calcium Release (CICR) channels in the SR

Close link between L-type channels and Ca2+ release channels

• 25% enters across sarcolemma, 75%
released from SR

Ca2+ binds to troponin C (Troponin T and I is there too)

Conformational change shifts tropomyosin to reveal myosin binding site on actin filament

Question 33

How does the body allow relaxation of cardiac myocytes?

Answer 33

• Must return [Ca2+]i to resting levels
• Most is pumped back into SR (SERCA) because they came from there and you don’t want to deplete the store

– Raised Ca2+ stimulates the pumps and the Ca2+ enters the SR

• Some Ca2+ exits across cell membrane
– Sarcolemmal Ca2+ATPase
– Na+/Ca2+ exchanger

Question 34

What controls the tone of blood vessels in the vascular system?

Answer 34

• Tone of blood vessels is
controlled by contraction and relaxation of vascular smooth muscle cells
– Smooth muscle is located in tunica media
(Tunica intima and adventitia)
– Present in arteries, arterioles (has the thickest smooth muscle walls) and
veins

Question 35

What are the names of the blood vessel’s layers? And which blood vessel has the most smooth muscle

Answer 35

Medial to Lateral:

Tunica intima
Tunica media
Tunica Adventitia

Tunica media has the thickest layer of smooth muscle cells

Question 36

The excitation contraction coupling in vessels and myocytes are different. By outlining the process, outline the ways in which are they similar and different?

Answer 36

Coupling is still activated by Ca2+

There are V-gated Ca2+ channels on vascular smooth muscle cells. When they open, it allows Ca2+ in

Alpha 1 receptors are activated by adrenaline or noradrenaline. They are G alpha q receptors they couple through IP3.

IP3 binds to the IP3 receptors on the SR membrane and this causes release of Ca2+ from the stores

The Ca2+ binds to Calmodulin = CaM (so troponin C doesn’t have a role here)

CaM then binds to MLCK enzyme (Myosin-light chain kinase)

This activates the MLCK

MLCK phosphorylates the light chain on the myosin head (in vascular smooth muscle cells the myosin head has a special light chain, which is a regulatory light chain)

When the light chain is not phosphorylated you cannot get bind with actin so no contraction can take place.

Myosin light chain phosphotase dephosphorylates the myosin light chain

Question 37

What is the role of MLCK?

Answer 37

Myosin light chain kinase = Regulation of contraction in VSM

• Ca2+ binds to calmodulin
– Activates Myosin Light Chain Kinase (MLCK) – MLCK phosphorylates the myosin light chain to permit interaction with actin

• Relaxation as Ca2+ levels decline
– Myosin light chain phosphatase dephosphorylates the myosin light chain

Question 38

What is MLCP? What does it do?

Answer 38

Myosin light chain phosphotase

It dephosphorylates - takes phosphate group off the myosin light chain

It’s constitutively active - unless if it’s actively turned off, it stays on

• Relaxation as Ca2+ levels decline
– Myosin light chain phosphatase dephosphorylates the myosin light chain

If you get activation of the alpha 1 adrenoreceptors you get Ca2+ released from SR, the dicylglycerel stimulates PKC, which inhibits the phophotase

Question 39

How is contraction of VSM regulated?

Answer 39

• Ca2+ binds to calmodulin
– Activates Myosin Light Chain Kinase (MLCK) – MLCK phosphorylates the myosin light chain to permit interaction with actin

• Relaxation as Ca2+ levels decline
– Myosin light chain phosphatase dephosphorylates the myosin light chain

• Note: MLCK can itself be phosphorylated

• Phosphorylation of MLCK by PKA inhibits the action of MLCK
– Therefore inhibits phosphorylation of the myosin light chain and inhibits contraction

Question 40

What is the regulatory factor in cardiac myocyte contraction and contraction of VSM cells?

Answer 40

1) Ca2+ binding to troponin C

2) Activation by MLCK – phosphorylates myosin light chain on the myosin head