Cardiac myocytes are excitable cells and in response to a stimulus they can generate an action potential (AP) associated with a contractile response. An AP is a reversible change of the membrane potential caused by a sequential activation of several ion currents generated by the diffusion of ions through the membrane downs their electrochemical gradient. Thus, during the cellular depolarization the resting membrane potential moves from negative values (-85 mV) to positive values (up to +20 or +30 mV) and then recover back to the basal resting membrane potencial during the repolarizing process.
The resting membrane potential of atrial and ventricular muscle cells and in cells from the His-Purkinje system is ~-85 mV. Following the application of a depolarizing pulse when the membrane potential exceeds the threshold potential (~ -65 mV) an AP is generated. The ionic currents involved in the genesis of the cardiac PA are summarized in Figures.
The phase 0 of rapid depolarization is a result of the massive influx of Na+ through voltage-gated channels which generates the fast inward Na+ current (INa). These channels are rapidly activated-opened during the depolarization, allowing the passage of Na+ for 1 to 2 ms and then they move into an inactive state (nonconductive closed state).
In the cardiac repolarization we can separate three three phases. The phase 1 of rapid repolarization is due to the activation of a current with fast activation and inactivation kinetics, the transient outward K+ current (Ito). The cardiac tissues in which the Ito predominates (i.e. His-Purkinje and ventricular epicardium) phase 1 is more marked. In atrial cells also contributes to phase 1 the ultrarapid delayed rectifier current IKur, however, this current is not present in the ventricle.
The phase 2 (or plateau) represents a balance between:
a) two inward currents: one of Na+ through the fraction of channels that have not been inactivated completely at the end of the phase 0, which generates the late Na+ (INaL), and one of Ca2+ through L-type channels, which generates the current ICa.
b) The three compopnents of the outward rectifier current: ultrarapid-IKur, rapid-IKr and slow-IKs. Ca2+ entry via the ICa triggers the contraction of the cardiac cell. This Ca2+ entry stimulates ryanodine receptors located on the surface of the sarcoplasmic reticulum (RyR2) and triggers the release of stored Ca2+ in this organelle. The released to the cytosol Ca2+ binds to the troponin C and starts the contractile process, coupling cardiac excitation and contraction. Furthermore, Ca2+ release from the sarcoplasmic reticulum inactivates the Ca2+ channels preventing an excessive entry of Ca2+ into the cell.
During phase 3 the repolarization is accelerated due to the inactivation of INa and ICa and the subsequent dominance of K+ currents activated repolarizantes during phase 2. At the end of phase 3 three inward-rectifier K+ currents are activated. They conduct K+ currents more in the inward direction than the outward direction and play an important role in setting the resting potential close to the equilibrium potential for K+ (EK, approximately - 90 mV) and in the repolarization of the AP. These currents are:
The inward rectifying current IK1 contributes to the end of the repolarisation phase and maintains the level of membrane potential (Em) during the diastolic interval (phase 4). At negative membrane potentials IK1 conductance is much larger than that of any other current, and so it clamps the resting membrane potential close to the resting membrane potential. Upon depolarization, K1 channels close almost immediately, remain closed throughout the plateau and open again at potentials negative to _ 20 mV. Thus, IK1 contributes to termINaL phase 3 of repolarization. IK1 density is higher in ventricular than in atrial myocytes, but is similar in epicardial, M and endocardial cells.
IKATP, that is inhibited by physiological intracellular ATP levels, i.e., its activity is regulated by the ATP/ADP ratio, coupling the metabolic state of the cell with its electrical activity.
The G-protein copuled ligand-activated channels activated by acetylcholine (IKACh) or adenosine (IKAdo) upon the interaction with M2 and A1 receptors, respectively, also contribute to f INaL repolarisation and resting membrane potential.
Figure. Ionic currents involved in the genesis of the atrial/ventricular AP. Tamargo y cols., 2004.
Figure. Schematic representation of the different phases of a ventricular AP, the different inward and outward ionic currents and the a subunits and the auxiliary subunits that form the various channels.
The resting membrane potential during the diastole (phase 4) in non-automatic cells is isoelectric. The concentration gradients for Na+ and K+ across the plasmalemma are restored by the Na+ pump, the (Na+-K+-ATPase), which extrudes 3 Na+ in exchange for 2 K+. Because of its electrogenic nature, the (Na+ -K+) -ATPase generates a hyperpolarising outward current that contributes to the resting membrane potential. Calcium entering the cell during the plateau phase is removed by the Na+ -Ca2+ exchanger (NCX1), which exchanges 3 Na+ for 1 Ca2+. The direction of movement of these ions (inward or outward) depends upon the membrane potential and the chemical gradient for the ions. When the membrane potential is negative (i.e., during phases 3 and 4 of the AP), the NCX1 transports Ca2+ out as Na+ enters the cell, while when the cell is depolarized (phases 0, 1 and 2 of the AP), the exchanger works in the opposite direction (i.e., Na+ leaves and Ca2+ enters the cell). Thus, NCX1 also contributes to Ca2+ entry during the plateau phase of the AP.
The cardiac action potentials present signficant morphological differences (Figure) depending on the heart tissue (atrium vs. ventricle) or even within the same tissue (endocardium vs. e picardium vs ventricular muscle. Purkinje cells), which reflects differences in ion channel expression levels.
1. Correlation between the cardiac action potential and the surface electrocardiogram
The phases of the cardiac action potential correspond to the surface ECG (ECG) (Figure). The P wave reflects atrial depolarization (phase 0), the PR interval reflects the conduction velocity through the AV node, the QRS complex the ventricular depolarization and QT interval the duration potential ventricular action. Gradients in ventricular repolarization are reflected in the T wave. Widening of the QRS complex reflects reduced intraventricular conduction velocity, which typically results from altered Na+ channel function. ST segment elevation reflects transmural voltage gradients during the AP plateau, a hallmark of the Brugada syndrome.
Figure. Schematic representation of the action potentials recorded in various cardiac tissues and its correlation with the surface electrocardiogram (ECG). T issues that generate Ca2+ - dependent (SA and AV nodes) and Na+ - dependent action potentials (atria, ventricles and His- Purkinje system. SA: sinoatrial node. AV: atrioventricular node.
Electrical excitation in the human heart originates in specialized pacemaker cells located in the sino-atrial (SA) node. The AP of these cells do not present an isoelectric diastolic potential but a spontaneous slow diastolic depolarization, which depolarizes the membrane potential back towards the excitation threshold generating rhythmic AP. The rate of this diastolic depolarization determines the rate and rhythm of the normal heartbeat.
However, the typical slow diastolic depolarization of SAN pacemaker cells do not rely on a single pacemaker channel, but rely on two separate but closely communicating pacemaker mechanisms (or ‘clocks’):
The membrane voltage clock due to the decay of the outward delayed rectifier K+ current (IKr and IKs) and the activation of several inward currents, including: the hyperpolarization-activated cyclic nucleotide-gated inward pacemaker current (If, HCN4 channels), the inward Na+ background current, the sustained inward (Ist) current, and the inward L- (ICaL, Cav1.2 and 1.3 channels) and T-type Ca2+ currents (ICaT, Cav3.1 channels). The pacemaker current If is activated at hyperpolarized potentials (between -65 to -40 mV), increases the permeability to Na+ and K+ and its amplitude is increased when the intracelular concentration of cAMP increases. The Na+-K+ and the Na+-Ca2+ exchanger (INCX) currents also contribute to pacemaker function.
The calcium clock, related to the rhythmic release of Ca2+ from the sarcoplasmic reticulum (SR) through the ryanodine type 2 receptor (RyR2). The subsequent increase in intracellular Ca2+ facilitates the uptake of Ca2+ through the sarco/endoplasmic reticulum Ca2+-ATPase (SERCA2) and activates the INCX (1Ca2+:3Na+).
When the membrane potantial of the SAN cells reach the maximum diastolic potential, the K+ conductance decreases and inward depolarizing currents (such as If and ICaL) increase, channels long believed to be the single major pacemaker inducing an spontaneous diastolic depolarization. The depolarization-induced Ca2+ entry facilitates the release of Ca2+ from the SR generatin a Ca2+ signal that activates the INCX. This results in NCX-mediated Na+ influx leads to a net gain of positive charges and membrane depolarization during late diastolic interval and accelerates the time for reaching the threshold potential.