Electrical and Molecular Mechanisms in the Heart & Vasculature Flashcards
How doe excitation lead to 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)
How do action potentials in the heart differ from neuronal APs
Action potentials in heart differ depending on cell location in heart
longer contraction than in neurones
plateau is when calcium ions move into cardiac myocytes - ICPP
Describe the ventricular action potential
Sodium channels open with depolarisation and then deactivate
K+ channels open to balance so it doesnt become very depolarised in plateau
towards end of plateau calcium channels inactivate and K+ channels open more - this brings the ventricular myocite potential back down towards resting potential
See slide for graph
What are the phase of the ventricular action potential
0 - rapid depolarisation 1- transient repolarisation 2 - plateau 3 - repolarisation 4 - resting potential
Give a summary of the cardiac action potential
• RMP due to background K+ channels
• Upstroke due to opening of voltage-gated Na+ channel - influx of Na+
• Initial repolarisation due to transient outward K+ channels (V-gated ito)
• Plateau due to opening of voltage-gated Ca2+ channels (L-type) - influx
of Ca2+
– Balanced with K+ efflux
• Repolarisation due to efflux of K+ through voltage-gated K+ channels
(iKV iKR) and others
Describe the SA node action potential
Cells dont really have a proper resting potential
most negative they get to is -60 BUt they dont stay there
pacemaker potential - slow depolarisation towards threshold - due to the “funny current” - ion channels usually activated by depolarisation but these ion channels activated by slow sodium current ????????? Rewatch calcium channels - t type
cant use vg sodium channels for upstroke
upstroke due to opening of vg calcium channels ( l type)
v gated calcium channels bring the membrane back
• Natural automaticity • Unstable membrane potential
– Pacemaker potential (slow depolarisation to threshold) –I
• Upstroke – opening of voltage-gated Ca2+ channels
• Down stroke (repolarisation|) – opening of voltage-gated K+ channels
f
funny current
In the pacemaker potential when are membrane potentials activated
- Initial slope to threshold - If (funny current)
- Activated at membrane potentials that are more negative than - 50mV
- The more negative, the more it activates
What are HCN channels?
– Hyperpolarisation-activated, Cyclic Nucleotide-gated channels – Allow influx of Na+ ions which depolarises the cells
What causes the upstroke and downstroke of he SA node action potential?
- Upstroke – opening of voltage-gated Ca2+ channels
* Down stroke (repolarisation|) – opening of voltage-gated K+ channels
How does the AP pass through the heart
• Action potential waveform varies throughout the heart • SA node is fastest to depolarise – Sets rhythm – Is the pacemaker – Other parts of the conducting system also have automaticity • slower AV node has automatic depolarisation but not as quickly as SAN
What problems can arise from abnormal action potentials?
- The triggering of a single action potential which spreads throughout the heart is responsible for contraction
- If action potentials fire too slowly → bradycardia (<60 bpm)
- If action potentials fail → asystole
- If action potentials fire too quickly → tachycardia (>100 bpm)
- If electrical activity becomes random → fibrillation
Why are are hypo- and hyper- kalaemia?
• Plasma K+ concentration must be controlled within a tight range
– 3.5 – 5.5 mmol/L-1
• If [K+] is too high or low it can cause problems, particularly for the heart
• Hyperkalaemia – Plasma K+ concentration is too high > 5.5 mmol.L -1
• Hypokalaemia – Plasma K+ concentration is too low < 3.5 mmol.L -1
Why are cardiac myocytes so sensitive to changes in [K+]
• K+ permeability dominates the resting membrane potential
• The heart has many different kinds of K+ channels
– Some behave in a peculiar way
What are the effects of hyperkalaemia
• If you raise plasma K+ then Ek gets less negative so the membrane potential depolarises a bit
• This inactivates some of the voltage-
gated Na+ channels – Slows upstroke
Hyperkalaemia depolarises the myocytes and slows down the upstroke of the action potential
What are the risks with hyperkalaemia
• The heart can stop – asystole
• May initially get an increase in excitability
• Depends on extent and how quickly it develops
• Mild 5.5 – 5.9 mmol/L
• Moderate 6.0 – 6.4 mmol/L
• Severe > 6.5 mmol/L
• Treatment
– Calcium gluconate
– Insulin + glucose
– These won’t work if heart already stopped
What are the effects of hypokalaemia
• Lengthens the action potential • Delays repolarisation Potassium conc outside below 3.5mmol/L ventricular ap tends to last longer some channels dowt work as well if k+ conc outside changes too much
What are the problems with hypokalaemia?
• Longer action potential can lead to early
after depolarisations (EADs)
• This can lead to oscillation in membrane
potential
• Can result in ventricular fibrillation (VF)
Early after depolarisations due to lengthened action portential
some recovery from Na/ca channels - oscillation sin memb potential which can lead to ventricular fibrillation
either can lead to arrythrima
heyper - asystole
hypo - fibrillation
keep k+ concs tightly controlled
Describe excitation-contraction coupling
• 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
How is cardiac myocyte contraction regulated?
- As with skeletal muscle
- Ca2+ binds to troponin C
- Conformational change shifts tropomyosin to reveal myosin binding site on actin filament
- Revise sliding filament mechanism
Describe the relaxation of cardiac myocytes
• Must return [Ca2+]i to resting levels • Most is pumped back into SR (SERCA) – Raised Ca2+ stimulates the pumps • Some exits across cell membrane – Sarcolemmal Ca2+ATPase – Na+/Ca2+ exchanger
How is the tone of blood vessels controlled?
• Tone of blood vessels is controlled by contraction and relaxation of vascular smooth muscle cells
– Located in tunica media
– Present in arteries, arterioles and veins
What allows actin-myosin interactions n smooth muscle?
myosin light chain must be phosphorylated to enable
actin-myosin interaction
Describe regulation of contraction in smooth muscle
Regulation of contraction in VSM
- calcium comes in though VG Ca2+ channels or by activation of alpha1 adrenoceptorsceptors - Gq - (ip3/dag pathway - release of Ca2+ from SER)
• 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 are differences in contraction between cardiac and smooth muscle?
Differences between cardiac muscle and smooth muscle
• Contraction of the heart is initiated by spread of APs from SA node
• Cardiac myocyte action potentials allow Ca2+ entry
– Further Ca2+ is released form SR – Increased intracellular Ca2+ – Ca2+ binding to troponin-C
• Contraction of vascular smooth muscle cells initiated by depolarisation or activation of α-adrenoceptors
– Increased intracellular Ca2+
– Ca2+ binding to calmodulin
– Activation of MLCK – phosphorylates myosin light chain
• Also consider Body Logistics - Table in work book session 1
