By Dr. Thomas Burnell and Dr. Bethany Turner
Next Lesson - Embryological Development of the CVS
Core
When an action potential (AP) reaches the cardiac muscle, it travels down the T-tubules (deep invaginations of the myocyte cell membrane).
The AP causes the opening of L-type calcium channels that are found in the T-tubule and cell surface membranes, causing an influx of calcium ions into the sarcoplasm.
Calcium within the cell binds to ryanodine receptors on the surface of the sarcoplasmic reticulum (SR, the muscle cell's internal calcium store). These are calcium-release channels, and they open to let calcium ions out of the sarcoplasmic reticulum. This is calcium-induced calcium release (CICR).
The calcium that has been released binds to troponin C, part of the troponin complex on the thin filament. This changes the shape of the troponin complex and lifts the block that tropomyosin (a rod-shaped protein lying along the filament) places over the binding sites on actin (the thin filament protein). The myosin heads (the motor parts of the thick filament protein) bind to these sites. This then allows the sliding filament mechanism to occur and for the cardiac muscle to contract.
To relax the muscle, calcium must leave the sarcoplasm. Most calcium is pumped back into the sarcoplasmic reticulum by sarcoplasmic reticulum calcium-ATPase (SERCA), a pump that uses ATP. The rest is transported out of the cell across the surface membrane, mainly by the Na+/Ca2+ exchanger (a transporter that moves sodium in as calcium goes out) and to a lesser extent by Ca2+-ATPase, another pump that uses ATP.
Diagram - The events involved in muscle contraction
SimpleMed original by Dr. Thomas Burnell
The conduction system in the heart is outlined in the Cardiac Cycle article. That article explains how the heart's contraction is co-ordinated. Here, we will discuss the regulation of the electrical activity in the heart.
Sino-Atrial Node Action Potential
The cells within the Sino-Atrial (SA) node slowly depolarise, triggering a wave of depolarisation that spreads through the conduction system of the heart and makes the heart beat.
The pacemaker potential is the gradual depolarisation between action potentials. Central SA node cells have no stable resting membrane potential. Hyperpolarisation (the membrane becoming more negative than usual) activates HCN channels (hyperpolarisation-activated, cyclic nucleotide-gated channels), which conduct both Na+ and K+. They carry the funny current (If), a net inward current (an overall flow of positive charge into the cell) at diastolic pacemaker voltages. If contributes to the pacemaker potential alongside calcium currents and a declining outward potassium current; it is not the name for the whole depolarising phase.
Calcium entry through T-type (transient) and L-type (long-lasting) calcium channels contributes as the membrane approaches threshold. The action-potential upstroke in central SA node cells is carried mainly by L-type Ca2+ channels. Repolarisation follows as these calcium channels inactivate (close and cannot reopen for a short time) and outward current through voltage-gated K+ channels increases.
Repolarisation returns the membrane towards its most negative voltage in the cycle, the maximum diastolic potential. Outward potassium current then declines and inward pacemaker currents bring the membrane towards threshold again. There is no stable resting phase between beats.
Cardiac sympathetic nerve endings release chiefly noradrenaline, while adrenaline reaches the heart chiefly through the circulation after release from the adrenal medulla (the inner part of the adrenal gland). Both can stimulate β1-adrenoceptors (receptors for adrenaline and noradrenaline) in SA node cells. The resulting increase in cyclic AMP (cAMP, an intracellular messenger) enhances pacemaker activity, helping the cells reach threshold sooner and increasing heart rate.
Diagram - SA node membrane potential. The orange phase is the pacemaker potential, the red upstroke is mainly calcium-dependent, and the blue phase is repolarisation towards the maximum diastolic potential. The pacemaker phase involves mixed Na+/K+ If, calcium entry and declining outward potassium current.
SimpleMed original by Dr. Bethany Turner
When the myocytes (muscle cells) in the ventricles receive an AP from the conduction system, they produce the ventricular action potential, which has a long plateau.
When depolarisation reaches the myocytes, the threshold is reached (about −70 mV) and the voltage-gated Na+ channels (VGNC) open to allow an influx of Na+ ions into the cell. This is the upstroke of the AP (the orange line on the diagram below).
The AP peaks at around +20 mV, where the VGNC close and some voltage-gated K+ channels (VGKC) open. This results in transient repolarisation, with some K+ ions moving out of the cell (small blue line).
L-type voltage-gated Ca2+ channels open and Ca2+ ions move into the cell. The influx of Ca2+ ions balances the efflux of K+ ions, so the membrane potential stays almost level (the plateau, purple line). This calcium entry also triggers calcium release from the sarcoplasmic reticulum, as described in the Cardiac Muscle Contraction section above. The calcium released then binds to troponin C, allowing muscle contraction to take place.
Later, the Ca2+ channels inactivate (close and cannot reopen for a short time) and more VGKCs open to allow more K+ ions out of the cell and cause repolarisation (final blue line).
The membrane returns to a stable resting potential of about −90 mV, maintained mainly by potassium conductance. The myocyte remains at rest until the next depolarising impulse arrives.
Diagram - The changes in the membrane potential in cardiac myocytes. The orange line represents the influx of sodium when the action potential arrives at the myocyte. There is a slight outward movement of potassium which causes a lowering of the membrane potential, represented by the blue line. This is followed by the influx of calcium into the cell which causes the membrane potential to plateau, represented by the purple line. The final blue line shows the return to the resting membrane potential by the outflow of potassium
SimpleMed original by Dr. Bethany Turner
There are changes to the ventricular action potential if a patient has hyperkalaemia or hypokalaemia:
- In hypokalaemia, there is a delay in repolarisation. This is because K+ channels do not work effectively as there is a decreased K+ ion concentration outside the cell.
- This delay in repolarisation lengthens the action potential. On the ECG it appears as a long QT interval (the time from the start of ventricular depolarisation to the end of repolarisation) and a prominent U wave. It can trigger early afterdepolarisations (extra depolarisations during the delayed repolarisation), especially when drugs that block the same K+ channels are also present. These can lead to torsades de pointes, a fast, irregular ventricular tachycardia (abnormally fast ventricular rhythm).
- In hyperkalaemia, there is less of a concentration gradient of K+ across the myocyte cell membrane.
- This leads to the equilibrium potential of K+ (the voltage at which K+ has no net movement across the membrane) becoming less negative (closer to 0). As a result, the cell depolarises slightly.
- Some VGNCs in the cell membrane become inactivated due to the slight depolarisation, and this causes a slower upstroke in the ventricular AP.
- The slower upstroke slows conduction of the impulse through the ventricles. Hyperkalaemia can also slow the heart rate, because it slows the firing of the SA node, and it can stop the heart if the K+ concentration outside the cell is very high. On the ECG, tall, narrow-based peaked T waves appear first, at about 5.5 to 7.0 mmol/L.
Diagram - The solid line shows the normal ventricular AP. The dotted line shows the ventricular action potential in hyperkalaemia. The upstroke is less rapid in hyperkalaemia
SimpleMed original by Dr. Bethany Turner
Edited by: Dr. Ben Appleby
Reviewed by: Dr. Marcus Judge
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