Non-Pacemaker Action Potentials

Atrial myocytes, ventricular myocytes and Purkinje cells are examples of non-pacemaker action potentials in the heart. Because these action potentials undergo very rapid depolarization, they are sometimes referred to as "fast response" action potentials.

Unlike pacemaker cells found in nodal tissue within the heart, non-pacemaker cells have a true resting membrane potential (phase 4) that remains near the equilibrium potential  for K⁺ (E_K). The resting membrane potential is very negative during phase 4 (about -90 mV) because potassium channels are open (K⁺ conductance [gK⁺] and K⁺ currents [I_K1] 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. At the same time, fast sodium channels and (L-type) slow calcium channels are closed.

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. This increases the inward directed, depolarizing Na⁺ currents (I_Na) that are responsible for the generation of these "fast-response" action potentials (see above figure). At the same time sodium channels open, gK⁺ and outward directed K⁺ currents fall as potassium channels close. These two conductance changes move the membrane potential away from E_K (which is negative) and closer toward the equilibrium potential for sodium (E_Na), which is positive. 

Phase 1 represents an initial repolarization that is caused by the opening of a special type of transient outward K⁺ channel (K_to), which causes a short-lived, hyperpolarizing outward K⁺ current (I_Kto). However, because of the large increase in slow inward gCa⁺⁺ occurring at the same time and the transient nature of I_Kto, the repolarization is delayed and there is a plateau phase in the action potential (phase 2). This inward calcium movement I_Ca(L) 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 and distinguishes cardiac action potentials from the much shorter action potentials found in nerves and skeletal muscle.

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

Therefore, the action potential in non-pacemaker cells is primarily determined by relative changes in fast Na⁺, slow Ca⁺⁺ and K⁺ conductances and currents. As described under the discussion on membrane potentials and summarized in the following relationship and in the figure to the right, the membrane potential (Em) is determined by the relative conductances of the major ions distributed across the cell membrane. When g'K⁺ is high and g'Na⁺ and g'Ca⁺⁺ are low (phases 3 and 4), the membrane potential will be more negative (resting state in the figure). When g'K⁺ is low and g'Na⁺ and/or g'Ca⁺⁺ are high, the membrane potential will be more positive (phases 0, 1 and 2) (depolarized state in the figure).

Em = g'K⁺ (−96 mV) + g'Na⁺ (+50 mV) + g'Ca⁺⁺ (+134 mV)

These fast-response action potentials in non-nodal tissue are altered by antiarrhythmic drugs that block specific ion channels. Sodium-channel blockers such as quinidine inactivate fast-sodium channels and reduce the rate of depolarization (decrease the slope of phase 0). Calcium-channel blockers such as verapamil and diltiazem affect the plateau phase (phase 2) of the action potential. Potassium-channel blockers delay repolarization (phase 3) by blocking the potassium channels that are responsible for this phase.

Effective Refractory Period

Once an action potential is initiated, there is a period of time comprising phases 0, 1, 2, 3 and early phase 4 that a new action potential cannot be initiated (see figure at top of page). This is termed the effective refractory period (ERP) or the absolute refractory period (ARP) of the cell. During the ERP, stimulation of the cell by an adjacent cell undergoing depolarization does not produce new, propagated action potentials. This occurs because fast sodium channels remain inactivated following channel closing during phase 1. They do not change to their closed, resting (excitable) state until some time after the membrane potential has fully repolarized. The ERP acts as a protective mechanism in the heart by preventing multiple, compounded action potentials from occurring (i.e., it limits the frequency of depolarization and therefore heart rate). This is important because at very high heart rates, the heart would be unable to adequately fill with blood and therefore ventricular ejection would be reduced.

Many antiarrhythmic drugs alter the ERP, thereby altering cellular excitability.  For example, drugs that block potassium channels (e.g., amiodarone, a Class III antiarrhythmic) delay phase 3 repolarization and increases the ERP.  Drugs that increase the ERP can be particularly effective in abolishing reentry currents that lead to tachyarrhythmias.

Transformation of non-pacemaker into pacemaker cells

It is important to note that non-pacemaker action potentials can change into pacemaker cells under certain conditions. For example, if a cell becomes hypoxic, the membrane depolarizes, which closes fast Na⁺ channels. At a membrane potential of about –50 mV, all the fast Na⁺ channels are inactivated. When this occurs, action potentials can still be elicited; however, the inward current are carried by Ca⁺⁺ (slow inward channels) exclusively. These action potentials resemble those found in pacemaker cells located in the SA node, and can sometimes display spontaneous depolarization and automaticity. This mechanism may serve as the electrophysiological mechanism behind certain types of ectopic beats and arrhythmias, particularly in ischemic heart disease and following myocardial infarction.

Normal Impulse Conduction

Sequence of Cardiac Electrical Activation

The action potentials generated by the SA node spread throughout the atria primarily by cell-to-cell conduction at a velocity of about 0.5 m/sec. There is some functional evidence for the existence of specialized conducting pathways within the atria (termed internodal tracts), although this is controversial. As the wave of action potentials depolarizes the atrial muscle, the cardiomyocytes contract by a process termed excitation-contraction coupling.

Normally, the only pathway available for action potentials to enter the ventricles is through a specialized region of cells (atrioventricular node, or AV node) located in the inferior-posterior region of the interatrial septum. The AV node is a highly specialized conducting tissue (cardiac, not neural in origin) that slows the impulse conduction considerably (to about 0.05 m/sec) thereby allowing sufficient time for complete atrial depolarization and contraction (systole) prior to ventricular depolarization and contraction.

The impulses then enter the base of the ventricle at the Bundle of His and then follow the left and right bundle branches along the interventricular septum.  These specialized fibers conduct the impulses at a very rapid velocity (about 2 m/sec).  The bundle branches then divide into an extensive system of Purkinje fibers that conduct the impulses at high velocity (about 4 m/sec) throughout the ventricles. This results in rapid depolarization of ventricular myocytes throughout both ventricles.

The conduction system within the heart is very important because it permits a rapid and organized depolarization of ventricular myocytes that is necessary for the efficient generation of pressure during systole. The time (in seconds) to activate the different regions of the heart are shown in the figure to the right. Atrial activation is complete within about 0.09 sec (90 msec) following SA nodal firing. After a delay at the AV node, the septum becomes activated (0.16 sec). All the ventricular mass is activated by about 0.23 sec.

Regulation of Conduction

The conduction of electrical impulses throughout the heart, and particularly in the specialized conduction system, is influenced by autonomic nerve activity. This autonomic control is most apparent at the AV node. Sympathetic activation increases conduction velocity in the AV node by increasing the rate of depolarization (increasing slope of phase 0) of the action potentials. This leads to more rapid depolarization of adjacent cells, which leads to a more rapid conduction of action potentials (positive dromotropy). Sympathetic activation of the AV node reduces the normal delay of conduction through the AV node, thereby reducing the time between atrial and ventricular contraction. The increase in AV nodal conduction velocity can be seen as a decrease in the P-R interval of the electrocardiogram.

Sympathetic nerves exert their actions on the AV node by releasing the neurotransmitter norepinephrine that binds to beta-adrenoceptors, leading to an increase in intracellular cAMP. Therefore, drugs that block beta-adrenoceptors (beta-blockers) decrease conduction velocity and can produce AV block.

Parasympathetic (vagal) activation decreases conduction velocity (negative dromotropy) at the AV node by decreasing the slope of phase 0 of the nodal action potentials. This leads to slower depolarization of adjacent cells, and reduced velocity of conduction. Acetylcholine, released by the vagus nerve, binds to cardiac muscarinic receptors, which decreases intracellular cAMP. Excessive vagal activation can produce AV block. Drugs such as digitalis, which increase vagal activity to the heart, are sometimes used to reduce AV nodal conduction in patients that have atrial flutter or fibrillation. These atrial arrhythmias lead to excessive ventricular rate (tachycardia) that can be suppressed by partially blocking impulses being conducted through the AV node.

Phase 0 of action potentials at the AV node is not dependent on fast sodium channels as in non-nodal tissue, but instead is generated by the entry of calcium into the cell through slow-inward, L-type calcium channels. Blocking these channels with a calcium-channel blocker such as verapamil or diltiazem reduces the conduction velocity of impulses through the AV node and can produce AV block.

Because conduction velocity depends on the rate of tissue depolarization, which is related to the slope of phase 0 of the action potential, conditions (or drugs) that alter phase 0 will affect conduction velocity.  For example, conduction can be altered by changes in membrane potential, which can occur during myocardial ischemia and hypoxia. In non-nodal cardiac tissue, cellular hypoxia leads to membrane depolarization, inhibition of fast Na⁺ channels, a decrease in the slope of phase 0, and a decrease in action potential amplitude. These membrane changes result in a decrease in speed by which action potentials are conducted within the heart. This can have a number of consequences. First, activation of the heart will be delayed, and in some cases, the sequence of activation will be altered. This can seriously impair ventricular pressure development. Second, damage to the conducting system can precipitate tachyarrhythmias by reentry mechanisms.