Ion Movement at Sa Node Funny Membrane Potential

Cardiac Action Potential

Principles of Electrophysiology

Lee Goldman MD , in Goldman-Cecil Medicine , 2020

The Cardiac Action Potential

The cardiac action potential ( Fig. 55-1) is a recording of a cell's membrane potential,V_m, versus time. During each cardiac cycle, ions move back and forth across the cardiomyocyte cell membrane, thereby changingV_m. The cardiac action potential, which reflects the integrated behavior of numerous individual ionic currents, is largely dominated by the movement of Na⁺, Ca²⁺, and K⁺ ions. These ions traverse the cell membrane through ion-selective pores formed by assemblies of integral membrane-spanning proteins and accessory proteins. The behavior of these ionic pathways is highly regulated, and permeation of specific ions is influenced by multiple factors, the most prominent of which are changes in membrane potential (i.e., voltage gating), ligand binding, second messengers such as cyclic adenosine monophosphate, and post-translational modification. Channel function and, by extension, action potential behavior are dynamically tuned in response to normal physiologic factors, especially heart rate. However, a number of pathologic stressors influence channel activity, including acquired syndromes that are associated with cardiac hypertrophy and failure, as well as an ever-growing number of congenital diseases. Regardless of the underlying pathology, the effects on action potential behavior may trigger arrhythmic activity.

The cardiac action potential is divided into phases, each reflecting the major ionic movements that take place. In working cardiomyocytes, such as ventricular or atrial myocytes, theresting membrane potential during diastole, or phase 4 of the cardiac action potential, is determined by the baseline ionic and charge gradients that exist across the sarcolemmal membrane. These gradients are generated by pumps and transporters, the most important of which is the Na⁺, K⁺-ATPase. This energy-requiring electrogenic pump, which is the major target of ouabain-like compounds such as digoxin, extrudes three Na⁺ ions from the intracellular compartment in exchange for two K⁺ ions, thereby resulting in directionally opposite gradients of Na⁺ ions (outside > inside) and K⁺ ions (inside > outside). Under resting conditions, a subset of membrane channels highly permeable to K⁺ is open, but those that allow for the passage of other ions such as Na⁺ or Ca²⁺ are only minimally permeable. As a consequence, the concentration gradient promotes the movement of potassium ions from inside to outside of the cell, until the resulting excess of negative charge within the cell balances the diffusional forces and an electrochemical equilibrium is established. The equilibrium potential for a given ion is calculated by theNernst equation, where E_eq is the equilibrium potential, R is the universal gas constant, T is the absolute temperature, z is the valence of the ionic species, and F is Faraday constant:

$E_{eq}=\frac{RT}{zF}ln\left(\frac{{\left[X\right]}_{out}}{{\left[X\right]}_{in}}\right)$

If the cell membrane wereonly permeable to K⁺ ions, at the measured concentrations of intracellular and extracellular K⁺, the resting membrane potential would be approximately −100 mV. However, because of the slight but measurable permeability to other ionic species, which have Nernst potentials that are less negative than that for K⁺, the actual resting membrane potential in a typical ventricular cardiac myocyte is closer to −85 mV.

ADME-Tox Approaches

A.M. Aronov , in Comprehensive Medicinal Chemistry II, 2007

5.40.2.1 QT Interval and QT Prolongation

Cardiac action potential consists of four distinct phases ( Figure 2a). In phase 0, upstroke occurs due to rapid transient influx of Na⁺. Later, Na⁺ channels are inactivated, combined with a transient efflux of K⁺. In phase 2, also known as the plateau phase, the efflux of K⁺ and the influx of Ca²⁺ are counterbalanced. At the end of the plateau, sustained repolarization occurs due to K⁺ efflux via the delayed rectifier K⁺ channels exceeding Ca²⁺ influx; this constitutes phase 3 of the action potential. Finally, as part of phase 4, resting potential in myocytes is maintained.

Figure 2. Cardiac action potential. (a) Voltage changes in the heart as a function of changes in ion currents into and out of the cell. (b) Schematic of an ECG tracing. Parameters derived from the ECG are depicted. QT interval is determined as the length of time separating the beginning of the QRS complex and the end of the T wave.

In the clinical setting, the QT interval is measured from the beginning of the QRS complex to the end of the T wave (Figure 2b). The QRS complex of the electrocardiogram corresponds to the action potential depolarization, while the T wave is associated with ventricular repolarization. Torsades de pointes is associated with the twisting of the QRS complex around the isoelectric line on the electrocardiogram. Since QT interval depends to a large degree on the heart rate, it is typically reported as QTc, a value normalized for a heart rate of 60   bpm. Bazzett's formula ²¹ is frequently used to introduce the heart rate correction. For reasons that are as yet unknown, QTc in adult females is about 20   ms longer than that in males. The normal limits of QTc in adults are 430   ms in males and 450   ms in females. ¹³ An increase of up to 20   ms is considered borderline, while longer QTc values correspond to prolonged QT interval.

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Mechanisms of Cardiac Arrhythmias

Douglas P. Zipes MD , in Braunwald's Heart Disease: A Textbook of Cardiovascular Medicine , 2019

Phases of the Cardiac Action Potential

The cardiac transmembrane action potential consists of five phases:phase 0, upstroke or rapid depolarization;phase 1, early rapid repolarization;phase 2, plateau;phase 3, final rapid repolarization; andphase 4, resting membrane potential and diastolic depolarization ( Fig. 34.2 and eFig. 34.1 ). These phases are the result of passive ion fluxes moving down their electrochemical gradients established by active ion pumps and exchange mechanisms. Each ion moves primarily through its own ion-specific channel. The following discussion explains the electrogenesis of each of these phases.

EFIGURE 34.1. Demonstration of action potentials recorded during impalement of a cardiac cell.Upper row, Shown are a cell (circle), two microelectrodes, and stages during impalement of the cell and its activation and recovery. Both microelectrodes are extracellular (A), and no difference in potential exists between them (0 potential). The environment inside the cell is negative, and the outside is positive, because the cell is polarized. One microelectrode has pierced the cell membrane (B) to record the intracellular resting membrane potential, which is −90 mV with respect to the outside of the cell. The cell has depolarized (C), and the upstroke of the action potential is recorded. At its peak voltage, the inside of the cell is approximately +30 mV with respect to the outside of the cell. The repolarization phase (D) is shown, with the membrane returning to its former resting potential (E).

General Considerations.

Ionic fluxes regulate membrane potential in cardiac myocytes in the following fashion. When only one type of ion channel opens, assuming that this channel is perfectly selective for that ion, the membrane potential of the entire cell would equal the Nernst potential of the permeant ion. By solving the Nernst equation for the four major ions across the plasma membrane, the following equilibrium potentials are obtained: sodium, +60 mV; potassium, −94 mV; calcium, +129 mV; and chloride, −83 to −36 mV ( Table 34.2 ). Therefore, if K⁺-selective channels open, such as the inwardly rectifying K⁺ (Kir) channel (see later), the membrane potential approaches E_K (−94 mV). If Na⁺-selective channels open, the transmembrane potential becomes E_Na (+60 mV). A quiescent cardiac myocyte (phase 4) has many more open potassium than sodium channels, and the cell's transmembrane potential is close to E_K. When two or more types of ion channels open simultaneously, each channel moves the membrane potential to the equilibrium potential of their respective permeant ions. The contribution of each ion type to the overall membrane potential at any given moment is determined by the instantaneous permeability of the plasma membrane to that ion. For example, deviation of the measured resting membrane potential from E_K (see Table 34.2 ) would predict that other ion types with equilibrium potentials positive to E_K are contributing to the resting membrane potential in cardiac myocytes. If it is assumed that Na⁺, K⁺, and Cl⁻ are the permeant ions at resting potential, their individual contributions to the resting membrane potential (V) can be quantified by the Goldman-Hodgkin-Katz (GHK) voltage equation:

$\mathrm{V}=\left(\text{RT}/\mathrm{F}\right)\ln [({\mathrm{P}}_{\mathrm{K}}{\left[\text{Na}\right]}_{\mathrm{o}}+{\mathrm{P}}_{\text{Cl}}{\left[\text{Cl}\right]}_{\mathrm{i}})/{\mathrm{P}}_{\mathrm{K}}{\left[\mathrm{K}\right]}_{\mathrm{i}}+{\mathrm{P}}_{\text{Na}}[\text{Na}]{\mathrm{P}}_{\text{Cl}}{\left[\text{Cl}\right]}_{\mathrm{o}}$

where the symbols have the meanings outlined previously. With only one permeant ion, V approximates the Nernst potential for that ion. With several permeant ion types, V is a weighted mean of all the Nernst potentials.

Resting Membrane Potential.

The intracellular potential during electrical quiescence in diastole is −50 to −95 mV, depending on the type of cell ( Table 34.2 ). Therefore the inside of the cell is 50 to 95 mV negative relative to the outside of the cell because of the transmembrane gradients of ions such as K⁺, Na⁺, and Cl⁻.

Because cardiac myocytes have an abundance of open K⁺ channels at rest, the cardiac transmembrane potential (in phase 4) is close to E_K. Outward potassium current through open, inwardly rectifying K⁺ channels (I_K1) under normal conditions contributes to the resting membrane potential mainly in atrial and ventricular myocytes, as well as in Purkinje cells. Deviation of the resting membrane potential from E_K is the result of movement of ions with an equilibrium potential greater than the E_K, for example, Cl⁻ efflux through activated chloride channels, such as I_Cl.cAMP, I_Cl.Ca, and I_Cl.swell. Calcium does not contribute directly to the resting membrane potential, but changes in intracellular free calcium concentration [Ca²⁺]_i can affect other membrane conductance values. For example, an increase in sarcoplasmic reticulum (SR) Ca²⁺ load can cause spontaneous intracellular Ca²⁺ waves, which in turn activate the Ca²⁺ -dependent chloride conductance I_Cl.Ca and thereby lead to spontaneous transient inward currents and concomitant membrane depolarization. Increases in [Ca²⁺]_i can also stimulate the Na⁺/Ca²⁺ exchanger I_Na/Ca. This protein exchanges three Na⁺ ions for one Ca²⁺ ion and thus generates a current; the direction depends on the [Na⁺] and [Ca²⁺] on the two sides of the membrane and the transmembrane potential difference (seeElectrogenic Transporters). At the resting membrane potential and during a spontaneous SR Ca²⁺-release event, this exchanger would generate a net Na⁺ influx, possibly causing transient membrane depolarization. ² Another transporter, the Na-K pump, electrogenically pumps Na⁺ out of the cell and simultaneously pumps K⁺ into the cell (three Na⁺ outward and two K⁺ inward) against their respective chemical gradients, keeping the intracellular K⁺ concentration high and the intracellular Na⁺ concentration low. The rate of Na⁺-K⁺ pumping to maintain the same ionic gradients must increase as the heart rate increases because the cell gains a small amount of Na⁺ and loses a small amount of K⁺ with each depolarization. Cardiac glycoside block of Na⁺,K⁺-ATPase increases contractility through an increase in intracellular Na⁺ concentration [Na⁺]_i, which in turn reduces Ca²⁺ extrusion through the Na⁺/Ca²⁺ exchanger and thereby increases myocyte contractility. ³

Phase 0: Upstroke or Rapid Depolarization.

A stimulus delivered to excitable tissues can evoke an action potential characterized by a sudden change in voltage caused by transient depolarization followed by repolarization. The action potential is conducted throughout the heart and is responsible for initiating each heartbeat. Electrical changes in the action potential follow a relatively fixed time and voltage relationship that differs according to specific cell types ( Fig. 34.3 ). In neurons, the entire process takes several milliseconds, whereas action potentials in human cardiac fibers last several hundred milliseconds. Normally, the action potential is independent of the size of the depolarizing stimulus if the latter exceeds a certain threshold potential. Small, subthreshold depolarizing stimuli depolarize the membrane in proportion to the strength of the stimulus. However, when the stimulus is sufficiently intense to reduce membrane potential to a threshold value in the range of −70 to −65 mV for normal Purkinje fibers, an "all-or-none" response results. More intense depolarizing stimuli do not produce larger action potential responses; in contrast, hyperpolarizing pulses, or stimuli that render the membrane potential more negative, elicit a response proportional to the strength of the stimulus.

Mechanism of Phase 0.

The upstroke of the cardiac action potential in atrial and ventricular muscle and His-Purkinje fibers is the result of a sudden increase in membrane conductance of Na ⁺. An externally applied stimulus or a spontaneously generated local membrane circuit current in advance of a propagating action potential depolarizes a sufficiently large area of membrane at an adequately rapid rate to open the Na⁺ channels and depolarize the membrane further. When the stimulus activates enough Na⁺ channels, Na⁺ ions enter the cell down their electrochemical gradient. The excited membrane no longer behaves like a K⁺ electrode, that is, exclusively permeable to K⁺, but more closely approximates an Na⁺ electrode, and the membrane voltage moves toward the Na⁺ equilibrium potential (+60 mV).

The rate at which depolarization occurs during phase 0, that is, the maximum rate of change in voltage over time, is indicated by the expression dV/dt_max or V̇max (see Table 34.2 ), which is an approximation of the rate and magnitude of Na⁺ entry into the cell and a determinant of conduction velocity for the propagated action potential. The transient increase in sodium conductance lasts 1 to 2 milliseconds. The action potential, or more properly the Na⁺ current (I_Na), is said to be regenerative; that is, intracellular movement of a little Na⁺ depolarizes the membrane more, which increases conductance of Na⁺ more and allows more Na⁺ to enter, and so on. As this process is occurring, however, [Na⁺]_i and positive intracellular charges increase and reduce the driving force for Na⁺ flux into the cell. When the equilibrium potential for Na⁺ (E_Na) is reached, the driving force acting on the ion to enter the cell balances the driving force acting on the ion to exit the cell, and no current flows. Importantly, Na⁺ conductance is time dependent, so when the membrane spends some time at voltages less negative than the resting potential, Na⁺ conductance decreases (inactivation). Therefore an intervention that reduces membrane potential for a time (acute myocardial ischemia), but not to threshold, partially inactivates Na⁺ channels, and if the threshold is now achieved, the magnitude and rate of Na⁺ influx are reduced, which causes conduction velocity to slow.

In cardiac Purkinje fibers, sinoatrial cells, and to a lesser extent, ventricular muscle, different populations of Na⁺ channels exist: the tetrodotoxin (TTX)-sensitive, neuronal Na⁺ channel isoforms and the TTX-resistant Nav1.5 isoform, the latter being the predominant isoform in cardiac muscle. ⁴ Although the precise roles of TTX-sensitive Na⁺ channels in ventricular or atrial cardiomyocytes have not been defined, these channels may be important modulators of sinoatrial node pacemaking, Purkinje myocyte action potential duration, and in arrhythmia production in some situations. ⁵ Neuronal Nav channels in the heart have been identified as regulators of contractility. ⁶

Normal atrial and ventricular muscle cells and fibers in the His-Purkinje system exhibit action potentials with very rapid, large-amplitude upstrokes calledfast responses. Action potentials in the normal sinoatrial (SA) and atrioventricular (AV) nodes and many types of diseased tissue have very slow, reduced-amplitude upstrokes and are calledslow responses (see Table 34.1 and Figs. 34.2 and 34.3 ). Upstrokes of slow responses are mediated by a slow inward, predominantly L-type voltage-gated (Cav) Ca²⁺ current (I_Ca.L) rather than by the fast inward I_Na and are referred to asslow response potentials because the time required for activation and inactivation of I_Ca.L is approximately an order of magnitude slower than that for the fast I_Na. The recovery of slow responses is delayed because of slow recovery of I_Ca,L from inactivation. Recovery of I_Ca,L slow-response channel requires establishment of the maximal diastolic potential (i.e., is voltage dependent) and more time before the channel can be activated again (i.e., time dependent), a phenomenon termedpostrepolarization refractoriness. Moreover, calcium entry and [Ca²⁺]_i promote inactivation and delay recovery of slow-response channels.

The prolonged time for reactivation of I_Ca.L probably accounts for the fact that SA and AV nodal cells remain refractory longer than the time that it takes for full voltage repolarization to occur. Thus, premature stimulation immediately after the membrane potential reaches full repolarization leads to action potentials with reduced amplitudes and upstroke velocities. Therefore, slow conduction and prolonged refractoriness are characteristic features of nodal cells. These cells also have a reduced "safety factor for conduction," which means that the stimulating efficacy of the propagating impulse is low, and conduction block occurs easily. The electrophysiologic changes accompanying acute myocardial ischemia may represent a depressed form of a fast response in the center of the ischemic zone and a slow response in the border area.

The threshold for activation of I_Ca.L is about −30 to −40 mV. In fibers of the fast-response type, I_Ca.L is normally activated during phase 0 by the regenerative depolarization caused by the fast I_Na. Current flows through both fast and slow channels during the latter part of the action potential upstroke. However, I_Ca.L is much smaller than the peak I_Na and therefore contributes little to the action potential until the fast I_Na is inactivated after completion of phase 0. Thus, I_Ca.L affects mainly the plateau of action potentials recorded in atrial and ventricular muscle and His-Purkinje fibers. In addition, I_Ca.L may play a prominent role in partially depolarized cells in which fast I_Na has been inactivated, if conditions are appropriate for slow-channel activation.

Ca²⁺ entry through activated L-type Cav channels triggers release of Ca²⁺ from SR stores and is an essential component of cardiac excitation-contraction coupling in atrial and ventricular myocardium (see Chapter 22 ). L-type Cav channels are expressed in SA and AV nodal cells, where they play a role in controlling automaticity and action potential propagation, respectively. Although T-type Cav channels have not been detected in human myocardium, experimental evidence in animals has suggested that these channels play an important role in determining SA node automaticity and AV nodal conduction. ⁷

Other significant differences exist between the fast and slow channels. Drugs that elevate cyclic adenosine monophosphate (cAMP) levels, such as beta-adrenoceptor agonists, phosphodiesterase inhibitors such as theophylline, and the lipid-soluble derivative of cAMP, dibutyryl cAMP, increase I_Ca.L. Although Nav channels are sensitive to increases in cAMP, the net effect (decrease versus increase) appears to be species and condition dependent. Acetylcholine reduces I_Ca.L by decreasing adenylate cyclase activity. However, acetylcholine stimulates the accumulation of cyclic guanosine monophosphate (cGMP). cGMP has negligible effects on basal I_Ca.L but decreases the I_Ca.L levels that have been elevated by beta-adrenoceptor agonists. This effect is mediated by cAMP hydrolysis through a cGMP-stimulated cyclic nucleotide phosphodiesterase.

Fast and slow channels can be differentiated on the basis of their pharmacologic sensitivity. Calcium channel antagonists that block the slow channel with a fair degree of specificity include verapamil, nifedipine, diltiazem, and D-600 (a methoxy derivative of verapamil). Antiarrhythmic agents such as lidocaine, quinidine, procainamide, and disopyramide affect the fast channel and not the slow channel (see Chapter 36 ).

Phase 1: Early Rapid Repolarization.

Following phase 0, the membrane repolarizes rapidly and transiently to almost 0 mV (early notch), partly because of inactivation of I_Na and concomitant activation of several outward currents.

The 4-aminopyridine–sensitive transient outward K⁺ current, commonly termed I_to (or I_to1), is turned on rapidly by depolarization and then rapidly inactivates. Both the density and the recovery of I_to from inactivation exhibit transmural gradients in the left and right ventricular free wall, with the density decreasing and reactivation becoming progressively prolonged from epicardium to endocardium. Transmural differences in the expression of KChIP2, the auxiliary subunit to Kv4.3 pore-forming alpha subunits, may also contribute to the transmural gradient in I_to properties and densities in the human heart. ⁸ This gradient gives rise to regional differences in action potential shape, with increasingly slower phase 1 restitution kinetics and diminution of the notch along the transmural axis ( eFig. 34.2 ).

EFIGURE 34.2. Action potential recordings demonstrating differences in the action potential shape of human ventricular myocytes of subepicardial(A) and subendocardial(B) origin. Subepicardial myocytes present a prominent notch during phase 1 repolarization of the action potential, most likely caused by a larger I_to in these cells. The notch is absent in subendocardial cells. The peak plateau potential is higher in subendocardial than in subepicardial myocytes, and the action potential duration tends to be shorter in subepicardial cells.C, Transmembrane action potential in a human ventricular cardiomyocyte from a failing heart. Note loss of the prominent phase 1 notch and delayed repolarization. Recording temperature = 35°C;V_m, membrane potential.

(A, B, From Näbauer M et al. Regional differences in current density and rate-dependent properties of the transient outward current in subepicardial and subendocardial myocytes of human left ventricle. Circulation 1996;93:168;C, from Priebe L, Beuckelmann DJ. Simulation studies of cellular electrical properties in heart failure. Circ Res 1998;82:1206.)

These regional differences might create transmural voltage gradients, thereby increasing dispersion of repolarization, a putative arrhythmogenic factor (Brugada syndrome;see Chapters 33 and 39 ). However, elimination of the physiologic repolarization gradient appears to be similarly arrhythmogenic. Downregulation of I_to is at least partially responsible for slowing of phase 1 repolarization in failing human myocytes. Studies have demonstrated that these changes in the phase 1 notch of the cardiac action potential cause a reduction in the kinetics and peak amplitude of the action potential–evoked intracellular Ca ²⁺ transient because of failed recruitment and synchronization of SR Ca²⁺ release through I_Ca.L ( eFig. 34.3 ). Thus, modulation of I_to appears to play a significant physiologic role in controlling cardiac excitation-contraction coupling, and it remains to be determined whether transmural differences in phase 1 repolarization translate into similar differences in regional contractility.

EFIGURE 34.3. Diminution of phase 1 amplitude ("notch") causes asynchronous sarcoplasmic reticulum (SR) Ca²⁺ release. Normal cardiomyocytes were voltage-clamped, with action potential profiles having a normal or heart failure wave shape(top), and local changes in intracellular calcium were recorded simultaneously. When the myocyte was clamped with a normal action potential profile having the early phase 1 repolarization notch(left), there was uniform Ca²⁺ release, reflected in the rapid and synchronous increase in fluorescence. However, when a congestive heart failure action potential profile without early rapid phase 1 repolarization was used(right), Ca²⁺ release was dyssynchronous. This dyssynchrony causes slowing in the rate of rise of the Ca²⁺ transient and loss of spatial and temporal release uniformity. F/F_0, Fluorescence of the Ca²⁺ indicator normalized to its baseline fluorescence.

(From Harris DM et al. Alterations in early action potential repolarization causes localized failure of sarcoplasmic reticulum Ca²⁺ release. Circ Res 2005;96:543. By permission of the American Heart Association.)

The 4-aminopyridine–resistant, Ca²⁺ -activated chloride current I_Cl.Ca (or I_to2) also contributes a significant outward current during phase 1 repolarization. ¹ This current is activated by the action potential–evoked intracellular Ca²⁺ transient. Therefore, interventions that augment the amplitude of the Ca²⁺ transient associated with the twitch (e.g., beta-adrenergic receptor stimulation) also enhance outward I_Cl.Ca. It is not currently known whether human cardiac myocytes express Ca²⁺-activated chloride channels. Other, time-independent chloride currents may also play a role in determining the time course of early repolarization, such as the cAMP- or swelling-activated chloride conductances I_Cl.cAMP and I_Cl.swell.

A third current contributing to early repolarization is outward Na⁺ movement through the Na⁺/Ca²⁺ exchanger operating in reverse mode. Sometimes, a transient depolarization follows phase 1 repolarization altering the initial voltage of the plateau (see eFig. 34.2 ).

Phase 2: Plateau.

During the plateau phase, which may last several hundred milliseconds, membrane conductance of all ions falls to rather low values; this is a time of high membrane resistance. Less change in current is required near plateau voltages than near resting potential levels to produce the same changes in transmembrane potential. The plateau is maintained by competition between the outward current carried by K⁺ and Cl⁻ ions and the inward current carried by Ca²⁺ moving through I_Ca,L and Na⁺ being exchanged for internal Ca²⁺ by the Na⁺/Ca²⁺ exchanger operating in forward mode. After depolarization, I_K1 conductance falls to plateau levels as a result of inward rectification, despite the large electrochemical driving force on K⁺ ions.

Several potassium currents are activated during the plateau phase, including the rapid (I_Kr) and slow (I_Ks) delayed rectifier currents (seeVoltage-Gated K⁺ Channels). The mechanism underlying rectification of the rapid component of the delayed rectifier K⁺ current (I_Kr) in cardiac cells is rapid inactivation that occurs during depolarizing pulses. More I_Kr channels enter the inactivated state with stronger depolarizations, thereby causing inward rectification. This fast inactivation mechanism is sensitive to changes in extracellular K⁺ in the physiologic range, with inactivation being more accentuated at low extracellular K⁺ concentrations. Thus, hypokalemia would decrease outward I_Kr, thereby prolonging the action potential duration (APD).

Outward K⁺ movement carried by I_Ks also contributes to plateau duration. Mutations in theKvLQT1 subunit, which in combination with the I_Ks ancillary subunit (KCNE1 encoding minK) reconstitutes the cardiac I_Ks current, are associated with abnormally prolonged ventricular repolarization (LQTS type 1;see Chapters 33 and 39 ). Although I_Ks activates slowly compared to the APD, it is only slowly inactivated. Therefore, increases in heart rate can cause this activation to accumulate during successive depolarizations, increasing K⁺ currents that are active during the plateau of the action potential and thus shortening the APD appropriately at higher heart rates.

In conditions of reduced intracellular adenosine triphosphate (ATP) concentration (e.g., hypoxia, ischemia), K⁺ efflux through activated K_ATP channels is enhanced, thereby shortening the plateau phase of the action potential. Other ionic mechanisms that control plateau potential and duration include the kinetics of inactivation of the L-type Ca²⁺ current. Reduced efficiency of intracellular free Ca²⁺ in inducing Ca²⁺-dependent inactivation, such as in myocytes from hypertrophic hearts, can result in delayed repolarization. Steady-state components of both I_Na and I_Ca.L (window currents) also shape the plateau phase. Na⁺,K⁺ -ATPase generates a net outward current by electrogenic ion exchange. Noninactivating chloride currents, such as I_Cl.swell and I_Cl.cAMP, may produce significant outward currents during the plateau phase under certain conditions, thereby significantly shortening the APD. A nonselective, swelling-induced cation current has been shown to cause prolongation of action potentials in myocytes from failing ventricles. ¹

Phase 3: Final Rapid Repolarization.

Repolarization of the terminal portion of the action potential proceeds rapidly in part because of two currents: time-dependent inactivation of I_CaL, with a decrease in the intracellular movement of positive charges, and activation of repolarizing K⁺ currents, including I_Ks and I_Kr and the inwardly rectifying K⁺ currents I_K1 and I_KACh, which all cause an increase in the movement of positive charges out of the cell. The net membrane current becomes more outward, and the membrane potential moves to the resting potential. A small-conductance Ca²⁺ -activated K⁺ current, I_KCa, expressed in human atrial myocytes, controls the time course of phase 3 repolarization. ⁹

Loss-of-function mutations in the human ether-a-go-go–related or hERG gene (KCNH2), which encodes the pore-forming subunit of I_Kr, prolong phase 3 repolarization, thereby predisposing to the development of torsades de pointes. Macrolide antibiotics such as erythromycin, antihistamines such as terfenadine, several neurologically active agents, and antifungal drugs such as ketoconazole inhibit I_Kr and have been implicated in acquired forms of LQTS (see Chapters 33 and 39 ). Similarly, mutations inKVLQT1, which encodes the pore-forming subunit of I_Ks, will prolong repolarization and predispose to lethal ventricular arrhythmias. A decrease in I_K1 activity, as is the case in left ventricular myocytes from failing hearts, causes prolongation of the action potential by slowing of phase 3 repolarization and resting membrane depolarization. A reduction in the outward potassium current through open inwardly rectifying K⁺ channels renders the failing cardiomyocyte more susceptible to the induction of delayed afterdepolarizations triggered by spontaneous intracellular Ca²⁺-release events and therefore plays a major role in arrhythmogenesis in the failing heart. ¹

Phase 4: Diastolic Depolarization.

Under normal conditions, the membrane potential of atrial and ventricular muscle cells remains steady throughout diastole. I_K1 is the current responsible for maintaining the resting potential near the K⁺ equilibrium potential and shuts off during depolarization in atrial, His-Purkinje, and ventricular cells. In other fibers found in certain parts of the atria, in the muscle of the mitral and tricuspid valves, in His-Purkinje fibers, and in the SA node and portions of the AV nodal tract, the resting membrane potential does not remain constant in diastole but gradually depolarizes (see Figs. 34.2 and 34.3 ). The property possessed by spontaneously discharging cells is called phase 4 diastolic depolarization, which leads to initiation of action potentials resulting in automaticity. The discharge rate of the SA node normally exceeds the discharge rate of other potentially automatic pacemaker sites and thus maintains dominance of the cardiac rhythm. The discharge rate of the SA node is usually more sensitive than the discharge rate of other pacemaker sites to the effects of norepinephrine and acetylcholine. Normal or abnormal automaticity at other sites can cause discharge at rates faster than the SA nodal discharge rate and can thus usurp control of the cardiac rhythm for one cycle or many (see Chapter 35 ).

Action Potential of the Fish Heart☆

M Vornanen , in Reference Module in Life Sciences, 2017

Effects of Temperature Changes

The cardiac AP is strongly changed by temperature (Fig. 4). Lowering of temperature increases the duration and reduces the rate of upstroke of cardiac AP. As a consequence, heart rate and velocity of impulse conduction over the heart are depressed, and the duration of contraction of each cardiac myocyte lasts longer. The longer duration of AP allows more time for calcium influx through the sarcolemma and at least partly compensates for the temperature-dependent decrease in calcium influx via I_Ca. Prolonged depolarization also allows more time for the myofilaments to generate force.

Fig. 4. Temperature has strong effect on the duration of fish cardiac AP and contraction. (Top) Continuous recording of AP from a ventricular myocyte of crucian carp when temperature was gradually elevated from 5 to 18°C. Note the shortening of AP duration and increase in RMP. (Middle and bottom) Effects of temperature change on ventricular AP and associated contractions in crucian carp heart at 4 and 18°C.

Modified from Paajanen, V., Vornanen, M., 2004. Regulation of action potential duration under acute heat stress by I_K,ATP and I_K1 in fish cardiac myocytes. American Journal of Physiology 286, R405–R415.

On the other hand, due to the prolonged AP contraction – relaxation cycle gets longer and may limit maximum heart rates at low temperatures. Due to these changes in electrical activity of cardiac myocytes, the fish heart becomes sluggish in the cold but may contract more forcefully. However, in several fish species chronic exposure to low temperatures results in compensatory changes in cardiac AP. Cold-induced increase in the density of I_Na partly alleviates the temperature-dependent depression in the rate of AP upstroke and velocity of impulse conduction, while upregulation of sarcolemmal potassium currents counteracts temperature-dependent prolongation of AP. These cold-induced changes in ion channel function make room for positive compensation in heart rate and hence cardiac output, which may be adaptive at seasonally changing temperature conditions at north-temperature latitudes.

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Cardiac Muscle; The Heart as a Pump and Function of the Heart Valves

John E. Hall PhD , in Guyton and Hall Textbook of Medical Physiology , 2021

What Causes the Long Action Potential and Plateau in Cardiac Muscle?

At least two major differences between the membrane properties of cardiac and skeletal muscle account for the prolonged action potential and the plateau in cardiac muscle. First, theaction potential of skeletal muscle is caused almost entirely by the sudden opening of large numbers offast sodium channels that allow tremendous numbers of sodium ions to enter the skeletal muscle fiber from the extracellular fluid. These channels are calledfast channels because they remain open for only a few thousandths of a second and then abruptly close. At the end of this closure, repolarization occurs, and the action potential is over within about another thousandth of a second.

In cardiac muscle, the action potential is caused by opening of two types of channels: (1) the samevoltage-activated fast sodium channels as those in skeletal muscle; and (2) another entirely different population ofL-type calcium channels (slow calcium channels), which are also calledcalcium-sodium channels. This second population of channels differs from the fast sodium channels in that they are slower to open and, even more importantly, remain open for several tenths of a second. During this time, a large quantity of both calcium and sodium ions flows through these channels to the interior of the cardiac muscle fiber, and this activity maintains a prolonged period of depolarization,causing the plateau in the action potential. Furthermore, the calcium ions that enter during this plateau phase activate the muscle contractile process, whereas the calcium ions that cause skeletal muscle contraction are derived from the intracellular sarcoplasmic reticulum.

The second major functional difference between cardiac muscle and skeletal muscle that helps account for both the prolonged action potential and its plateau is that immediately after the onset of the action potential, the permeability of the cardiac muscle membrane for potassium ionsdecreases about fivefold, an effect that does not occur in skeletal muscle. This decreased potassium permeability may result from the excess calcium influx through the calcium channels just noted. Regardless of the cause, the decreased potassium permeability greatly decreases the efflux of positively charged potassium ions during the action potential plateau and thereby prevents early return of the action potential voltage to its resting level. When the slow calcium-sodium channels do close at the end of 0.2 to 0.3 second, and the influx of calcium and sodium ions ceases, the membrane permeability for potassium ions also increases rapidly. This rapid loss of potassium from the fiber immediately returns the membrane potential to its resting level, thus ending the action potential.

DESIGN AND PHYSIOLOGY OF THE HEART | Cardiac Excitation–Contraction Coupling: Routes of Cellular Calcium Flux

H.A. Shiels , in Encyclopedia of Fish Physiology, 2011

Introduction

The cardiac action potential (AP) and the ion channels that open and close to excite the cardiac myocyte are discussed in DESIGN AND PHYSIOLOGY OF THE HEART | Action Potential of the Fish Heart; this article focuses on the cellular Ca fluxes that result from the cardiac AP and lead to myocyte contraction. Specifically, this article explores the sources and routes of Ca movement during each contraction–relaxation cycle. The contraction–relaxation cycle is the cellular equivalent of the heartbeat. Video Clip 1 shows the contraction and relaxation cycle of a rainbow trout (Oncorhynchus mykiss) ventricular myocyte.Routes of cellular Ca flux associated with the contraction–relaxation cycle are very important for understanding heart contractility because the rate (how fast) and magnitude (how much) Ca movement directly determines the rate and strength heart contraction. How Ca actually causes contraction the myofilaments in fish cardiac cells is explained in DESIGN AND PHYSIOLOGY OF THE HEART | Cardiac Excitation–Contraction Coupling: Calcium and the Contractile Element.

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Calcium/Calmodulin-Dependent Protein Kinase II

A. Hudmon , H. Schulman , in Encyclopedia of Biological Chemistry (Second Edition), 2013

CaMKII in Heart

The cardiac action potential stimulates CaMKII with each heartbeat, which then performs the function of a master regulator of multiple downstream physiological responses across a range of heart rates and timescales. These include Ca ²⁺ homeostasis, excitation–contraction coupling, arrhythmia and automaticity, and cardiomyocyte hypertrophy. The kinase is concentrated along the Z band in ventricular myocytes in association with its substrates (L-type Ca²⁺ channel (LTCC) and the ryanodine receptor), where it is poised to regulate Ca²⁺ influx into the cell as well as release from intracellular stores. CaMKII mediates an important feed-forward effect relevant for both normal physiology and pathophysiology. Ca²⁺ entry via the LTCC activates the kinase, which phosphorylates the channel to facilitate subsequent Ca²⁺ current by shifting channel gating to frequent long openings. This frequency-dependent regulation of cardiac contraction functions to enhance blood flow through the heart despite the shorter duration of the cardiac cycle at high heart rates (i.e., force–frequency relationship or the 'treppe' effect). This and other actions are consistent with proarrhythmic electrical remodeling in myocardial hypertrophy and heart failure, actions that are enhanced in transgenic animals overexpressing CaMKII and are blocked in transgenic animals expressing a peptide inhibitor of CaMKII.

CaMKII responds to hormonal as well as electrical stimulation of the heart. Paradoxically, the β-adrenergic receptor-mediated stimulation of the heart, which is a classical example of cAMP acting on protein kinase A (PKA) and on a cyclic nucleotide-gated ion channel, also leads to increases in Ca²⁺ and CaMKII activation. In the sinoatrial node that paces heart rate, β-adrenergic stimulation leads to a faster action potential that is the basis of the 'fight or flight' response. In mice, this β-adrenergic response is primarily mediated by CaMKII, as it is retained in animals lacking the cyclic nucleotide-gated ion channel and is blocked by inhibition of CaMKII. The pro-oxidant angiotensin II pathway in the heart demonstrates a novel modulation of CaMKII by reactive oxygen species (ROS). ROS leads to oxidation of two methionines Met²⁸¹/Met²⁸² with consequences similar to autophosphorylation of Thr²⁸⁷ of the cardiac CaMKIIδ isoform. Oxidation disables the autoinhibitory domain so that the kinase remains active after dissociation of Ca²⁺/CaM. It usurps a mechanism used by autophosphorylation that links oxidative stress mediated by angiotensin II and ischemia with CaMKII activation and resulting downstream effects, including myocardial apoptosis.

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The Cardiac Action Potential

Joseph Feher , in Quantitative Human Physiology (Second Edition), 2012

Summary

The cardiac action potential takes a different form in different cardiac cells, which include SA nodal cells, atrial muscle cells, AV nodal cells, Purkinje fibers, and ventricular muscle cells. We consider here the action potential of SA nodal cells and ventricular muscle cells. The SA node contains the most excitable cells in the heart, and so it sets the pace of the heart. The SA nodal cells have an unstable resting membrane potential that spontaneously depolarizes due to a pacemaker potential. This is caused by the "funny" Na ⁺ current and a decrease in the conductance of the inward rectifier K⁺ channel. On reaching a threshold of about −55   mV, an action potential begins by the progressive opening of T-type and L-type Ca²⁺ channels. The spike returns to baseline because of an increase in the delayed rectifier K⁺ current. The slope of the pacemaker potential and the resting membrane potential determine the time necessary to reach threshold: the sooner threshold is reached, the sooner an action potential is fired and the faster the heart rate. Sympathetic stimulation increases the slope of the pacemaker potential and depolarizes the resting membrane potential. Both of these help increase the heart rate. Sympathetic stimulation releases norepinephrine that acts on the SA node through β ₁ receptors that are coupled to a G _s protein. This increases [cAMP] within the cell, which activates protein kinase A that subsequently phosphorylates a number of target proteins. Parasympathetic stimulation is coupled to M2 receptors that decrease [cAMP] and therefore opposes the positive chronotropic effect of sympathetic stimulation. Parasympathetic stimulation releases acetylcholine at terminals of the vagus nerve in the heart, which lowers the pacemaker potential and hyperpolarizes the cell. This reduces the frequency of action potentials originating at the SA node.

The action potential in ventricular cardiomyocytes begins with a rapid upstroke (phase 0) caused by the regenerative opening of fast Na⁺ channels. This is followed by a partial repolarization (phase 1) caused by closing of the fast channels, opening of a transient outward K⁺ channel, and reduced conductance of the inward rectifier K⁺ channel. The membrane potential enters the plateau phase (phase 2) due to inward Ca²⁺ currents carried by the L-type Ca²⁺ channel. The repolarization phase, phase 3, occurs because these Ca²⁺ channels gradually inactivate and delayed rectifier K⁺ channels contribute to an outward K⁺ current. During repolarization, the fast Na⁺ channels revert to their resting state of closed but activatable.

The action potential spreads passively throughout regions of ventricular cardiomyocytes through the gap junction connections between cells.

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Ionic Fluxes and Genesis of the Cardiac Action Potential

Yanggan Wang , ... Joseph A. Hill , in Muscle, 2012

Determinants of Action Potential Generation

The cardiac AP is initiated by a stimulus that depolarizes the membrane to the point where an all-or-nothing response is triggered. When the membrane is depolarized to this threshold potential, an AP is fired by the opening of Na⁺ channels in working myocytes and Ca²⁺ channels in nodal cells. Whether the stimulation current can induce an AP depends critically on the efficacy of this current to the depolarize cell. This, in turn, is determined by multiple "safety factors", including the magnitude of the stimulus, coupling resistance, and the excitability of the cell. In heart, myocytes are connected by way of gap junctions, proteins that allow ions to pass easily, with low resistance, to coupled neighboring cells. Therefore, AP initiation depends critically on the excitability of the myocyte, which is determined by the difference between the threshold membrane potential and the resting membrane potential, the input resistance, and the availability of membrane ion channels. Atrial myocytes manifest different excitability as compared with ventricular myocytes due to the much greater magnitude of the inward rectifying potassium current (I _K1 ) in ventricular cells and an apparently lower availability of inward I_Na current in atrial myocytes. These differences may be important in allowing atrial cells to be excited consistently by normal regions of automaticity (e.g. the sino-atrial node), whereas ventricular myocytes, with their lower level of excitability, would suppress AP initiation from a region of abnormal automaticity (e.g. an ectopic focus) (179).

After an AP is triggered, the cardiac myocyte is unable to initiate another AP for some duration of time (which is slightly shorter than the duration of action potential itself). This period of time is referred to as the refractory period. The refractory period is usually subdivided into an absolute refractory period, the interval during which a second AP absolutely cannot be initiated no matter how large a stimulus is applied, and relative refractory period, an interval immediately following the absolute refractory period during which initiation of a second AP is inhibited but not impossible. The myocyte is "absolutely" refractory when a critical mass of Na⁺ channels is unavailable for the all-or-nothing response (because they are inactivated). Na⁺ channels remain inactivated after activation and during depolarization until the membrane hyperpolarizes, at which point they transition to a closed state and undergo de-inactivation, regaining the ability to open in response to a stimulus. In the relative refractory period, enough Na⁺ channels have recovered from inactivation but K⁺ conductance of the membrane is sufficiently high that a large magnitude stimulus is required in order to reach the initiation threshold for a second AP.

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Structure and Function of Calcium Release Channels

Derek R. Laver , in Current Topics in Membranes, 2010

III RyR2 in Cardiac Contraction and Pacemaking

The cardiac action potential triggers DHPRs causing a rise in [Ca ²⁺]_C and activation of RyR2 channels in the SR via their cytoplasmic facing Ca²⁺-activation sites. The subsequent release of Ca²⁺ from the SR further increases [Ca²⁺]_C by feeding back to cause further RyR2 activation. This process, known as Ca²⁺-induced Ca²⁺ release (CICR), provides a strong positive feedback to open more RyR2. In this way, Ca²⁺ release from the SR contributes up to 95% of the Ca²⁺ entering the cytoplasm during E–C coupling (Bers, 2002). Shortly after this, the positive feedback cycle of CICR is broken due to the large resultant decrease of Ca²⁺ in the SR lumen ([Ca²⁺]_L) which causes RyR2 to close and hence SR Ca²⁺ release ceases. The excess Ca²⁺ in the cytoplasm is either pumped back into the SR by ATP-driven Ca²⁺ pumps in the SR membrane (SERCA2a) or extruded from the cell by the Na/Ca exchanger (NCX) in the sarcolemma during diastole. The major Ca²⁺ fluxes are Ca²⁺ uptake and release from the SR by SERCA2a and RyR2 and uptake and release from the cell by DHPRs and the NCX (Dibb, Graham, Venetucci, Eisner, & Trafford, 2007). These mechanisms serve a fundamental role in the large changes in free [Ca²⁺] in the cytoplasm ([Ca²⁺]_C  ~   0.1–1   μM) and SR lumen ([Ca²⁺]_L  ~   1–0.3   mM) between diastole and systole, respectively (Bers, 2002).

It was first shown that oscillations in Ca²⁺ uptake and release across the SR underlie pacemaking in lymphatic smooth muscle (Van Helden, 1993) and that these provide the pacemaker mechanism by interacting as coupled oscillators within and between cells (Van Helden & Imtiaz, 2003). The SR in the heart has this same capability. The oscillating Ca²⁺ uptake/release occurs in two phases: First, SERCA2a causes loading of the SR to a point where Ca²⁺ refill causes spontaneous opening of RyR2 due to elevated [Ca²⁺]_L. Second, during Ca²⁺ release, CICR provides positive reinforcement of RyR2 activity which continues until the stores sufficiently deplete to cause closure of RyR2 channels. Ca²⁺ release in turn activates the NCX to extrude Ca²⁺ out of the cell causing a net depolarization of the sarcolemma (i.e., 3 Na⁺ enter for every Ca²⁺ extruded) and triggers an action potential. This prospect has generated considerable interest and there is now substantive evidence that the SR has a role in heart pacemaking (Ju & Allen, 1998, 2007; Rigg & Terrar, 1996; Vinogradova, Maltsev, Bogdanov, Lyashkov, & Lakatta, 2005).

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