Electrical And Molecular Mechanisms In The Heart & Vasculature Flashcards
What is responsible for setting the resting membrane potential in excitable cells?
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+
What is the cardiac output of an average 70kg man?
5 litres per minute
What channel type is responsible for the upstroke of the action potential in pacemaker cells?
L-type Calcium channels
Why do you see different absolute values of ion concentrations?
May be looking at different cell types
How does K+ permeability set the RMP?
- 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
Why is it that the RMP is not exactly equal to Ek?
Not solely permeable to K+
Very small permeability to other ion species at rest
What is the point of electrical excitation of the heart?
How does it carry out this role?
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)
What is the difference between AP in heart, neurone and sketelal muscle?
Length of AP is longer in cardiac ventricle and SAN (heart in general
Skeletal muscle and neuron - 0.5ms
In heart - 100ms
Describe the phases of the ventricular (cardiac) action potential.
- 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
Which is longer, diastole or systole?
Diastole is 2/3rds the cycle
It is 2/3rds longer than the duration of systole
Systole is 1/3rd
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?
X axis = Time (ms)
Y axis = Membrane potential (mV)
AP - 200ms
Resting (diastole) - 400ms
What are the phases of the cardiac AP?
0 - NA+ influx
1 - Transient K+
2 - Ca2+ influx and K+ efflux
3 - Ca2+ channel inactivation and K+ efflux
4 - rest
Briefly talk about the different types of K+ channels
• 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
What are pacemaker cells?
Specialised myocytes that do not need any nerve impulse or depolarisation from neighbouring cell to activate them
Outline the process of SA node action potential generation
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
What is the initial slope of the pacemaker potential caused by?
What is it activated by?
I f - funny current
Activated at membrane potentials that are more negative than -50mV
The more negative, the more it activates
What is the funny current due to?
HCN channels
– Hyperpolarisation- activated, Cyclic Nucleotide-gated channels
They allow influx of Na+ ions which depolarises the cells
What is the difference between the SAN and AVN?
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
Describe the differences seen in the AP through the the heart.
1) SAN
2) AVN
3) Atrial muscle
4) Ventricular muscle
5) Purkinje fibres
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
What is responsible for heart muscle contraction?
The triggering of a single action potential which spreads throughout the heart is responsible for contraction
What happens if the AP is:
1) Too slow
2) Fails
3) Too quick
4) Random
- 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
What is hyperkalaemia and hypokalaemia?
- Hyperkalaemia – Plasma K+ concentration is too high > 5.5 mmol.L -1
- Hypokalaemia – Plasma K+ concentration is too low < 3.5 mmol.L -1
What is the normal range for plasma K+?
• Plasma K+ concentration must be controlled within a tight range
– 3.5 – 5.5 mmol/L-1
Why are cardiac myocytes so sensitive to changes in [K+]?
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
What are the effects of hyperkalaemia?
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
What are the risks with hyperkalaemia?
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.
What are the severity ranges of hyperkalaemia?
- Mild 5.5 – 5.9 mmol/L
- Moderate 6.0 – 6.4 mmol/L
- Severe > 6.5 mmol/L
What are the treatment options available for hyperkalaemia?
– 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.
What are the effects of hypokalaemia?
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
Why is hypokalaemia a problem?
- 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
In what cases is hypokalaemia most dangerous?
Hypokalaemia is not dangerous in all patients
More dangerous to those already on arrthymic drugs or if they have heart failures
Briefly explain the excitation-contraction coupling process in cardio myocytes
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
How does the body allow relaxation of cardiac myocytes?
- 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
What controls the tone of blood vessels in the vascular system?
• 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
What are the names of the blood vessel’s layers? And which blood vessel has the most smooth muscle
Medial to Lateral:
Tunica intima
Tunica media
Tunica Adventitia
Tunica media has the thickest layer of smooth muscle cells
The excitation contraction coupling in vessels and myocytes are different. By outlining the process, outline the ways in which are they similar and different?
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
What is the role of MLCK?
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
What is MLCP? What does it do?
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
How is contraction of VSM regulated?
• 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
What is the regulatory factor in cardiac myocyte contraction and contraction of VSM cells?
1) Ca2+ binding to troponin C
2) Activation by MLCK – phosphorylates myosin light chain on the myosin head
