Cardiac action potential

From Wikipedia, the free encyclopedia - View original article

Jump to: navigation, search

As in other cells, the cardiac action potential is a short-lasting event in which the difference of potential between the interior and the exterior of each cardiac cell rises and falls following a consistent trajectory.[1]

The cardiac action potential differs significantly in different portions of the heart. The heart is provided with a special excitatory system and a contractile system necessary to perform this function.

This differentiation of the action potentials allows the different electrical characteristics of the different portions of the heart. For instance, the specialized excitatory system of the heart has the special property of depolarizing without any external influence with a slow, positive increase in voltage across the cell's membrane (the membrane potential) that occurs between the end of one action potential and the beginning of the next action potential. This increase in membrane potential typically permits the membrane potential to reach the threshold potential at which it fires the next action potential (pacemaker potential). Thus, the pacemaker potential is what drives the self-generated rhythmic firing. This is known as cardiac muscle automaticity.[2]

Pacemaker potentials are fired by sinoatrial node (SAN), but also by the other foci. However, the last ones have firing frequencies slower than the SAN's. When other foci attempt to fire at their intrinsic rate, they can't because they have been discharged by the previous electric impluse coming from the SAN before their pacemaker potential threshold is reached. This is called "overdrive suppression".[3] Rate dependence of action potential is a fundamental property of cardiac cells. This is important for the QT interval, measured from the beginning of the QRS complex to the end of the T wave. This interval must be corrected for the cardiac rhythm QTc. A prolonged QTc, long QT syndrome, induced by drugs or disease congenital or acquired, increases the possibility of developing severe ventricular arrhythmias and sometimes sudden death.[4]

The electrical activity of the specialized excitatory tissues is not apparent on the surface electrocardiogram (ECG). This is due to the relatively small time duration. It is not possible, for example, to see on the ECG the sinus node activity but the resulting atrial myocardium contraction is apparent as a wave: the P wave. The electrical activity of the conducting system can be seen on the ECG (for example the AV node delay and the so-called PR segment).[5]


Intra- and extracellular ion concentrations (mmol/L)
SodiumNa+135 - 1451014:1
PotassiumK+3.5 - 5.01551:30
ChlorideCl-95 - 11010 - 204:1
CalciumCa2+210−42 x 104:1
Although intracellular Ca2+ content is about 2 mM, most of this is bound or sequestered in intracellular organelles (mitochondria and sarcoplasmic reticulum).[6]

Action potentials are generated by the movement of ions through the transmembrane ion channels in the cardiac cells.[7]

Cardiac muscle bears some similarities to skeletal muscle, as well as important differences. Like skeletal myocytes (and axons for that matter), in the resting state a given cardiac myocyte has a negative membrane potential. Within the cell, K+ is the principal cation, and phosphate and the conjugate bases of organic acids are the dominant anions. Outside the cell, Na+ and Cl- predominate. A notable difference between skeletal and cardiac myocytes is how each elevates the myoplasmic Ca2+ to induce contraction. When skeletal muscle is stimulated by somatic motor axons, influx of Na+ quickly depolarizes the skeletal myocyte and triggers calcium release from the sarcoplasmic reticulum. However, in cardiac myocytes the release of Ca2+ from the sarcoplasmic reticulum is induced by Ca2+ influx into the cell through voltage-gated calcium channels on the sarcolemma. This phenomenon is called calcium-induced calcium release and increases the myoplasmic free Ca2+ concentration causing muscle contraction. In both muscle types, after a delay (the absolute refractory period), potassium channels reopen and the resulting flow of K+ out of the cell causes repolarization. The voltage-gated calcium channels in the cardiac sarcolemma are generally triggered by an influx in sodium during the "0" phase of the action potential (see below). Cardiac muscle is a syncytium in which the cardiac muscle cells are so tightly bound that when one of these cells is excited the action potential spreads to all of them.[8][9]

Note that there are important physiological differences between excitatory cells and muscular cells; the specific differences in ion channels and mechanisms of polarization give rise to unique properties of excitatory cells, most importantly the spontaneous depolarization (cardiac muscle automaticity) necessary for the SAN pacemaker activity.[7]

Phases of the cardiac action potential[edit]

Image 1: Standard model of a cardiomyocyte action potential[7]
Image 2: The cardiac pacemaker cell action potential

The standard model used to understand the cardiac action potential is the action potential of the ventricular myocyte. The action potential has 5 phases (numbered 0-4).

Phase 4[edit]

Phase 4 is the resting membrane potential, and describes the membrane potential when the cell is not being stimulated. So in the standard myocyte model this phase will be a horizontal line. This is what happens in 99% of cardiac cells which are contractile cells.[7] The resting membrane potential is caused by the difference in ionic concentrations and conductances across the cell membrane during phase 4 of the action potential. The normal resting membrane potential in the ventricular myocardium is about -85 to -95 mV. This potential is determined by the selective permeability of the cell membrane to various ions. The membrane is most permeable to K+ and relatively impermeable to other ions. The resting membrane potential is therefore dominated by the K+ equilibrium potential according to the K+ gradient across the cell membrane. The membrane potential can be calculated using the Goldman-Hodgkin-Katz voltage equation. The maintenance of this electrical gradient is due to various ion pumps and exchange mechanisms, including the Na+-K+ ion exchange pump, the Na+-Ca2+ exchanger current and the IK1 inwardly rectifying K+ current. I is the symbol for an electric current.[10]

However, phase 4 is also special and very important as all cardiac cells which belong to the excitatory system[nb 1] have an unstable phase 4 - is the pacemaker potential.[11] All can fire an electric impulse as the SAN does. So, in these cells, the phase 4 is as the image 2 shows: the membrane slowly depolarizes until it reaches a threshold potential (around -40mV) or until it is depolarized by an electrical impulse coming from another cell. The reason for this pacemaker potential is an increased inward current of sodium (Na+) through voltage-dependent channels, but also an increased inward Ca2+ current and a slowly decreasing K+ outward current. These Na+ channels, in cardiac pacemaker cells, have a particular behavior because, contrary to what usually happens in other cells, they open when the voltage is more negative, immediately after the end of a previous action potential. For this reason they are called "funny channels".[7]

The little Purkinje fibers [nb 2] usually don't depolarize spontaneously simply because, before reaching the threshold potential, they are depolarized by an impulse coming from the SAN: their pacemaker potential is suppressed by the more rapid rate of the sinus node pacemaker. In phase 4 of the SAN, spontaneous depolarisation occurs faster than in all the other cardiac cells (60-100 action potentials per minute), so it leads the cardiac rhythm and maintains a hierarchy.[7] However, under some circumstances the little Purkinje fibres can depolarize and originate an atrial or ventricular premature beat. An example of ventricular premature contraction without pathology is the classic athletic heart syndrome: the sustained training induces a cardiac adaptation in a way that the resting SAN rate is slower (sometimes around 40/min) and this gives time to some ventricular cells to spontaneously reach the threshold potential (-40mV) and depolarize. Typically, these individuals have premature beats at rest which disappear at higher SAN frequencies.[12]

Phase 4 is associated with heart diastole so is called diastolic depolarization. These cardiac cells (the SAN cells especially) are self-activating. Though they do receive some input from the autonomic nervous system, they need no stimulus to fire. It is the duration of this slow diastolic depolarization which controls the cardiac chronotropism. It is also important to point out that the modulation by the autonomic system of the cardiac SAN rate also takes place in this phase. Sympathetic stimuli induce the acceleration of rate by increasing the slope of the pacemaker phase, while parasympathetic activation exerts the opposite action.[13]

Phase 0[edit]

Once the cell is electrically stimulated (typically by an electric current from an adjacent cell), it begins a sequence of actions involving the influx and efflux of cations and anions that together produce the action potential of the cell. Phase 0 is the rapid depolarization phase. Action potentials are all-or-none signals, since either they occur fully or they do not occur at all.[14][15]

The slope of phase 0 represents the maximum rate of potential change and is known as dV/dtmax. Its behavior is different in contractile and pacemaker heart cells.

In heart muscle cells, this slope is directly proportional to the net ionic current.[16] This phase is due to the opening of the fast Na+ channels causing a rapid increase in the membrane conductance to Na+ (gNa)[nb 3] and thus a rapid influx of Na+ ions (INa) into the cell; a Na+ current. The ability of the cell to open the fast Na+ channels during phase 0 is related to the membrane potential at the moment of excitation. If the membrane potential is at its baseline (about -85 mV), all the fast Na+ channels are closed, and excitation will open all of them, causing a large influx of Na+ ions. If, however, the membrane potential is less negative, some of the fast Na+ channels will be in an inactivated state insensitive to opening, thus causing a lesser response to excitation of the cell membrane and a lower Vmax. For this reason, if the resting membrane potential becomes too positive, the cell may not be excitable, and conduction through the heart may be delayed, increasing the risk of arrhythmias.[17]

In heart pacemaker cells, phase 0 depends on the activation of L-type calcium channels instead of the fast Na+ current. For this reason, this slope is slower (image 2).[18]

Phase 1[edit]

Phase 1 of the myocyte action potential occurs with the inactivation of the fast Na+ channels. The transient net outward current causing the small downward deflection of the action potential is due to the movement of K+ and Cl- ions, carried by the Ito1 and Ito2 currents, respectively. Particularly the Ito1 contributes to the "notch" of some ventricular cardiomyocyte action potentials (image 1).

It has been suggested that Cl- ions movement across the cell membrane during Phase I is as a result of the change in membrane potential, from K+ efflux, and is not a contributory factor to the initial repolarization ("notch").

In cardiac pacemaker cells this phase is due to a rapid outflow of K+ and the closure of the L-type Ca2+ channels.[19]

Phase 2[edit]

This "plateau" phase of the cardiac action potential (absent in pacemaker cells), is sustained by a balance between inward movement of Ca2+ (ICa) through L-type calcium channels and outward movement of K+ through the slow delayed rectifier K channel, IKs. The sodium-calcium exchanger current, INa,Ca and the sodium/potassium pump current, INa,K also play minor roles during phase 2. It sustains muscle contraction.[20] During the plateau phase there is reduced potassium ion permeability. The ion particularly responsible for Plateau formation is Na+ (influx).

Phase 3[edit]

During phase 3 (the "rapid repolarization" phase) of the action potential, the L-type Ca2+ channels close, while the slow delayed rectifier (IKs) K+ channels are still open. This ensures a net outward current, corresponding to negative change in membrane potential, thus allowing more types of K+ channels to open. These are primarily the rapid delayed rectifier K+ channels (IKr) and the inwardly rectifying K+ current, IK1. This net outward, positive current (equal to loss of positive charge from the cell) causes the cell to repolarize. The delayed rectifier K+ channels close when the membrane potential is restored to about -80 to -85 mV, while IK1 remains conducting throughout phase 4, contributing to set the resting membrane potential.[21]

Refractory period[edit]

From the beginning of phase 0 until nearly the end of phase 2, each cell is in an absolute refractory period, during which it is impossible to evoke another action potential, followed, until phase 4, by a relative refractory period, during which a stronger-than-usual stimulus is required.[22][23] These two refractory periods are caused by changes in the state of sodium and potassium channel molecules. When closing after an action potential, sodium channels enter an "inactivated" state, in which they cannot be opened regardless of the membrane potential—this gives rise to the absolute refractory period. Even after a sufficient number of sodium channels have transitioned back to their resting state, it frequently happens that a fraction of potassium channels remains open, making it difficult but possible for depolarization to occur, and thereby giving rise to the relative refractory period.[24]


As explained above, action potential is due to ion's motion inward and outward the cell. This ion current happens through the so-called Ion channels. Each ion has his specific channel or channels. On the other hand, each channel has gates which open and close under multiple triggering events. These channels are proteins composed by several subunits and under a stimulus these subunits open a gate creating an aqueous channel which permits the ion fast move through it. Without this aqueous medium ion's movement would be slow, crossing the lipid bilayer cellular membrane.[25]

These channels are selective for ions so there are Na+, K+, Ca2+, Cl- channels, among others. And each ion can have some different channels which are used in different situations. Most of them are controlled by the membrane potential and are the so-called voltage-gated ion channels. Others, are ligand-gated channels what means they need the presence of a chemical ligand to open its gate.[25]

Major currents during the cardiac ventricular action potential[8]
IonCurrent (I)α subunit proteinα subunit genePhase / role
K+Ito1KV4.2/4.3KCND2/KCND31, notch
K+IKrKV11.1 (hERG)KCNH23
Na+, Ca2+INaCa3Na+-1Ca2+-exchangerNCX1 (SLC8A1)ion homeostasis
Na+, K+INaK3Na+-2K+-ATPaseATP1Aion homeostasis
Ca2+IpCaCa2+-transporting ATPaseATP1Bion homeostasis

Voltage-gated ion channels have transmembrane voltage sensors. Ligand-gated channels have receptors where the ligand will be bound to unleash an action. Everything is regulated by genes. Most of these mechanisms are yet under research and belong to molecular biology. The complexity of this subject is enormous and here is not the right place to discuss it.[28] As an example here is a table with the major ion currents their subunit proteins, some of their controlling genes and the action potential phase where they act.

Funny channels[edit]

Excitatory cells have the so-called pacemaker channels of the HCN family channels, Hyperpolarization-activated, Cyclic Nucleotide-gated channels. These poorly selective cation channels conduct more current as the membrane potential becomes more negative, or hyperpolarized. They conduct both potassium and sodium ions. The activity of these channels in the SAN cells causes the membrane potential to slowly become more positive (depolarize). They are the so-called "funny" channels and are responsible for the phase 4 diastolic depolarization.[7]

The fast Na+ channel[edit]

Main article: sodium channel

The fast sodium channels are voltage-dependent and have a very important role in cardiac action potential as explained above. these channels have three main functions: they permit Na+ to go in, keep K+ from going out and prevent Ca2+ from getting stuck in the channel and interfering with Na+ permeability.[29]

Potassium channels[edit]

Main article: Potassium channel

There are two main types of K+ channels but all have a basic common function: the creation of a transmembrane "leak" of potassium ions. This leak is the cause of an hyperpolarization.

The voltage gated (Kv) channels are activated by a specific depolarizing voltage change. They are located mainly inside the cellular membrane.[29]

The inward-rectifier channels (Kir) are gated by nucleotides and G proteins among others and most of them are located outside the cellular membrane.[30]

Calcium channels[edit]

Two voltage-dependent calcium channels play critical roles in the electro-physiology of cardiac muscle: L-type calcium channel ('L' for Long-lasting) and T-type calcium channels ('T' for Transient) voltage-gated calcium channels.

These channels respond to voltage changes across the membrane differently: L-type channels respond to higher membrane potentials, open more slowly, and remain open longer than T-type channels.

Because of these properties, L-type channels are important in sustaining an action potential, while T-type channels are important in initiating them.[19]

Because of their rapid kinetics, T-type channels are commonly found in cells undergoing rhythmic electrical behavior. For example, T-type channels are commonly found in some neuron cell bodies involved in rhythmic activity such as walking and breathing. These T-type calcium channels are also found in pacemaker cells, the sinoatrial node and the atrioventricular node.[19]


In heart physiology, automaticity is the ability of cardiac cells to depolarize spontaneously, i.e. without external electrical stimulation from the nervous system. This spontaneous depolarization is due to the special phase 4 as described above. Automaticity is controlled by the sinoatrial node (SAN), the so-called "Heart Pacemaker". Abnormalities in automaticity may result in rhythm disorders. Cells which can undergo the fastest spontaneous depolarization are the non-pacemaker cells, and set the heart rate. Usually, these cells belong to the atrial and ventricular myocytes. Electrical activity that originates from the SAN is propagated to the rest of the heart through the His-Purkinje network, the fastest conduction pathway. This is the electrical conduction system of the heart. All this network operates as latent pacemakers and have the possibility to take the rhythm control if the SAN fails but at a slower rhythm. They do it in an hierarchy order: AV node (40-60/min)- His bundle - Purkinje cells (20-40/min - enough to maintain the patient alive in supine position until the emergency team arrives).[31]

Regulation by the autonomic nervous system[edit]

The depolarization rate and duration of the action potential in pacemaker cells is affected by autonomic nervous system activity. Acetylcholine (ACh) binds to M2 (muscarinic) receptors and, via the βγ subunit of a G protein, open a special set of potassium channels. The resulting increase in potassium efflux which hyperpolarizes the cell and the resting potential is lower. So, phase 4 takes longer to reach the threshold voltage. At same time counteracts the typical reduction of K+ permeability at phase 4. In addition, activation of M2 receptors decreases cAMP in the cells and this slows the opening of Na+ and Ca2+ "L" channels. The result is a decrease in the firing rate.[32]

Conversely, sympathetic stimulation via β1 receptors results in an increase in cAMP levels which facilitates the opening of calcium channels thereby increasing the rate of depolarization.[32]

See also[edit]


  1. ^ The excitatory system is the heart tissue which has the possibility to generate an automatic rhythm - the sinoatrial node (60-100 action potential per minute), the atrioventricular node (40-60 action potential per minute), the bundle of His and Purkinje fibers (20-40action potential per minute)
  2. ^ Purking fibers are small terminal fibers coming from the His bundle and present everywhere in the cardiac muscle as the little branches of a tree
  3. ^ The symbol g is the conductance of an ion channel


  1. ^ *Klabunde, R.E. (2005). "Electrical Activity of the Heart". Cardiovascular Physiology Concepts. Lippincott Williams & Wilkins. ISBN 078175030X. [page needed]
  2. ^ Berne, Robert; Levy, Matthew; Koeppen, Bruce; Stanton, Bruce (2004). Physiology. Elsevier Mosby. p. 276. ISBN 0824303482. 
  3. ^ Vassalle, M. (1977). "The relationship among cardiac pacemakers: Overdrive suppression". Circulation Research 41 (3): 269–77. doi:10.1161/01.res.41.3.269. PMID 330018. 
  4. ^ Viswanathan, PC; Shaw, RM; Rudy, Y (1999). "Effects of IKr and IKs heterogeneity on action potential duration and its rate dependence". Circulation 99 (18): 2466–74. doi:10.1161/01.CIR.99.18.2466. PMID 10318671. 
  5. ^ Fuster, V.; O'Rourke, R.A. (2001). Hurts's The Heart (10th [International] ed.). McGraw-Hill. pp. 283–8. ISBN 0071162968. 
  6. ^ Lote, C. (2012). Principles of Renal Physiology (5th ed.). p. 150. ISBN 9781461437840. 
  7. ^ a b c d e f g Sherwood 2012, pp. 310-1.
  8. ^ a b Sherwood 2008, pp. 248-50.
  9. ^ "Muscle physiology". Sinoe Medical Assoc. Retrieved 2013-03-10. [unreliable medical source?]
  10. ^ Hille, Bertil (2001). Ion Channels of Excitable Membranes (3rd ed.). Sunderland, MA: Sinauer. p. 151. ISBN 0878933212. 
  11. ^ Sherwood 2008, p. 311.
  12. ^ Maron, B.J; Pelliccia, A. (2006). "The heart of trained athletes: Cardiac remodeling and the risks of sports, including sudden death". Circulation 114 (15): 1633–44. PMID 17030703. 
  13. ^ Sherwood 2012, pp. 310-5.
  14. ^ Purves et al. 2008, pp. 26–8.
  15. ^ Rhoades & Bell 2009, p. 45.
  16. ^ Carmeliet, E.; Vereecke, J. (2002). Cardiac Cellular Electrophysiology. Basic Science for the Cardiologist 9. Springer Science+Business Media. p. 24. ISBN 9780792375449. 
  17. ^ "Molecular analysis of the Na+ channel blocking actions of the novel class I anti-arrhythmic agent RSD 921". Retrieved 2013-03-12. 
  18. ^ Sherwood 2012, p. 311.
  19. ^ a b c Sherwood 2008, p. 309.
  20. ^ Sherwood 2008, p. 314.
  21. ^ Kubo, Y; Adelman, JP; Clapham, DE; Jan, LY et al. (2005). "International Union of Pharmacology. LIV. Nomenclature and molecular relationships of inwardly rectifying potassium channels". Pharmacol Rev 57 (4): 509–26. doi:10.1124/pr.57.4.11. PMID 16382105. 
  22. ^ Purves et al. 2008, p. 49.
  23. ^ Bullock, TH; Orkand, R; Grinnell, A (1977). Introduction to Nervous Systems. New York: W. H. Freeman. p. 151. ISBN 0716700301. 
  24. ^ Sherwood 2008, p. 316.
  25. ^ a b Rhoades & Bell 2009, pp. 26-7.
  26. ^ "SCN5A sodium channel, voltage-gated, type V, alpha subunit [Homo sapiens (human)]". National Center for Biotechnology Information. 
  27. ^ Lacerda, AE; Kim, HS; Ruth, P; Perez-Reyes, E et al. (August 1991). "Normalization of current kinetics by interaction between the alpha 1 and beta subunits of the skeletal muscle dihydropyridine-sensitive Ca2+ channel". Nature 352 (6335): 527–30. doi:10.1038/352527a0. PMID 1650913. 
  28. ^ Sheng, Morgan. "Ion channels and receptors". Retrieved 2013-03-14. 
  29. ^ a b Armstrong 1998, pp. 371–80[full citation needed]
  30. ^ Miller, C. "An overview of the potassium channel family". Genome Biology 1 (reviews0004-reviews0004.5). doi:10.1186/gb-2000-1-4-reviews0004. PMC 138870. PMID 11178249. 
  31. ^ Sherwood 2008, pp. 309-10.
  32. ^ a b Sherwood 2008, p. 327.


  • Rudy, Yoram (March 2008). "Molecular Basis of Cardiac Action Potential Repolarization". Annals of the New York Academy of Sciences 1123 (Control and Regulation of Transport Phenomena in the Cardiac System): 113–8. doi:10.1196/annals.1420.013. 
  • Purves, D; Augustine, GJ; Fitzpatrick, D; Hall, WC et al. (2008). Neuroscience (4th ed.). Sunderland, MA: Sinauer Associates. ISBN 9780878936977. 

External links[edit]