The electrical excitability of cardiac cells is a function of the unequal distribution of ions across the plasma membrane—chiefly sodium (Na+), potassium (K+), calcium (Ca2+), and chloride (Cl−)—and the relative permeability of the membrane to each ion. The gradients are generated by transport mechanisms that move these ions across the membrane against their concentration gradients. The most important of these transport mechanisms is the Na+/K+-ATPase, or sodium pump, described in Chapter 13. It is responsible for keeping the intracellular sodium concentration low and the intracellular potassium concentration high relative to their respective extracellular concentrations. Other transport mechanisms maintain the gradients for calcium and chloride.
As a result of the unequal distribution, when the membrane becomes permeable to a given ion, that ion tends to move down its concentration gradient. However, because of its charged nature, ion movement is also affected by differences in the electrical charge across the membrane, or the transmembrane potential. The potential difference that is sufficient to offset or balance the concentration gradient of an ion is referred to the equilibrium potential (Eion) for that ion, and for a monovalent cation at physiologic temperature, it can be calculated by a modified version of the Nernst equation: where Ce and Ci are the extracellular and intracellular ion concentrations, respectively. Thus, the movement of an ion across the membrane of a cell is a function of the difference between the transmembrane potential and the equilibrium potential. This is also known as the “electrochemical gradient” or “driving force.”
The relative permeability of the membrane to different ions determines the transmembrane potential. However, ions contributing to this potential difference are unable to freely diffuse across the lipid membrane of a cell. Their permeability relies on aqueous channels (specific pore-forming proteins). The ion channels that are thought to contribute to cardiac action potentials are illustrated in Figure 14–2. Most channels are relatively ion-specific, and the current generated by the flux of ions through them is controlled by “gates” (flexible portions of the peptide chains that make up the channel proteins). Sodium, calcium, and some potassium channels are thought to have two types of gates—one that opens or activates the channel and another that closes or inactivates the channel. For the majority of the channels responsible for the cardiac action potential, the movement of these gates is controlled by voltage changes across the cell membrane; that is, they are voltage-sensitive. However, certain channels are primarily ligandrather than voltage-gated. Furthermore, the activity of many voltage-gated ion channels can be modulated by a variety of other factors, including permeant ion concentrations, tissue metabolic activity, and second messenger signaling pathways.
Pumps and exchangers that contribute indirectly to the membrane potential by creating ion gradients (as discussed above) can also contribute directly because of the current they generate through the unequal exchange of charged ions across the membrane. Such transporters are referred to as being “electrogenic.” An important example is the sodium-calcium exchanger (NCX). Throughout most of the cardiac action potential, this exchanger couples the movement of one calcium ion out of the cell for every three sodium ions that move in, thus generating a net inward or depolarizing current. Although this current is typically small during diastole, when intracellular calcium levels are low, spontaneous release of calcium from intracellular storage sites can generate a depolarizing current that contributes to pacemaker activity as well as arrhythmogenic events called delayed afterdepolarizations (see below).
The Active Cell Membrane
In atrial and ventricular cells, the diastolic membrane potential (phase 4) is typically very stable. This is because it is dominated by a potassium permeability or conductance that is due to the activity of channels that generate an inward-rectifying potassium current (IK1). This keeps the membrane potential near the potassium
SCN5A/Nav 1.5 Ca2+