CARDIAC MUSCLE IS SIMILAR TO OTHER MUSCLE TYPES Cardiac muscle, like skeletal muscle, is a striated muscle and much of the mechanism of contraction is similar between the two muscle types. The electrophysiology of the two muscles differs dramatically, however. In skeletal muscle an action potential in the synaptic terminal of a motor neuron coming from the central nervous system releases a transmitter substance, acetylcholine, which triggers a very brief action potential on the muscle cell, causing it to contract...
Skeletal muscle contracts in an all-or-none fashion and the force generated, for any given length, will be the same for every twitch (for a review, see paragraph 7). The action potential is so short in skeletal muscle that a single action potential generates an insignificant amount of force. Usable force can only be achieved by stimulating the fiber repeatedly with a train of neural discharges (temporal summation). Individual motor units can be stimulated within a muscle as a further means of control. Cardiac muscle differs in several important respects. First, the cardiac action potential is not initiated by neural activity. Instead, specialized cardiac muscle tissue in the heart itself initiates the action potential, which then spreads directly from muscle cell to muscle cell. Neural influences have only a modulatory effect on the heart rate. Second, the duration of the cardiac action potential is quite long. As a result, the full force of cardiac contraction results from a single action potential. The force of contraction is not the same for every beat of the heart and can be modulated by the cardiac nerves. Finally, all cells in the heart contract together as a unit in a coordinated fashion with every beat. This paragraph examines the electrical properties of the cardiac muscle cells. We begin by looking at the different types of cells in the heart. The properties and ionic mechanism of cardiac action potentials, the processes of excitation–contraction coupling, and the regulation of the heart rate will be explained.
EXCITATION ORIGINATES WITHIN THE HEART MUSCLE CELLS Two broad types of cells are found within the heart: (1) contractile cells and (2) conductile cells. Contractile cells are the cells of the working myocardium and constitute the bulk of the muscle cells that make up the atria and the ventricles. An action potential in any one of these cells leads to a mechanical contraction of that cell. Furthermore, an action potential in one cardiac muscle cell will stimulate neighboring cells to undergo an action potential, such that activation of any single cell will be propagated over the whole heart. Conductile cells are specialized muscle cells that are involved with the initiation or propagation of action potentials but have little mechanical capability. The principal conductile cells are indicated in paragraph 1. Of critical importance is the sinoatrial (SA) node. The SA node (sometimes called the sinus node) lies in the right atrium near the vena cava. SA nodal cells generate spontaneous action potentials and act as the normal pacemaker for the heart. Because the SA node is located in the atria, action potentials will first be propagated over the atria, making them the first structures in the heart to contract. Action potentials spreading across the atria eventually reach another conducting structure known as the atrioventricular (AV) node. The AV node is located in the interatrial septum between the ostium of the coronary sinus and the septal leaflet of the tricuspid valve. The AV node serves two important functions. One is to relay the wave of depolarization from the atria to the ventricles. A sheet of connective tissue associated with the atrioventricular valves separates the atria from the ventricles, and the AV node is the only conductive link between the atria and the ventricles. The second function is to delay the spread of excitation from the atria to the ventricles. The AV node cells are specialized to conduct very slowly. This delay permits the atria to eject their blood and therefore fill the ventricles before the latter begin to contract. The fibers of the AV node give rise to fibers of the AV bundle (common bundle or bundle of His), which in turn divides into two major branches, the left bundle branch and the right bundle branch. These branches then divide into an extensive network of Purkinje fibers. The Purkinje fibers are conductile cells that conduct action potentials very rapidly. They are interwoven among the contractile cells of the ventricles and serve to quickly spread the wave of excitation throughout the ventricles. Because they conduct so rapidly, all muscle cells of the ventricles appear to contract in unison. It is important to emphasize that all of these conductile structures (e.g., SA node, AV node, Purkinje network) are not nervous tissue but, rather, specialized cardiac muscle cells.
EXCITATION IS CONDUCTED FROM CELL TO CELL THROUGH GAP JUNCTIONS Figure 2 is a micrograph of adjacent contractile cells from the ventricle. Like all striated muscle, ventricular muscle has the typical pattern of cross striations because of its highly organized contractile proteins (see paragraph 7 and paragraph 3). The region at which the cell membranes of adjacent myocytes adjoin is termed the intercalated disc. The myocytes are arranged in the heart in a staggered pattern, much like bricks in a wall. The intercalated discs occur at the junction between the myocytes and would be analogous to the mortar between the bricks. The discs run transversely where the ends of two adjacent myocytes abut. The disc then turns 90_ and runs longitudinally between the myocytes until another end-abutment begins. The transverse aspect of the intercalated disc is filled with structures called desmosomes. The desmosomes make strong mechanical attachments between the cells and transmit the force of contraction. The transverse aspect as well as the longitudinally oriented region of the intercalated disc are rich in low-resistance connections between the cells called gap junctions. Small pores in the center of each gap junction allow ions and even small peptides to flow from one cell to another along their electrochemical gradients. Cardiac muscle gap junctions serve an identical function as the gap junctions at electrical synapses between nerve cells (paragraph 6) and nexuses in smooth muscle cells (paragraph 8). An action potential in one muscle cell is propagated to adjacent muscle cells via direct electrotonic propagation across the gap junctions. The gap junctions cause every cell in the heart to be electrically coupled to its neighboring cells and that is what causes the heart to behave like a single motor unit. Theoretically, an ion inside an SA nodal cell could travel through every cell in the heart without ever having to enter the extracellular space. The Purkinje cells are still muscle cells but contain fewer contractile proteins than contractile cells. They are specialized not for contraction but, rather, for fast electrical propagation. The large diameter of the Purkinje cells gives them a high conduction velocity. (Recall from paragraph 5 that the greater the diameter of a nerve axon, the greater the propagation velocity of nerve action potentials.) A Purkinje fiber has a particularly high density of gap junctions between its cells, and they will conduct action potentials at about 4 m/sec over the ventricle. Atrial and ventricular muscle cells on the other hand conduct at only 1 m/sec.
Cells of the SA and AV nodes, like the Purkinje fibers, also have a reduced quantity of contractile proteins. As discussed later, nodal cells lack fast sodium channels and that reduces the rate at which they depolarize. They also are much smaller than either the contractile or Purkinje cells. Both of these properties cause them to have a low conduction velocity. AV nodal cells also have a reduced density of gap junctions that even further depresses their conduction velocity to only about 0.05 m/sec. It is the low propagation velocity of the AV nodal cells that provides the delay between atrial and ventricular contraction. The ultrastructural features of a typical cardiac muscle cell are illustrated in paragraph 3. At first glance, the ultrastructure appears much like a skeletal muscle cell (see paragraph 7). Common features include characteristic A, I, and Z bands, a T-tubule system, and sarcoplasmic reticulum (SR). Some subtle differences exist, however, between cardiac muscle and the skeletal muscle ultrastructure. One difference lies in the T tubules (which stands for ‘‘transverse’’ tubules because they are transversely oriented to the long axis of the cell). They are centered on the Z band with only one tubule per sarcomere. Mammalian skeletal muscle is modified to have two T tubules per sarcomere, which reduces the distance over which calcium must diffuse to reach the sliding filaments. This results in an extremely fast twitch that can provide an important survival benefit. Cardiac muscle does not require such a fast activation time and, hence, a single T tubule per sarcomere is sufficient. The SR in cardiac contractile cells consists of two types of structures: (1) the sarcotubular network, making up the bulk of the SR, is in proximity to the contractile machinery, and (2) the subsarcolemma cisternae, the region at which the SR abuts the T tubules. The subsarcolemma cisternae are equivalent to the terminal cisternae of skeletal muscle cells. Finally, cardiac myocytes contain a large quantity of mitochondria reflecting the aerobic nature of cardiac muscle metabolism. Most of the metabolic energy of the heart comes from oxidative metabolism of fatty acids and lactate, with glucose accounting for only a small fraction of the energy source. Although the heart can derive some energy by anaerobic glycolysis of glucose, it is not enough to keep up with the high energy demands of a beating heart. As a result, interruption of the heart’s oxygen supply will cause a cessation of mechanical activity within less than 1 min and irreversible injury of the cells will begin within 20 min if the oxygen supply is not restored.
CARDIAC MUSCLE EXPERIENCES AN ACTION POTENTIAL Figure 4 shows an action potential typical of what would be recorded from a contractile cell in the ventricle. Superficially, this action potential appears similar to the action potentials seen in nerve, skeletal, and smooth muscle cells (paragraphs 6, 7, and 8). One major difference, however, is its duration. Note that the action potential remains in a depolarized state for about 300 msec (almost a third of a second) giving it a shape like a plateau. In contrast, an action potential in a nerve or skeletal muscle cell lasts only about 1 msec. It is the plateaued action potential that keeps the heart activated long enough to develop a forceful contraction from a single action potential. The rapid phase of depolarization is termed phase 0. Phase 1 is a trasient repolarization following the overshooting of Phase 0. Phase 1 is followed by a long period during which the membrane potential remains depolarized, the plateau phase or phase 2. After the plateau phase, a phase of repolarization occurs during which the membrane potential returns to its resting level. This phase is termed phase 3. The resting potential between beats is referred to as phase 4.
CARDIAC MUSCLE EXHIBITS BOTH DIVERSITY AND SPECIALIZATION Just as there is morphologic diversity and specialization of individual cells in the heart, there is also electrical diversity and specialization. Figure 5 illustrates action potentials recorded in several different regions of the heart. Action potentials in contractile and Purkinje cells are associated with a very rapid depolarizing phase and a broad plateau region. Both the rapidity of depolarization as well as the plateau phase are less prominent in action potentials recorded from nodal cells. None of these cells experiences a hyperpolarizing afterpotential, as is the case for action potentials in nerve and skeletal muscle cells. Finally, note that the phase 4 baseline is normally stable in contractile and Purkinje cells, but is not stable in the SA nodal cells.
PROLONGED OPENING OF CALCIUM CHANNEL CAUSES THE PLATEAU PHASE OF THE ACTION POTENTIAL In a nerve cell or a muscle cell, a rapid increase in Naþ permeability (actually conductance, because we are talking about charge movement) is seen that depolarizes the cell, followed by an increase in Kþ conductance that repolarizes it. The peculiar shape of the cardiac action potential suggests that the ionic mechanisms are different in heart cells, as indeed they are. Figure 6A shows an action potential from a normal contractile cell, whereas paragraph 6B shows the action potential after treating the cell with tetrodotoxin (TTX). TTX selectively blocks the voltage-gated fast sodium channels. TTX does not completely block the action potential, as it does in nerve or muscle; rather, it only attenuates the rate of phase 0 depolarization. Clearly, a sustained increased Naþ conductance is not what prolongs the duration of the cardiac action potential. The long plateau phase is actually due to a prolonged increase in Ca2þ conductance through voltage-dependent calcium channels, often referred to as L-type calcium channels. These channels are similar to those seen in the presynaptic terminal (paragraph 6) or in smooth muscle (paragraph 8). An increase in Ca2þ permeability will depolarize the cell just as an increase in Naþ permeability does. The concentration of Ca2þ is much higher outside the cell than inside, with an equilibrium potential of about þ120 mV. Therefore, if the membrane were freely permeable to Ca2þ, the voltage inside the cell would then approach þ120 mV. Compare the action potential in the TTX-treated contractile cell of paragraph 6 to the nodal cells in paragraph 5. The slow phase 0 and lack of overshoot in the nodal cells is due to the fact that fast sodium channels are not expressed in these cells. The action potential in nodal tissue is maintained entirely by the L-type calcium channels. As expected, TTX has no effect on the action potential in nodal cells.
PROLONGED REFRACTORY PERIODS PREVENT THE HEART FROM BEING TETANIZED The fast sodium channels trigger action potentials in contractile and Purkinje cells. They have actually two gates that control passage of Naþ through the channel. The activation gate normally blocks the channel. Because it is voltage-gated it opens only when the membrane potential reaches threshold creating phase 0. Shortly after the activation gate opens a second part of the molecule, the inactivation gate closes the channel, causing phase 0 to end. The inactivation gate is voltage sensitive and does not reopen until the membrane repolarizes. Only when the inactivation gate finally opens will the cell be receptive to restimulation. This causes an absolute refractory period all through phase 2 and into phase 3, making it impossible to tetanize cardiac muscle. The refractory period ensures that the heart will relax between beats, allowing it to refill with the blood that will be pumped on the next beat. As the inactivation gates begin to open, the heart goes through a relative refractory period late in phase 3 where it can be restimulated but the threshold required for stimulation is elevated. Also an attenuated contraction will result because not all cells have their inactivation gates open yet. In nodal tissue lacking fast sodium channels the L-type calcium channels are also refractory to restimulation well into electrical diastole. As the wave of excitation finishes traversing the ventricles, the entire heart is in a refractory period, causing the wave to die out and the heart to relax. Sometimes conduction can be slowed in a diseased region to the point where the rest of the heart is out of the refractory period by the time the wave emerges from the depressed segment. When that occurs the heart can be restimulated by this delayed impulse causing a reentrant rhythm, in which the cycle repeats itself over and over. Under those conditions the heart may beat very rapidly or even fibrillate.
IONIC FLUXES IN THE CARDIAC MUSCLE CELLS Figure 7 summarizes some of the key changes in ion permeability that contribute to the cardiac action potential. The upper trace shows a typical cardiac action potential and the lower traces illustrate the changes in permeability to Naþ, Kþ, and Ca2þ. As a consequence of a depolarizing stimulus, a voltagedependent increase in Naþ conductance occurs. A regenerative cycle is initiated, which tends to depolarize the cell toward the equilibrium potential of Naþ. This regenerative increase in Naþ conductance rapidly moves the membrane potential to its peak level of þ20 mV. Thus, the voltage-dependent increase in Naþ conductance underlies phase 0 and 1 of the action potential. The inactivation gates in the sodium channels spontaneously close within a millisecond or two after activation gate opening. Although the cell remains depolarized, Naþ conductance quickly returns to its resting level. Changes in Ca2þ permeability are shown in the bottom panel of paragraph 7. The initial depolarization of the membrane causes Ca2þ conductance to increase in a voltage-dependent manner. Unlike the sodium channels, the calcium channels are slow to close and there is a sustained increase in Ca2þ conductance, which maintains the plateau of the cardiac action potential. Another factor contributing to the plateau of the cardiac action potential is the change in Kþ conductance (paragraph 7). At rest, the Kþ conductance of cardiac cells is high, just as it is in nerve and skeletal muscle cells. The similarity, however, ends here. When nerve and muscle cells repolarize, a transient increase is observed in Kþ conductance over the resting value, which quickly terminates the action potential and momentarily hyperpolarizes the cell. In contrast, in cardiac muscle Kþ conductance decreases with depolarization (paragraph 7), and during repolarization Kþ conductance simply returns to its phase 4 value. That is why cardiac muscle has no hyperpolarizing afterpotential. We should mention that there are many different types of potassium channels in the cardiomyocyte and their individual functions in controlling Kþ conductance through the action potential are complex. A detailed description of these is beyond the scope of this paragraph.
EXCITATION–CONTRACTION COUPLING IS ACCOMPLISHED BY CALCIUM IONS Cardiac muscle cells, like skeletal muscle cells, have an extensive SR (see paragraph 3). Excitation–contraction coupling in cardiac muscle cells is similar to that in skeletal muscle cells. Specifically, an action potential travels down the T tubules and causes the release of Ca2þ from the SR, which in turn activates the contractile machinery. Three pools of Ca2þ are important to the cardiac muscle cell, as shown in paragraph 8: (1) in the extracellular fluid, (2) in the SR, and (3) in the cytoplasm. Only the cytoplasmic pool is available to bind with the troponin-binding sites and initiate contraction. Consider the consequences of an action potential. Ca2þ entry through the sarcolemma increases the concentration of Ca2þ in the cytoplasm. Because the amount of Ca2þ entering is relatively small, it accounts for only a fraction of the activation of the contractile proteins and, hence, is indicated by a dashed line in paragraph 8. In skeletal muscle, action potentials on the T tubules electrically stimulate the SR to release calcium. That is not the case in cardiac muscle however. Rather the small amount of Ca2þ entering the cell through the L-type calcium channels actually triggers the release of the sequestered Ca2þ within the SR. The trigger calcium acts at ryanodine receptors located on the SR. These are actually calcium-gated calcium channels that open in the presence of cytosolic calcium. The name derives from the original observation that they bind the toxin ryanodine, which blocks these release channels in the SR and hence contraction. The importance of this trigger calcium is evidenced by the fact that heart muscle will not contract when the influx of Ca2þ across the sarcolemma is blocked, even though adequate stores of Ca2þ are still present in the
SR. RELAXATION IS ACCOMPLISHED BY REMOVING Ca2þ FROM THE CYTOSOL In cardiac muscle, as in skeletal muscle, there is a Ca2þ pump in the SR membranes termed the sarcoendoplasmic reticulum Ca2þ-ATPase (SERCA). SERCA (paragraph 8) removes Ca2þ from the contractile pool and pumps it into the SR. When enough Ca2þ is removed from the cytosol, the muscle relaxes. With each action potential some additional Ca2þ moves into the cell during phase 2. After a period of time, the intracellular Ca2þ concentration, if left unchecked, would be the same as that outside. Clearly, a mechanism is needed to remove Ca2þ from the cell. The Naþ-Ca2þ exchange system in the sarcolemma is primarily responsible for removing calcium from the cytosol. The exchanger, which is not a pump, derives its energy from the Naþ-Kþ pump. The exchanger will pass three Naþ ions in one direction for one Ca2þ ion in the other direction, but, being an exchanger rather than a pump, will do so only along a favorable energy gradient. Because the Naþ-Kþ pump maintains a strong transmembrane gradient for sodium, any free Ca2þ in the cytosol will be favorably exchanged for three Naþ ions in the extracellular fluid. There are also true calcium pumps in the sarcolemma, but they account for only a small percentage of the calcium flux. At a steady state, the exact same amount of Ca2þ that entered the cell is removed with each beat. In this system the sarcolemmal exchanger and the SERCA compete for cytosolic Ca2þ during diastole. The amount of Ca2þ available for release in the SR is therefore dependent on the net outcome of this competition.
STRENGTH OF CONTRACTION CAN BE MODULATED IN CARDIAC MUSCLE The force generated by cardiac muscle cells depends on the cells’ contractility, sometimes called the inotropic state. An increased contractility means that for any given length of the muscle it contracts with a greater force. It is important to note that the amount of Ca2þ released from the SR with each action potential is not sufficient to fully cover all of the troponin binding sites and thus activate all of the contractile proteins. Therefore, any manipulation that leads to enhanced release of Ca2þ from the SR will result in more troponin binding sites being occupied by Ca2þ and hence more force being generated by the muscle. The Ca2þ fluxes can, in turn, be altered by a variety of physiological control systems. Three commonly encountered modulators of contractility will be considered next: (1) stimulation frequency, (2) catecholamines, and (3) cardiac glycosides. Stimulation Frequency When the frequency of contraction increases, so does the tension generated by each contraction. This phenomenon, known as the positive staircase effect, was first described by Bowditch, an early cardiovascular physiologist, and is illustrated in paragraph 9. When Bowditch stimulated the heart, he found that a different tension was produced for each rate of stimulation. Stimulation at low rates was associated with a low tension and when the frequency of the stimulation was increased, the tension increased as well. The tension associated with a new rate of stimulation is not achieved instantaneously; it instead takes a period of time and appears to develop in a stepwise fashion. Hence the name ‘‘staircase.’’ The positive staircase effect is an example of a positive inotropic effect, because it is associated with increased contractility. The model of excitation–contraction coupling illustrated in paragraph 8 can explain the positive staircase phenomenon. Increasing the heart rate increases the number of action potentials per unit of time and, thus, the rate of Ca2þ influx from the extracellular compartment. At the same time, it shortens the duration of diastole when the exchanger removes Ca2þ. As a result, more cytosolic Ca2þ is pumped into the SR than is removed by the Naþ-Ca2þ exchange mechanism, causing more Ca2þ to be available for release from the SR with each beat. Because the new equilibrium will take several beats to be reached, the increased contractility is seen to increase stepwise. Catecholamines When the catecholamines norepinephrine and epinephrine secreted by the sympathetic nerve endings and by the adrenal medulla bind to the heart’s _1-adrenergic receptors, they exert a profound effect on the cardiac its contractile state. Receptor binding, as shown in paragraph 10, causes adenylyl cyclase to make cyclic adenosine monophosphate (cAMP), which in turn activates cAMP-dependent kinase (PKA). Catecholamines exert their effect by influencing both of the sarcolemmal and SR Ca2þ fluxes. PKA phosphorylates the L-type calcium channels, which causes more Ca2þ to enter the cell with each action potential. If more Ca2þ enters the cell, more will be available to be pumped into the SR, causing more to be available for release with subsequent action potentials (the same basic argument was used to explain the positive staircase effect discussed earlier). The second action of catecholamines is to increase the activity of SERCA. This is accomplished when PKA phosphorylates a protein called phospholamban on the SR. If the activity of SERCA is increased, a greater portion of the cytosolic Ca2þ will be pumped into the SR, making a greater amount available for release by a subsequent action potential. Catecholamines also tend to shorten phase 2 and thus shorten the duration of systole. Inhibition of the Sodium Pump by Cardiac Glycosides Cardiac glycosides such as digitalis were traditionally used to treat congestive heart failure. The rationale for their use as a therapeutic agent at first may seem questionable, because at the molecular level cardiac glycosides block the Naþ-Kþ pump in all of the body’s cells, including those in the heart, and are therefore potent poisons. The key strategy in their use is to carefully adjust the dose so that only a partial block of the Naþ-Kþ pump occurs. When this is done, cardiac glycosides lead to enhanced contractility of the heart by the following mechanism. Due to decreased activity of the Naþ-Kþ pump, the intracellular concentration of Naþ in cardiac cells increases, decreasing the driving force for Naþ to enter the cell. Because the Naþ gradient is the energy source for the Naþ-Ca2þ exchanger, the latter will remove less Ca2þ from the cell. Intracellular levels of Ca2þ will increase, with more Ca2þ available to be pumped into the SR.
PACEMAKER CELLS CONTROL THE HEART RATE The SA node is the normal pacemaker of the heart. The action potentials in the SA node are somewhat different from the action potentials in contractile cells. The most obvious difference is that the phase 4 resting potentials are unstable, as shown in paragraph 11. Note that the resting potential starts from its maximum value of about _60 mV, then slowly depolarizes until it reaches threshold and undergoes a regenerative action potential. On completion of the action potential, the cell again begins to depolarize and another action potential is initiated. This process occurs about 60–100 times each minute, resulting in the cardiac rhythm. The progressive depolarization of the phase 4 potential is known as the pacemaker potential. The ionic mechanism underlying the pacemaker potential is not fully understood, but it is thought to be due to an inward sodium leakage current. Cells in the AV node also have pacemaker potentials but they are slower (only about 40 beat/min) and thus the SA node dominates with its faster rhythm. An isolated strip of Purkinje fibers will spontaneously generate action potentials with a frequency of about 25 action potentials per minute, a rate slower than that of either SA or AV nodal cells. The AV node and Purkinje fibers are called latent pacemakers because they will assume the pacemaker role should the signal from the SA node be interrupted. Atrial and ventricular cells have virtually no pacemaker activity.
AUTONOMIC NERVES MODULATE PACEMAKER ACTIVITY The sympathetic and parasympathetic divisions of the autonomic nervous system have profound influences on the heart rate. The transmitter substance of the parasympathetic division, acetylcholine (ACh), reduces the heart rate, a negative chronotropic effect, whereas the transmitter substances of the sympathetic division, epinephrine and norepinephrine, increase the heart rate, a positive chronotropic effect. The dashed line in paragraph 11 illustrates the effect of ACh on the SA node. ACh binds to Gi-coupled muscarinic cholinergic receptors, which results in an increase in Kþ conductance. The increase in Kþ conductance hyperpolarizes the cell so that it takes a longer time to reach threshold. ACh also slows the rate of rise of the pacemaker potential itself. Both of the preceding effects tend to decrease the firing rate. If the vagus nerve is intensely stimulated, the cells in the SA node will be so hyperpolarized that the pacemaker potential will not reach threshold to fire the cells and the heart will stop beating. After a short time, however, the heart will resume beating with escape beats. The escape rate is much slower because the latent pacemakers in the AV node or the Purkinje network have now taken control. Catecholamines from the sympathetic nerves increase the heart rate. The dashed line in paragraph 12 shows a recording made after the addition of a catecholamine. Note that the catecholamine increases the rate at which the pacemaker potential approaches threshold. The ionic mechanism causing this increased slope in the pacemaker potential is thought to be an increased Naþ conductance. For many years the channels responsible for this current were not fully characterized and so the current became known as the ‘‘funny’’ current, If. It is now thought that If occcurs through the hyperpolarizing- activated cyclic nucleotide-gated cation channel (HCN). Transmitter substances of the autonomic nervous system also affect the cell-to-cell conduction velocity in both the atria and the ventricles. ACh slows the rate of propagation, and catecholamines increase the rate of propagation. Intense vagal stimulation can easily depress conduction through the AV node to the point at which conduction to the ventricle fails, a condition called heart block. The ionic mechanisms that underlie these changes in propagation velocity are still not well understood.
Skeletal muscle contracts in an all-or-none fashion and the force generated, for any given length, will be the same for every twitch (for a review, see paragraph 7). The action potential is so short in skeletal muscle that a single action potential generates an insignificant amount of force. Usable force can only be achieved by stimulating the fiber repeatedly with a train of neural discharges (temporal summation). Individual motor units can be stimulated within a muscle as a further means of control. Cardiac muscle differs in several important respects. First, the cardiac action potential is not initiated by neural activity. Instead, specialized cardiac muscle tissue in the heart itself initiates the action potential, which then spreads directly from muscle cell to muscle cell. Neural influences have only a modulatory effect on the heart rate. Second, the duration of the cardiac action potential is quite long. As a result, the full force of cardiac contraction results from a single action potential. The force of contraction is not the same for every beat of the heart and can be modulated by the cardiac nerves. Finally, all cells in the heart contract together as a unit in a coordinated fashion with every beat. This paragraph examines the electrical properties of the cardiac muscle cells. We begin by looking at the different types of cells in the heart. The properties and ionic mechanism of cardiac action potentials, the processes of excitation–contraction coupling, and the regulation of the heart rate will be explained.
EXCITATION ORIGINATES WITHIN THE HEART MUSCLE CELLS Two broad types of cells are found within the heart: (1) contractile cells and (2) conductile cells. Contractile cells are the cells of the working myocardium and constitute the bulk of the muscle cells that make up the atria and the ventricles. An action potential in any one of these cells leads to a mechanical contraction of that cell. Furthermore, an action potential in one cardiac muscle cell will stimulate neighboring cells to undergo an action potential, such that activation of any single cell will be propagated over the whole heart. Conductile cells are specialized muscle cells that are involved with the initiation or propagation of action potentials but have little mechanical capability. The principal conductile cells are indicated in paragraph 1. Of critical importance is the sinoatrial (SA) node. The SA node (sometimes called the sinus node) lies in the right atrium near the vena cava. SA nodal cells generate spontaneous action potentials and act as the normal pacemaker for the heart. Because the SA node is located in the atria, action potentials will first be propagated over the atria, making them the first structures in the heart to contract. Action potentials spreading across the atria eventually reach another conducting structure known as the atrioventricular (AV) node. The AV node is located in the interatrial septum between the ostium of the coronary sinus and the septal leaflet of the tricuspid valve. The AV node serves two important functions. One is to relay the wave of depolarization from the atria to the ventricles. A sheet of connective tissue associated with the atrioventricular valves separates the atria from the ventricles, and the AV node is the only conductive link between the atria and the ventricles. The second function is to delay the spread of excitation from the atria to the ventricles. The AV node cells are specialized to conduct very slowly. This delay permits the atria to eject their blood and therefore fill the ventricles before the latter begin to contract. The fibers of the AV node give rise to fibers of the AV bundle (common bundle or bundle of His), which in turn divides into two major branches, the left bundle branch and the right bundle branch. These branches then divide into an extensive network of Purkinje fibers. The Purkinje fibers are conductile cells that conduct action potentials very rapidly. They are interwoven among the contractile cells of the ventricles and serve to quickly spread the wave of excitation throughout the ventricles. Because they conduct so rapidly, all muscle cells of the ventricles appear to contract in unison. It is important to emphasize that all of these conductile structures (e.g., SA node, AV node, Purkinje network) are not nervous tissue but, rather, specialized cardiac muscle cells.
EXCITATION IS CONDUCTED FROM CELL TO CELL THROUGH GAP JUNCTIONS Figure 2 is a micrograph of adjacent contractile cells from the ventricle. Like all striated muscle, ventricular muscle has the typical pattern of cross striations because of its highly organized contractile proteins (see paragraph 7 and paragraph 3). The region at which the cell membranes of adjacent myocytes adjoin is termed the intercalated disc. The myocytes are arranged in the heart in a staggered pattern, much like bricks in a wall. The intercalated discs occur at the junction between the myocytes and would be analogous to the mortar between the bricks. The discs run transversely where the ends of two adjacent myocytes abut. The disc then turns 90_ and runs longitudinally between the myocytes until another end-abutment begins. The transverse aspect of the intercalated disc is filled with structures called desmosomes. The desmosomes make strong mechanical attachments between the cells and transmit the force of contraction. The transverse aspect as well as the longitudinally oriented region of the intercalated disc are rich in low-resistance connections between the cells called gap junctions. Small pores in the center of each gap junction allow ions and even small peptides to flow from one cell to another along their electrochemical gradients. Cardiac muscle gap junctions serve an identical function as the gap junctions at electrical synapses between nerve cells (paragraph 6) and nexuses in smooth muscle cells (paragraph 8). An action potential in one muscle cell is propagated to adjacent muscle cells via direct electrotonic propagation across the gap junctions. The gap junctions cause every cell in the heart to be electrically coupled to its neighboring cells and that is what causes the heart to behave like a single motor unit. Theoretically, an ion inside an SA nodal cell could travel through every cell in the heart without ever having to enter the extracellular space. The Purkinje cells are still muscle cells but contain fewer contractile proteins than contractile cells. They are specialized not for contraction but, rather, for fast electrical propagation. The large diameter of the Purkinje cells gives them a high conduction velocity. (Recall from paragraph 5 that the greater the diameter of a nerve axon, the greater the propagation velocity of nerve action potentials.) A Purkinje fiber has a particularly high density of gap junctions between its cells, and they will conduct action potentials at about 4 m/sec over the ventricle. Atrial and ventricular muscle cells on the other hand conduct at only 1 m/sec.
Cells of the SA and AV nodes, like the Purkinje fibers, also have a reduced quantity of contractile proteins. As discussed later, nodal cells lack fast sodium channels and that reduces the rate at which they depolarize. They also are much smaller than either the contractile or Purkinje cells. Both of these properties cause them to have a low conduction velocity. AV nodal cells also have a reduced density of gap junctions that even further depresses their conduction velocity to only about 0.05 m/sec. It is the low propagation velocity of the AV nodal cells that provides the delay between atrial and ventricular contraction. The ultrastructural features of a typical cardiac muscle cell are illustrated in paragraph 3. At first glance, the ultrastructure appears much like a skeletal muscle cell (see paragraph 7). Common features include characteristic A, I, and Z bands, a T-tubule system, and sarcoplasmic reticulum (SR). Some subtle differences exist, however, between cardiac muscle and the skeletal muscle ultrastructure. One difference lies in the T tubules (which stands for ‘‘transverse’’ tubules because they are transversely oriented to the long axis of the cell). They are centered on the Z band with only one tubule per sarcomere. Mammalian skeletal muscle is modified to have two T tubules per sarcomere, which reduces the distance over which calcium must diffuse to reach the sliding filaments. This results in an extremely fast twitch that can provide an important survival benefit. Cardiac muscle does not require such a fast activation time and, hence, a single T tubule per sarcomere is sufficient. The SR in cardiac contractile cells consists of two types of structures: (1) the sarcotubular network, making up the bulk of the SR, is in proximity to the contractile machinery, and (2) the subsarcolemma cisternae, the region at which the SR abuts the T tubules. The subsarcolemma cisternae are equivalent to the terminal cisternae of skeletal muscle cells. Finally, cardiac myocytes contain a large quantity of mitochondria reflecting the aerobic nature of cardiac muscle metabolism. Most of the metabolic energy of the heart comes from oxidative metabolism of fatty acids and lactate, with glucose accounting for only a small fraction of the energy source. Although the heart can derive some energy by anaerobic glycolysis of glucose, it is not enough to keep up with the high energy demands of a beating heart. As a result, interruption of the heart’s oxygen supply will cause a cessation of mechanical activity within less than 1 min and irreversible injury of the cells will begin within 20 min if the oxygen supply is not restored.
CARDIAC MUSCLE EXPERIENCES AN ACTION POTENTIAL Figure 4 shows an action potential typical of what would be recorded from a contractile cell in the ventricle. Superficially, this action potential appears similar to the action potentials seen in nerve, skeletal, and smooth muscle cells (paragraphs 6, 7, and 8). One major difference, however, is its duration. Note that the action potential remains in a depolarized state for about 300 msec (almost a third of a second) giving it a shape like a plateau. In contrast, an action potential in a nerve or skeletal muscle cell lasts only about 1 msec. It is the plateaued action potential that keeps the heart activated long enough to develop a forceful contraction from a single action potential. The rapid phase of depolarization is termed phase 0. Phase 1 is a trasient repolarization following the overshooting of Phase 0. Phase 1 is followed by a long period during which the membrane potential remains depolarized, the plateau phase or phase 2. After the plateau phase, a phase of repolarization occurs during which the membrane potential returns to its resting level. This phase is termed phase 3. The resting potential between beats is referred to as phase 4.
CARDIAC MUSCLE EXHIBITS BOTH DIVERSITY AND SPECIALIZATION Just as there is morphologic diversity and specialization of individual cells in the heart, there is also electrical diversity and specialization. Figure 5 illustrates action potentials recorded in several different regions of the heart. Action potentials in contractile and Purkinje cells are associated with a very rapid depolarizing phase and a broad plateau region. Both the rapidity of depolarization as well as the plateau phase are less prominent in action potentials recorded from nodal cells. None of these cells experiences a hyperpolarizing afterpotential, as is the case for action potentials in nerve and skeletal muscle cells. Finally, note that the phase 4 baseline is normally stable in contractile and Purkinje cells, but is not stable in the SA nodal cells.
PROLONGED OPENING OF CALCIUM CHANNEL CAUSES THE PLATEAU PHASE OF THE ACTION POTENTIAL In a nerve cell or a muscle cell, a rapid increase in Naþ permeability (actually conductance, because we are talking about charge movement) is seen that depolarizes the cell, followed by an increase in Kþ conductance that repolarizes it. The peculiar shape of the cardiac action potential suggests that the ionic mechanisms are different in heart cells, as indeed they are. Figure 6A shows an action potential from a normal contractile cell, whereas paragraph 6B shows the action potential after treating the cell with tetrodotoxin (TTX). TTX selectively blocks the voltage-gated fast sodium channels. TTX does not completely block the action potential, as it does in nerve or muscle; rather, it only attenuates the rate of phase 0 depolarization. Clearly, a sustained increased Naþ conductance is not what prolongs the duration of the cardiac action potential. The long plateau phase is actually due to a prolonged increase in Ca2þ conductance through voltage-dependent calcium channels, often referred to as L-type calcium channels. These channels are similar to those seen in the presynaptic terminal (paragraph 6) or in smooth muscle (paragraph 8). An increase in Ca2þ permeability will depolarize the cell just as an increase in Naþ permeability does. The concentration of Ca2þ is much higher outside the cell than inside, with an equilibrium potential of about þ120 mV. Therefore, if the membrane were freely permeable to Ca2þ, the voltage inside the cell would then approach þ120 mV. Compare the action potential in the TTX-treated contractile cell of paragraph 6 to the nodal cells in paragraph 5. The slow phase 0 and lack of overshoot in the nodal cells is due to the fact that fast sodium channels are not expressed in these cells. The action potential in nodal tissue is maintained entirely by the L-type calcium channels. As expected, TTX has no effect on the action potential in nodal cells.
PROLONGED REFRACTORY PERIODS PREVENT THE HEART FROM BEING TETANIZED The fast sodium channels trigger action potentials in contractile and Purkinje cells. They have actually two gates that control passage of Naþ through the channel. The activation gate normally blocks the channel. Because it is voltage-gated it opens only when the membrane potential reaches threshold creating phase 0. Shortly after the activation gate opens a second part of the molecule, the inactivation gate closes the channel, causing phase 0 to end. The inactivation gate is voltage sensitive and does not reopen until the membrane repolarizes. Only when the inactivation gate finally opens will the cell be receptive to restimulation. This causes an absolute refractory period all through phase 2 and into phase 3, making it impossible to tetanize cardiac muscle. The refractory period ensures that the heart will relax between beats, allowing it to refill with the blood that will be pumped on the next beat. As the inactivation gates begin to open, the heart goes through a relative refractory period late in phase 3 where it can be restimulated but the threshold required for stimulation is elevated. Also an attenuated contraction will result because not all cells have their inactivation gates open yet. In nodal tissue lacking fast sodium channels the L-type calcium channels are also refractory to restimulation well into electrical diastole. As the wave of excitation finishes traversing the ventricles, the entire heart is in a refractory period, causing the wave to die out and the heart to relax. Sometimes conduction can be slowed in a diseased region to the point where the rest of the heart is out of the refractory period by the time the wave emerges from the depressed segment. When that occurs the heart can be restimulated by this delayed impulse causing a reentrant rhythm, in which the cycle repeats itself over and over. Under those conditions the heart may beat very rapidly or even fibrillate.
IONIC FLUXES IN THE CARDIAC MUSCLE CELLS Figure 7 summarizes some of the key changes in ion permeability that contribute to the cardiac action potential. The upper trace shows a typical cardiac action potential and the lower traces illustrate the changes in permeability to Naþ, Kþ, and Ca2þ. As a consequence of a depolarizing stimulus, a voltagedependent increase in Naþ conductance occurs. A regenerative cycle is initiated, which tends to depolarize the cell toward the equilibrium potential of Naþ. This regenerative increase in Naþ conductance rapidly moves the membrane potential to its peak level of þ20 mV. Thus, the voltage-dependent increase in Naþ conductance underlies phase 0 and 1 of the action potential. The inactivation gates in the sodium channels spontaneously close within a millisecond or two after activation gate opening. Although the cell remains depolarized, Naþ conductance quickly returns to its resting level. Changes in Ca2þ permeability are shown in the bottom panel of paragraph 7. The initial depolarization of the membrane causes Ca2þ conductance to increase in a voltage-dependent manner. Unlike the sodium channels, the calcium channels are slow to close and there is a sustained increase in Ca2þ conductance, which maintains the plateau of the cardiac action potential. Another factor contributing to the plateau of the cardiac action potential is the change in Kþ conductance (paragraph 7). At rest, the Kþ conductance of cardiac cells is high, just as it is in nerve and skeletal muscle cells. The similarity, however, ends here. When nerve and muscle cells repolarize, a transient increase is observed in Kþ conductance over the resting value, which quickly terminates the action potential and momentarily hyperpolarizes the cell. In contrast, in cardiac muscle Kþ conductance decreases with depolarization (paragraph 7), and during repolarization Kþ conductance simply returns to its phase 4 value. That is why cardiac muscle has no hyperpolarizing afterpotential. We should mention that there are many different types of potassium channels in the cardiomyocyte and their individual functions in controlling Kþ conductance through the action potential are complex. A detailed description of these is beyond the scope of this paragraph.
EXCITATION–CONTRACTION COUPLING IS ACCOMPLISHED BY CALCIUM IONS Cardiac muscle cells, like skeletal muscle cells, have an extensive SR (see paragraph 3). Excitation–contraction coupling in cardiac muscle cells is similar to that in skeletal muscle cells. Specifically, an action potential travels down the T tubules and causes the release of Ca2þ from the SR, which in turn activates the contractile machinery. Three pools of Ca2þ are important to the cardiac muscle cell, as shown in paragraph 8: (1) in the extracellular fluid, (2) in the SR, and (3) in the cytoplasm. Only the cytoplasmic pool is available to bind with the troponin-binding sites and initiate contraction. Consider the consequences of an action potential. Ca2þ entry through the sarcolemma increases the concentration of Ca2þ in the cytoplasm. Because the amount of Ca2þ entering is relatively small, it accounts for only a fraction of the activation of the contractile proteins and, hence, is indicated by a dashed line in paragraph 8. In skeletal muscle, action potentials on the T tubules electrically stimulate the SR to release calcium. That is not the case in cardiac muscle however. Rather the small amount of Ca2þ entering the cell through the L-type calcium channels actually triggers the release of the sequestered Ca2þ within the SR. The trigger calcium acts at ryanodine receptors located on the SR. These are actually calcium-gated calcium channels that open in the presence of cytosolic calcium. The name derives from the original observation that they bind the toxin ryanodine, which blocks these release channels in the SR and hence contraction. The importance of this trigger calcium is evidenced by the fact that heart muscle will not contract when the influx of Ca2þ across the sarcolemma is blocked, even though adequate stores of Ca2þ are still present in the
SR. RELAXATION IS ACCOMPLISHED BY REMOVING Ca2þ FROM THE CYTOSOL In cardiac muscle, as in skeletal muscle, there is a Ca2þ pump in the SR membranes termed the sarcoendoplasmic reticulum Ca2þ-ATPase (SERCA). SERCA (paragraph 8) removes Ca2þ from the contractile pool and pumps it into the SR. When enough Ca2þ is removed from the cytosol, the muscle relaxes. With each action potential some additional Ca2þ moves into the cell during phase 2. After a period of time, the intracellular Ca2þ concentration, if left unchecked, would be the same as that outside. Clearly, a mechanism is needed to remove Ca2þ from the cell. The Naþ-Ca2þ exchange system in the sarcolemma is primarily responsible for removing calcium from the cytosol. The exchanger, which is not a pump, derives its energy from the Naþ-Kþ pump. The exchanger will pass three Naþ ions in one direction for one Ca2þ ion in the other direction, but, being an exchanger rather than a pump, will do so only along a favorable energy gradient. Because the Naþ-Kþ pump maintains a strong transmembrane gradient for sodium, any free Ca2þ in the cytosol will be favorably exchanged for three Naþ ions in the extracellular fluid. There are also true calcium pumps in the sarcolemma, but they account for only a small percentage of the calcium flux. At a steady state, the exact same amount of Ca2þ that entered the cell is removed with each beat. In this system the sarcolemmal exchanger and the SERCA compete for cytosolic Ca2þ during diastole. The amount of Ca2þ available for release in the SR is therefore dependent on the net outcome of this competition.
STRENGTH OF CONTRACTION CAN BE MODULATED IN CARDIAC MUSCLE The force generated by cardiac muscle cells depends on the cells’ contractility, sometimes called the inotropic state. An increased contractility means that for any given length of the muscle it contracts with a greater force. It is important to note that the amount of Ca2þ released from the SR with each action potential is not sufficient to fully cover all of the troponin binding sites and thus activate all of the contractile proteins. Therefore, any manipulation that leads to enhanced release of Ca2þ from the SR will result in more troponin binding sites being occupied by Ca2þ and hence more force being generated by the muscle. The Ca2þ fluxes can, in turn, be altered by a variety of physiological control systems. Three commonly encountered modulators of contractility will be considered next: (1) stimulation frequency, (2) catecholamines, and (3) cardiac glycosides. Stimulation Frequency When the frequency of contraction increases, so does the tension generated by each contraction. This phenomenon, known as the positive staircase effect, was first described by Bowditch, an early cardiovascular physiologist, and is illustrated in paragraph 9. When Bowditch stimulated the heart, he found that a different tension was produced for each rate of stimulation. Stimulation at low rates was associated with a low tension and when the frequency of the stimulation was increased, the tension increased as well. The tension associated with a new rate of stimulation is not achieved instantaneously; it instead takes a period of time and appears to develop in a stepwise fashion. Hence the name ‘‘staircase.’’ The positive staircase effect is an example of a positive inotropic effect, because it is associated with increased contractility. The model of excitation–contraction coupling illustrated in paragraph 8 can explain the positive staircase phenomenon. Increasing the heart rate increases the number of action potentials per unit of time and, thus, the rate of Ca2þ influx from the extracellular compartment. At the same time, it shortens the duration of diastole when the exchanger removes Ca2þ. As a result, more cytosolic Ca2þ is pumped into the SR than is removed by the Naþ-Ca2þ exchange mechanism, causing more Ca2þ to be available for release from the SR with each beat. Because the new equilibrium will take several beats to be reached, the increased contractility is seen to increase stepwise. Catecholamines When the catecholamines norepinephrine and epinephrine secreted by the sympathetic nerve endings and by the adrenal medulla bind to the heart’s _1-adrenergic receptors, they exert a profound effect on the cardiac its contractile state. Receptor binding, as shown in paragraph 10, causes adenylyl cyclase to make cyclic adenosine monophosphate (cAMP), which in turn activates cAMP-dependent kinase (PKA). Catecholamines exert their effect by influencing both of the sarcolemmal and SR Ca2þ fluxes. PKA phosphorylates the L-type calcium channels, which causes more Ca2þ to enter the cell with each action potential. If more Ca2þ enters the cell, more will be available to be pumped into the SR, causing more to be available for release with subsequent action potentials (the same basic argument was used to explain the positive staircase effect discussed earlier). The second action of catecholamines is to increase the activity of SERCA. This is accomplished when PKA phosphorylates a protein called phospholamban on the SR. If the activity of SERCA is increased, a greater portion of the cytosolic Ca2þ will be pumped into the SR, making a greater amount available for release by a subsequent action potential. Catecholamines also tend to shorten phase 2 and thus shorten the duration of systole. Inhibition of the Sodium Pump by Cardiac Glycosides Cardiac glycosides such as digitalis were traditionally used to treat congestive heart failure. The rationale for their use as a therapeutic agent at first may seem questionable, because at the molecular level cardiac glycosides block the Naþ-Kþ pump in all of the body’s cells, including those in the heart, and are therefore potent poisons. The key strategy in their use is to carefully adjust the dose so that only a partial block of the Naþ-Kþ pump occurs. When this is done, cardiac glycosides lead to enhanced contractility of the heart by the following mechanism. Due to decreased activity of the Naþ-Kþ pump, the intracellular concentration of Naþ in cardiac cells increases, decreasing the driving force for Naþ to enter the cell. Because the Naþ gradient is the energy source for the Naþ-Ca2þ exchanger, the latter will remove less Ca2þ from the cell. Intracellular levels of Ca2þ will increase, with more Ca2þ available to be pumped into the SR.
PACEMAKER CELLS CONTROL THE HEART RATE The SA node is the normal pacemaker of the heart. The action potentials in the SA node are somewhat different from the action potentials in contractile cells. The most obvious difference is that the phase 4 resting potentials are unstable, as shown in paragraph 11. Note that the resting potential starts from its maximum value of about _60 mV, then slowly depolarizes until it reaches threshold and undergoes a regenerative action potential. On completion of the action potential, the cell again begins to depolarize and another action potential is initiated. This process occurs about 60–100 times each minute, resulting in the cardiac rhythm. The progressive depolarization of the phase 4 potential is known as the pacemaker potential. The ionic mechanism underlying the pacemaker potential is not fully understood, but it is thought to be due to an inward sodium leakage current. Cells in the AV node also have pacemaker potentials but they are slower (only about 40 beat/min) and thus the SA node dominates with its faster rhythm. An isolated strip of Purkinje fibers will spontaneously generate action potentials with a frequency of about 25 action potentials per minute, a rate slower than that of either SA or AV nodal cells. The AV node and Purkinje fibers are called latent pacemakers because they will assume the pacemaker role should the signal from the SA node be interrupted. Atrial and ventricular cells have virtually no pacemaker activity.
AUTONOMIC NERVES MODULATE PACEMAKER ACTIVITY The sympathetic and parasympathetic divisions of the autonomic nervous system have profound influences on the heart rate. The transmitter substance of the parasympathetic division, acetylcholine (ACh), reduces the heart rate, a negative chronotropic effect, whereas the transmitter substances of the sympathetic division, epinephrine and norepinephrine, increase the heart rate, a positive chronotropic effect. The dashed line in paragraph 11 illustrates the effect of ACh on the SA node. ACh binds to Gi-coupled muscarinic cholinergic receptors, which results in an increase in Kþ conductance. The increase in Kþ conductance hyperpolarizes the cell so that it takes a longer time to reach threshold. ACh also slows the rate of rise of the pacemaker potential itself. Both of the preceding effects tend to decrease the firing rate. If the vagus nerve is intensely stimulated, the cells in the SA node will be so hyperpolarized that the pacemaker potential will not reach threshold to fire the cells and the heart will stop beating. After a short time, however, the heart will resume beating with escape beats. The escape rate is much slower because the latent pacemakers in the AV node or the Purkinje network have now taken control. Catecholamines from the sympathetic nerves increase the heart rate. The dashed line in paragraph 12 shows a recording made after the addition of a catecholamine. Note that the catecholamine increases the rate at which the pacemaker potential approaches threshold. The ionic mechanism causing this increased slope in the pacemaker potential is thought to be an increased Naþ conductance. For many years the channels responsible for this current were not fully characterized and so the current became known as the ‘‘funny’’ current, If. It is now thought that If occcurs through the hyperpolarizing- activated cyclic nucleotide-gated cation channel (HCN). Transmitter substances of the autonomic nervous system also affect the cell-to-cell conduction velocity in both the atria and the ventricles. ACh slows the rate of propagation, and catecholamines increase the rate of propagation. Intense vagal stimulation can easily depress conduction through the AV node to the point at which conduction to the ventricle fails, a condition called heart block. The ionic mechanisms that underlie these changes in propagation velocity are still not well understood.