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Maintenance of Intracellular Homeostasis

With each action potential, the cell interior gains Na+ ions and loses K+ ions. The Na+,K+-ATPase is activated in most cells to maintain intracellular homeostasis, extruding 3 Na+ ions for every 2 K+ ions shuttled from the exterior of the cell to the interior; as a result, the act of pumping itself generates a net outward (repolarizing) current.

Normally, intracellular Ca2+ is maintained at very low levels (<100 nM). In cardiac myocytes, the entry of Ca2+ during each action potential is a signal to the sarcoplasmic reticulum to release its Ca2+ stores. The resulting increase in intracellular Ca2+ then triggers Ca2+-dependent contraction. Removal of intracellular Ca2+ occurs by both an ATP-dependent Ca2+ pump (which moves Ca2+ ions back to storage sites in the sarcoplasmic reticulum) and an electrogenic Na+-Ca2+ exchange mechanism in the cell membrane, which usually exchanges 3 Na+ions from the exterior for each Ca2+ ion extruded. Abnormal regulation of intracellular Ca2+, characterized by contractile dysfunction, may contribute to arrhythmias in the setting of heart failure. The initial rise in Ca2+, which serves as the trigger for Ca2+ release from intracellular stores, results from the opening of Ca2+ channels in the cell membrane or from Ca2+ entry through Na+-Ca2+ exchange; i.e., in response to phase 0 entry of Na+, the Na+-Ca2+ exchange protein may transiently extrude Na+ ions in exchange for Ca2+ ions (Figure 34—1).

Impulse Propagation and the Electrocardiogram

Normal cardiac impulses originate in the sinus node. Once impulses leave the sinus node, they propagate rapidly throughout the atria, resulting in atrial systole and the P wave of the electrocardiogram (ECG; Figure 34—1). Propagation slows markedly through the AV node, where the inward current (through Ca2+ channels) is much smaller than the Na+ current in atria, ventricles, or the subendocardial conducting system. This conduction delay allows the atrial contraction to propel blood into the ventricle, thereby optimizing cardiac output. Once impulses exit the AV node, they enter the conducting system, where Na+ currents are larger than in any other tissue. Hence propagation is correspondingly faster, up to 0.75 m/s longitudinally, and manifests as the QRS complex on the ECG as impulses spread from the endocardium to the epicardium, stimulating coordinated ventricular contraction. Ventricular repolarization results in the T wave of the ECG.

The ECG can be used as a rough guide to some cellular properties of cardiac tissue: (1) Heart rate reflects sinus node automaticity, (2) PR-interval duration reflects AV nodal conduction time, (3) QRS duration reflects conduction time in the ventricle, and (4) the QT interval is a measure of ventricular action potential duration.

Refractoriness: Fast-Response versus Slow-Response Tissue

If a single action potential, such as that shown in Figure 34—1, is restimulated very early during the plateau, no Na+ channels are available to open, no inward current results, and no action potential is generated: The cell is refractory. On the other hand, if a stimulus occurs after the cell has repolarized completely, Na+ channels have recovered, and a normal Na+ channel-dependent upstroke results. When a stimulus occurs during phase 3 of the action potential, the magnitude of the resultant Na+ current depends on the number of Na+ channels that have recovered, which depends on the voltage at which the extra stimulus was applied. Thus, in atrial, ventricular, and His-Purkinje cells ("fast-response" cells), refractoriness is determined by the voltage-dependent recovery of Na+ channels from inactivation. The effective refractory period is the shortest interval at which a premature stimulus results in a propagated response and often is used to describe drug effects in intact tissue.

The situation is different in Ca2+ channel-dependent ("slow-response") tissue such as the AV node. The major factor controlling recovery from inactivation of Ca2+ channels is time. Thus, even after a Ca2+ channel-dependent action potential has repolarized to its initial resting potential, not all Ca2+ channels are available for reexcitation. Therefore, an extra stimulus applied shortly after repolarization is complete generates a reduced Ca2+ current, which may propagate slowly to adjacent cells prior to extinction. An extra stimulus applied later will result in a larger Ca2+ current and faster propagation. Thus, in Ca2+ channel-dependent tissues, which include not only the AV node but also tissues whose underlying characteristics have been altered by factors such as myocardial ischemia, refractoriness is time-dependent, and propagation occurs slowly. Slow conduction in the heart, a critical factor in the genesis of reentrant arrhythmias (see below), also can occur when Na+ currents are depressed by disease or membrane depolarization (e.g., elevated [K]o), resulting in decreased steady-state Na+ channel availability.

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