The normal cardiac cell at rest maintains a transmembrane potential ~80—90 mV negative to the exterior; this gradient is established by pumps, especially the Na+, K+-ATPase, and fixed anionic charges within cells. At rest, the normal cardiac cell is permeable to K+ (because inward rectifier channels are open) and [K]o is the major determinant of resting potential.
If an atrial or ventricular cell at rest is depolarized above a threshold potential, Na+ channels change conformation from the "closed" (resting) state to the "open" (conducting) state, allowing up to 107 Na+/second to enter each cell and moving the transmembrane potential toward the equilibrium potential for Na+, ENa (+65 mV). This surge of Na+ ions lasts only about a millisecond, after which the Na+ channel protein rapidly changes conformation from the "open" state to an "inactivated," nonconducting state. The changes in transmembrane potential generated by the inward Na+ current produce, in turn, a series of openings (and in some cases subsequent inacti-vation) of other channels (Figure 34-1). For example, when a cell from the epicardium or the His-Purkinje conducting system is depolarized, "transient outward" K+ channels change conformation to enter an open, or conducting, state; since the transmembrane potential at the end of phase 0 is positive relative to EK the opening of transient outward channels results in an outward, or repolarizing, K+ current (termed ITO), which contributes to the phase 1 "notch" seen in action potentials from these tissues. Transient outward K+ channels, like Na+ channels, inactivate rapidly. During the phase 2 plateau of a normal cardiac action potential, inward, depolarizing currents, primarily through Ca2+ channels, are balanced by outward, repolarizing currents primarily through K+ ("delayed rectifier") channels. Delayed rectifier currents (collectively termed IK) increase with time, whereas Ca2+ currents inactivate; as a result, cardiac cells repolarize (phase 3) several hundred milliseconds after the initial Na+ channel opening.
A common mechanism whereby drugs prolong cardiac action potentials and provoke arrhythmias is through inhibition of a specific delayed rectifier current, IKr, generated by expression of the human ether-a-go-go related gene (HERG). The ion channel protein generated by HERG expression differs from other ion channels in important structural features that make it much more susceptible to drug block. Avoiding IKr/HERG channel block has become a major issue in the development of new antiarrhythmic drugs.
Differing Action Potential Behaviors among Cardiac Cells
This general description must be modified for certain cell types (Figure 34-1) presumably because of variability in the ion channel proteins expressed in individual cells. Atrial cells have very short action potentials probably because ITO is larger, and an additional repolarizing K+ current, activated by acetylcholine, is present. As a result, vagal stimulation further shortens atrial action potentials. Cells of the sinus and atrioventricular (AV) nodes lack substantial Na+ currents. In addition, these cells, as well as cells from the conducting system, normally display the phenomenon of spontaneous diastolic, or phase 4, depolarization and thus spontaneously reach threshold for regeneration of action potentials. The rate of spontaneous firing usually is fastest in sinus node cells, which therefore serve as the natural pacemaker of the heart. Specialized K+ channels underlie the pacemaker current in the heart.
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