Excitation: The Cardiac Action Potential

Objectives

1.
Characterize the types of cardiac action potentials.
2.
Define the ionic basis of the resting potential.
3.
Define the ionic basis of cardiac action potentials.
4.
Describe the characteristics of the fast- and slow-response action potentials.
5.
Explain the temporal changes in cardiac excitability.

Experiments on “animal electricity” conducted by Galvani and Volta more than two centuries ago led to the discovery that electrical phenomena were involved in the spontaneous contractions of the heart. In 1855 Kölliker and Müller observed that when the nerve of an innervated skeletal muscle preparation contacted the surface of a frog’s heart, the muscle twitched with each cardiac contraction.

The electrical events that normally occur in the heart initiate its contraction. Disorders in electrical activity can induce serious and sometimes lethal rhythm disturbances.

Cardiac Action Potentials Consist of Several Phases

The potential changes recorded from a typical ventricular muscle fiber are illustrated in Fig. 2.1A . When two microelectrodes are placed in an electrolyte solution near a strip of quiescent cardiac muscle, no potential difference (time a) is measurable between the two electrodes. At point b, one microelectrode was inserted into the interior of a cardiac muscle fiber. Immediately the voltmeter recorded a potential difference (V _m ) across the cell membrane; the potential of the cell interior was about 90 mV lower than that of the surrounding medium. Such electronegativity of the resting cell interior is also characteristic of skeletal and smooth muscles, nerves, and indeed most cells within the body.

$Fig. 2.1, Changes in transmembrane potential recorded from fast-response (A) and slow-response (B) cardiac fibers in isolated cardiac tissue immersed in an electrolyte solution from phase 0 to phase 4. (A) At time a, the microelectrode was in the solution surrounding the cardiac fiber. At time b, the microelectrode entered the fiber. At time c, an action potential was initiated in the impaled fiber. Time c to d represents the effective refractory period (ERP); time d to e represents the relative refractory period (RRP). (B) An action potential recorded from a slow-response cardiac fiber. Note that in comparison with the fast-response fiber, the resting potential of the slow fiber is less negative, the upstroke (phase 0) of the action potential is less steep, and the amplitude of the action potential is smaller; also, phase 1 is absent, and the RRP extends well into phase 4, after the fiber has fully repolarized.$

At point c, an electrical stimulus excited the ventricular cell. The cell membrane rapidly depolarized and the potential difference reversed (positive overshoot), such that the potential of the interior of the cell exceeded that of the exterior by about 20 mV. The rapid upstroke of the action potential is designated phase 0. Immediately after the upstroke, there was a brief period of partial repolarization (phase 1), followed by a plateau (phase 2) of sustained depolarization that persisted for about 0.1 to 0.2 seconds (s). The potential then became progressively more negative (phase 3), until the resting state of polarization was again attained (at point e). Repolarization (phase 3) is a much slower process than depolarization (phase 0). The interval from the end of repolarization until the beginning of the next action potential is designated phase 4.

The temporal relationship between the action potential and cell shortening is shown in Fig. 2.2 . Rapid depolarization (phase 0) precedes cell shortening, repolarization is complete just before peak shortening is attained, and the duration of contraction is slightly longer than the duration of the action potential.

Fig. 2.2, Temporal relationship between the changes in transmembrane potential and the cell shortening that occurs in a single ventricular myocyte.

The Principal Types of Cardiac Action Potentials Are the Slow and Fast Types

Two main types of action potentials are observed in the heart, as shown in Fig. 2.1 . One type, the fast response, occurs in the ordinary atrial and ventricular myocytes and in the specialized conducting fibers ( Purkinje fibers ). The other type of action potential, the slow response , is found in the sinoatrial (SA) node , the natural pacemaker region of the heart, and in the atrioventricular (AV) node , the specialized tissue that conducts the cardiac impulse from atria to ventricles.

As shown in Fig. 2.1 , the membrane resting potential (phase 4) of the fast response is considerably more negative than that of the slow response. Also, the slope of the upstroke (phase 0), the action potential amplitude, and the overshoot of the fast response are greater than those of the slow response. The action potential amplitude and the steepness of the upstroke are important determinants of propagation velocity, as explained later. Hence, conduction velocity is much slower in slow-response fibers than in fast-response fibers. Slow conduction increases the likelihood of certain rhythm disturbances.

Clinical Box

Fast responses may change to slow responses under certain pathological conditions. For example, in patients with coronary artery disease, when a region of cardiac muscle is deprived of its normal blood supply, the K ⁺ concentration in the interstitial fluid that surrounds the affected muscle cells rises because K ⁺ is lost from the inadequately perfused ( ischemic ) cells. The action potentials in some of these cells may then be converted from fast to slow responses (see Fig. 2.18 ). An experimental conversion from a fast to a slow response through the addition of tetrodotoxin , which blocks fast Na ⁺ channels in the cardiac cell membranes, is illustrated in Fig. 2.3 .

Fig. 2.3, Effect of tetrodotoxin on the action potential recorded in a calf Purkinje fiber perfused with a solution containing epinephrine and 10.8 mM K + . The concentration of tetrodotoxin was 0 M in A, 3 × 10− 8 M in B, 3 × 10− 7 M in C, and 3 × 10− 6 M in D and E; E was recorded later than D.

The Ionic Basis of the Resting Potential

The various phases of the cardiac action potential are associated with changes in cell membrane permeability , mainly to Na ⁺ , K ⁺ , and Ca ⁺⁺ . Changes in cell membrane permeability alter the rate of ion movement across the membrane. The membrane permeability to a given ion defines the net quantity of the ion that will diffuse across each unit area of the membrane per unit concentration difference across the membrane. Changes in permeability are accomplished by the opening and closing of ion channels that are selective for individual ions.

Just as with all other cells in the body, the concentration of K ⁺ inside a cardiac muscle cell, [K ⁺ ] _i , greatly exceeds the concentration outside the cell, [K ⁺ ] _o , as shown in Fig. 2.4 . The reverse concentration gradient exists for free Na ⁺ and for free Ca ⁺⁺ (not bound to protein). Estimates of the extracellular and intracellular concentrations of Na ⁺ , K ⁺ , and Ca ⁺⁺ , and of the equilibrium potentials (defined later) for these ions, are compiled in Table 2.1 .

Fig. 2.4, The balance of chemical and electrostatic forces acting on a resting cardiac cell membrane, based on a 30:1 ratio of the intracellular to extracellular K + concentrations and the existence of a nondiffusible anion (A − inside but not outside the cell.)

TABLE 2.1

Intracellular and Extracellular Ion Concentrations and Equilibrium Potentials in Cardiac Muscle Cells

Modified from Ten Eick, R. E., Baumgarten, C. M., & Singer, D. H. (1981). Ventricular dysrhythmias: Membrane bias, or, of currents, channels, gates, and cables. Progress in Cardiovascular Diseases, 24 , 157-188.

ION	Extracellular Concentrations (mM)	Intracellular Concentrations (mM) ^a	Equilibrium Potential (mV)
Na ⁺	145	10	71
K ⁺	4	135	–94
Ca ⁺⁺	2	1 × 10− ⁴	132

a The intracellular concentrations are estimates of the free concentrations in the cytoplasm.

The resting cell membrane is relatively permeable to K ⁺ but much less so to Na ⁺ and Ca ⁺⁺ . Hence K ⁺ tends to diffuse from the inside to the outside of the cell, in the direction of the concentration gradient, as shown on the right side of the cell in Fig. 2.4 .

Any flux of K ⁺ that occurs during phase 4 takes place through certain specific K ⁺ channels . Several types of K ⁺ channels exist in cardiac cell membranes. Some of these channels are controlled (i.e., opened and closed) by the transmembrane voltage, whereas others are controlled by some chemical signal (e.g., a neurotransmitter). The specific K ⁺ channel through which K ⁺ passes during phase 4 is a voltage-regulated channel called i _K1 , which is an inwardly rectifying K ⁺ current , as explained later ( Fig. 2.5 ). Many of the anions (labeled A ⁻ ) inside the cell, such as the proteins, are not free to diffuse out with the K ⁺ (see Fig. 2.4 ). Therefore as the K ⁺ diffuses out of the cell and the A ⁻ remains behind, the cation deficiency causes the interior of the cell to become electronegative.

Fig. 2.5, The K + currents recorded from a rabbit ventricular myocyte when the potential was changed from a holding potential of −80 mV to various test potentials. Positive values along the vertical axis represent outward currents; negative values represent inward currents. The V m coordinate of the point of intersection (open circle) of the curve with the X-axis is the reversal potential; it denotes the Nernst equilibrium potential (E K ) at which the chemical and electrostatic forces are equal.

Therefore two opposing forces regulate K ⁺ movement across the cell membrane. A chemical force, based on the concentration gradient, results in the net outward diffusion of K ⁺ . The counterforce is electrostatic; the positively charged K ⁺ ions are attracted to the interior of the cell by the negative potential that exists there, as shown on the left side of the cell in Fig. 2.4 . If the system comes into equilibrium, the chemical and electrostatic forces are equal.

This equilibrium is expressed by the Nernst equation for K ⁺ , as follows:

E_{K} = 61.5 log ({[K^{+}]}_{o} / {[K^{+}]}_{i})

$E_{K} = 61.5 log ({[K^{+}]}_{o} / {[K^{+}]}_{i})$

The term to the right of the equals sign represents chemical potential difference at the body temperature of 37°C. The term to the left, E _K , called the potassium equilibrium potential , represents the electrostatic potential difference that would exist across the cell membrane if K ⁺ were the only diffusible ion.

An experimental disturbance in the equilibrium between electrostatic and chemical forces imposed by voltage clamping would cause K ⁺ to move through the K ⁺ channels (see Fig. 2.5 ). If the transmembrane potential (V _m ) were clamped at a level negative to E _K , the electrostatic force would exceed the diffusional force, and K ⁺ would be attracted into the cell (i.e., the K ⁺ current would be inward ). Conversely, if V _m were clamped at a level positive to E _K , the diffusional force would exceed the electrostatic force, and K ⁺ would leave the cell (i.e., the K ⁺ current would be outward ).

When the measured concentrations of [K ⁺ ] _i and [K ⁺ ] _o for mammalian myocardial cells are substituted into the Nernst equation, the calculated value of E _K equals about −94 mV (see Table 2.1 ). This value is close to, but slightly more negative than, the resting potential actually measured in myocardial cells. Therefore the electrostatic force is slightly weaker than the chemical (diffusional) force, and K ⁺ tends to leave the resting cell.

The balance of forces acting on Na ⁺ is entirely different from that acting on the K ⁺ in resting cardiac cells. The intracellular Na ⁺ concentration, [Na ⁺ ] _i , is much lower than the extracellular Na ⁺ concentration, [Na ⁺ ] _o . At 37°C, the sodium equilibrium potential , E _Na , expressed by the Nernst equation is as follows:

E_{Na} = 61.5 log ({[{N a}^{+}]}_{o} / {[{Na}^{+}]}_{i})

$E_{Na} = 61.5 log ({[{N a}^{+}]}_{o} / {[{Na}^{+}]}_{i})$

For cardiac cells, E _Na is about 70 mV (see Table 2.1 ). Therefore at equilibrium a transmembrane potential of about +71 mV would be necessary to counterbalance the chemical potential for Na ⁺ . However, the actual voltage of the resting cell is just the opposite. The resting membrane potential of cardiac cells is about −90 mV (see Fig. 2.1A ). Hence both chemical and electrostatic forces favor entry of extracellular Na ⁺ into the cell. The influx of Na ⁺ through the cell membrane is small because the permeability of the resting membrane to Na ⁺ is very low. Nevertheless, it is mainly this small inward current of Na ⁺ that causes the potential of the resting cell membrane to be slightly less negative than the value predicted by the Nernst equation for K ⁺ .

The steady inward leak of Na ⁺ would gradually depolarize the resting cell were it not for the metabolic pump that continuously extrudes Na ⁺ from the cell interior and pumps in K ⁺ . The metabolic pump involves the enzyme Na ⁺ , K ⁺ -ATPase , which is located in the cell membrane. Pump operation requires the expenditure of metabolic energy because the pump moves Na ⁺ against both a chemical gradient and an electrostatic gradient. Increases in [Na ⁺ ] _i or in [K ⁺ ] _o accelerate the activity of the pump. The quantity of Na ⁺ extruded by the pump exceeds the quantity of K ⁺ transferred into the cell by a 3:2 ratio. Therefore the pump itself tends to create a potential difference across the cell membrane, and thus it is termed an electrogenic pump . If the pump is partially inhibited, as by digitalis , the resting membrane potential becomes less negative than normal.

The dependence of the transmembrane potential, V _m , on the intracellular and extracellular concentrations of K ⁺ and Na ⁺ and on the conductances (g _K and g _Na , respectively) of these ions is described by the chord conductance equation , as follows:

V_{m} = [E_{K} (g_{k} {/g}_{Na} + g_{k})] + [E_{Na} (g_{Na} / g_{Na} + g_{k})]

$V_{m} = [E_{K} (g_{k} {/g}_{Na} + g_{k})] + [E_{Na} (g_{Na} / g_{Na} + g_{k})]$

For a given ion (X), the conductance (g _x ) is defined as the ratio of the current (i _x ) carried by that ion to the difference between the V _m and the Nernst equilibrium potential (E _x ) for that ion; that is,

g_{x} = i_{x} / (V_{m} - E_{x})

$g_{x} = i_{x} / (V_{m} - E_{x})$

The chord conductance equation reveals that the relative, not the absolute, conductances to Na ⁺ and K ⁺ determine the resting potential. In the resting cardiac cell, g _K is about 100 times greater than g _Na . Therefore the chord conductance equation reduces essentially to the Nernst equation for K ⁺ .

When the ratio [K ⁺ ] _o /[K ⁺ ] _i is increased experimentally by a rise in [K ⁺ ] _o , the measured value of V _m ( Fig. 2.6 ) approximates that predicted by the Nernst equation for K ⁺ . For extracellular K ⁺ concentrations above 5 mM, the measured values correspond closely with the predicted values. The measured levels of V _m are slightly less negative than those predicted by the Nernst equation because of the small but finite value of g _Na . For values of [K ⁺ ] _o below 5 mM, the effect of the Na ⁺ gradient on the transmembrane potential becomes more important, as predicted by Eq. 2.3 . This increase in the relative importance of g _Na accounts for the greater deviation of the measured V _m from that predicted by the Nernst equation for K ⁺ at very low levels of [K ⁺ ] _o (see Fig. 2.6 ).

Fig. 2.6, The transmembrane potential (V m ) of a cardiac muscle fiber varies inversely with the potassium (K + ) concentration of the external medium (curved line) . The straight line represents the change in transmembrane potential predicted by the Nernst equation for E K .

The Fast Response Depends Mainly on Voltage-Dependent Sodium Channels

Genesis of the Upstroke

Any process that abruptly depolarizes the resting membrane to a critical potential value (called the threshold ) induces a propagated action potential. The characteristics of fast-response action potentials are shown in Fig. 2.1A . The initial rapid depolarization (phase 0) is related almost exclusively to Na ⁺ influx by virtue of a sudden increase in g _Na . The action potential overshoot (the peak of the potential during phase 0) varies linearly with the logarithm of [Na ⁺ ] _o , as shown in Fig. 2.7 . When [Na ⁺ ] _o is reduced from its normal value of about 140 mM to about 20 mM, the cell is no longer excitable.

Fig. 2.7, The concentration of sodium in the external medium is a critical determinant of the amplitude of the action potential in cardiac muscle ( upper line ) but has relatively little influence on the resting potential ( lower line ).

Specific voltage-dependent Na ⁺ channels (often called fast Na ⁺ channels ) exist in the cell membrane. These channels can be blocked selectively by the puffer fish toxin tetrodotoxin (see Fig. 2.3 ) and by local anesthetics . A voltage-gated Na ⁺ channel is depicted in Fig. 2.8 ; it contains an α subunit composed of four domains (I–IV) and two β subunits (only one is shown). Each domain has six transmembrane α-helical segments linked by external and internal peptide loops. Transmembrane segment 4 serves as a sensor whose conformation changes with applied voltage and is responsible for channel opening (activation). The intracellular loop that connects domains III and IV functions as the inactivation gate. After depolarization, this loop swings into the mouth of the channel to block ion conductance. The extracellular portions of the loops that connect helices 5 and 6 in each domain form the pore region and participate in the determination of ion selectivity. The Ca ⁺⁺ channels that form the basis of the slow response (see later) are similar in overall structure to Na ⁺ channels but have a different ion selectivity.

Fig. 2.8, Schematic structure of a voltage-gated Na + channel. The α subunit is composed of 4 domains (I–IV), each of which has 6 transmembrane helices; the N and C termini are cytoplasmic. Transmembrane segment 4 is a voltage sensor whose conformation changes with applied voltage. The 4 domains are arranged around a central pore lined by the extracellular loops of transmembrane segments 5 and 6. The β2 subunit is shown on the left. P, phosphorylation sites; ScTX, scorpion toxin binding site.

The physical and chemical forces responsible for the transmembrane movements of Na ⁺ are explained in Fig. 2.9 . The regulation of Na ⁺ flux through the fast Na ⁺ channels can be understood in terms of the “gate” concept. One of these gates, the m gate , tends to open as V _m becomes less negative than the threshold potential and is therefore called an activation gate . The other, the h gate , tends to close as V _m becomes less negative and hence is called an inactivation gate . The m and h designations were originally employed by Hodgkin and Huxley in their mathematical model of ionic currents in nerve fibers.

Fig. 2.9, The gating of a sodium channel in a cardiac cell membrane during phase 4 (A) and during various stages of the action potential upstroke (B to E). The positions of the m and h gates in the fast Na + channels are shown at the various levels of V m . The electrostatic forces are represented by the white arrows , and the chemical (diffusional) forces by the dark arrows .

Panel A in Fig. 2.9 represents the resting state (phase 4) of a cardiac myocyte. With the cell at rest, V _m is −90 mV and the m gates are closed while the h gates are wide open. The electrostatic force in Fig. 2.9A is a potential difference of 90 mV, and it is represented by the white arrow. The chemical force, based on the difference in Na ⁺ concentration between the outside and inside of the cell, is represented by the dark arrow. For an Na ⁺ concentration difference of about 130 mM, a potential difference of 60 mV (inside more positive than the outside) is necessary to counterbalance the chemical, or diffusional, force, according to the Nernst equation for Na ⁺ ( Equation 2 ). Therefore we may represent the net chemical force favoring the inward movement of Na ⁺ in Fig. 2.9 (dark arrows) as equivalent to a potential of 60 mV. With the cell at rest, the total electrochemical force favoring the inward movement of Na ⁺ is 150 mV (panel A). The m gates are closed, however, and the conductance of the resting cell membrane to Na ⁺ is very low. Hence, the inward Na ⁺ current is negligible.

Any process that makes V _m less negative tends to open the m gates and thereby activates the fast Na ⁺ channels so that Na ⁺ enters the cell (see Fig. 2.9B ) via the chemical and electrostatic forces. Thus activation of the fast channels is a voltage-dependent phenomenon . The precise potential at which the m gates swing open is called the threshold potential . The entry of Na ⁺ into the interior of the cell neutralizes some of the negative charges inside the cell and thereby diminishes further the transmembrane potential, V _m (see Fig. 2.9B ).

The rapid opening of the m gates in the fast Na ⁺ channels is responsible for the large and abrupt increase in Na ⁺ conductance, g _Na , coincident with phase 0 of the action potential (see Fig. 2.12 ). The rapid influx of Na ⁺ accounts for the steep upstroke of V _m during phase 0. The maximal rate of change of V _m (dV _m /dt) varies from 100 to 300 V/s in myocardial cells and from 500 to 1000 V/s in Purkinje fibers. The actual quantity of Na ⁺ that enters the cell is so small and occurs in such a limited portion of the cell’s volume that the resulting change in the intracellular Na ⁺ concentration cannot be measured precisely. The chemical force remains virtually constant, and only the electrostatic force changes throughout the action potential. Hence the lengths of the dark arrows in Fig. 2.9 remain constant at 60 mV, whereas the white arrows change in magnitude and direction.

As Na ⁺ enters the cardiac cell during phase 0, it neutralizes the negative charges inside the cell and V _m becomes less negative. When V _m becomes zero (see Fig. 2.9C ), an electrostatic force no longer pulls Na ⁺ into the cell. As long as the fast Na ⁺ channels are open, however, Na ⁺ continues to enter the cell because of the large concentration gradient. This continuation of the inward Na ⁺ current causes the cell interior to become positively charged (see Fig. 2.9D ). This reversal of the membrane polarity is the overshoot of the cardiac action potential. Such a reversal of the electrostatic gradient tends to repel the entry of Na ⁺ (see Fig. 2.9D ). However, as long as the inwardly directed chemical forces exceed these outwardly directed electrostatic forces, the net flux of Na ⁺ is still inward, although the rate of influx is diminished.

The inward Na ⁺ current finally ceases when the h (inactivation) gates close (see Fig. 2.9E ). The opening of the m gates occurs very rapidly, in about 0.1 to 0.2 milliseconds (ms), whereas the closure of the h gates is slower, requiring 10 ms or more. Inactivation of the fast Na ⁺ channels is completed when the h gates close. The h gates remain closed until the cell has partially repolarized during phase 3 (at about time d in Fig. 2.1A ). From time c to time d, the cell is in its effective refractory period and does not respond to excitation. This mechanism prevents a sustained, tetanic contraction of cardiac muscle that would interfere with the normal intermittent pumping action of the heart. A period of myocardial relaxation, sufficient to permit the cardiac ventricles to fill with venous blood during each cardiac cycle, is as essential to the normal pumping action of the heart as is a strong cardiac contraction.

About midway through phase 3 (time d in Fig. 2.1A ), the m and h gates in some of the fast Na ⁺ channels resume the states shown in Fig. 2.9A . Such channels are said to have recovered from inactivation . The cell can begin to respond again to excitation ( Fig. 2.10 ). Application of a suprathreshold stimulus to a region of normal myocardium during phase 3 evokes an action potential. As the stimulus is delivered progressively later during the course of phase 3, the slopes of the action potential upstrokes and the amplitudes of the evoked action potentials progressively increase. Throughout the remainder of phase 3, the cell completes its recovery from inactivation. By time e in Fig. 2.1A , the h gates have reopened and the m gates have reclosed in the remaining fast Na ⁺ channels, as shown in Fig. 2.9A .

$Fig. 2.10, The changes in action potential amplitude and slope of the upstroke as action potentials are initiated at different stages of the relative refractory period of the preceding excitation.$

Statistical Characteristics of the “Gate” Concept

The patch clamp technique has made it possible to measure ionic currents through single membrane channels. The individual channels open and close repeatedly in a random manner. This process is illustrated in Fig. 2.11 , which shows the current flow through single Na ⁺ channels in a myocardial cell. To the left of the arrow, the membrane potential was clamped at −85 mV. At the arrow, the potential was suddenly changed to −45 mV, at which value it was held for the remainder of the record.

Fig. 2.11, The current flow (in picoamperes) through two individual Na + channels in a cultured cardiac cell, recorded by the patch-clamping technique. The membrane potential had been held at −85 mV but was suddenly changed to −45 mV at the arrow and held at this potential for the remainder of the record.

Fig. 2.11 indicates that immediately after the membrane potential was made less negative, one Na ⁺ channel opened three times in sequence. It remained open for about 2 or 3 ms each time and closed for about 4 or 5 ms between openings. In the open state, it allowed 1.5 pA of current to pass. During the first and second openings of this channel, a second channel also opened, but for periods of only 1 ms. During the brief times that the two channels were open simultaneously, the total current was 3 pA. After the first channel closed for the third time, both channels remained closed for the rest of the recording, even though the membrane was held constant at −45 mV.

The overall change in ionic conductance of the entire cell membrane at any given time reflects the number of channels that are open at that time. Because the individual channels open and close randomly, the overall membrane conductance represents the statistical probability of the open or closed state of the individual channels. The temporal characteristics of the activation process then represent the time course of the increasing probability that the specific channels will be open, rather than the kinetic characteristics of the activation gates in the individual channels. Similarly, the temporal characteristics of inactivation reflect the time course of the decreasing probability that the channels will be open and not the kinetic characteristics of the inactivation gates in the individual channels.

Genesis of Early Repolarization

In many cardiac cells that have a prominent plateau, phase 1 constitutes an early, brief period of limited repolarization between the end of the action potential upstroke and the beginning of the plateau ( Fig. 2.12 ). Phase 1 reflects the activation of a transient outward current , i _to , mostly carried by K ⁺ . Activation of these K ⁺ channels leads to a brief efflux of K ⁺ from the cell because the interior of the cell is positively charged, and because the internal K ⁺ concentration greatly exceeds the external concentration (see Table 2.1 ). This brief efflux of K ⁺ brings about the brief, limited repolarization (phase 1 ).

Fig. 2.12, Changes in depolarizing ( upper panels ) and repolarizing ion currents during the various phases of the action potential in a fast-response cardiac ventricular cell. The inward currents include the fast Na + and L-type Ca ++ currents. Outward currents are I K1 , I to , and the rapid (I Kr ) and slow (I Ks ) delayed rectifier K + currents. The clones and respective genes for the principal ionic currents are also tabulated.

Phase 1 is prominent in Purkinje fibers (see Fig. 2.3 ) and in epicardial fibers from the ventricular myocardium ( Fig. 2.13 ); it is much less developed in endocardial fibers. When the basic cycle length at which the epicardial fibers are stimulated is increased from 300 to 2000 ms, phase 1 becomes more pronounced and the action potential duration is increased substantially. The same increase in basic cycle length has no effect on the early portion of the plateau in endocardial fibers, and it has a smaller effect on the action potential duration than it does in epicardial fibers (see Fig. 2.13 ).

Fig. 2.13, Action potentials recorded from canine epicardial and endocardial strips driven at basic cycle lengths (BCLs) of 300 and 2000 ms.

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Objectives

Cardiac Action Potentials Consist of Several Phases

The Principal Types of Cardiac Action Potentials Are the Slow and Fast Types

The Ionic Basis of the Resting Potential

The Fast Response Depends Mainly on Voltage-Dependent Sodium Channels

Genesis of the Upstroke

Statistical Characteristics of the “Gate” Concept

Genesis of Early Repolarization

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