4 - Electrical + Molecular Mechanisms in the Heart + Vasculature Flashcards
How is the resting membrane potential set up
- K+ permeability sets the resting membrane potential (RMP)
- Sodium-potassium ATPase helps set up the concentration gradient of K+ and Na+, maintaining the membrane potential
- There is a greater [K+] inside cell, and more [Na+] outside cell
- This would mean that K+ would move out of cell, and Na+ in, but cells are mainly permeable to K+ at rest
- K+ move out of the cell, down their concentration gradient
- This means less cations inside cell, so inside cell is more positive than outside cell
What is Ek
equilibrium potential for K+ ions
* At resting membrane, net outflow of K+ until Ek reached
* At Ek, there is no net movement of K+ ions
* Membrane potential is close to Ek (not equal, due to small permeability to other ions at rest)
* Permeability of K+ is the main determinant of RMP
Features of cardiac myocytes (excitation + contraction)
- Cardiac myocytes are electrically active (meaning they fire action potentials)
- Cardiac myocytes are electrically coupled to one another due to cap junctions → allows depolarisation to spread from one cardiac myocyte to another
- Action potential triggers increase in cytosolic (inside cell) Ca2+ calcium
- A rise in calcium is required to allow actin + myosin interaction → contraction
- Cardiac myocytes have much longer action potentials (eg 100ms) in comparison to other body cells (eg axon + skeletal muscle are 50ms)
Ventricular (cardiac) action potential
- ‘Resting’ membrane potential of about -90 mv due to background K+ channels open at rest
- Rapid upstroke due to the opening of voltage gated sodium channels (rapid influx of positive charge)
- Initial small repolarisation due to transient outward K+ channels (so some K+ leaving the cell, making more negative)
- Plateau due to opening of L-type voltage-gated Ca2+ channels, causing influx of Ca2+ into cell, balanced with K+ efflux
- Repolarisation due to efflux of K+ through voltage-gated K+ channels
note that this is simplified: 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
Pacemaker cells
- These exist in the SA and AV node
- They have very little contractability
- They are specialised myocytes that can spontaneously depolarise + fire action potentials
- They have a very different mix of ion channels which enable spontaneous depolarisation
- SA node cells are the fastest to depolarise
SA node action potential
- Doesn’t really have a resting potential, as it is never really at rest
- Slow depolarisation to threshold = ‘funny current (If)’
- This wave of depolarisation will spread through the conduction system of the heart, causing it to beat
- This depolarisation is initiated when the membrane is hyperpolarised after the previous AP
- At this negativity, there is opening of the HCN (hyperpolarisation-activated cyclic nucleotide gated Na+ channels)
- This causes influx of Na+, slowly, causing gradual depolarisation
- Once threshold is reached, L-type Ca2+ channels open
- This causes a fast influx of Ca2+ into cell, causing rapid depolarisation
- Potential peaks at around +20mv, where L-type Ca2+ channels inactivate, and voltage-gated K+ channels (VGKCs) open
- This allows K+ out of the cell → repolarisation
- At ‘resting’ membrane potential, VGKCs close, HCNs open = cycle restarts
Features of the SA node
- Has pacemaker cells that are the fastest to depolarise
- Sets the rhythm = pacemaker
- Has natural automaticity = depolarise spontaneously
- Other parts of the conducting system (eg AVN + Purkinje fibres) also have automaticity, but are slower at depolarisation
What is it called if action potentials fire too slowly/fast/fail/randomly
fire too slowly = bradycardia
fire too fast = tachycardia
fire randomly = fibrillation
fail = asystole (no electrical activity)
K+ and cardiac myocytes sensitivity to K+
- Plasma [K+] must be tightly controlled
- Range of 3.5 - 5.5 mmol/L
- If [K+] is too high or low → heart arrythmias
- Too low = hypokalaemia
- Too high = hyperkalaemia
why the heart is so sensitive to changes in [K+]
- there are mechanisms to buffer blood K+ levels, but not so much for the heart
- K+ permeability dominates the resting membrane potential
- The heart has many different kinds of K+ channels, and some behave in a peculiar way
Hyperkalaemia
- If you raise plasma K+ → Ek gets less negative → membrane potential depolarises a bit
- This inactivates some of the voltage-gated Na+ channels
- hyperkalaemia depolarises the myocytes and slows down the upstroke of the AP
- Therefore slower + shorter AP
risks
- Heart can stop = asystole
- May initially get an increase in excitability
- Depends on extent + how quickly it can develop
Treatment for hyperkalaemia
- calcium gluconate to reduce excitability
- insulin + glucose as insulin to encourage cell uptake of K+, and glucose to compensate for effect of insulin
- These treatments won’t work if heart has already stopped
Hypokalaemia
- Decreased K+ concentration outside cell
- Therefore K+ channels won’t work as effectively
- This causes a delay in repolarisation
- Lengthens the action potential
- Longer action potentials can lead to EADs (early after depolarisations)
- This can lead to oscillations in membrane potential
- Can result in VF
- Ventricular fibrillation is life-threatening
Cardiac muscle contraction overview
- When an AP reaches cardiac muscle, travels down T-tubules
- This causes opening of L-type calcium channels (found on cell surface of membrane)
- This causes influx of Ca2+ into sarcoplasm
- Calcium within cell binds to ryanodine receptors on SR surface
- This results in release of Ca2+ from SR (this process is known as CICR – calcium induced calcium release)
- The calcium that has been released binds to troponin C
- conformational change in tropomyosin → exposes binding site on actin
- myosin heads bind to these sites
- this allows sliding filament mechanism to occur
after contraction: most Ca2+ is pumped back into SR by SERCA (SR calcium ATPase), and the rest is transported across the cell membrane back into T-tubules by Ca2+ ATPase + sodium-calcium exchanger
After contraction of cardiac muscle, how does the Ca2+ get back into the sarcoplasmic reticulum?
- most Ca2+ is pumped back into SR by SERCA (SR calcium ATPase)
- the rest is transported across the cell membrane back into T-tubules by Ca2+ ATPase and sodium-calcium exchanger
contractions in vascular system
tone of BVs is controlled by contraction + relaxation of vascular smooth muscle cells
- located in tunica media
- present in arteries, arterioles + veins
- excitation contraction coupling works differently to other muscle cells, as no troponin
the process
- depolarisation opens voltage-gated calcium channels
- noradrenaline activates α1 receptors
- these lead to increase in Ca2+ inside the cell
- Ca2+ binds to calmodulin
- Calmodulin activates MLCK (myosin light chain kinase)
- MLCK allows phosphorylation of myosin head → able to interact with actin filament to allow contraction
- Activation of α1 receptor by noradrenaline allows DAG to stimulate PKC (protein kinase C)
- PKC inhibits MLCP (myosin light chain phosphatase) → this makes sure that the myosin head stays phosphorylated
- relaxation as Ca2+ levels decline - MLCP dephosphorylates the myosin light chain
