Ionic Equilibrium

The lipid bilayer of the cell membrane is hydrophobic and impermeable to water-soluble substances such as ions. Hence, for the hydrophilic ions to be able to cross the membrane, they need hydrophilic paths that span the membrane (i.e., pores), which are provided by transmembrane proteins called ion channels. Once a hydrophilic pore is available, ions move passively across the membrane driven by two forces: the electrical gradient (voltage difference) and the chemical gradient (concentration difference). The chemical gradient forces the ions to move from a compartment of a higher concentration to one of lower concentration. The electrical gradient forces ions to move in the direction of their inverse sign (i.e., cations [positively charged ions] move toward a negatively charged compartment, whereas anions [negatively charged ions] move toward a positively charged compartment). Because the chemical and electrical gradients can oppose each other, the direction of net ion movement will depend on the relative contributions of chemical gradient and electrical potential (i.e., the net electrochemical gradient), so that ions tend to move spontaneously from a higher to a lower electrochemical potential.^1–3

The movement of an ion down its chemical gradient in one direction across the cell membrane results in build-up of excess charge carried by the ion on one side of the membrane, which generates an electrical gradient that impedes continuing ionic movement in the same direction. When the driving force of the electrical gradient across the membrane becomes equal and opposite to the force generated by the chemical gradient, the ion is said to be in electrochemical equilibrium, and the net transmembrane flux (or current) of that particular ion is zero. In this setting, the electrical potential is called the equilibrium potential (E_ion) (reversal potential or Nernst potential) of that individual ion. The E_ion for a given ion depends on its concentration on either side of the membrane and the temperature, and it measures the voltage that the ion concentration gradient generates when it acts as a battery. At membrane voltages more positive to the reversal potential of the ion, passive ion movement is outward, whereas it is inward at a membrane potential (also known as transmembrane potential; E_m) more negative to the Nernst potential of that channel.^1,3

When multiple ions across a membrane are removed from their electrochemical equilibrium, each ion will tend to force the E_m toward its own E_ion. The contribution of each ion type to the overall E_m at any given moment is determined by the instantaneous permeability of the plasma membrane to that ion. The larger the membrane conductance to a particular ion, the greater is the ability of that ion to bring the E_m toward its own E_ion. Hence, the E_m is the average of the E_ion of all the ions to which the membrane is permeable, weighed according to the membrane conductance of each individual ion relative to the total ionic conductance of the membrane.^1,2

Transmembrane Potentials

All living cells, including cardiomyocytes, maintain a difference in the concentration of ions across their membranes. There is a slight excess of positive ions on the outside of the membrane and a slight excess of negative ions on the inside of the membrane, resulting in a difference in the electrical charge (i.e., voltage difference) across the cell membrane, called the membrane potential (E_m). A membrane that exhibits an E_m is said to be polarized.²

In nonexcitable cells, and in excitable cells in their baseline states (i.e., not conducting electrical signals), the E_m is held at a relatively stable value, called the resting potential. All cells have a negative resting E_m (i.e., the cytoplasm is electrically negative relative to the extracellular fluid), which arises from the interaction of ion channels and ion pumps embedded in the membrane that maintain different ion concentrations on the intracellular and extracellular sides of the membrane.²

When an ion channel opens, it allows ion flux across the membrane that generates an electrical current (I). This current affects the E_m, depending on the membrane resistance (R), which refers to the ratio between the E_m and electrical current, as shown in Ohm’s law: E = I × R or R = E/I. Resistance arises from the fact that the membrane impedes the movement of charges across it; hence, the cell membrane functions as a resistor. Conductance describes the ability of a membrane to allow the flux of charged ions in one direction across the membrane. The more permeable the membrane is to a particular ion, the greater is the conductance of the membrane to that ion. Membrane conductance (g) is the reciprocal of R: g = 1/R.¹

Because the lipid bilayer of the cell membrane is very thin, accumulation of charged ions on one side gives rise to an electrical force (potential) that pulls oppositely charged particles toward the other side. Hence, the cell membrane functions as a capacitor. Although the absolute potential differences across the cell membrane are small, they give rise to enormous electrical potential gradients because they occur across a very thin surface. As a consequence, apparently small changes in E_m can produce large changes in potential gradient and powerful forces that are able to induce molecular rearrangement in membrane proteins, such as those required for opening and closing ion channels embedded in the cell membrane. The capacitance of the membrane is generally fixed and unaffected by the molecules that are embedded in it. In contrast, membrane resistance is highly variable and depends on the conductance of ion channels embedded in the membrane.^2,3

The sodium (Na⁺), potassium (K⁺), calcium (Ca²⁺), and chloride (Cl⁻) ions are the major charge carriers, and their movement across the cell membrane creates a flow of current that generates excitation and signals in cardiac myocytes. The electrical current generated by the flux of an ion across the membrane is determined by the membrane conductance to that ion (g_ion) and the potential (voltage) difference across the membrane. The potential difference represents the potential at which there is no net ion flux (i.e., the E_ion) and the actual E_m: current = g_ion × (E_m − E_ion).^1,4

By convention, an inward current increases the electropositivity within the cell (i.e., causes depolarization of the E_m [to be less negative]) and can result from either the movement of positively charged ions (most commonly Na⁺ or Ca²⁺) into the cell or the efflux of negatively charged ions (e.g., Cl⁻) out of the cell. An outward current increases the electronegativity within the cell (i.e., causes hyperpolarization of the E_m [to become more negative]) and can result from either the movement of anions into the cell or the efflux of cations (most commonly K⁺) out of the cell.³

Opening and closing of ion channels can induce a departure from the relatively static resting E_m, called a depolarization if the interior voltage rises (becomes less negative) or a hyperpolarization if the interior voltage becomes more negative. The most important ion fluxes that depolarize or repolarize the membrane are passive (i.e., the ions move down their electrochemical gradient without requiring the expenditure of energy), occurring through transmembrane ion channels. In excitable cells, a sufficiently large depolarization can evoke a short-lasting all-or-none event called an action potential, in which the E_m very rapidly undergoes specific and large dynamic voltage changes.¹

Both resting E_m and dynamic voltage changes such as the action potential are caused by specific changes in membrane permeabilities for Na⁺, K⁺, Ca²⁺, and Cl⁻, which, in turn, result from concerted changes in functional activity of various ion channels, ion transporters, and exchangers.³

The Cardiac Action Potential

During physiological electrical activity, the E_m is a continuous function of time. The current flowing through the cell membrane is, at each instant, provided by multiple channels and transporters carrying charge in opposite directions because of their different ion selectivity. The algebraic summation of these contributions is referred to as net transmembrane current.¹

The cardiac action potential reflects a balance between inward and outward currents. When a depolarizing stimulus (typically from an electric current from an adjacent cell) abruptly changes the E_m of a resting cardiomyocyte to a critical value (the threshold level), the properties of the cell membrane and ion conductances change dramatically, precipitating a sequence of events involving the influx and efflux of multiple ions that together produce the action potential of the cell. In this fashion, an electrical stimulus is conducted from one cell to all the cells that are adjacent to it.²

Unlike skeletal muscle, cardiac muscle is electrically coupled so that the wave of depolarization propagates from one cell to the next, independent of neuronal input. The heart is activated by capacitive currents generated when a wave of depolarization approaches a region of the heart that is at its resting potential. Unlike ionic currents, which are generated by the flux of charged ions across the cell membrane, capacitive currents are generated by the movement of electrons toward and away from the surfaces of the membrane.^2,3 The resulting decrease in positive charge at the outer side of the cell membrane reduces the negative charge on the intracellular surface of the membrane. These charge movements, which are carried by electrons, generate a capacitive current. When an excitatory stimulus causes the E_m to become less negative and beyond a threshold level (approximately −65 mV for working atrial and ventricular cardiomyocytes), Na⁺ channels activate (open) and permit an inward Na⁺ current (I_Na), resulting in a rapid shift of the E_m to a positive voltage range. This event triggers a series of successive opening and closure of selectively permeable ion channels. The direction and magnitude of passive ion movement (and the resulting current) at any given transmembrane voltage are determined by the ratio of the intracellular and extracellular concentrations and the reversal potential of that ion, with the net flux being larger when ions move from the more concentrated side.³

The threshold is the lowest E_m at which opening of enough Na⁺ channels (or Ca²⁺ channels in the setting of nodal cells) is able to initiate the sequence of channel openings needed to generate a propagated action potential. Small (subthreshold) depolarizing stimuli depolarize the membrane in proportion to the strength of the stimulus and cause only local responses because they do not open enough Na⁺ channels to generate depolarizing currents large enough to activate nearby resting cells (i.e., insufficient to initiate a regenerative action potential). On the other hand, when the stimulus is sufficiently intense to reduce the E_m to a threshold value, regenerative action potential results, whereby intracellular movement of Na⁺ depolarizes the membrane more, a process that increases conductance to Na⁺ more, which allows more Na⁺ to enter, and so on. In this fashion, the extent of subsequent depolarization becomes independent of the initial depolarizing stimulus, and more intense stimuli do not produce larger action potential responses; rather, an all-or-none response results.²

Electrical changes in the action potential follow a relatively fixed time and voltage relationship that differs according to specific cell types. Whereas the entire action potential takes several milliseconds in nerve cells, the cardiac action potential lasts several hundred milliseconds. The course of the action potential can be divided into five phases (numbered 0 to 4). Phase 4 is the resting E_m, and it describes the E_m when the cell is not being stimulated.

During the action potential, membrane voltages fluctuate in the range of −94 to +30 mV (Fig. 1-1). With physiological external K⁺, the reversal potential of K⁺ (E_K) is approximately −94 mV, and passive K⁺ movement during an action potential is out of the cell. On the other hand, because the calculated reversal potential of a cardiac Ca²⁺ channel (E_Ca) is +64 mV, passive Ca²⁺ flux is into the cell.⁵

FIGURE 1-1 A, Depiction of a standard ECG tracing with respect to its underlying ventricular action potential (AP). B, The different ionic currents (see text) that contribute to action potential generation and the putative encoding genes are shown. Depolarizing currents are shown in yellow, repolarizing currents in blue.

(Modified with permission from Saenena JB, Vrints CJ: Molecular aspects of the congenital and acquired long QT syndrome: clinical implications. J Mol Cell Cardiol 44:633-646, 2007.)

In normal atrial and ventricular myocytes and in His-Purkinje fibers, action potentials have very rapid upstrokes, mediated by the fast inward I_Na. These potentials are called fast response potentials. In contrast, action potentials in the normal sinus and atrioventricular (AV) nodal cells and many types of diseased tissues have very slow upstrokes, mediated by a slow inward, predominantly L-type voltage-gated Ca²⁺ current (I_CaL), rather than by the fast inward I_Na (Fig. 1-2). These potentials have been termed slow response potentials.^2,5

FIGURE 1-2 Action potential waveforms, displaced in time to reflect the temporal sequence of propagation, vary in different regions of the heart. AV = atrioventricular (node); endo = endocardial; epi = epicardial; mid = midmyocardial; LV = left ventricle; RV = right ventricle; SA = sinoatrial.

(Modified with permission from Nerbonne JM: Heterogeneous expression of repolarizing potassium currents in the mammalian myocardium. In Zipes DP, Jalife J, editors: Cardiac electrophysiology: from cell to bedside, ed 5, Philadelphia, 2009, Saunders, pp 293-305.)

The Fast Response Action Potential

Phase 4: The Resting Membrane Potential

The E_m of resting atrial and ventricular cardiomyocytes remains steady throughout diastole. The resting E_m is caused by the differences in ionic concentrations across the membrane and the selective membrane permeability (conductance) to various ions. Large concentration gradients of Na⁺, K⁺, Ca²⁺, and Cl⁻ across the cell membrane are maintained by the ion pumps and exchangers (Table 1-1).

TABLE 1-1 Intracellular and Extracellular Ion Concentrations and Equilibrium Potentials in Cardiomyocytes

Under normal conditions, the resting membrane is most permeable to K⁺ and relatively impermeable to other ions. K⁺ has the largest resting membrane conductance (g_K is 100 times greater than g_Na) because of the abundance of open K⁺ channels at rest, whereas Na⁺ and Ca²⁺ channels are generally closed. Thus, K⁺ exerts the largest influence on the resting E_m. As a consequence, the resulting E_m is almost always close to the K⁺ reversal potential (E_m approximates E_K). The actual resting E_m is slightly less negative than E_K because the cell membrane is slightly permeable to other ions.²

The inwardly rectifying K⁺ (Kir) channels underlie an outward K⁺ current (I_K1) responsible for maintaining the resting potential near the E_K in atrial, His-Purkinje, and ventricular cells, under normal conditions.^6,7 Kir channels preferentially allow currents of K⁺ ions to flow into the cell with a strongly voltage-dependent decline of K⁺ efflux (i.e., reduction of outward current) on membrane depolarization. As such, I_K1 is a strong rectifier that passes K⁺ currents over a limited range of E_m (see Chap. 2 for detailed discussion on the concept of rectification); at a negative E_m, I_K1 conductance is much larger than that of any other current, thus, it clamps the resting E_m close to the reversal potential for K⁺ (E_K). I_K1 density is much higher in ventricular than in atrial myocytes, a feature that protects the ventricular cell from pacemaker activity. By contrast, I_K1 is almost absent in sinus and AV nodal cells, thus allowing for relatively more depolarized resting diastolic potentials compared with atrial and ventricular myocytes (Table 1-2).²

TABLE 1-2 Regional Differences in Cardiac Action Potential

A unique property of Kir currents is the unusual dependence of rectification on extracellular K⁺ concentration. Specifically, on increase in extracellular K⁺, the I_K1 current-voltage relationship shifts nearly in parallel with the E_K and leads to a crossover phenomenon. One important consequence of such behavior is that at potentials positive to the crossover, K⁺ conductance increases rather than decreases, against an expectation based on a reduced driving force for K⁺ ions as a result of elevated extracellular K⁺ concentration.^6–8

The resting E_m also is powered by the Na⁺-K⁺ adenosine triphosphatase (ATPase) (the Na⁺-K⁺ pump), which helps establish concentration gradients of Na⁺ and K⁺ across the cell membrane. Under physiological conditions, the Na⁺-K⁺ pump transports two K⁺ ions into the cell against its chemical gradient and three Na⁺ ions outside against its electrochemical gradient at the cost of one adenosine triphosphate (ATP) molecule. Because the stoichiometry of ion movement is not 1:1, the Na⁺-K⁺ pump is electrogenic and generates a net outward movement of positive charges (i.e., an outward current). At faster heart rates, the rate of Na⁺-K⁺ pumping increases to maintain the same ionic gradients, thus counteracting the intracellular gain of Na⁺ and loss of K⁺ with each depolarization.

Although Ca²⁺ does not contribute directly to the resting E_m (since the voltage-activated Ca²⁺ channels are closed at the hyperpolarized resting E_m), changes in intracellular free Ca²⁺ concentration can affect other membrane conductance values. Increases in intracellular Ca²⁺ levels can stimulate the Na⁺-Ca²⁺ exchanger (I_Na-Ca), which exchanges three Na⁺ ions for one Ca²⁺ ion; the direction depends on the Na⁺ and Ca²⁺ concentrations on the two sides of the membrane and the E_m difference. At resting E_m and during a spontaneous sarcoplasmic reticulum Ca²⁺ release event, this exchanger would generate a net Na⁺ influx, possibly causing transient membrane depolarizations.³

Phase 0: The Upstroke—Rapid Depolarization

On excitation of the cardiomyocyte by electrical stimuli from adjacent cells, its resting E_m (approximately −85 mV) depolarizes, leading to opening (activation) of Na⁺ channels from its resting (closed) state and enabling a large and rapid influx of Na⁺ ions (inward I_Na) into the cell down their electrochemical gradient. As a consequence of increased Na⁺ conductance, the excited membrane no longer behaves like a K⁺ electrode (i.e., exclusively permeable to K⁺), but more closely approximates an Na⁺ electrode, and the membrane potential moves toward the Na⁺ E_ion (E_Na; see Table 1-1). Once an excitatory stimulus depolarizes the E_m beyond the threshold for activation of Na⁺ channels (approximately −65 mV), the activated I_Na is regenerative and no longer depends on the initial depolarizing stimulus; the influx of Na⁺ ions further depolarizes the membrane and thereby increases conductance to Na⁺ more, which allows more Na⁺ to enter.^2,9

Normally, activation of Na⁺ channels is transient; fast inactivation (closing of the pore) starts simultaneously with activation, but because inactivation is slightly delayed relative to activation, the channels remain transiently (less than 1 millisecond) open to conduct I_Na during phase 0 of the action potential before it closes. Additionally, the influx of Na⁺ into the cell increases the positive intracellular charges and reduces the driving force for Na⁺. When the E_Na is reached, no further Na⁺ ions enter the cell.⁹

The rate at which depolarization occurs during phase 0, that is, the maximum rate of change of voltage over time, is indicated by the expression dV/dt_max, which is a reasonable approximation of the rate and magnitude of Na⁺ entry into the cell and a determinant of conduction velocity for the propagated action potential.²

The threshold for activation of I_CaL is approximately −30 to −40 mV. Although I_CaL is normally activated during phase 0 by the regenerative depolarization caused by the fast I_Na, I_CaL is much smaller than the peak I_Na. The amplitude of I_CaL is not maximal near the action potential peak because of the time-dependent nature of I_CaL activation, as well as the low driving force (E_m − E_Ca) for I_CaL. Therefore, I_CaL contributes little to the action potential until the fast I_Na is inactivated, after completion of phase 0. As a result, I_CaL affects mainly the plateau of action potentials recorded in atrial and ventricular muscle and His-Purkinje fibers. On the other hand, I_CaL can play a prominent role in the upstroke of slow response action potentials in partially depolarized cells in which the fast Na⁺ channels have been inactivated.²

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