Electrical And Moleuclar Mechanisms In The Heart And Vasculature Flashcards
Cellular and molecular events in the CVS
Setting up the resting potential —>
Ventricular myocyte action potential —>
Sino-atrial node action potential —>
Hyper and hypokalaemia
Mechanism of contraction in cardiac myocytes
Mechanism of contraction in vascular smooth muscle cells
K+ permeability sets the resting membrane potential (RMP)
Cardiac myocytes are permeable to K+ ions - these move out of the cells (down the conc gradient) in order to reach Ek (K+ equilibrium over the membrane)
- due to them leaving the cell the relative charge becomes negative with respect to outside the cell
As charge builds up an electrical gradient is established
Resting membrane potential doesn’t exactly equal Ek
K+ would continue to flow out of the cell until it reached Ek (~-95mV) - but RMP is more positive than this (-90 - -85mV)
This is due to the membrane being very slightly permeable to Na+ and Ca2+ coming into the cell at rest
Excitation and 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)
The ventricular (cardiac) AP
- Increase phase is the opening of the voltage gated Na+ channels - this drives the memebrane potential towards ENa (which is near +40)
- The potential dips down due to a transient outward K+ current
- Plateau phase is opening of L type voltage gated Ca2+ (ca2+ into cells) - which act to elongate the depolarisation and prolong AP
- These ca channels then inactivate and voltage gated K+ channels open causing K+ to exit the cell, causing the AP to decease as the potential goes back towards RMP
Cardiac AP summary
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 (iKV)
Repolarisation due to efflux of K+ through voltage-gated K+ channels (iKV iKR) and others
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
The Sino-atrial node action potential
Long slow depolarisation to threshold, starts around -60, these cells dont rest - when repolarisation occurs depolarisation starts again
Pacemaker potential - the influx of Na+ (not voltage gated channels) - called funny current - as the more you hyperpolarise (more negative) you make the cell the more they activate
Depolarisation is caused by opening of Voltage gated Ca2+ channels (not Na+ channels)
Opening of voltage gated K+ channels is the cause of repolarisation
The pacemaker potential - Initial slope to threshold - (funny current) Activated at membrane potentials that are more negative than -50mV
The more negative, the more it activates
HCN channels
– Hyperpolarisation-activated, Cyclic Nucleotide-gated channels
– Allow influx of Na+ ions which depolarises the cells
Other currents involved as well
Turning off of the K+ current
Transient (T-type) and L-type Ca2+ channels
Summary of SA Node Action Potential
Natural automaticity
Unstable membrane potential
– Pacemaker potential (slow depolarisation to threshold) – I f funny current
Upstroke – opening of voltage-gated Ca2+ channels
Down stroke (repolarisation) – opening of voltage-gated K+ channels
Action potential throughout the heart
Action potential waveform varies throughout the heart
SA node is fastest to depolarise (if SA node wasn’t working AV node would take over as pacemaker) – Sets rhythm – Is the pacemaker, if the AV node wasn’t working then the ventricles itself would be its own pacemaker - but it would be very slow
– Other parts of the conducting system also have automaticity i.e slower
The triggering of a single action potential which spreads throughout the heart is responsible for contraction
If action potentials fire too slowly
Effects of hyperkalaemia and hypokalaemia
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
Effect of hyperkalaemia - Hyperkalaemia depolarises the myocytes and slows down the upstroke of the AP
Due to the increase in K+ outside the cell Ek now
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
Calcium binds to Troponin C (TnC)
Conformational change shifts tropomyosin (TnI) to reveal myosin binding site on actin filament
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
Excitation contraction coupling in vascular smooth muscle cells
Tone of blood vessels is controlled by contraction and relaxation of vascular smooth muscle cells
– Located in tunica media layers of tunica
– Present in arteries, arterioles and veins
VG calcium channel opens and lets Ca come into vascular smooth muscles cells (these dont rely on troponin)
4 x Ca2+ binds to calmodulin (Ca2+ could be from VGCC or from SR)
Calmodulin bound with calcium binds to myosin like chain kinase (MLCK) which transfers a phosphate group (phosphorylates) to a myosin head therefore activating it
Myosin like chain phosphatase then removes the phosphate to inactivate the myosin
Myosin light chain must be phosphorylated to enable actin-myosin interaction
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
Note: MLCK can itself be phosphorylated
DePhosphorylation of MLCK by PKA inhibits the action of MLCK
– Therefore inhibits phosphorylation of the myosin light chain and inhibits contraction
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
- Myosin head is phosphorylated by ATP not MLCK
Contraction of vascular smooth muscle cells initiated by depolarisation or activation of alpha - adrenoceptors
– Increased intracellular Ca2+
– Ca2+ binding to calmodulin
– Activation of MLCK – phosphorylates myosin light chain
