Ionic Basis for the Membrane
Action Potential
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).
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 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).
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.
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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