Sample Chapter The Mosby Physiology Monograph Series Cardiovascular Physiology 10e by Pappano To Order Call Sms At 91-8527622422
11Experiments on “animal electricity” con-ducted by Galvani and Volta two centuries ago led tothe discovery that electrical phenomena were involvedin the spontaneous contractions of the heart. In 1855Kölliker and Müller observed that when the nerve ofan innervated skeletal muscle preparation contactedthe surface of a frog’s heart, the muscle twitched witheach cardiac contraction.The electrical events that normally occur in theheart initiate its contraction. Disorders in electricalactivity can induce serious and sometimes lethalrhythm disturbances.CARDIAC ACTION POTENTIALSCONSIST OF SEVERAL PHASESThe potential changes recorded from a typical ventric-ular muscle ﬁber are illustrated in Figure 2-1A: Whentwo microelectrodes are placed in an electrolyte solu-tion near a strip of quiescent cardiac muscle, no poten-tial difference (time a) is measurable between the twoelectrodes. At point b, one microelectrode was insertedinto the interior of a cardiac muscle ﬁber. Immediatelythe voltmeter recorded a potential difference (Vm)across the cell membrane; the potential of the cell inte-rior was about 90 mV lower than that of the surround-ing medium. Such electronegativity of the resting cellinterior is also characteristic of skeletal and smoothmuscles, nerves, and indeed most cells within the body.At point c, an electrical stimulus excited the ven-tricular cell. The cell membrane rapidly depolarizedand the potential difference reversed (positive over-shoot), such that the potential of the interior of the cellexceeded that of the exterior by about 20 mV. Therapid upstroke of the action potential is designatedphase 0. Immediately after the upstroke, there was abrief period of partial repolarization (phase 1), fol-lowed by a plateau (phase 2) of sustained depolariza-tion that persisted for about 0.1 to 0.2 seconds (s). Thepotential then became progressively more negative(phase 3), until the resting state of polarization wasagain attained (at point e). Repolarization (phase 3) isa much slower process than depolarization (phase 0).The interval from the end of repolarization until the2O B J E C T I V E S1. 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.EXCITATION: THE CARDIACACTION POTENTIAL
CARDIOVASCULAR PHYSIOLOGY12beginning of the next action potential is designatedphase 4.The temporal relationship between the actionpotential and cell shortening is shown in Figure 2-2.Rapid depolarization (phase 0) precedes force develop-ment, repolarization is complete just before peak forceis attained, and the duration of contraction is slightlylonger than the duration of the action potential.The Principal Types of Cardiac ActionPotentials Are the Slow and Fast TypesTwo main types of action potentials are observed inthe heart, as shown in Figure 2-1. One type, the fastresponse, occurs in the ordinary atrial and ventricularmyocytes 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, andin the atrioventricular (AV) node, the specialized tis-sue that conducts the cardiac impulse from atria toventricles.e400–40–80ab c01 23dERP RRPFast responseA B Slow response0 100 200 300 0 100 200 30003442ERP RRPTime (ms)MillivoltsFIGURE 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 fromphase 0 to phase 4. A, At time a, the microelectrode was in the solution surrounding the car-diac ﬁber. At time b the microelectrode entered the ﬁber. At time c an action potential wasinitiated in the impaled ﬁber. Time c to d represents the effective refractory period (ERP); timed to e represents the relative refractory period (RRP). B, An action potential recorded from aslow-response cardiac ﬁber. Note that in comparison with the fast-response ﬁber, the restingpotential of the slow ﬁber is less negative, the upstroke (phase 0) of the action potential is lesssteep, and the amplitude of the action potential is smaller; also, phase 1 is absent, and theRRP extends well into phase 4, after the ﬁber has fully repolarized.50 mV7 m400 ms– 0 –FIGURE 2-2 ■ Temporal relationship between the changesin transmembrane potential and the cell shortening thatoccurs in a single ventricular myocyte. (From Pappano A:Unpublished record, 1995.)
EXCITATION: THE CARDIAC ACTION POTENTIAL 13As shown in Figure 2-1, the membrane restingpotential (phase 4) of the fast response is considerablymore negative than that of the slow response. Also, theslope of the upstroke (phase 0), the action potentialamplitude, and the overshoot of the fast response aregreater than those of the slow response. The actionpotential amplitude and the steepness of the upstrokeare important determinants of propagation velocity, asexplained later. Hence, conduction velocity is muchslower in slow-response ﬁbers than in fast-responseﬁbers. Slow conduction increases the likelihood of cer-tain rhythm disturbances.The Ionic Basis of the Resting PotentialThe various phases of the cardiac action potential areassociated with changes in cell membrane permeabil-ity, mainly to Na+, K+, and Ca++. Changes in cell mem-brane permeability alter the rate of ion movementacross the membrane. The membrane permeability to agiven ion deﬁnes the net quantity of the ion that will dif-fuse across each unit area of the membrane per unit con-centration difference across the membrane. Changes inpermeability are accomplished by the opening and clos-ing of ion channels that are speciﬁc for individual ions.Just as with all other cells in the body, the concen-tration of K+ inside a cardiac muscle cell, [K+]i, greatlyexceeds the concentration outside the cell, [K+]o, asshown in Figure 2-4. The reverse concentration gradi-ent exists for free Na+ and for free Ca++ (not bound toprotein). Estimates of the extracellular and intracellu-lar concentrations of Na+, K+, and Ca++, and of theequilibrium potentials (deﬁned later) for these ions,are compiled in Table 2-1.The resting cell membrane is relatively permeableto K+ but much less so to Na+ and Ca++. Hence K+tends to diffuse from the inside to the outside of thecell, in the direction of the concentration gradient, asshown on the right side of the cell in Figure 2-4.Any ﬂux of K+ that occurs during phase 4 takesplace through certain speciﬁc K+ channels. Severaltypes of K+ channels exist in cardiac cell membranes.Some of these channels are controlled (i.e., openedand closed) by the transmembrane voltage, whereasothers are controlled by some chemical signal (e.g., aneurotransmitter). The speciﬁc K+ channel throughwhich K+ passes during phase 4 is a voltage-regulatedchannel called iK1, which is an inwardly rectifying K+current, as explained later (Figure 2-5). Many of theCLINICAL BOXFast responses may change to slow responses undercertain pathological conditions. For example, inpatients with coronary artery disease, when a regionof cardiac muscle is deprived of its normal blood sup-ply, the K+ concentration in the interstitial ﬂuid thatsurrounds the affected muscle cells rises because K+ islost from the inadequately perfused (ischemic) cells.The action potentials in some of these cells may thenbe converted from fast to slow responses (see Figure2-18). An experimental conversion from a fast to aslow response through the addition of tetrodotoxin,which blocks fast Na+ channels in the cardiac cellmembranes, is illustrated in Figure 2-3.++++−−−−−−−−Electrostatic:EKK+A–K+150 mEq/L 5 mEq/LK+Chemical:–61.5 log ([K+]i/[K+]0)FIGURE 2-4 ■ The balance of chemical and electrostaticforces acting on a resting cardiac cell membrane, based ona 30:1 ratio of the intracellular to extracellular K+ concen-trations and the existence of a nondiffusible anion (A−inside but not outside the cell.)100mV1sA B C D EFIGURE 2-3 ■ Effect of tetrodotoxin on the action potentialrecorded in a calf Purkinje ﬁber perfused with a solutioncontaining epinephrine and 10.8 mM K+. The concentra-tion of tetrodotoxin was 0 M in A, 3 × 10−8 M in B, 3 × 10−7M in C, and 3 × 10−6 M in D and E; E was recorded laterthan D. (Redrawn from Carmeliet E, Vereecke J: Adrenaline andthe plateau phase of the cardiac action potential. Importance ofCa++, Na+ and K+ conductance. Pﬂügers Arch 313:300, 1969.)
CARDIOVASCULAR PHYSIOLOGY14anions (labeled A−) inside the cell, such as the pro-teins, are not free to diffuse out with the K+ (see Figure2-4). Therefore, as the K+ diffuses out of the cell andthe A− remains behind, the cation deﬁciency causesthe interior of the cell to become electronegative.Therefore, two opposing forces regulate K+ move-ment across the cell membrane. A chemical force,based on the concentration gradient, results in the netoutward diffusion of K+. The counterforce is electro-static; the positively charged K ions are attracted to theinterior of the cell by the negative potential that existsthere, as shown on the left side of the cell in Figure 2-4.If the system comes into equilibrium, the chemical andelectrostatic forces are equal.This equilibrium is expressed by the Nernst equa-tion for K+, as follows:. (1)The term to the right of the equals sign representschemical potential difference at the body temperatureof 37° C. The term to the left, EK, called the potassiumequilibrium potential, represents the electrostaticpotential difference that would exist across the cellmembrane if K+ were the only diffusible ion.An experimental disturbance in the equilibriumbetween electrostatic and chemical forces imposed byvoltage clamping would cause K+ to move through theK+ channels (see Figure 2-5). If the transmembranepotential (Vm) were clamped at a level negative to EK,the electrostatic force would exceed the diffusionalforce, and K+ would be attracted into the cell (i.e., theK+ current would be inward). Conversely, if Vm wereclamped at a level positive to EK, the diffusional forcewould exceed the electrostatic force, and K+ wouldleave 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 substitutedinto the Nernst equation, the calculated value of EKequals about −94 mV (see Table 2-1). This value is closeto, but slightly more negative than, the resting potentialactually measured in myocardial cells. Therefore theelectrostatic 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 dif-ferent from that acting on the K+ in resting cardiaccells. The intracellular Na+ concentration, [Na+]i, ismuch lower than the extracellular Na+ concentration,[Na+]o. At 37° C, the sodium equilibrium potential,ENa, expressed by the Nernst equation is as follows:. (2)For cardiac cells, ENa is about 70 mV (see Table2-1). Therefore at equilibrium a transmembranepotential of about +71 mV would be necessary tocounterbalance the chemical potential for Na+.TABLE 2-1Intracellular and Extracellular Ion Concentrationsand Equilibrium Potentials in Cardiac Muscle CellsION EXTRACELLULARCONCENTRATIONS(mM)INTRACELLULARCONCENTRA-TIONS (mM)*EQUILIBRIUMPOTENTIAL(mV)Na+ 145 10 71K+ 4 135 –94Ca++ 2 1 × 10−4 132Modiﬁed from Ten Eick RE, Baumgarten CM, Singer DH: ProgCardiovasc Dis 24:157, 1981.*The intracellular concentrations are estimates of the free concentra-tions in the cytoplasm.−120 −80 −40 0 40Vm (mV)20−2−4K+current(nA)Phase 4EK Phase 2FIGURE 2-5 ■ The K+ currents recorded from a rabbit ven-tricular myocyte when the potential was changed from aholding potential of −80 mV to various test potentials.Positive values along the vertical axis represent outwardcurrents; negative values represent inward currents. The Vmcoordinate of the point of intersection (open circle) of thecurve with the X axis is the reversal potential; it denotes theNernst equilibrium potential (EK) at which the chemicaland electrostatic forces are equal. (Redrawn from Giles WR,Imaizumi Y: Comparison of potassium currents in rabbit atrial andventricular cells. J Physiol [Lond] 405:123, 1988.)
EXCITATION: THE CARDIAC ACTION POTENTIAL 15However, the actual voltage of the resting cell is just theopposite. The resting membrane potential of cardiaccells is about −90 mV (see Figure 2-1A). Hence bothchemical and electrostatic forces favor entry of extra-cellular Na+ into the cell. The inﬂux of Na+ throughthe cell membrane is small because the permeability ofthe resting membrane to Na+ is very low. Nevertheless,it is mainly this small inward current of Na+ that causesthe potential of the resting cell membrane to be slightlyless negative than the value predicted by the Nernstequation for K+.The steady inward leak of Na+ would graduallydepolarize the resting cell were it not for the metabolicpump that continuously extrudes Na+ from the cellinterior and pumps in K+. The metabolic pumpinvolves the enzyme Na+,K+-ATPase, which is locatedin the cell membrane. Pump operation requires theexpenditure of metabolic energy because the pumpmoves Na+ against both a chemical gradient and anelectrostatic gradient. Increases in [Na+]i or in [K+]oaccelerate the activity of the pump. The quantity ofNa+ extruded by the pump exceeds the quantity of K+transferred into the cell by a 3:2 ratio. Therefore, thepump itself tends to create a potential difference acrossthe cell membrane, and thus it is termed an electro-genic pump. If the pump is partially inhibited, as bydigitalis, the resting membrane potential becomes lessnegative than normal.The dependence of the transmembrane potential,Vm, on the intracellular and extracellular concentra-tions of K+ and Na+ and on the conductances (gK andgNa, respectively) of these ions is described by thechord conductance equation, as follows:(3)For a given ion (X), the conductance (gx) is deﬁnedas the ratio of the current (ix) carried by that ion to thedifference between the Vm and the Nernst equilibriumpotential (Ex) for that ion; that is,(4)The chord conductance equation reveals that therelative, not the absolute, conductances to Na+ and K+determine the resting potential. In the resting cardiaccell, gK is about 100 times greater than gNa. Thereforethe chord conductance equation reduces essentially tothe Nernst equation for K+.When the ratio [K+]o/[K+]i is increased experimen-tally by a rise in [K+]o, the measured value of Vm (Figure2-6) approximates that predicted by the Nernst equa-tion for K+. For extra-cellular K+ concentrations above5 mM, the measured values correspond closely with thepredicted values. The measured levels of Vm are slightlyless negative than those predicted by the Nernst equa-tion because of the small but ﬁnite value of gNa. For val-ues of [K+]o below 5 mM, the effect of the Na+ gradienton the transmembrane potential becomes more impor-tant, as predicted by Equation 3. This increase in therelative importance of gNa accounts for the greater devi-ation of the measured Vm from that predicted by theNernst equation for K+ at very low levels of [K+]o (seeFigure 2-6).The Fast Response Depends Mainly onVoltage-Dependent Sodium ChannelsGenesis of the UpstrokeAny process that abruptly depolarizes the restingmembrane to a critical potential value (called thethreshold) induces a propagated action potential. Thecharacteristics of fast-response action potentials areshown in Figure 2-1A. The initial rapid depolarization(phase 0) is related almost exclusively to Na+ inﬂux byVm–100EK–50–15001 2 3 5 10 20 30 50 100External K concentration (mM)Potentialdifference(mV)FIGURE 2-6 ■ The transmembrane potential (Vm) of a car-diac muscle ﬁber varies inversely with the potassium (K)concentration of the external medium (curved line). Thestraight line represents the change in transmembrane poten-tial predicted by the Nernst equation for EK. (Redrawn fromPage E: The electrical potential difference across the cell membraneof heart muscle. Biophysical considerations. Circulation 26:582,1962.)
CARDIOVASCULAR PHYSIOLOGY16virtue of a sudden increase in gNa. The action potentialovershoot (the peak of the potential during phase 0)varies linearly with the logarithm of [Na+]o, as shownin Figure 2-7. When [Na+]o is reduced from its normalvalue of about 140 mM to about 20 mM, the cell is nolonger excitable.Speciﬁc voltage-dependent Na+ channels (oftencalled fast Na+ channels) exist in the cell membrane.These channels can be blocked selectively by the pufferﬁsh toxin tetrodotoxin (see Figure 2-3) and by localanesthetics. A voltage-gated Na+ channel is depictedin Figure 2-8; it contains an α subunit composed offour domains (I-IV) and two β subunits (only one isshown). Each domain has six transmembrane α-helicalsegments linked by external and internal peptideloops. Transmembrane segment 4 serves as a sensorwhose conformation changes with applied voltage andis responsible for channel opening (activation). Theintracellular loop that connects domains III and IVfunctions as the inactivation gate. After depolariza-tion, this loop swings into the mouth of the channel toblock ion conductance. The extracellular portions ofthe loops that connect helices 5 and 6 in each domainform the pore region and participate in the determina-tion of ion selectivity. The Ca++ channels that form thebasis of the slow response (see later) are similar inoverall structure to Na+ channels but have a differention selectivity.The physical and chemical forces responsible forthe transmembrane movements of Na+ are explainedin Figure 2-9. The regulation of Na+ ﬂux through thefast Na+ channels can be understood in terms of the“gate” concept. One of these gates, the m gate, tends toopen as Vm becomes less negative than the thresholdpotential and is therefore called an activation gate.The other, the h gate, tends to close as Vm becomes lessnegative and hence is called an inactivation gate. Them and h designations were originally employed byHodgkin and Huxley in their mathematical model ofionic currents in nerve ﬁbers.Panel A in Figure 2-9 represents the resting state(phase 4) of a cardiac myocyte. With the cell at rest, Vmis −90 mV and the m gates are closed while the h gatesare wide open. The electrostatic force in Figure 2-9A isa potential difference of 90 mV, and it is representedby the white arrow. The chemical force, based on thedifference in Na+ concentration between the outsideand 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 positivethan the outside) is necessary to counterbalance thechemical, or diffusional, force, according to the Nernstequation for Na+ (Equation 2). Therefore we may rep-resent the net chemical force favoring the inwardmovement of Na+ in Figure 2-9 (dark arrows) asequivalent to a potential of 60 mV. With the cell atrest, the total electrochemical force favoring theinward movement of Na+ is 150 mV (panel A). The mgates are closed, however, and the conductance of theresting cell membrane to Na+ is very low. Hence, theinward Na+ current is negligible.Any process that makes Vm less negative tends toopen the m gates and thereby activates the fast Na+channels so that Na+ enters the cell (Figure 2-9B) viathe chemical and electrostatic forces. Thus, activationof the fast channels is a voltage-dependent phenome-non. The precise potential at which the m gates swingopen is called the threshold potential. The entry ofNa+ into the interior of the cell neutralizes some of the–100–80–60–40–20020408 10 15 20 50 100 150External Na concentration(% of normal)Membranepotential(mV)Peak membranepotentialResting membranepotentialFIGURE 2-7 ■ The concentration of sodium in the externalmedium is a critical determinant of the amplitude of theaction potential in cardiac muscle (upper line) but has rela-tively little inﬂuence on the resting potential (lowerline). (Redrawn from Weidmann S: Elektrophysiologie derHerzmuskelfaser, Bern, 1956, Verlag Hans Huber.)
EXCITATION: THE CARDIAC ACTION POTENTIAL 17negative charges inside the cell and thereby diminishesfurther the transmembrane potential, Vm (Figure2-9B).The rapid opening of the m gates in the fast Na+channels is responsible for the large and abruptincrease in Na+ conductance, gNa, coincident withphase 0 of the action potential (see Figure 2-12). Therapid inﬂux of Na+ accounts for the steep upstroke ofVm during phase 0. The maximal rate of change of Vm(dVm/dt) varies from 100 to 300 V/s in myocardialcells and from 500 to 1000 V/s in Purkinje ﬁbers. Theactual quantity of Na+ that enters the cell is so smalland occurs in such a limited portion of the cell’s vol-ume that the resulting change in the intracellular Na+concentration cannot be measured precisely. Thechemical force remains virtually constant, and onlythe electrostatic force changes throughout the actionpotential. Hence the lengths of the dark arrows inFigure 2-9 remain constant at 60 mV, whereas thewhite arrows change in magnitude and direction.As Na+ enters the cardiac cell during phase 0, itneutralizes the negative charges inside the cell and Vmbecomes less negative. When Vm becomes zero (Figure2-9C), an electrostatic force no longer pulls Na+ intothe cell. As long as the fast Na+ channels are open,however, Na+ continues to enter the cell because of thelarge concentration gradient. This continuation of theinward Na+ current causes the cell interior to becomepositively charged (Figure 2-9D). This reversal of themembrane polarity is the overshoot of the cardiacaction potential. Such a reversal of the electrostaticgradient tends to repel the entry of Na+ (Figure 2-9D).However, as long as the inwardly directed chemicalforces exceed these outwardly directed electrostaticforces, the net ﬂux of Na+ is still inward, although therate of inﬂux is diminished.The inward Na+ current ﬁnally ceases when the h(inactivation) gates close (Figure 2-9E). The opening ofthe m gates occurs very rapidly, in about 0.1 to 0.2 mil-liseconds [ms], whereas the closure of the h gates isϩH3NScTXExtracellularIntracellularCO2ϪϪO2C1 2 3 4 56ϩH3NPP P PPHP␤1 ␣ϪϪϪϪ Ϫ ϪϪ ϪFIGURE 2-8 ■ Schematic structure of a voltage-gated Na+ channel. The α subunit is composed of 4 domains (I-IV), each ofwhich has 6 transmembrane helices; the N and C termini are cytoplasmic. Transmembrane segment 4 is a voltage sensor whoseconformation changes with applied voltage. The 4 domains are arranged around a central pore lined by the extracellular loopsof transmembrane segments 5 and 6. The β2 subunit is shown on the left. P, phosphorylation sites; ScTX, scorpion toxin bind-ing site. (Redrawn from Squire LR, Roberts JL, Spitzer NC, et al: Fundamental neuroscience, ed 2, San Diego, CA, Academic Press, 2002.)
CARDIOVASCULAR PHYSIOLOGY18slower, requiring 10 ms or more. Inactivation of the fastNa+ channels is completed when the h gates close. Theh gates remain closed until the cell has partially repolar-ized during phase 3 (at about time d in Figure 2-1A).From time c to time d, the cell is in its effective refrac-tory period and does not respond to excitation. Thismechanism prevents a sustained, tetanic contraction ofcardiac muscle that would interfere with the normalintermittent pumping action of the heart. A period ofmyocardial relaxation, sufﬁcient to permit the cardiacventricles to ﬁll with venous blood during each cardiaccycle, is as essential to the normal pumping action ofthe heart as is a strong cardiac contraction.About midway through phase 3 (time d in Figure2-1A), the m and h gates in some of the fast Na+ chan-nels resume the states shown in Figure 2-9A. Suchchannels are said to have recovered from inactiva-tion. The cell can begin to respond again to excitation(Figure 2-10). Application of a suprathreshold stimu-lus to a region of normal myocardium during phase 3Na+Na+ 6065 Na+ 600Vm = –65 mV Vm = 0 mVNa+A, During phase 4, the chemical(60 mV) and electrostatic (90 mV)forces favor influx of Na+from theextracellular space. Influx is negligible,however, because the activation (m)gates are closed.B, If Vm is brought to aboutϪ65 V, the m gates begin to swingopen, and Na+begins to enter the cell.This reduces the negative chargeinside the cell. The change in Vm alsoinitiates the closure of inactivation (h)gates, which operate more slowly thanthe m gates.C, The rapid influx of Na+rapidlydecreases the negativity of Vm. AsVm approaches 0, the electrostaticforce attracting Na+into the cell isneutralized. Na+continues to enterthe cell, however, because of thesubstantial concentration gradient,and Vm begins to become positive.D, When Vm is positive by about 20 mV, Na+continues to enter the cell, because the diffusionalforces (60 mV) exceed the opposing electrostaticforces (20 mV). The influx of Na+is slow, however,because the net driving force is small, and many ofthe inactivation gates have already closed.E, When Vm reaches about 30 mV, the hgates have now all closed, and Na+influx ceases.The h gates remain closed until the first half ofrepolarization, and thus the cell is absolutelyrefractory during this entire period. During thesecond half of repolarization, the m and h gatesapproach the state represented by panel A, andthus the cell is relatively refractory.Na+Na+ 6090Vm = –90 mVNa+Na+ 6020Vm = ϩ20 mVNa+Na+ 6030Vm = ϩ30 mVmhm h mhm h m hϪ ϪϪ ϪϪϪϪϪϪϪϪϪϪϪϪ ϪϪ ϪϪϪϪϪϪϪϪϪϪϪϩ ϩϩ ϩϩϩϩϩϩϩϩϩϩϩϩϩϩϩϩϩFIGURE 2-9 ■ The gating of a sodium channel in a cardiac cell membrane during phase 4 (A) and during various stages ofthe action potential upstroke (B to E). The positions of the m and h gates in the fast Na+ channels are shown at the variouslevels of Vm. The electrostatic forces are represented by the white arrows, and the chemical (diffusional) forces by the darkarrows.
EXCITATION: THE CARDIAC ACTION POTENTIAL 19evokes an action potential. As the stimulus is deliveredprogressively later during the course of phase 3, theslopes of the action potential upstrokes and the ampli-tudes of the evoked action potentials progressivelyincrease. Throughout the remainder of phase 3, thecell completes its recovery from inactivation. By time ein Figure 2-1A, the h gates have reopened and the mgates have reclosed in the remaining fast Na+ channels,as shown in Figure 2-9A.Statistical Characteristics of the “Gate” ConceptThe patch-clamp technique has made it possible tomeasure ionic currents through single membranechannels. The individual channels open and closerepeatedly in a random manner. This process isillustrated in Figure 2-11, which shows the currentﬂow through single Na+ channels in a myocardial cell.To the left of the arrow, the membrane potential wasclamped at −85 mV. At the arrow, the potentialwas suddenly changed to −45 mV, at which value itwas held for the remainder of the record.Figure 2-11 indicates that immediately after themembrane potential was made less negative, one Na+channel opened three times in sequence. It remainedopen for about 2 or 3 ms each time and closed forabout 4 or 5 ms between openings. In the open state, itallowed 1.5 pA of current to pass. During the ﬁrst andsecond openings of this channel, a second channel alsoopened, but for periods of only 1 ms. During the brieftimes that the two channels were open simultaneously,the total current was 3 pA. After the ﬁrst channelclosed for the third time, both channels remainedclosed for the rest of the recording, even though themembrane was held constant at −45 mV.The overall change in ionic conductance of theentire cell membrane at any given time reﬂects thenumber of channels that are open at that time. Becausethe individual channels open and close randomly, theoverall membrane conductance represents the statisti-cal probability of the open or closed state of the indi-vidual channels. The temporal characteristics of theactivation process then represent the time course ofthe increasing probability that the speciﬁc channelswill be open, rather than the kinetic characteristics ofthe activation gates in the individual channels. Simi-larly, the temporal characteristics of inactivationreﬂect the time course of the decreasing probabilitythat the channels will be open and not the kinetic char-acteristics of the inactivation gates in the individualchannels.4020020406080100Vm(mV)100 ms+–FIGURE 2-10 ■ The changes in action potential amplitudeand slope of the upstroke as action potentials are initiatedat different stages of the relative refractory period of thepreceding excitation. (Redrawn from Rosen MR, Wit AL, Hoff-man BF: Electrophysiology and pharmacology of cardiac arrhyth-mias. I. Cellular electrophysiology of the mammalian heart. AmHeart J 88:380, 1974.)Channel #1 currentChannel #2 current01.534.5pA10 msFIGURE 2-11 ■ The current ﬂow (in picoamperes) through two individual Na+ channels in a cultured cardiac cell, recordedby the patch-clamping technique. The membrane potential had been held at −85 mV but was suddenly changed to −45mV at the arrow and held at this potential for the remainder of the record. (Redrawn from Cachelin AB, DePeyer JE, KokubunS, et al: Sodium channels in cultured cardiac cells. J Physiol 340:389, 1983.)
CARDIOVASCULAR PHYSIOLOGY20Genesis of Early RepolarizationIn many cardiac cells that have a prominent plateau,phase 1 constitutes an early, brief period of limitedrepolarization between the end of the action potentialupstroke and the beginning of the plateau (Figure2-12). Phase 1 reﬂects the activation of a transientoutward current, ito, mostly carried by K+. Activationof these K+ channels leads to a brief efﬂux of K+ fromthe cell because the interior of the cell is positivelycharged and because the internal K+ concentrationgreatly exceeds the external concentration (see Table2-1). This brief efﬂux of K+ brings about the brief, lim-ited repolarization (phase 1).Phase 1 is prominent in Purkinje ﬁbers (see Figure2-3) and in epicardial ﬁbers from the ventricular myo-cardium (Figure 2-13); it is much less developed inendocardial ﬁbers. When the basic cycle length atwhich the epicardial ﬁbers are stimulated is increasedfrom 300 to 2000 ms, phase 1 becomes more pro-nounced and the action potential duration is increasedsubstantially. The same increase in basic cycle lengthhas no effect on the early portion of the plateau inendocardial ﬁbers, and it has a smaller effect on theaction potential duration than it does in epicardialﬁbers (see Figure 2-13).Genesis of the PlateauDuring the plateau (phase 2) of the action potential,Ca++ enters the cell through calcium channels thatactivate and inactivate much more slowly than do thefast Na+ channels. During phase 2 (see Figure 2-12),this inﬂux of Ca++ is balanced by the efﬂux of an equalamount of K+. The K+ exits through various speciﬁcK+ channels, as described in the next section.INaICa,LINa/CaNav1.5Cav1.2NCX1IK1Ito,1Ito,2IKrIKsDepolarizingRepolarizingVoltageTime12340 mV–0Current CloneSCN5ACACNA1CNCX1GeneKv4.2/4.3Kv1.4/1.7HERGKir2.1/2.2KCND2/3KCNA4Kv4.3 (LQT1) KCNQ1KCNH2KCNJ2FIGURE 2-12 ■ Changes in depolarizing (upper panels) and repolarizing ion currents dur-ing 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 currentsare IK1, Ito and the rapid (IKr) and slow (IKs) delayed rectiﬁer K+ currents. The clones andrespective genes for the principal ionic currents are also tabulated. (Redrawn fromTomaselli G, Marbán E: Electrophysiological remodeling in hypertrophy and heart failure. Cardio-vasc Res 42:270. 1999.)
EXCITATION: THE CARDIAC ACTION POTENTIAL 21Ca++ Conductance during the PlateauThe Ca++ channels are voltage-regulated channels thatare activated as Vm becomes progressively less negativeduring the upstroke of the action potential. Two typesof Ca++ channels (L-type and T-type) have been iden-tiﬁed in cardiac tissues. Some of their important char-acteristics are illustrated in Figure 2-14, which displaysthe Ca++ currents generated by voltage-clamping anisolated atrial myocyte. Note that when Vm is suddenlyincreased to +30 mV from a holding potential of −30mV (lower panel), an inward Ca++ current (denotedby a downward deﬂection) is activated. After theinward current reaches maximum (in the downwarddirection), it returns toward zero very gradually (i.e.,the channels inactivate very slowly). Thus, current thatpasses through these channels is long lasting, and theyhave been designated L-type channels. They are thepredominant type of Ca++ channels in the heart, andthey are activated during the action potential upstrokewhen Vm reaches about −30 mV. The L-type channelsare blocked by Ca++ channel antagonists, such asverapamil, nifedipine, and diltiazem.The T-type (transient) Ca++ channels are much lessabundant in the heart. They are activated at more neg-ative potentials (about −70 mV) than are the L-typechannels. Note in Figure 2-14 (upper panel) that whenVm is suddenly increased to −20 mV from a holdingpotential of −80 mV, a Ca++ current is activated andthen is inactivated very quickly.Opening of the Ca++ channels is reﬂected by anincrease in Ca++ current (ICa,L), that begins during thelater phase of the upstroke of the action potential(Figure 2-15). When the Ca++ channels open, Ca++enters the cell throughout the plateau because theintracellular Ca++ concentration is much less than theextracellular Ca++ concentration (see Table 2-1). TheCa++ that enters the myocardial cell during the plateauis involved in excitation-contraction coupling, asdescribed in Chapter 4.Neurohumoral factors may inﬂuence gCa. An increasein gCa by catecholamines, such as isoproterenol andnorepinephrine, is probably the principal mechanism bywhich catecholamines enhance cardiac muscle contrac-tility. Catecholamines interact with β-adrenergic recep-tors located on cardiac cell membranes. This interactionstimulates the membrane-bound enzyme, adenylylcyclase, which raises the intracellular concentration ofcyclicAMP adenosine monophosphate) (see Figure 4-8).This change enhances the voltage-dependent activationEpicardium Endocardium0−820100 ms50mV2000BCL300BCL3002000FIGURE 2-13 ■ Action potentials recorded from canine epi-cardial and endocardial strips driven at basic cycle lengths(BCLs) of 300 and 2000 ms. (From Litovsky SH, Antzelevitch C:Rate dependence of action potential duration and refractoriness incanine ventricular endocardium differs from that of epicardium: role ofthe transient outward current J Am Coll Cardiol 14:1053, 1989.)–80mV–20mVT currentControl4 MIsoproterenol100 ms0Ϫ50Ϫ100–30mV+30mV0Ϫ1Ϫ2Ϫ3Ϫ4L currentControl4 M IsoproterenoliCa2+(pA)iCa2+(nA)FIGURE 2-14 ■ Effects of isoproterenol on the Ca++ currentsconducted by T-type (upper panel) and L-type (lower panel)Ca++ channels in canine atrial myocytes. Upper panel, Poten-tial changed from −80 to −20 mV; lower panel, potentialchanged from −30 to +30 mV. (Redrawn from Bean BP: Twokinds of calcium channels in canine atrial cells. Differences in kinet-ics, selectivity, and pharmacology. J Gen Physiol 86:1, 1985.)
CARDIOVASCULAR PHYSIOLOGY22of the L-type Ca++ channels in cell membrane (see Figure2-14, lower panel) and thus augments Ca++ inﬂux intothe cells from the interstitial ﬂuid. However, catechol-amines have little effect on the Ca++ current through theT-type channels (see Figure 2-14, upper panel).K+ Conductance during the PlateauDuring the plateau of the action potential, the concen-tration gradient for K+ between the inside and outsideof the cell is virtually the same as it is during phase 4,but the Vm is positive. Therefore the chemical andelectrostatic forces greatly favor the efﬂux of K+ fromthe cell during the plateau (see Figure 2-12). If gK1were the same during the plateau as it is during phase4, the efﬂux of K+ during phase 2 would greatly exceedthe inﬂux of Ca++, and a plateau could not be sus-tained. However, as Vm approaches and attains posi-tive values near the end of phase 0, gK1 suddenlydecreases as does IK1 (see Figure 2-12).The changes in gK1 during the different phases ofthe action potential may be appreciated through anexamination of the current-voltage relationship forthe IK1 channels (the channels that mainly determinegK during phase 4). An example of this relationship inan isolated ventricular myocyte is shown in Figure2-5. Note that the current-voltage curve intersects thevoltage axis at a Vm of about −80 mV. The absence ofionic current ﬂow at the intersection indicates that theelectrostatic forces must have been equal to the chem-ical (diffusional) forces (see Figure 2-4) at this poten-tial. Thus in this isolated ventricular cell, the Nernstequilibrium potential (EK) for K+ was −80 mV; in amyocyte in the intact ventricle, EK is normally about−95 mV.When the membrane potential was clamped at lev-els negative to −80 mV in this isolated cell (see Figure2-5), the electrostatic forces exceeded the chemicalforces and an inward K+ current was induced (asdenoted by the negative values of K+ current over thisrange of voltages). Note also that for Vm more negativethan −80 mV, the curve has a steep slope. Thus whenVm equals or is negative to EK, a small change in Vminduces a substantial change in K+ current; that is, gK1is large. During phase 4, the Vm of a myocardial cell isslightly less negative than EK (see Figure 2-6).When the transmembrane potential of this isolatedmyocyte was clamped at levels less negative than −70 mVThe Ca++ channel antagonists decrease gCa during theaction potential. By reducing the amount of Ca++ thatenters the myocardial cells during phase 2, thesedrugs diminish cardiac contractility and are negativeinotropic agents (see Figure 2-15). These drugs alsodiminish the contraction of the vascular smooth mus-cle by suppressing Ca++ entry caused by depolariza-tion or by neurotransmitters such as norepinephrine,and thereby induce arterial vasodilation. This effectreduces the counterforce (afterload) that opposesthe propulsion of blood from the ventricles into thearterial system, as explained in Chapters 4 and 5.Hence vasodilator drugs, such as the Ca++ channelantagonists, are often referred to as afterload reduc-ing drugs. This ability to diminish the counterforceActionpotentialForcemV20050 msC and 31030CmN0.5050 ms31030FIGURE 2-15 ■ The effects of diltiazem, a Ca++ channelblocking drug, on the action potentials (in millivolts) andisometric contractile forces (in millinewtons) recordedfrom an isolated papillary muscle of a guinea pig. The trac-ings were recorded under control conditions (C) and in thepresence of diltiazem, in concentrations of 3, 10, and 30µmol/L. (Redrawn from Hirth C, Borchard U, Hafner D: Effectsof the calcium antagonist diltiazem on action potentials, slowresponse and force of contraction in different cardiac tissues. J MolCell Cardiol 15:799, 1983.)enables the heart to provide a more adequate cardiacoutput, despite the direct depressant effect that thesedrugs exert on myocardial ﬁbers.
EXCITATION: THE CARDIAC ACTION POTENTIAL 23(see Figure 2-5), the chemical forces exceeded the elec-trostatic forces. Therefore the net K+ currents were out-ward (as denoted by the positive values along thecorresponding section of the Y axis).During phase 4 of the cardiac cycle, the drivingforce for K+ (the difference between Vm and EK)favored the efﬂux of K+, mainly through the iK1 chan-nels. Note that for Vm values positive to −80 mV, thecurve is relatively ﬂat; this is especially pronounced forvalues of Vm positive to −40 mV. A given change involtage causes only a small change in ionic current(i.e., gK1 is small). Thus gK1 is small for outwardlydirected K+ currents but substantial for inwardlydirected K+ currents; that is, the iK1 current is inwardlyrectiﬁed. The rectiﬁcation is most marked over theplateau (phase 2) range of transmembrane potentials(see Figures 2-5 and 2-12). This characteristic preventsexcessive loss of K+ during the prolonged plateau, duringwhich the electrostatic and chemical forces both favor theefﬂux of K+.The delayed rectifier K+ channels, which con-duct the iK current, are also activated at voltagesthat prevail toward the end of phase 0. However,activation proceeds very slowly, over several hun-dreds of milliseconds. Hence activation of thesechannels tends to increase IKr (see next section)slowly and slightly during phase 2. These channelsplay only a minor role during phase 2, but they docontribute to repolarization (phase 3), as describedin the next section. The action potential plateaupersists as long as the efflux of charge carried by cer-tain cations (mainly K+) is balanced by the influx ofcharge carried by other cations (mainly Ca++). Theeffects of altering this balance are demonstrated byadministration of diltiazem, a calcium channelantagonist. Figure 2-15 shows that with increasingconcentrations of diltiazem, the plateau voltagebecomes less positive and the duration of the pla-teau diminishes. Similarly, administration of cer-tain K+ channel antagonists prolongs the actionpotential substantially.Genesis of Final RepolarizationThe process of ﬁnal repolarization (phase 3) starts atthe end of phase 2, when the efﬂux of K+ from the car-diac cell begins to exceed the inﬂux of Ca++. At leastfour outward K+ currents (Ito, IKr, IKs, and IK1)contribute to the rapid repolarization (phase 3) of thecardiac cell (see Figure 2-12).The transient outward current (Ito) not onlyaccounts for the brief, partial repolarization (phase 1),as previously described, but also helps determine theduration of the plateau; hence it also helps initiaterepolarization. For example, the transient outwardcurrent is much more pronounced in atrial than inventricular myocytes. In atrial cells, therefore, the out-ward K+ current exceeds the inward Ca++ current earlyin the plateau, whereas the outward and inward cur-rents remain equal for a much longer time in ventricu-lar myocytes. Hence the plateau of the action potentialis much less pronounced in atrial than in ventricularmyocytes (Figure 2-16).The delayed rectiﬁer K+ currents (IKr and IKs) areactivated near the end of phase 0, but activation is veryslow. Therefore these outward IK currents tend toincrease gradually throughout the plateau. Concur-rently, the Ca++ channels are inactivated after the begin-ning of the plateau, and therefore the inward Ca++current decreases. As the efﬂux of K+ begins to exceedthe inﬂux of Ca++, Vm becomes progressively less posi-tive, and repolarization occurs. Two types of delayedrectiﬁer K+ currents, IK, are present in cardiac myocytes.The distinction is based mainly on the speed of activa-tion. The currents that activate more rapidly are desig-nated IKr, whereas the currents that are activated moreslowly are designated IKs. The action potentials recordedfrom myocytes in the endocardial, central, and epicar-dial regions of the left ventricle differ substantially induration. Figure 2-13 illustrates some of the differencesthat prevail in the epicardial and endocardial layers ofthe ventricle. Such differences are induced, at least inpart, by differences in the distributions of these twotypes of delayed rectifying IK channels.The inwardly rectiﬁed K+ current (iK1) contributessubstantially to the later repolarization phase. As thenet efﬂux of cations causes Vm to become more nega-tive during phase 3, the conductance of the channelsthat carry the iK1 current progressively increases. Thisincrease is reﬂected by the hump that is evident in theﬂat portion of the current-voltage curve at Vm valuesbetween −20 and −80 mV in Figure 2-5. Thus as Vmpasses through this range of values less negative thanEK, the outward K+ current increases and therebyaccelerates repolarization.
CARDIOVASCULAR PHYSIOLOGY24Restoration of Ionic ConcentrationsThe excess Na+ that entered the cell rapidly duringphase 0 and more slowly throughout the action poten-tial is removed from the cell by the action of theenzyme Na+,K+-ATPase. This enzyme ejects Na+ inexchange for the K+ that had exited mainly duringphases 2 and 3.Similarly, most of the excess Ca++ that had enteredthe cell during phase 2 is eliminated by a Na+/Ca++ anti-porter, which exchanges 3 Na+ for 1 Ca++. However, asmall fraction of the Ca++ is eliminated by an adenosinetriphosphate (ATP)–driven Ca++ pump (see Figure 4-8).Ionic Basis of the Slow ResponseFast-response action potentials (see Figure 2-1A) maybe considered to consist of four principal components:an upstroke (phase 0), an early repolarization (phase1), a plateau (phase 2), and a period of ﬁnal repolariza-tion (phase 3). In the slow response (see Figure 2-1,B),phase 0 is much less steep, phase 1 is absent, phase 2 isbrief and not ﬂat, and phase 3 is not separated verydistinctly from phase 2. In the fast response, theupstroke is produced by the inﬂux of Na+ through thefast channels (see Figure 2-12).When the fast Na+ channels are blocked, slowresponses may be generated in the same ﬁbers underACBVentricle100 msecϩ200Ϫ20Ϫ40Ϫ60Ϫ80Ϫ1000Ϫ20ϩ20Ϫ40Ϫ60Ϫ80ϩ200Ϫ20Ϫ40Ϫ60Ϫ80Ϫ100200 msec100 msecAtriumSA node1100022333444FIGURE 2-16 ■ Typical action potentials (in millivolts)recorded from cells in the ventricle (A), sinoatrial (SA) node(B), and atrium (C). Note that the time calibration in B dif-fers from that in A and C. (From Hoffman BF, Craneﬁeld PF:Electrophysiology of the heart, New York, McGraw-Hill, 1960.)CLINICAL BOXThe cardiac action potential is generated by the inter-play among ionic channels whose currents are pro-duced at appropriate times and voltages (see Figure2-12). Long QT syndrome (LQTS) is a condition thatcan lead to cardiac arrhythmias. LQTS can be detectedby a prolonged QT interval on an electrocardiogram.Molecular genetic studies show that mutations ingenes encoding cardiac ion channels are linked to con-genital LQTS. Mutations in KCNQ1, KCNH2, andSCN5A account for most of the inherited forms ofLQTS. Mutations in these genes alter the function ofthe corresponding cardiac ion channel proteins(Kv4.3, hERG, and Nav1.5). Thus, loss-of-functionmutation of the KCNQ1 gene alters the KVLQT1 pro-tein in the Ks channel, resulting in the LQT1 syndrome.A gain-of-function mutation of the SCN5A gene thatproduces the Nav 1.5 protein for the fast Na+ channelunderlies the LQT3 syndrome. Animal and stem cellmodels of LQTS based on hERG channel mutationsshow reduced ionic currents, prolonged action poten-tials, and early afterdepolarizations. Inherited LQTS isrelatively rare, but there is an acquired form of LQTSthat is quite common. Acquired LQTS is due to theblockade of hERG potassium channels by drugs.
EXCITATION: THE CARDIAC ACTION POTENTIAL 25appropriate conditions. The Purkinje ﬁber action poten-tials shown in Figure 2-3 clearly exhibit the two responsetypes. In the control tracing (panel A), a prominentnotch (phase 1) separates the upstroke from the plateau.Action potential A in Figure 2-3 is a typical fast-responseaction potential. In action potentials in panels B to E,progressively larger quantities of tetrodotoxin wereadded to the bathing solution to gradually block the fastNa+ channels. The sharp upstroke becomes progres-sively less prominent in action potentials in panels B toD, and it disappears entirely in panel E. Thus, tetrodo-toxin had a pronounced effect on the steep upstroke andonly a negligible inﬂuence on the plateau. With elimina-tion of the steep upstroke (panel E), the action potentialresembles a typical slow response.Certain cells in the heart, notably those in the SAand AV nodes, are normally slow-response ﬁbers. Insuch ﬁbers, depolarization is achieved by the inwardcurrent of Ca++ through the Ca++ channels. Theseionic events closely resemble those that occur duringthe plateau of fast-response action potentials.CONDUCTION IN CARDIAC FIBERSDEPENDS ON LOCAL CIRCUITCURRENTSThe propagation of an action potential in a cardiacmuscle ﬁber by local circuit currents is similar to theprocess that occurs in nerve and skeletal muscle ﬁbers.In Figure 2-17, consider that the left half of the cardiacﬁber has already been depolarized, whereas the righthalf is still in the resting state. The ﬂuids normally incontact with the external and internal surfaces of themembrane are electrolyte solutions and are good elec-trical conductors. Hence current (in the abstract sense)ﬂows from regions of higher potential to those oflower potential, denoted by the plus and minus signs,respectively. In the external ﬂuid, current ﬂows fromright to left between the active and resting zones, andit ﬂows in the reverse direction intracellularly. In elec-trolyte solutions, current is caused by a movement ofcations in one direction and anions in the oppositedirection. At the cell exterior, for example, cationsﬂow from right to left, and anions from left to right(Figure 2-17). In the cell interior, the opposite migra-tions occur. These local currents tend to depolarize theregion of the resting ﬁbers adjacent to the border. Rep-etition of this process causes propagation of the excita-tion wave along the length of the cardiac ﬁber.For propagation of the impulse from one cell toanother, consider the left half of Figure 2-17 a depolar-ized cell and the right half a cell in the resting state.When the wave of depolarization reaches the end ofthe cell, the impulse is conducted to adjacent cellsthrough gap junctions or nexuses (see Figures 4-2 and4-3). Gap junctions are preferentially located at theends of the cell and are rather sparse along lateral cellborders. Therefore, impulses pass more readily longi-tudinally (isotropic) than laterally from cell to cell(anisotropic). Gap junction channels are composed ofproteins called connexins that form electrical connec-tions between cells. Connexins vary in their composi-tion and in their tissue distribution within the heart.Each cell synthesizes a hemichannel consisting of sixconnexons arranged like barrel staves. The hemichan-nel is transported to the gap junction locus on the cellmembrane, where it docks with a hemichannel froman adjacent cell to form an ion channel. These chan-nels are rather nonselective in their permeability toions and have a low electrical resistance that allowsionic current to pass from one cell to another. Theelectrical resistance of gap junctions is similar to thatof cytoplasm. The ﬂow of charge from cell to cell fol-lows the principles of local circuit currents and there-fore allows intercellular propagation of the impulse.Conduction of the Fast ResponseIn the fast response, the fast Na+ channels are activatedwhen the transmembrane potential is suddenly brought+ + + + + + +− − − − − − −+ + + + + + +− − − − − − −DepolarizedzonePolarizedzone− − − − − − −Propagation+ + + + + + ++ + + + + + +− − − − − − −FIGURE 2-17 ■ The role of local currents in the propagationof a wave of excitation down a cardiac ﬁber.
CARDIOVASCULAR PHYSIOLOGY26from a resting value of about −90 mV to the thresholdvalue of about −70 mV. The inward Na+ current thendepolarizes the cell very rapidly at that site. This por-tion of the ﬁber becomes part of the depolarized zone,and the border is displaced accordingly (to the right inFigure 2-17). The same process then begins at the newborder.At any given point on the ﬁber, the greater theamplitude and the greater the rate of change ofpotential (dVm/dt) of the action potential duringphase 0, the more rapid is the conduction down theﬁber. The amplitude of the action potential equals thedifference in potential between the fully depolarizedand the fully polarized regions of the cell interior (seeFigure 2-17). The magnitude of the local currents isproportional to this potential difference. Becausethese local currents shift the potential of the restingzone toward the threshold value, they are the localstimuli that depolarize the adjacent resting portion ofthe ﬁber to its threshold potential. The greater thepotential difference between the depolarized and polar-ized regions (i.e., the greater the amplitude of theaction potential), the more efﬁcacious are the local stim-uli, and the more rapidly the wave of depolarization ispropagated down the ﬁber.The rate of change of potential (dVm/dt) during phase0 is also an important determinant of the conductionvelocity. The reason can be appreciated by referringagain to Figure 2-17. If the active portion of the ﬁberdepolarized very gradually, the local currents acrossthe border between the depolarized and polarizedregions would be very small. Thus the resting regionadjacent to the active zone would be depolarized veryslowly, and consequently each new section of the ﬁberwould require more time to reach threshold.The level of the resting membrane potential is also animportant determinant of conduction velocity. This fac-tor operates through its inﬂuence on the amplitudeand maximal slope of the action potential. The restingpotential may vary for several reasons: (1) it can bealtered experimentally through varying of [K+]o (seeFigure 2-6); (2) in cardiac ﬁbers that are intrinsicallyautomatic, Vm becomes progressively less negativeduring phase 4 (see Figure 2-16B); and (3) during apremature excitation, repolarization may not havebeen completed when the next excitation arrives (seeFigure 2-10). In general, the less negative the level ofVm, the less is the velocity of impulse propagation,regardless of the reason for the change in Vm.The results of an experiment in which the restingVm of a bundle of Purkinje ﬁbers was varied by alteringthe value of [K+]o are shown in Figure 2-18. When[K+]o was 3 mM (panels A and F), the resting Vm was−82 mV and the slope of phase 0 was steep. At the endof phase 0, the overshoot attained a value of 30 mV.Hence the amplitude of the action potential was 112mV. When [K+]o was increased gradually to 16 mM(panels B to E), the resting Vm became progressivelyless negative. Concomitantly, the amplitudes anddurations of the action potentials and the steepness ofBA CD E FK+ = 3 mM K+ = 7 K+ = 10K+ = 14 K+ = 16 K+ = 30 mV50 ms20 mV0 mVStFIGURE 2-18 ■ The effect of changes in external potassium (K+) concentration on the transmembrane action potentialsrecorded from a Purkinje ﬁber. The ﬁber bundle was stimulated at some distance from the impaled cell, and the stimulusartifact (St) appears as a biphasic spike to the left of the upstroke of the action potential. The time from this artifact to thebeginning of phase 0 is inversely proportional to the conduction velocity. The horizontal lines near the peaks of the actionpotentials denote 0 mV. (From Myerburg RJ, Lazzara R. In Fisch E, editor: Complex electrocardiography, Philadelphia, 1973, FADavis.)
EXCITATION: THE CARDIAC ACTION POTENTIAL 27the upstrokes all diminished. As a consequence, theconduction velocity diminished progressively, as indi-cated by the distances from the stimulus artifacts tothe upstrokes. At the [K+]o levels of 14 and 16 mM(panels D and E), the resting Vm had attained levelssufﬁcient to inactivate all the fast Na+ channels. Theaction potentials in panels D and E are characteristicslow responses, mediated by the inward Ca++ current.When the [K+]o concentration of 3 mM was reestab-lished (panel F), the action potential was again charac-teristic of the normal fast response (as in panel A).Conduction of the Slow ResponseLocal circuits (see Figure 2-17) are also responsible forpropagation of the slow response. However, the char-acteristics of the conduction process differ quantita-tively from those of the fast response. The thresholdpotential is about −40 mV for the slow response, andconduction is much slower than for the fast response.The conduction velocities of the slow responses in theSA and AV nodes are about 0.02 to 0.1 m/s. The fast-response conduction velocities are about 0.3 to 1 m/sfor myocardial cells and 1 to 4 m/s for the specializedconducting ﬁbers in the atria and ventricles. Conduc-tion in slow-response ﬁbers is more likely to be blockedthan conduction in fast-response ﬁbers. Also, impulsesin slow-response ﬁbers cannot be conducted at suchrapid repetition rates.CARDIAC EXCITABILITY DEPENDSON THE ACTIVATION ANDINACTIVATION OF SPECIFICCURRENTSDetailed knowledge of cardiac excitability is essentialbecause of the rapid development of artiﬁcial pacemak-ers and other electrical devices for correcting seriousdisturbances of rhythm. The excitability characteristicsof cardiac cells differ considerably, depending onwhether the action potentials are fast or slow responses.Fast ResponseOnce the fast response has been initiated, the depolar-ized cell is no longer excitable until about the middleof the period of ﬁnal repolarization (see Figures 2-1A,2-10). The interval from the beginning of the actionpotential until the ﬁber is able to conduct anotheraction potential is called the effective refractoryperiod. In the fast response, this period extends fromthe beginning of phase 0 to a point in phase 3 whenrepolarization has reached about −50 mV (time c totime d in Figure 2-1A). At about this value of Vm, somefast channels have recovered sufﬁciently from inacti-vation to permit a feeble response to stimulation.Full excitability is not regained until the cardiacﬁber has been fully repolarized (time e in Figure 2-1A).During period d to e in the ﬁgure, an action potentialmay be evoked, but only when the stimulus is strongerthan one that could elicit a response during phase 4.Period d to e is called the relative refractory period.When a fast response is evoked during the relativerefractory period of a previous excitation, its charac-teristics vary with the membrane potential that existsat the time of stimulation. The nature of this voltagedependency is illustrated in Figure 2-10. As the ﬁber isstimulated later and later in the relative refractoryperiod, the amplitude of the response and the rate ofrise of the upstroke increase progressively. As a conse-quence of the greater amplitude and upstroke slope ofthe evoked response, the propagation velocity increasesas the cell is stimulated later in the relative refractoryCLINICAL BOXMost of the experimentally induced changes in trans-membrane potential shown in Figure 2-18 also takeplace in patients with coronary artery disease. Whenblood ﬂow to a region of the myocardium is dimin-ished, the supply of oxygen and metabolic substratesdelivered to the ischemic tissues is insufﬁcient. TheNa+,K+-ATPase in the membrane of the cardiac myo-cytes requires considerable metabolic energy to main-tain the normal transmembrane exchanges of Na+and K+. When blood ﬂow is inadequate, the activity ofthe Na+,K+-ATPase is impaired, and the ischemicmyocytes gain excess Na+ and lose K+ to the surround-ing interstitial space. Consequently, the K+ concentra-tion in the extracellular ﬂuid surrounding the ischemicmyocytes is elevated, and therefore the myocytes areaffected by the elevated K+ concentration in much thesame way as was the myocyte depicted in Figure 2-18.Such changes may lead to serious aberrations of car-diac rhythm and conduction.
CARDIOVASCULAR PHYSIOLOGY28period. Once the ﬁber is fully repolarized, the responseis constant no matter what time in phase 4 the stimu-lus is applied. By the end of phase 3, the fast Na+ chan-nels recover fully from inactivation after severalmilliseconds in fully repolarized cells. This reﬂects thefact that recovery from inactivation depends on timeas well as voltage.Slow ResponseThe relative refractory period during the slow responseextends well beyond phase 3 (see Figure 2-1B). Evenafter the cell has completely repolarized, it may be dif-ﬁcult to evoke a propagated response for some time.This characteristic, called postrepolarization refrac-toriness, arises from the long time constant for recov-ery from inactivation.Action potentials evoked early in the relative refrac-tory period are small, and the upstrokes are not verysteep (Figure 2-19). The amplitudes and upstrokeslopes gradually increase as action potentials are elic-ited later and later in the relative refractory period.The recovery of full excitability is much slower thanfor the fast response. Impulses that arrive early in therelative refractory period are conducted much moreslowly than those that arrive late in that period. Thelengthy refractory periods also lead to conductionblocks. Even when slow responses recur at a low repe-tition rate, the ﬁber may be able to conduct only a frac-tion of those impulses.Effects of Cycle LengthChanges in cycle length alter the action potentialduration of cardiac cells and thus change their refrac-tory periods. Consequently, the changes in cyclelength are important factors in the initiation or ter-mination of certain dysrhythmias. Changes in actionpotential durations produced by stepwise reductionsin cycle length from 2000 to 200 ms in a Purkinjeﬁber are shown in Figure 2-20. Note that as the cyclelength is diminished, the action potential durationdecreases.This direct correlation between action potentialduration and cycle length is ascribable mainly tochanges in gK that involve the delayed rectiﬁer K+CL = 2000 msAPD = 200 msCL = 630 msAPD = 180 msCL = 400 msAPD = 170 msCL = 250 msAPD = 140 msCL = 200 msAPD = 130 msFIGURE 2-20 ■ The effect of changes in cycle length (CL) onthe action potential duration (APD) of canine Purkinjeﬁbers. (Modiﬁed from Singer D, Ten Eick RE: Aberrancy: electro-physiologic aspects. Am J Cardiol 28:381, 1971.)+200–20–40–60–80–100mV200 msabcFIGURE 2-19 ■ The effects of excitation at various timesafter the initiation of an action potential in a slow-responseﬁber. In this ﬁber, excitation very late in phase 3 (or early inphase 4) induces a small, nonpropagated (local) response(a). Later in phase 4, a propagated response (b) may beelicited; its amplitude is small and the upstroke is not verysteep. This response, which displays postrepolarizationrefractoriness, is conducted very slowly. Still later in phase4, full excitability is regained, and the response (c) displaysits normal characteristics. (Modiﬁed from Singer DH,Baumgarten CM, Ten Eick RE: Cellular electrophysiology of ven-tricular and other dysrhythmias: studies on diseased and ischemicheart. Prog Cardiovasc Dis 24:97, 1981.)
EXCITATION: THE CARDIAC ACTION POTENTIAL 29channels. The iKr current activates slowly, remainsactivated for hundreds of milliseconds before inacti-vation, and is inactivated very slowly. Consequently,as the basic cycle length is diminished, each actionpotential tends to occur earlier in the inactivationperiod of the iKr current initiated by the precedingaction potential. Therefore, the shorter the basic cyclelength, the greater the outward K+ current will beduring phase 2. Hence the action potential durationdiminishes.S U M M A R Y■ The transmembrane action potentials that can berecorded from cardiac myocytes comprise the fol-lowing ﬁve phases (0 to 4):■ Phase 0, upstroke. A suprathreshold stimulusrapidly depolarizes the membrane by activatingthe fast Na+ channels.■ Phase 1, early partial repolarization. Achieved bythe efﬂux of K+ through channels that conductthe transient outward current, Ito.■ Phase 2, plateau. Achieved by a balance betweenthe inﬂux of Ca++ through Ca++ channels and theefﬂux of K+ through several types of K+channels.■ Phase 3, ﬁnal repolarization. Initiated when theefﬂux of K+ exceeds the inﬂux of Ca++. Theresulting partial repolarization rapidly increasesthe K+ conductance and rapidly restores fullrepolarization.■ Phase 4, resting potential. The transmembranepotential of the fully repolarized cell is deter-mined mainly by the conductance of the cellmembrane to K+.■ Two principal types of action potentials may berecorded from cardiac cells:■ Fast-response action potentials may be recordedfrom atrial and ventricular myocardial ﬁbers andfrom specialized conducting (Purkinje) ﬁbers. Theaction potential is characterized by a large-ampli-tude, steep upstroke, which is produced by the acti-vation of the fast Na+ channels. The effectiverefractory period begins at the upstroke of theaction potential and persists until about midwaythrough phase 3.■ Slow-response action potentials may be recordedfrom normal sinoatrial (SA) and atrioventricular(AV) nodal cells and from abnormal myocardialcells that have been partially depolarized. The actionpotential is characterized by a less negative restingpotential, a smaller amplitude, and a less steepupstroke than is the fast-response action potential.The upstroke is produced by the activation of Ca++channel.ADDITIONAL READINGCarmeliet E: Cardiac ionic currents and acute ischemia: from chan-nels to arrhythmias, Physiol Rev 79:917, 1999.Grant AO: Cardiac Ion Channels, Circ Arrhythmia Electrophysiol2:185, 2009.Noble D: Modeling the heart–from genes to cells to the whole organ,Science 295:1678, 2002.Priori SG: The ﬁfteen years of discoveries that shaped molecularelectrophysiology: time for appraisal, Circ Res 107:451, 2010.Sanguinetti MC: HERG1 channelopathies, Pﬂügers Arch. 460:265,2010.ten Tusscher KH, Noble D, Noble PJ, Panﬁlov AV: A model forhuman ventricular tissue, Am J Physiol 286:H1573, 2004.Zipes DP, Jalife J: Cardiac electrophysiology: from cell to bedside, ed 4,Philadelphia, 2004, WB Saunders.C A S E 2 - 1HISTORYA 63-year-old man suddenly felt a crushing painbeneath his sternum. He became weak, he wassweating profusely, and he noticed his heart wasbeating rapidly. He called his physician, who madethe diagnosis of myocardial infarction. The testsmade at the hospital conﬁrmed his doctor’s suspi-cion that the patient had suffered a “heart attack”;that is, a major coronary artery to the left ventriclehad suddenly become occluded. An electrocardio-gram indicated that the SA node was the source of
CARDIOVASCULAR PHYSIOLOGY30the rapid heart rate. Two hours after admission tothe hospital, the patient suddenly became muchweaker. His arterial pulse rate was only about 40beats/min. An electrocardiogram at this timerevealed that the atrial rate was about 90 beats/minand that conduction through the AV junction wascompletely blocked, undoubtedly because the infarctaffected the AV conduction system. Electrodes of anartiﬁcial pacemaker were inserted into the patient’sright ventricle, and the ventricle was paced at a fre-quency of 75 beats/min. The patient felt strongerand more comfortable almost immediately.QUESTIONS1. Soon after coronary artery occlusion, theinterstitial ﬂuid K+ concentration rosesubstantially in the ﬂow-deprived region. Inthis region, the high extracellular K+concentration:a. increased the propagation velocity of themyocardial action potentials.b. decreased the postrepolarizationrefractoriness of the myocardial cells.c. changed the resting (phase 4)transmembrane potential to a less negativevalue.d. diminished the automaticity of themyocardial cells.e. decreased the likelihood of reentrydysrhythmias.2. The attending physician was alerted to thepossibility of an arrhythmia because the highextracellular K+ concentration could:a. directly increase the entry of Na+ throughfast Na+ channels.b. hyperpolarize the resting membrane.c. increase the rate of slow diastolicdepolarization in SA node cells.d. slow conduction velocity by reducing Na+channel availability.e. decrease the release of norepinephrine fromcardiac sympathetic nerves.3. The most likely mechanism responsible for thepatient’s arterial pulse rate of about 40 beats/min after impulse conduction through the AVjunction was blocked is:a. excitation of the ventricles via an AV bypasstract.b. conversion of ventricular myocardial ﬁbersto automatic cells.c. ﬁring of ventricular ectopic cells that havethe same electrophysiologicalcharacteristics as SA node cells.d ﬁring of automatic cells (Purkinje ﬁbers) inthe specialized conduction system of theventricles.e. excitation of ventricular cells by therhythmic activity in the autonomicneurons that innervate the heart.4. While the heart was being paced, thecardiologist discontinued ventricular pacingperiodically to test the patient’s cardiacstatus. The cardiologist found that theventricles did not begin beating spontaneouslyuntil about 5 to 10 s after cessation of pacing,because the preceding period of pacing led to:a. overdrive suppression of the automatic cellsin the ventricles.b. release of norepinephrine from the cardiacsympathetic nerves.c. release of neuropeptide Y from the cardiacsympathetic nerves.d. fatigue of the ventricular myocytes.e. release of acetylcholine from the cardiacparasympathetic nerves.