Cardiac Action Potentials

Chapter 43

Cardiac Action Potentials Gordon M. Wahler

Chapter Outline I. Summary II. Introduction III. Resting Membrane Potential IV. Currents During the Action Potential Phases IVA. Overview IVB. Phase 0 IVC. Phase 1 IVD. Phase 2 IVE. Phase 3 IVF. Phase 4 V. Additional Currents Contributing to the Action Potential VA. Pump Current VB. Naþ-Ca2þ Exchange Current VC. Chloride Current VD. ATP-Sensitive Potassium Current

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VI. Regional Differences in Action Potentials VIA. Overview VIB. Sinoatrial Node VIC. Atria VID. Atrioventricular Node VIE. Purkinje Fibers VII. Automaticity VIIA. Overview VIIB. Mechanisms of Automaticity VIIB1. Automaticity in Purkinje Fibers VIIB2. Automaticity in Nodal Cells VIIC. Modulation of Automaticity by the Autonomic Nervous System VIII. Channelopathies Bibliography

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I. SUMMARY

II. INTRODUCTION

Action potentials (APs) in the heart are generated by the complex time-dependent interplay of several currents carried primarily by Naþ, Kþ and Ca2þ ions. Ventricular APs have very long duration compared to nerve and skeletal muscle APs, due to a plateau phase during which there is an approximate balance between depolarizing and repolarizing currents. Some cardiac cells display automaticity, due to the presence of a cyclical spontaneous depolarization. The cells of the sinoatrial node normally exhibit the fastest spontaneous depolarization of automatic cells in the heart and are therefore the normal pacemaker cells. Automaticity in nodal cells is initiated by several currents, including a hyperpolarization-activated cation current (the “funny current”), a small background Naþ current, the delayed rectifier Kþ current and Ca2þ currents. The sympathetic and parasympathetic nerves play important (and opposite) roles in regulating the force of myocardial contraction and heart rate via their effects on several currents. Mutations in a number of ion channels can lead to arrhythmias.

The electrophysiological behavior of heart cells subserves the function of the heart; namely to pump blood to the body. Heart cells are similar to other cell types in that their internal ionic composition is quite different from the extracellular ionic environment. For example, measurement of the intracellular versus extracellular ionic composition shows that the intracellular ionic composition is low in sodium ions (Naþ) and high in potassium ions (Kþ), while the reverse is true of the extracellular ionic composition. These concentration differences, together with the selective permeability characteristics of the cell membrane, generate a potential difference of between 80 and 90 mV across the cell membrane of the resting cardiac cell, with the inside being negative with respect to the outside. Additionally, heart cells are excitable cells. That is, they are capable of generating all-or-none electrical responses known as action potentials (APs). The cardiac AP is caused by the complex interaction of a number of different ionic currents. This chapter reviews the characteristics of the cardiac AP, with emphasis on the major

Cell Physiology Sourcebook. DOI: 10.1016/B978-0-12-387738-3.00043-3 Copyright Ó 2012 Elsevier Inc. All rights reserved.

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currents responsible for the various components or phases of the ventricular APs, as well as the regional differences in cardiac APs. The electrical activity of cardiac cells has been studied for several decades by impaling the cells with high-resistance microelectrodes. The development of methods to isolate viable single adult cardiac cells, together with the development of the patch-clamp technique for recording single-channel (microscopic) currents and whole-cell (macroscopic) currents from single cells, led to an explosion of information on the currents responsible for generation of the cardiac AP. The use of molecular biology techniques to clone and express channel subunits is further revolutionizing our understanding of the precise nature of various currents. While most of the information on cardiac ion currents has been necessarily obtained from cardiac cells isolated from experimental animals, studies on human cardiac myocytes (e.g. Coraboeuf and Nargeot, 1993) suggest that the currents in the human heart are generally similar to those observed in other animals.

III. RESTING MEMBRANE POTENTIAL Details on the origin of the resting potential (RP) have been given in a previous chapter. In brief, the cardiac cell membrane is quite permeable to Kþ and relatively impermeable to Naþ and other ions when at rest. Thus, Kþ flows out of the cell down its concentration gradient, resulting in rapid build up of a negative potential inside the cell. As the electric potential build up increases in magnitude, it becomes sufficient to counterbalance the chemical driving force generated by the concentration gradient. At this potential, called the equilibrium potential, the net ion flux is zero. Note that this does not mean there is no flux of the ion, only that the inward and outward fluxes of the ion are equal and opposite. The Nernst equation describes the relationship between the intracellular and extracellular concentrations of a single ion and its equilibrium potential. The equilibrium potential for ion X (EX) is calculated by the Nernst equation: Ex ¼

RT ½Xi In ZF ½Xo

where T is the absolute temperature (in degrees Kelvin), z is the valence (or charge) of the ion (for Kþ it is þ1, for Ca2þ it is þ2, etc.), R is the universal gas constant, F is the Faraday constant, [X]i is the ion concentration inside the cell, [X]o is the ion concentration outside the cell and ln is the natural logarithm. The intracellular and extracellular concentrations of Kþ are such that the equilibrium potential for Kþ (EK) is approximately 90 mV at 37 C. Since the ventricular cell at rest (i.e. between APs) is very permeable to Kþ and not

Muscle and Other Contractile Systems

FIGURE 43.1 Ventricular action potential. This is a diagrammatic representation of a typical adult mammalian ventricular AP. The five phases of the ventricular AP are labeled (0e4).

very permeable to other ions, the RP should be close to the calculated EK. Indeed, this is the case. For example, in Fig. 43.1, the resting membrane potential is approximately 87 mV. The RP does not quite reach EK because at rest there is a small, but finite, permeability to Naþ ions. In addition, there are other ion transport systems (primarily the electrogenic Naþ-Kþ-ATPase) which contribute slightly to the RP.

IV. CURRENTS DURING THE ACTION POTENTIAL PHASES IVA. Overview Cardiac cells have certain properties in common with other excitable cells, such as nerve and skeletal muscle cells. However, the behavior of cardiac cells also differs from the behavior of nerve and skeletal muscle cells in some important respects. The nerve and skeletal muscle APs are relatively brief, consisting primarily of a rapid depolarization phase (when the inside of the cell becomes more positive) followed immediately by a rapid repolarization phase (when the inside of the cell returns to a more negative potential). The depolarization phase of nerve and skeletal muscle cells is caused by the rapid influx of positive sodium ions into the cell, down the electrochemical gradient for Naþ, which makes the cell interior more positive. The subsequent repolarization is caused by the effiux of positive potassium ions from the cell, down the electrochemical gradient for Kþ, which returns the cell interior to its original more negative resting membrane potential. The entire process of the nerve or skeletal muscle APs is largely complete within a few milliseconds. In cardiac cells, the APs are more complex and generally much longer in duration. Thus, for example, a typical cardiac ventricular

Chapter | 43

Cardiac Action Potentials

AP may be 200 ms or more in duration (see Fig. 43.1). Additionally, unlike for nerve and skeletal muscle cells, APs from different regions of the heart vary substantially in shape. There are two primary types of cardiac cells. One cell type is found in the working (contractile) cells of the atria and ventricles and also in the specialized conduction cells of the HisePurkinje network. These cells have a high resting Kþ permeability between APs. The APs in these cells are generated by a fast Naþ current and are known as fast APs. The prolonged duration of the AP in ventricular cells and Purkinje fibers is caused by an approximate balance of inward depolarizing currents (primarily a Ca2þ current) and outward repolarizing Kþ currents, which results in a prominent plateau phase. Atrial cells have a less prominent plateau. The second type of cardiac cell is found in the sinoatrial and atrioventricular nodes. These nodal cells have a low Kþ permeability between APs and are automatic (i.e. they fire APs spontaneously). The upstroke of these nodal APs is generated by a Ca2þ current, which is smaller and slower than the fast Naþ current. Because of this, and the comparatively low density of Ca2þ channels when compared to the density of Naþ channels in fast cells, conduction in nodal cells is much slower than conduction in regions having Naþ-dependent APs. These nodal APs are known as slow APs. Slow APs (a.k.a. slow responses) may sometimes also occur in cells that normally have fast APs when fast Naþ current (INa) is blocked pharmacologically or pathophysiologically by tetrodotoxin or voltage inactivation by depolarization with high extracellular Kþ. The shape of the fast cardiac AP is generally divided into phases. The spike and slow wave (plateau) phases were described for isolated cardiac muscle (Hoshiko and Sperelakis, 1962). The following description details all of the five phases found in ventricular cells (phases 0 through 4) and indicates the current or currents that are primarily responsible for each phase. The phases of the ventricle and primary currents responsible are summarized in Table 43.1. Phase 0 is the upstroke of the AP, phase 1 is the early repolarization phase, phase 2 is the plateau phase, phase 3 is the primary repolarization phase and phase 4 is the resting membrane potential phase of the ventricular AP. Additional information about regional differences in the AP phases and currents will be also presented. It should be noted that an isolated single myocardial cell in cell culture exhibits a cardiac AP almost identical to that of a myocardial cell in the intact heart (Sperelakis and Lehmkuhl, 1964).

IVB. Phase 0 Phase 0 is the rapid upstroke of the AP in ventricular cells, as well as in the cells of the atria and HisePurkinje

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TABLE 43.1 Phases of the Ventricular Action Potential and Primary Currents Responsible Phase

Current

Channel Protein

Phase 0

INa

Nav1.5

Phase 1

Ito [Ito1 (Ito,f & Ito,s)]

Kv4.2/4.3 [Ito,f], Kv1.4 [Ito,s]

Phase 2

ICa(L) Ito IK INa “window current”

Cav1.2 (as in phase 1) (as in phase 3) Nav1.5

Phase 3

IK [IKs, IKr, IKur] IK1

Kv7.1 (a.k.a. KvLQT1) [IKs] Kv11.1 (a.k.a. HERG1 or ERG1) [IKr] Kv1.5 [IKur] (as in phase 4)

Phase 4

IK1

Kir2.1/2.2

network. This upstroke is dependent on a fast Naþ current (INa) quite similar to the current responsible for the upstroke of the nerve or skeletal muscle APs. However, the cardiac channel has a much lower sensitivity to the neurotoxin tetrodotoxin (e.g. Yu and Catterall, 2003). The voltage-gated channel protein (Nav1.5) responsible for this current in cardiac myocytes is encoded by the gene SCN5A. As expected, the Nav1.5 channels are expressed in atrial and ventricular myocytes and the HisePurkinje conduction cells, but not in nodal cells that do not fire fast APs (Nerbonne and Kass, 2005). This current is designated as fast because it exhibits very rapid activation and inactivation kinetics in comparison to other currents. Thus, in the vast majority of openings, the channel is open for less than 1ms. Because of the fast upstroke and fast conduction of the ventricular APs, the APs of these cells (and those of atrial and Purkinje fiber cells) are referred to as fast APs, as noted earlier. Figure 43.2 illustrates the kinetics and voltage-dependence of INa. Following a large depolarization, INa reaches a peak in less than 1ms, even at room temperature. Following this peak activation of INa the amplitude of this current spontaneously decreases. This decay of INa is due to inactivation of the fast Naþ channels; thus, INa is nearly zero after only a few milliseconds. The fast activation and large magnitude of INa often causes difficulties in accurately recording this current in voltage-clamped cardiac cells. Thus, INa can generally only be recorded in adult cardiac cells at reduced [Naþ]o levels and/or at low temperatures. Alternatively, INa can be studied in very small cells, such as the embryonic chick ventricular cell (e.g. Fig. 43.2) in which INa (and other currents) are at least an order of magnitude smaller

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potential approaches ENa. Thus, the peak INa occurs between 30 and 20 mV. The membrane potential never reaches ENa for several reasons: (1) as the membrane potential gets closer to ENa, the driving force for Naþ influx is diminished; (2) the Naþ channels close (inactivate) shortly after opening (beginning after about 1ms), thus, some Naþ channels are already closing during the latter part of the upstroke; (3) repolarizing currents are beginning to activate during the latter portion of the upstroke. Nevertheless, the upstroke causes a substantial voltage change (110e120 mV) within 1e2 ms in ventricular myocytes and other fast cardiac cells.

IVC. Phase 1

FIGURE 43.2 Sodium current (INa) recorded from a small embryonic chick ventricular cell. INa in these cells is much smaller than in adult cells, due to the very small size of these cells. Additionally, the small spherical shape of these cells and lack of t-tubules also contribute to better voltage control. Upper panel: shown are the original INa currents obtained upon stepwise depolarization from 100 mV to the indicated voltages. The current peaks in less than 1ms at very depolarized potentials and then rapidly inactivates. Lower panel: the currentevoltage curve of the peak current at each voltage. Note that the threshold for INa is approximately 70 mV and the current peaks at approximately 25 mV.

than in adult cells. For the rapid upstroke of phase 0 to occur, the cell needs to be depolarized to the voltage necessary to open some of the fast Naþ channels. When the Naþ channels begin to open, Naþ flows down its electrochemical gradient into the cell. This causes the cell to depolarize further (i.e. the inside becomes more positive), which opens additional Naþ channels. Therefore, once sufficient Naþ channels open, the process becomes selfperpetuating (i.e. a positive-feedback loop), resulting in rapid depolarization (i.e. the membrane potential rapidly moves toward the equilibrium potential for Naþ). The voltage at which a sufficient number of Naþ channels open to initiate the AP is the threshold for firing of the fast AP (approximately 55 mV). As the cell begins to depolarize further beyond the threshold, INa increases as more Naþ channels are activated. Eventually, with even greater depolarization, INa begins to decline as the membrane

Phase 1 of the cardiac AP is the transient and relatively small repolarization phase which immediately follows the upstroke of the AP. The size of phase 1 repolarization varies greatly between species and also between different regions of the heart within a given species. Thus, APs recorded from the outer (epicardial) layer of ventricular cells display a more prominent phase 1, whereas APs recorded from the inner (endocardial) layer of ventricular cells, display a small phase 1 repolarization (e.g. Antzelevitch and Dumaine, 2002). Phase 1 is also very large in Purkinje fibers and in atrial cells, but is largely absent in nodal cells. Phase 1 repolarization is primarily due to a transient outward current (Ito). Ito turns on rapidly with depolarization (i.e. beginning during the final portion of the AP upstroke) and is only active at very depolarized potentials; the threshold for activation is approximately 30 mV (Fig. 43.3). Ito has a characteristic transient shape because the rapid activation of this current is followed by inactivation during the AP plateau. Ito is actually composed of separate currents (Ito1 and Ito2) which are carried through three physically distinct channels (Tseng and Hoffman, 1989). One of the currents (Ito1) is a Kþ current that is independent of the internal Ca2þ concentration ([Ca2þ]i) and is sensitive to the Kþ channel blocker 4-aminopyridine (4-AP) (Fig. 43.3). This component of Ito is very similar to the IA current recorded in nerve fibers. In cardiac myocytes, Ito1 consists of fast and slow components (Ito,f and Ito,s) (Xu et al., 1999) which are pharmacologically separable due to the sensitivity of Ito,f to Heteropoda spider toxins (Sanguinetti et al., 1997). A heteromultimer made up of channel proteins Kv4.2 and Kv4.3, and encoded by genes KCND2 and KCND3, corresponds to Ito,f. Kv1.4 is the channel protein for Ito,s (for review, see Grunnet, 2010). In addition to Ito1, another component of Ito (Ito2) is sometimes observed. Ito2 is a Ca2þ-dependent Cl current (Zygmunt and Gibbons, 1992) that is less sensitive to 4-AP, but is more sensitive to another Kþ channel blocker,

Chapter | 43

Cardiac Action Potentials

FIGURE 43.3 Transient outward current (Ito) recorded from a 21-dayold rat ventricular cell. Upper panel: shown are the original currents obtained upon stepwise depolarization from 80 mV. Ito activates rapidly and then inactivates. Currents were recorded in the presence of tetrodotoxin to eliminate INa and cadmium to eliminate overlapping ICa. Lower panel: the current-voltage curve shows increasing activation of this current at voltages above approximately 30 mV (indicated by open circles). This current is the Ca2þ-independent, 4-aminopyridine-sensitive component of Ito (i.e. Ito1) and is therefore readily blocked by 4-aminopyridine (4-AP, indicated by closed circles).

tetraethylammonium ion (TEAþ). Under physiological conditions, Ito1 is much larger than Ito2. Thus, efflux of Kþ through the Ito1 channels is normally responsible for the vast majority of phase 1 repolarization. The second component (Ito2) may become more important when intracellular levels of Ca2þ become too high. That is, under Ca2þ-overload conditions, Ito2 would be activated and shorten the AP duration, thereby indirectly abbreviating the duration of Ca2þ current, resulting in a reduced Ca2þ influx. Thus, activation of Ito2 by intracellular Ca2þ likely acts as a protective negative feedback mechanism that reduces calcium overload.

IVD. Phase 2 Phase 2 is commonly called the plateau phase. It follows the early repolarization phase (phase 1) and is a period of time during which the membrane potential remains relatively constant (see Fig. 43.1). The presence of this

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prominent plateau phase is responsible for the long AP duration in cardiac cells, which is the major difference between cardiac cells and nerve or skeletal muscle fibers. The plateau is caused by an approximate balance of positive inward (depolarizing) and positive outward (repolarizing) currents. The primary inward current during this phase is a Ca2þ current. The primary outward current during the plateau phase of ventricular cells, particularly during the latter part of the plateau, is the slowly activating Kþ current known as the delayed rectifier, which is described in greater detail under phase 3 repolarization. The transient outward Kþ current, Ito, also contributes to the early plateau phase in those cells that have a substantial Ito. As a result of its voltage dependence and time course (see Fig. 43.3), Ito significantly overlaps (and opposes) the inward L-type Ca2þ current (which is the primary depolarizing current during the plateau phase). In addition to the Ca2þ and Kþ currents, there is a small contribution of the voltage-gated Naþ current (INa) to the plateau. Thus, while INa largely inactivates within a few milliseconds after depolarization, a very small fraction (approximately 1%) of the INa inactivates slowly (see Fig. 43.2), causing a late Naþ current known as the sodium window current, which is sufficient to affect the plateau of the AP and, hence, AP duration (Attwell et al., 1979). The inward Ca2þ current (ICa) exhibits activation and inactivation much like INa but on a slower time scale (Fig. 43.4). This second inward current peaks within a few ms, but requires a few hundred ms to inactivate completely. ICa is at least one order of magnitude smaller than INa in a given cell. The threshold for activation of ICa is approximately 40 mV, the current is maximal near 0 mVand the ECa is around þ100 mV. Thus, ICa is active over a more positive (depolarized) potential range than INa. This classical Ca2þ current is commonly referred to as the L-type (for “Longlasting” or “Large”) calcium current (ICa(L)) to distinguish it from the T-type (for “Transient” or “Tiny”) Ca2þ current (ICa(T)) described later. The L-type channel is Cav1.2 encoded by CACNA1C (Catterall, 2000). These channels are located throughout the heart, i.e. they are expressed in the contractile cells of the atria and ventricles, the conduction cells of the HisePurkinje system and the nodal cells (Boyett et al., 2000). The L-type Ca2þ current is central to many aspects of cardiac function. For example, it is the primary link in excitationecontraction coupling in heart muscle. Thus, the influx of Ca2þ ions during the plateau of the AP is what links the electrical events of the AP to the mechanical event, namely contraction. Ca2þ influx via ICa(L) stimulates Ca2þ release from internal (sarcoplasmic reticular) stores, replenishes the internal Ca2þ stores available for subsequent release and also directly activates the contractile proteins. ICa(L) is also very important in automaticity and conduction, due to the Ca2þ dependence of the nodal APs.

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effect on ICa(L). For information about the Ca2þ channels in developing hearts, the reader is referred to Chapter 25.

IVE. Phase 3

FIGURE 43.4 L-type calcium current (ICa(L)) recorded from an adult guinea pig ventricular cell. Upper panel: shown are the original currents obtained upon stepwise depolarization from 80 mV to the indicated voltages. INa was inactivated by briefly pulsing to 40 mV prior to applying the indicated test pulse. The Ca2þ currents show the same general shape as the Naþ currents (see Fig. 43.2.), i.e. they activate upon depolarizing steps and inactivate during the voltage pulse. However, both activation and inactivation are much slower than for INa (note difference in time scale). Lower panel: the currentevoltage curve shows a similar shape to the INa currentevoltage relationship; however, both the threshold voltage and peak voltage are shifted approximately 30 mVin the depolarizing direction. ICa(L) is roughly the same size as the INa example shown in Fig. 43.2 only because this cell is so much larger than the embryonic chick cell used in Fig. 43.2, INa in this guinea pig cell would be approximately 20 nA or more and could not be voltage-clamped under these conditions.

The L-type Ca2þ channel is also a major regulatory site in control of cardiac electrical activity and contraction by neurotransmitters, hormones, intracellular ions, etc. Perhaps the most important regulator of ICa(L) in the heart is the autonomic nervous system. Thus, release of norepinephrine from cardiac sympathetic nerves or release of epinephrine from the adrenal gland stimulates the b-adrenergic receptors of the cardiac myocyte. The net result of b-adrenergic stimulation is that ICa(L), and thereby force of contraction, is augmented. For a detailed review of this process, see Chapter 23. The parasympathetic neurotransmitter, acetylcholine (ACh) has a smaller, inhibitory (anti-adrenergic)

Phase 3 is the late or final repolarization phase following the AP plateau. It is similar to the repolarization observed in nerve and skeletal muscle cells. Phase 3 repolarization is primarily caused by the unbalance of the currents that were relatively balanced during phase 2. ICa(L) decreases with time (due to inactivation) and the delayed rectifier current (IK) increases (due to slow activation). This gradually leads to the outward current, the delayed rectifier (IK), overwhelming the inward current (ICa(L)). IK is the primary repolarizing current in most ventricular preparations. The classical delayed rectifier activates slowly, compared to most other currents and does not inactivate significantly with time. Thus, IK increases gradually during sustained depolarization at voltages around the plateau level. This current is similar to the delayed rectifier in nerve cells, although slower. IK can be clearly distinguished from Ito by slow activation, lack of inactivation and different pharmacology. The classical delayed rectifier current is divided into a very slowly activating component (IKs) and a more rapidly activating component (IKr) (see Grunnet, 2010). The IKs channel is Kv7.1 encoded by KCNQ1 (a.k.a. KVLQT1). The b-adrenergic-cAMP cascade can stimulate IKs, similar to its ability to stimulate ICa(L) (e.g. Walsh and Kass, 1988; Sanguinetti and Jurkiewicz, 1990), which would tend to shorten the AP. Thus, b-adrenergic stimulation tends to lengthen the AP duration by enhancing ICa(L) and, at the same time, tends to shorten AP duration by enhancing IK. The overall effect of b-adrenergic stimulation on AP duration is thus determined by the relative contribution of the changes in these two currents (and perhaps also a contribution of ICl, see later discussion). Some ventricular preparations also exhibit a Ca2þ-dependent IK (Tohse, 1990). This component may also help to shorten the AP duration. The other, so-called rapid component of the traditional delayed rectifier (IKr) opens during phase 3 because the deactivation process is much slower than the rapid recovery from inactivation (following a very transient early opening). This IKr channel is Kv11.1 (a.k.a. HERG1 or ERG1) encoded by KCNH2 (Grunnet, 2010). An ultrarapid-activating delayed rectifier Kþ current (IKur) also contributes to phase 3 repolarization in many preparations. IKur has slow deactivation and different pharmacology than IKs and IKf. It is made up of Kv1.5/3.1 encoded by KCNA5 and KCNA1, respectively (Grant, 2009). As the repolarization nears the RP, the inwardly rectifying Kþ current (IK1, which is the primary determinant of the RP; see below) also begins to contribute to phase 3 repolarization. Thus, a number of Kþ currents contribute to phase 3 repolarization of the AP.

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IVF. Phase 4 In ventricular cells, and most other cardiac cells, phase 4 is the RP. The RP is defined as the stable negative potential that occurs between APs in non-spontaneous cells. The resulting negative membrane potential is maintained by the Naþ-Kþ pump. The RP is very near EK due to a relatively high permeability of the resting ventricular cell membrane to Kþ and a very low permeability to other ions (e.g. Naþ). Thus, the RP of non-automatic cardiac cells is similar to the RP in skeletal muscle cells. The RP is largely set by a Kþ, current known as the inward rectifier, IK1, made up of Kir2.1/2.2 encoded by KCNJ2/J12 (Grant, 2009). Inward rectification means that, instead of a linear “ohmic” relationship between voltage and current, this channel passes current more readily in the inward direction than in the outward direction. This characteristic is evident in Fig. 43.5. Of course, the outward Kþ current is the only one occurring physiologically, since the membrane potential does not normally hyperpolarize beyond EK. In most preparations, IK1 actually demonstrates a negative slope region in the outward direction. That is, as the cell is depolarized from near its resting membrane potential to progressively more depolarized potentials, the outward current first increases and then decreases with further depolarization, with the outward current dropping to very low levels at voltages positive to 40 mV (Fig. 43.5). Thus, the contribution of IK1 to repolarization tends to be less at potentials near the plateau and greater as the membrane potential approaches the resting membrane potential (from approximately 40 mV to the resting membrane potential), at the same time that IK is declining. Therefore, IK1 contributes significantly to late phase 3 repolarization. The inward rectification of the IK1 channel current is thought to be due to blockade of the channels by intracellular Mg2þ (Matsuda et al., 1987) and polyamines (Lopatin et al., 1994), which is removed late in phase 3 as the interior of the cell becomes quite negative (Lopatin and Nichols, 2001). The large expression of IK1 channels in ventricular cells reduces the possibility of ventricular automaticity.

V. ADDITIONAL CURRENTS CONTRIBUTING TO THE ACTION POTENTIAL VA. Pump Current The Naþ,Kþ-ATPase, or pump, is the primary transport system that maintains the normal ionic imbalance between the cell exterior and interior. Each pump cycle extrudes three Naþ ions out of the cell and transports two Kþ ions into the cell, thus building up [Kþ]i and reducing [Naþ]i. Because of the exchange of three positive ions for two positive ions, each pump cycle generates a net loss of one

FIGURE 43.5 Inwardly-rectifying Kþ current (IK1) recorded from an adult guinea pig ventricular cell. Upper panel: shown are the original barium-subtracted currents obtained upon stepwise hyperpolarization and depolarization from a holding potential of 40 mV. The current displays the typical inward rectification. That is, the current is smaller in the outward (physiological) direction than the inward direction. Lower panel: the currentevoltage curve for IK1. The current also displays a negative slope region between approximately 60 mV and 30 mV. Thus, larger depolarizations actually result in a decrease in outward Kþ flux during this voltage range, such that the current at 30 mV is less than half as large as at 60 mV. The net result is that during repolarization (phase 3) the Kþ current increases as the membrane potential approaches the resting membrane potential.

positive charge, which generates a small pump current (Ip). At the RP, Ip is an outward current which may hyperpolarize the membrane potential slightly. In addition, Ip can cause considerable shortening of the AP when [Naþ]i increases pathologically (Gadsby, 1984). Additionally, blockade of the pump with toxic concentrations of digitalis may lead to a significant increase in intracellular [Naþ]i, which may in turn activate a Naþ-dependent Kþ current (IK(Na)) (Luk and Carmeliet, 1990). However, the primary role of the Naþ,Kþ-ATPase is to set up and maintain the ionic gradients that generate the electrochemical driving forces for the currents responsible for the AP.

VB. NaD-Ca2D Exchange Current An Naþ-Ca2þ exchanger (NCX) also exists in the cardiac sarcolemma. Working in the “normal mode” NCX

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exchanges intracellular Ca2þ for extracellular Naþ; thus, the exchanger is an important mechanism whereby Ca2þ is removed from the cytoplasm. The exchanger may also work in the “reverse” mode, exchanging intracellular Naþ for extracellular Ca2þ. Under these conditions, during the initial part of phase 2, NCX contributes a small Ca2þ influx for excitationecontraction coupling. The exchanger transports three Naþ for each Ca2þ under most conditions, leading to the net movement of one positive charge. Thus, NCX generates a current which can also contribute to the action potential. The equilibrium potential for this NaþCa2þ exchange current (INCX) is generally slightly negative to 0 mV; therefore, near the resting membrane potential, the exchanger works in the normal mode and INCX is an inward current. During the initial portion of the plateau, the NaþCa2þ exchanger transiently works in the reverse mode and briefly generates an outward current prior to returning to the normal mode. Thus, INCX may contribute to the shape of the AP (for review, see Janvier and Boyett, 1996).

VC. Chloride Current Under basal conditions, the Cl current (ICl) in the heart is relatively small and probably does not contribute a great deal to the configuration of the AP. However, when cAMP levels are stimulated (as with sympathetic nerve stimulation), a significant time-independent Cl current develops that is separate from the Cl current responsible for Ito2. Activation of this current by b-adrenergic stimulation can cause a small depolarization of the resting membrane potential and significant shortening of the action potential (Harvey, 1996).

VD. ATP-Sensitive Potassium Current Many details of this current have been given in the preceding chapter. When the oxygen supply declines, as occurs during ischemia, AP duration shortens. The shortening of the AP duration accelerates inactivation of ICa thereby reducing contractility. The reduced contractility greatly decreases the energy demands of the cell, thereby sparing ATP. This mechanism contributes to the survival of the myocardial cell during temporary ischemia. However, in addition to this beneficial effect, regional shortening of the AP can also lead to arrhythmias, due to the dispersion of refractory periods. The shortening of the AP during ischemia is largely caused by activation of a unique outward Kþ current, which is inhibited by intracellular ATP. The decreased oxygen supply reduces ATP levels in the cell and IK1 is inhibited. At the same time, the fall in ATP disinhibits the ATPsensitive Kþ current (IK(ATP)) (Noma, 1983), since the current is inhibited by physiological levels of intracellular ATP (Fig. 43.6) and thus appears to contribute little to the AP configuration under conditions of adequate oxygenation. However, during inadequate oxygenation, the AP is

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FIGURE 43.6 ATP-sensitive Kþ current IK(ATP) recorded from an insideout patch from an adult rat ventricular cell. Single-channel currents shown were recorded in the absence of ATP (upper traces) and in the presence of physiological levels of ATP (3mM, lower traces). Channel openings are downward. In the absence of ATP, channel activity is high. Thus, up to two channels are open simultaneously (number of open channel levels are indicated at the side). In the presence of 3mM ATP, the channels are rarely open. In the presence of ATP, the openings are extremely brief, such that they do not appear to reach the normal open level (1).

shortened as IK(ATP) replaces IK1. This is in large part because IK(ATP) displays less inward rectification than IK1 and, thus, has a greater effect on repolarization. This shortening of the AP leads to a shortened phase 2. The intracellular ATP levels reached during acute ischemia are generally not sufficiently low to open a substantial number of IK(ATP) channels on its own. However, the decreasing intracellular pH and increasing lactate accumulation that accompany ischemia also enhance IK(ATP) channel opening (Fan and Makielski, 1993) in addition to a fall in intracellular ATP levels. Furthermore, opening of only a small fraction of the large number of IK(ATP) channels may be sufficient to shorten substantially the AP (Faivre and Findlay, 1990). The physical characteristics of the IK(ATP) channel (e.g. ATP sensitivity and/or degree of rectification) are altered in some pathophysiological states, such as hypertrophy (Cameron et al., 1988) or diabetic cardiomyopathy (Smith and Wahler, 1996; Shimoni et al., 1998). This may be an important factor in the abnormal responses to ischemia in these conditions. Other channels may also be activated by ischemia, in addition to IK(ATP) channels; e.g. lysophosphatidylcholine and long-chain acylcamitine resulting from membrane phospholipid metabolism rapidly accumulate in early ischemia and may activate the arachidonic acid-activated Kþ channel (IK(AA)) and the phosphatidylcholine-activated Kþ channel (IK(PC)) (Montsuez, 1997).

VI. REGIONAL DIFFERENCES IN ACTION POTENTIALS VIA. Overview The normal pathway for electrical activation of the heart is the following: sinoatrial (SA) node, atria, atrioventricular

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(AV) node, bundle of His, Purkinje fibers, ventricles. The APs differ from region to region, reflecting the different roles played by the different cell types. The following description characterizes the APs for each region and indicates how each differs from the ventricular AP.

VIB. Sinoatrial Node The SA node contains specialized cells that generate APs that are quite different from the ventricular APs described above (Fig. 43.7). Unlike ventricular APs, these cells do not have a true resting membrane potential; i.e. the membrane potential between APs is not stable but rather exhibits a slow spontaneous depolarization known as phase 4 depolarization, or the pacemaker potential. Since there is no resting membrane potential in these cells, the most negative potential the cell reaches between APs is called the maximum diastolic potential. This potential is less negative than the resting membrane potential of ventricular cells, due to a lower Kþ permeability (caused by a lack of IK1 in these cells). The maximum diastolic potential ranges from approximately 55 mV for true primary pacemaker cells, to approximately 70 mV for transitional cells on the border between the SA node and atria. The pacemaker potential takes the nodal cell from the maximum diastolic potential to the threshold for generating an AP in these cells (approximately 40 mV). Thus, these cells are spontaneously active and the slope of the phase 4 depolarization is an important determinant of the rate of AP generation and, thereby, heart rate.

VIC. Atria Atrial cells have APs that are similar in many aspects to the ventricular APs described above. Thus, the resting

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membrane potential (phase 4) is approximately 85 mV and there is a fast upstroke (phase 0) generated by INa. The most distinguishing feature of the atrial AP is that it has a more triangular appearance than the ventricular AP. That is, atrial cells do not always have a distinct plateau. This is likely due to the relatively large Ito in atrial cells.

VID. Atrioventricular Node The cells of the AV node generate APs that are quite similar to the APs of the SA node. Thus, these cells fire Ca2þdependent APs and also display spontaneous phase 4 depolarization (i.e. automaticity). However, the rate of the phase 4 depolarization in AV nodal cells is much slower than the rate of phase 4 depolarization in SA nodal cells. Thus, the SA node cells fire APs before the AV node cells fire, which is why the SA node cells are the normal pacemaker cells of the heart.

VIE. Purkinje Fibers Purkinje APs are in most respects similar to the ventricular APs. Thus, these cells have a negative resting membrane potential between APs (phase 4) and a very rapid upstroke (phase 0) generated by INa. Purkinje fibers do differ from ventricular cells in that they have a more prominent phase 1 repolarization and a longer plateau (phase 2). The plateau is followed by a phase 3 repolarization that is virtually identical to phase 3 in ventricular cells. Cells in the bundle of His appear to have APs similar to those in the Purkinje fibers; however, in general, bundle of His cells have not been studied in detail. Additionally, Purkinje cells may exhibit automaticity, especially when the extracellular Kþ concentration is low. Thus, under some conditions, they exhibit phase 4 depolarization. Purkinje cells have all the currents found in ventricular cells, described above. However, Purkinje cells also have some additional currents, which are absent or very small in ventricular cells, that are related to the latent pacemaker function of these cells. These additional currents are described in the following section on automaticity.

VII. AUTOMATICITY VIIA. Overview

FIGURE 43.7 Sinoatrial node action potential. This is a diagrammatic representation of a typical sinoatrial node AP in the mammalian heart. Note the pacemaker potential and the absence of a resting membrane potential and the slower upstroke compared to the fast AP of the ventricular cell (see Fig. 43.1).

Automaticity refers to the ability of some cardiac cells to depolarize and fire repetitive APs spontaneously. Thus, as noted above, automatic cells (e.g. in the SA node) do not have a stable resting membrane potential between APs, but rather have a maximum diastolic potential followed by a spontaneous phase 4 depolarization, known as the pacemaker potential. The spontaneous depolarization to threshold generates the AP in that cell type. Following repolarization of

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the AP, the spontaneous phase 4 depolarization occurs again. The slope of the pacemaker potential (i.e. rate of spontaneous phase 4 depolarization) largely determines the rate of AP firing. Because the rate of firing of APs is normally fastest in the primary pacemaker cells of the SA node, this region acts as the normal pacemaker of the heart. Once this region fires an AP, the wave of depolarization is propagated to other regions of the heart, ultimately leading to contraction of the heart. Automatic cells in other regions of the heart (e.g. AV node) normally do not have the opportunity to fire spontaneously before the wave of depolarization arising from the SA node drives them to threshold.

current (ICa(L)). The T-type Ca2þ current is small to nonexistent in adult ventricular cells, but is present in Purkinje cells. There may be a small contribution of the T-type Ca2þ current to the latter stages of the pacemaker potential in Purkinje cells. During pacemaker activity, a small amount of Naþ through INa channels may also contribute to the final phase of the pacemaker potential in Purkinje cells, as the membrane potential approaches the threshold for AP generation. Then, as sufficient voltage-gated Naþ channels are opened, the Purkinje fiber will fire an AP which is generated by essentially the same mechanisms as previously described for ventricular cells.

VIIB. Mechanisms of Automaticity

VIIB2. Automaticity in Nodal Cells

Automaticity is a property of several cell types in the heart under physiological conditions (for review, see Mangoni and Nargeot, 2008). Under pathophysiological conditions, even normally non-spontaneous cells (e.g. ventricular cells) may exhibit automaticity. Physiologically, the most important pacemaker potential is that of the normal pacemaker cells in the SA node. However, technical difficulties have limited our understanding of the pacemaker process in nodal cells and more is known about automaticity in other automatic cell types (e.g. Purkinje fibers).

Several factors contribute to the pacemaker potential in nodal cells. Because of the very low density of IK1 channels in nodal cells, the resting Kþ permeability is much lower in nodal cells than in ventricular cells. The large resting Kþ permeability in ventricular cells generated by IK1 tends to keep the interior of the cells negative, opposing depolarization of the cell toward threshold by “clamping” the membrane potential near EK. A much smaller current is sufficient to depolarize the nodal cells due to the much lower resting Kþ permeability, leading to a very high input resistance. Thus, currents which may be too small to measure accurately using present electrophysiological techniques (small background currents or currents produced by various electrogenic transport mechanisms) could produce sufficient current to affect the pacemaker potential. Because of this limitation, the analysis of the relative contribution of various currents to the pacemaker potential in nodal cells is much less clear than for Purkinje cells, leading to considerable controversy regarding the precise mechanism of automaticity in SA node cells. The major depolarizing current during the pacemaker potential of Purkinje cells, If, is also present in nodal cells. The hyperpolarization-activated cyclic nucleotide-gated (HCN) channels responsible for If are encoded by four gene isoforms (HCN1e4) (for review, see Baruscotti et al., 2010). HCN2 and HCN4 are expressed in the heart, with HCN4 being the predominant isoform in the SA node. As noted earlier, If is an unusual depolarizing current in that it is activated by hyperpolarization (DiFrancesco, 1993). As a result, If is thought to contribute significantly to the early part of the pacemaker potential in SA node cells. There is a low density of HCN channels found in ventricular myocytes (see Baruscotti et al., 2010). In contrast to the situation in nodal cells, HCN are normally non-functional in ventricular myocytes because the voltage-dependence of the channels is quite different from HCN channels in nodal cells. That is, the channels can only be activated at unphysiologically negative voltages in ventricular cells (Yu et al., 1993). However, in certain

VIIB1. Automaticity in Purkinje Fibers Under physiological conditions, Purkinje fibers can have an extremely slow phase 4 pacemaker potential. In contrast to SA node cells, the mechanisms for automaticity in Purkinje cells are fairly well understood. As noted above, the Purkinje cells have all the currents that ventricular cells have, plus some additional currents not found to any significant degree in adult ventricular cells. The large IK1 current in Purkinje cells tends to clamp the membrane potential near EK and, therefore, a large depolarizing current is needed to overcome this clamping effect. The primary current responsible for the pacemaker potential in Purkinje cells has some unusual properties, earning it the designation as the “funny current” (If). If is a slowly activating inward depolarizing current which is present in automatic cells. It is a mixed cation current carrying both Naþ and Kþ ions. In Purkinje cells, If is responsible for most of the depolarizing current which generates the pacemaker potential. The molecular basis of If will be described in detail below (see Section VIIB2). In addition to ICa(L), pacemaker cells have an additional Ca2þ current which is activated at more negative potentials and exhibits a much more rapid activation and inactivation than ICa(L) (Hagiwara et al., 1988). This second Ca2þ current (carried by Cav3.1 and Cav3.2) has been named the transient T-type Ca2þ current (ICa(T)) in contrast to the classical, slowly inactivating long-lasting L-type Ca2þ

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pathological conditions (e.g. heart failure), the voltagedependence of the If channels in ventricular myocytes shifts to a more positive level (Mangoni and Nargeot, 2008), suggesting that If may contribute to ventricular arrhythmias under such conditions. Other small currents, e.g. the sodium-potassium ATPase pump current (Ip) and the Naþ-Ca2þ exchange current (INCX), also likely contribute to and/or modulate the pacemaker potential in nodal cells. For example, in SA node cells, Ip may help set the maximum diastolic potential (Noma and Irisawa, 1975). A novel involvement of SR calcium release in contributing to the pacemaker potential has also been proposed (see Mangoni and Nargeot, 2008). In this mechanism, local Ca2þ-induced-Ca2þ release near the sarcolemma leads to a depolarizing current that contributes to the pacemaker potential due to the electrogenic (swapping three Naþ for one Ca2þ) nature of the exchanger. As noted earlier, the upstroke (phase 0) of nodal cells is generated by an L-type Ca2þ current (ICa(L)) rather than a voltage-gated Naþ current (INa). The channel responsible appears identical to the classic L-type Ca2þ channel (Cav1.2) for the plateau in ventricular cells. Interestingly, in nodal cells, another ICa(L) channel isoform (Cav1.3) has been reported that has a slightly more negative threshold (approximately 50 mV). This component of ICa(L) is thought to contribute to the late phase of the pacemaker potential and effectively lower the threshold for ICa(L) (for review, see Mangoni et al., 2003). The complex interaction of so many different currents leads to the following hypothesis of the generation of the pacemaker potential by sequential activation of several different currents: (1) activation of If in late phase 3 repolarization is largely responsible for generating the early part of the pacemaker potential; (2) this early diastolic depolarization depolarizes the cells to the threshold for opening of T-type Ca2þ channels, leading to further depolarization; (3) the next threshold to be reached is the threshold for opening of Cav1.3 channels, causing further depolarization; (4) ultimately, at the very end of the pacemaker potential, Cav1.3 channels are opened; (5) opening of sufficient number of L-type channels leads to the upstroke of the Ca2þ-dependent action potential. Thus, opening of each channel in the sequence depolarizes the cell to the threshold for the opening of the next channel. An alternative proposal to the sequential activation of If and various ICa components hypothesizes that the interaction between a depolarizing voltage- and time-independent background current (Ib) and the decay of the delayed rectifier (IK) develops the pacemaker potential in nodal cells. This small, constant depolarizing current (Ib) in nodal cells is a cation current carried primarily by Naþ ions (Hagiwara et al., 1992). Due to the small size of this current, relatively little is known about its magnitude and

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characteristics in mammalian SA node cells; however, indirect evidence suggests that it may be a very important component in determining automaticity (Campbell et al., 1992; Dokos et al., 1996). The role of a constant Ib in generating a variable pacemaker potential results from the interaction of Ib with IK. IK is the primary current responsible for repolarization in nodal cells, as in other cardiac cells. Similar to ventricular cells, IK has also been shown to consist of at least two components (IKs and IKr) (Dokos et al., 1996). IK displays essentially no inactivation during a prolonged depolarizing pulse, but displays a slow decay upon repolarization toward EK. The time course of the IK decay is very slow at membrane potentials in the voltage range of the pacemaker potential in nodal cells. The depolarizing action of Ib is opposed by IK. Thus, the depolarization due to a constant background current Ib effectively increases progressively over time due to a gradual loss of opposing repolarizing current (IK), thereby leading to diastolic depolarization in nodal cells. Since the relative contribution of the various currents to the pacemaker potential in nodal cells cannot be accurately determined experimentally, there has been considerable controversy over which depolarizing current (If or Ib) plays the greater role in generating the pacemaker potential in these cells. It is likely that both play a significant role in contributing to automaticity in nodal cells.

VIIC. Modulation of Automaticity by the Autonomic Nervous System The pacemaker cells of the SA node are richly innervated by sympathetic and parasympathetic nerves. These actions of norepinephrine (NE) and acetylcholine (ACh) on several currents in SA node cells are the basis of the stimulating and inhibiting effect on heart rate of sympathetic or parasympathetic nerve stimulation. If and ICa(L) are both enhanced by the sympathetic neurotransmitter, norepinephrine and inhibited by the parasympathetic neurotransmitter, acetylcholine. Thus, NE increases the slope of the pacemaker potential, the threshold is reached sooner and heart rate increases. In contrast, ACh decreases the slope of the pacemaker potential. The If channel is directly activated by cAMP (DiFrancesco and Mangoni, 1994). Thus, the effects of NE and ACh are mediated by raising and lowering the intracellular cAMP concentration, respectively. In addition to the cAMP-mediated effects on If and ICa(L), ACh activates a G-protein-coupled inwardlyrectifying Kþ current (IK(ACh)) whose structure is similar to IK1. Cardiac IK(ACh) channels are tetramers made up of Kir3.1 and Kir3.4 subunits expressed by KCNJ3 and KCNJ5 and are highly expressed in the SA and AV nodes and atria, but not ventricles (Wickman et al., 1999). Binding of ACh to muscarinic M-2 receptors causes the

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release of G-protein Gai and Gbg subunits. The Gbg subunit then activates the IK(ACh) channel, causing hyperpolarization (which drives the maximum diastolic potential further from threshold) and a reduction of the slope of the pacemaker potential (for review, see Mangoni and Nargeot, 2008). The end result of activation of IK(ACh) is that it takes SA node cells a longer time to reach threshold and the heart rate is decreased.

VIII. CHANNELOPATHIES Mutations in the genes encoding IKr, IKs and INa have been reported to be responsible for long QT syndrome, a familial disorder characterized by slowed repolarization, recurrent syncope, increased incidence of torsades de pointes arrhythmias and an increased risk for sudden death (Veldkamp, 1998; Vizgirda, 1999). Interestingly, APs are normally longer in adult females than males, resulting in a greater QT interval. This suggests that the repolarizing currents may be smaller in females than males, which may explain the greater incidence of torsades de pointes arrhythmias in females (Vizgirda, 1999). Gain-of-function mutations in the genes that cause long QT syndrome can cause the opposite effect, namely more rapid repolarization, leading to short QT syndrome (Priori and Cerrone, 2005). Other mutations in the genes for these ion channels are responsible for a number of other familial arrhythmogenic conditions, such as Brugada syndrome and catecholaminergic polymorphic ventricular tachycardia (Clancy and Kass, 2005; Tester and Ackerman, 2009). It is certain that more electrophysiological abnormalities will be found to have their origins in mutations of genes encoding numerous channel proteins and associated regulatory proteins.

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