Cardiac action potential

Cardiac action potential from SA node to Purkinje fibers

There are differences:

SA and AV node

cardiac pacemaker action potential

No phase 1 and 2, only phase 4,0 and 3

Phase 4

  • At the end of repolarization, when the membrane potential is very negative (about -60 mV), ion channels open that conduct slow, inward (depolarizing) Na+ currents. These currents are called “funny” currents and abbreviated as “If”. These depolarizing currents cause the membrane potential to begin to spontaneously depolarize, thereby initiating Phase 4.
  • As the membrane potential reaches about -50 mV, another type of channel opens. This channel is called transient or T-type Ca++ channel. As Ca++ enters the cell through these channels down its electrochemical gradient, the inward directed Ca++ currents further depolarize the cell. When the membrane depolarizes to about -40 mV, a second type of Ca++ channel opens. These are the so-called long-lasting, or L-type Ca++ channels. Opening of these channels causes more Ca++ to enter the cell and to further depolarize the cell until an action potential threshold is reached (usually between -40 and -30 mV).
  • It should be noted that a hyperpolarized state is necessary for pacemaker channels to become activated. Without the membrane voltage becoming very negative at the end of phase 3, pacemaker channels (funny current) remain inactivated, which suppresses pacemaker currents and decreases the slope of phase 4.

Phase 0

  • Depolarization is primarily caused by increased Ca++ conductance (gCa++) through the L-type Ca++ channels that began to open toward the end of Phase 4.

Phase 3

  • K+ channels open (increased gK+) thereby increasing the outward directed, hyperpolarizing K+ currents. At the same time, the L-type Ca++ channels become inactivated and close, which decreases gCa++ and the inward depolarizing Ca++ currents.

Purkinje fibers and ventricular myocardium

ventricular action potential

Phase 4

  • Non-pacemaker cells have a true resting membrane potential (phase 4) that remains near the equilibrium potential for K+ (EK). The resting membrane potential is very negative during phase 4 (about -90 mV) because potassium channels are open (K+ conductance [gK+] and K+ currents [IK] are high).
  • As shown in the figure, phase 4 is associated with K+ currents, in which positive potassium ions are leaving the cell and thereby making the membrane potential more negative inside.

Phase 0

  • When these cells are rapidly depolarized to a threshold voltage of about -70 mV (e.g., by an action potential in an adjacent cell), there is a rapid depolarization (phase 0) that is caused by a transient increase in fast Na+-channel conductance (gNa+) through fast sodium channels.
  • At the same time sodium channels open, gK+ and outward directed K+ currents fall as potassium channels close.

Phase 1 and 2

  • Phase 1 represents an initial repolarization that is caused by the opening of a special type of transient outward K+ channel (Kto), which causes a short-lived, hyperpolarizing outward K+ current (IKto).
  • However, because of the large increase in slow inward gCa++ occurring at the same time and the transient nature of IKto, the repolarization is delayed and there is a plateau phase in the action potential (phase 2). This inward calcium movement is through long-lasting (L-type) calcium channels that open up when the membrane potential depolarizes to about -40 mV. This plateau phase prolongs the action potential duration.

Phase 3

  • Repolarization (phase 3) occurs when gK+ (and therefore IK) increases, along with the inactivation of Ca++ channels (decreased gCa++).

Relationship with ECG

Clinical significance

1. Anti-arryhthmic drugs

  • Class 1: sodium channel blocking properties of class 1c > 1a > 1b, ability to prolong effective refractory period (ERP) 1a > 1c > 1b

    – By blocking phase 0 (sodium channels), ventricular depolarization is prolonged, thereby causing a wider QRS duration in ECG.
    – In addition, sodium channel blockers can also prolong ERP long QT interval), rendering the ventricular impulse (eg in VT) unable to recirculate inside the ventricle due to refractoric period. However, a long QT can predispose to Torsades de pointes, a type of VT caused by after-depolarization.
    – After-depol is an spontaneous depol during either phase 3 or 4 of an action potential (called “afterdepolarizations”). It is more likely to occur when the action potential duration is abnormally long

    ** Early form is responsive to CCB (which decreases calcium influx) or lidocaine (which shortens the ERP)
    – Note that sodium channel blockers have NO effect in AV or SA node cardiac AP
  • Type 3 (Potassium channel blockers eg amiodarone, sotalol)
    – By blocking potassium channels, it prolongs repolarization in non-pacemaker cells and pacemaker cells. The ERP in non-pacemaker and pacemaker cells are therefore prolonged.
    – They also have additional properties eg amiodarone also blocks calcium and sodium channels, sotalol also blocks beta-receptors.
  • Type 4 (calcium channel blockers eg verapamil, diltiazem)
    – Main action is in SA and AV node (phase 4 and 0), delaying the depolarization in the pacemakers therefore delaying the conduction of the impulse.

2. Hyperkalemia

  • Resting membrane potential of non-pacemakers depend on the gradient between extracellular K (low) and intracellular K (high). If this gradient is decreased in hyperkalemia, resting membrane potential increases (as there is more K+ left inside the cell so more positively charged) eg from -90 to -80 mV
  • Value of resting membrane potential determines the number of sodium channels activated during phase 1. The number decreases when the resting membrane potential becomes more positive.
  • In the same time, the threshold also decreases (meaning easier to be excited), but the degree of decrement is smaller than the increment in the resting membrane potential, eg from -75 to -70 mV
  • As a result, mild hyperkalemia causes more excitability of cardiac cells, but severe one causes myocardial depression, & flatter phase 0, leading to widened QRS pattern.
  • For reasons that are not well understood, one of the potassium currents, Ikr, responsible for phase 2 and 3 are sensitive to extracellular potassium levels, and as the potassium levels increase in the extracellular space, potassium conductance through these currents is increased  so that more potassium leaves the myocyte in any given time period.
    ** It has been suggested that extracellular K+ ions are required to open the Ikr.
  • This leads to shortening of plateau phase (shortening of ERP) and increase slope of phase 3 (shortening of RRP).

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  • Use of Calcium gluconate/chloride reverses the condition. It restores the normal resting membrane potential and the threshold. Also, it also speeds up the conduction in pacemaker cells, therefore overcoming the myocardial depression seen in severe hyperkalemia.

3. Hypokalemia

  • Equally confusing. For more understanding, please refer here:
    https://journals.viamedica.pl/cardiology_journal/article/viewFile/21240/16844
  • HypoK leads to hyperpolarization and more negative RMP, causing reduced excitability of the cells,
  • Due to effect on Ikr, plateau phase is shortened (imbalance between Ca++ influx and K+ efflux; shortening of ERP) but phase 3 slope is decreased (producing a “tail” like curve and therefore prolonging the RRP).
  • A longer RRP (QT interval) enhances the transmural dispersion of repolarization and increases the risk of Tdp.
  • In addition, If net inward currents during phase 3 become larger than outward currents, this can form an EAD, which also leads to Tdp
  • See this link for excellent discussion of EADs, dispersion of repol and DADs:
    http://tmedweb.tulane.edu/pharmwiki/doku.php/cellular_basis_for_arrhythmias.
    Untitled1

3. Hypothermia

  • May work by
    – slowing down AP propagation
    – altering the ions conductance across the channels
    – causing hypokalemia (by potassium redistribution in cold)
    – increasing intra-myocardial Ca++ which result in prolongation of plateau phase and the refractoric period, contributing to afterdepolarization.
    See more here http://anesthesiology.pubs.asahq.org/article.aspx?articleid=1949544

4. Hypoxia

  • Hypoxia alters phase 3 hyperpolarization in pacemaker cells. Therefore, opening of funny current channels is delayed, producing bradycardia.

5. Bradycardic drugs for angina eg ivabradine

  • Blocks funny current channels, therefore delaying phase 4 and leading to bradycardia.

Reference:

http://cvphysiology.com/Arrhythmias/A004.htm

Walter A. Parham et al. Hyperkalemia Revisited. Tex Heart Inst J 2006;33:40-7

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