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Chapter: Modern Pharmacology with Clinical Applications: Pharmacological Management of Chronic Heart Failure

Cardiac Electrophysiology: Ionic Basis for the Membrane Action Potential

Ionic Basis for the Membrane Action Potential

Ionic Basis for the Membrane Action Potential

Phase 0: Rapid Depolarization

Phase 0 of the action potential encompasses the rapid depolarization of the myocyte induced principally by the opening of voltage gated sodium channels. The sodium channels open rapidly in response to membrane depolarization and close within 1 to 2 milliseconds in a time-dependent fashion. The conformation of the chan-nels changes, and they enter an inactivated state in which they cannot be recruited to participate in gener-ating a subsequent action potential for a defined inter-val. The interval during which the myocyte cannot be stimulated is the absolute refractory period. After the myocyte returns to a hyperpolarized resting potential, the channels cycle through the inactivated state back to the rested or closed conformation and again are avail-able to open in response to a stimulus of sufficient in-tensity. The rate of recovery of the NA+ channels from voltage-dependent inactivation is one determinant of the cell’s ability to generate a subsequent action poten-tial. The refractory period defines the maximal rate at which the cardiac cells will respond to applied stimuli and propagate impulses to neighboring cells. The den-sity of available sodium channels in the cell membrane also determines the rate at which an impulse is con-ducted from one cell to another. The maximal upstroke velocity of phase 0 (Vmax) is a major determinant of the speed of impulse conduction within the myocardium and therefore is important in initiation and mainte-nance of arrhythmia. Genetic mutations in the sodium channel resulting in a sustained inward leak current have been identified and underlie one form of the long QT syndrome (LQTS 3).

Phase 1

At the peak of the action potential upstroke, a short rapid period of repolarization occurs and the membrane potential returns toward 0 mV. This produces a spike and dome configuration of the action potential and is a result of the inactivation of the INa and activation of a short-lived outward current called the transient outward current (Ito). Ito is composed of two distinct channels car-ried by either potassium or chloride. The distribution of Ito is heterogeneous throughout the myocardium and varies from species to species. Ito is present in both the atrium and the ventricular myocardium. Within the ven-tricle, Ito is present in the epicardium and absent in the endocardium. Consequently, the epicardium repolarizes more rapidly than the endocardium; this is the basis for the QRS complex and the T-wave on the surface elec-trocardiogram having an identical axis as opposed to an opposite axis. Abnormalities in the function of Ito have been implicated in Brugada syndrome, a potentially lethal genetic disease resulting in ventricular tachycardia and fibrillation.

Phase 2: Action Potential Plateau

Phase 2 is characterized by a net balance between in-ward (depolarizing) and outward (repolarizing) ion cur-rents maintaining the myocyte in a depolarized state. During this phase, Ca++ enters the cell, causing Ca++ re-lease from intracellular stores and linking electrical de-polarization with mechanical contraction. Interestingly, the current flow during the plateau phase is small, and therefore, perturbations in any of the currents partici-pating in this phase (either through genetic mutations or pharmacologically) may result in profound alter-ations in the action potential. Ca++ enters the cell through voltage-dependent channels highly selective for Ca++ that open when the membrane is depolarized above 40 mV. The channel (L-type calcium channel) possesses slow inactivation kinetics resulting in a long-lasting current.

Outward repolarizing K+ currents oppose the effect of the inward ICa on the plateau phase. This current is carried predominantly through delayed rectifier potas-sium channels (IK). These channels are voltage sensitive, with slow inactivation kinetics. Three distinct subpopu-lations of IK with differing activation and inactivation kinetics have been described. A rapidly activating sub-set (IKr), a slowly inactivating subset (IKs), and an ul-tra–rapidly activating subset to date are identified only in atrial tissue (IKur).

Phase 3: Late Phase of Repolarization

Termination of phase 2 of the action potential plateau oc-curs when time-dependent, voltage-dependent, and in-tracellular Ca++ –dependent inactivation of ICa results in the unopposed repolarizing effects of the outward K+ currents. The combination of these effects results in rapid repolarization with a return to the hyperpolarized resting membrane potential. Pharmacological interventions that inhibit IK prolong the membrane action potential by de- laying repolarization. Mutations in the genes encoding the various subtypes of IK inhibit proper channel function and result in the LQTS.

Phase 4

In normal atrial and ventricular myocytes, phase 4 is electrically stable, with the resting membrane potential held at approximately 90 mV and maintained by the outward potassium leak current and ion exchangers previously described. It is during phase 4 that the NA+ channels necessary for atrial and ventricular myocyte depolarization recover completely from inactivation. In myocytes capable of automaticity, the membrane po-tential slowly depolarizes during this period to initiate an action potential (discussed later).

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