Resting Potential

Cardiac myocytes, like other excitable cells, maintain a transmembrane electrical gradient, with the interior of the cell negative with respect to the exterior. This transmembrane potential is generated by an unequal distribution of charged ions between intracellular and extracellular compartments (Table 22-1). Ions can traverse the sarcolemmal membrane only through selective channels or via pumps and exchangers. The resting potential is an active, energy-dependent process, relying on these channels, pumps and exchangers, and large intracellular immobile anionic proteins. Critical components include the Na⁺/K⁺-adenosine triphosphatase (ATPase) and the inwardly rectifying K⁺ channel (I_K). The Na⁺/K⁺-ATPase exchanges 3 Na⁺ ions from inside of the cell for 2 K⁺ ions outside, resulting in a net outward flow of positive charge.

TABLE 22–1 Typical Ion Concentrations

The unequal distribution of these ions across the membrane leads to both electrical and chemical forces causing charged ions to move into or out of the cell. If a membrane is permeable to only a single ion, then for that ion, there is an “equilibrium potential” at which there is no net driving force. This can be calculated using the Nernst equation;

(22-1)

Action Potentials

The cardiac action potential is divided into five phases as illustrated in Figure 22-2. The injection of current into a cardiac myocyte, or local current flow from an adjoining cell, can cause the membrane potential to depolarize (become less negative). If the resting potential exceeds a certain threshold, voltage-gated Na⁺ channels open (Fig. 22-3). Electrical and chemical gradients drive Na⁺ into the cell, making the membrane potential less negative. During phase 0, there is rapid depolarization of the action potential, Na⁺ influx is the dominant conductance, and the membrane potential approaches the equilibrium potential for Na⁺ (+64 mV). However, Na⁺ channels are open for only a very short time and close quickly. They also cycle through an inactivated state in which they are unable to open and participate in another action potential. Therefore, if a significant percentage of Na⁺ channels are in the inactivated state, the cell is refractory to further stimulation. The maximal rate of depolarization defines how fast electrical impulses can be passed from cell to cell, determining conduction velocity within a tissue. Slowing of conduction caused by inhibition of Na⁺ channels is the basis for the actions of Class I antiarrhythmic drugs. Action potentials in nonpacemaker cells are referred to as fast responses because their rate of depolarization is extremely rapid.

FIGURE 22–2 Phase of action potential (with respect to potential on extracellular side of cell membrane) in a nonpacemaker cell (left) and in a pacemaker cell (right). Numbers refer to phases. Nonpacemaker cell: 0, rapid depolarization: 1, initial repolarization; 2, action potential plateau; 3, repolarization; 4, resting potential. Pacemaker cell: 0, rapid depolarization; 3, plateau and repolarization; 4, slow diastolic depolarization (pacemaker potential).

FIGURE 22–3 Postulated conformational arrangements of cardiac Na⁺ channels compatible with concept of resting, activated, and inactivated states. Transitions among resting, activated, and inactivated states are dependent on membrane potential and time. Activation gate is shown as I and inactivation gate as II. Potentials typical for each state are shown under each channel schema as a function of time.

In pacemaker cells, like those in the SA and AV nodes, the resting membrane potential is less negative, and Na⁺ channels are inactivated and do not participate in initiation of the action potential. In these cells phase 0 is mediated almost entirely by increased conductance of Ca⁺⁺ through opening of voltage-gated Ca⁺⁺ channels. These “slow” action potentials exhibit much slower depolarization.

The voltage and time dependence of currents through individual ion channels are unique. Na⁺ channels open at more negative voltages than Ca⁺⁺ channels, and current kinetics are quite different. Physical structures, known as activation and inactivation gates, help regulate the flow of ions. Because of these gates, Na⁺ channels are believed to exist in at least three distinct states during the cardiac action potential, as shown in Figure 22-3. At the resting potential, most Na⁺ channels are in a resting state, available for activation. Upon depolarization, most channels become activated, allowing Na⁺ to flow into the cell and cause a rapid depolarization. Na⁺ channels quickly become inactivated, limiting the time for Na⁺ entry to a few milliseconds or less.

Near the end of phase 0, an overshoot of the action potential occurs. This is the most positive potential achieved and represents an abrupt transition between the end of depolarization and the onset of repolarization, known as phase 1 or initial rapid repolarization. This phase of initial repolarization is caused by two factors: inactivation of the inward Na⁺ current and activation of a transient outward current, which is composed of both a K⁺ and Cl⁻ component.

Phase 2, or the plateau phase of the cardiac action potential, is one of its most distinguishing features. In contrast to action potentials in nerves and other cells (see Chapter 13), the cardiac action potential has a relatively long duration of 200 to 500 msec, depending on the cell (see Fig. 22-2). The plateau results from a voltage-dependent decrease in K⁺ conductance (the inward rectifier) and is maintained by the influx of Ca⁺⁺ through Ca⁺⁺ channels that inactivate only slowly at positive membrane potentials. During this phase, another outward K⁺ current, the delayed rectifier, is slowly activated, which nearly balances the maintained influx of Ca⁺⁺. As a result, there is only a small change in potential during the plateau, because net current flow is small.

As the plateau phase transitions to repolarization, the voltage-activated Ca⁺⁺ channels close, leaving the outward hyperpolarizing K⁺ current unopposed, known as phase 3 repolarization. The hyperpolarizing current during phase 3 is carried through three distinct K⁺ channels, the slowly activating delayed rectifier (I_Ks), the rapidly activating delayed rectifier (I_Kr), and the ultra-rapidly activating delayed rectifier (I_Kur). The importance of these currents to ventricular repolarization is underscored by the clinical significance of abnormalities of these channels. The potentially lethal “long QT syndrome” results from abnormalities in the ion channels responsible for repolarization, causing a delay in repolarization and producing an arrhythmic substrate in the ventricles.

In a nonpacemaker cell, phase 4, or the resting potential, is characterized by a return of the membrane to its resting potential. Atrial and ventricular myocytes maintain a constant resting potential awaiting the next depolarizing stimulus, established by a voltage-activated K⁺ channel, I_K1. The resting potential remains slightly depolarized relative to the equilibrium potential of K⁺, due to an inward depolarizing leak current likely carried by Na⁺. During the terminal portions of phase 3, and all of phase 4, voltage-gated Na⁺ channels are transitioning from the inactivated to the resting state and preparing to participate in another action potential. In a pacemaker cell, however, there is a slow depolarization during diastole. This brings the membrane potential near threshold for activation of a regenerative inward current, which initiates a new action potential (see Fig. 22-2). This is called phase 4 depolarization. In a pacemaker cell in the SA node, phase 4 depolarization brings the membrane potential to a level near the threshold for activation of the inward Ca⁺⁺ current.