DƯỢC LÍ Goodman & Gilman's The Pharmacological Basis of Therapeutics 12th, 2010

As a result, impulses spread along cells two to three times faster than
across cells. This “anisotropic” (direction-dependent) conduction
may be a factor in the genesis of certain arrhythmias described later
(Priori et al., 1999). Once impulses leave the sinus node, they propagate
rapidly throughout the atria, resulting in atrial systole and the
P wave of the surface electrocardiogram (ECG; Figure 29–4).
Propagation slows markedly through the AV node, where the inward
current (through Ca 2+ 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 elsewhere and propagation is correspondingly faster,
up to 0.75 m/s longitudinally. Activation spreads from the
His–Purkinje system on the endocardium of the ventricles throughout
the rest of the ventricles, stimulating coordinated ventricular contraction.
This electrical activation manifests itself as the QRS
complex on the ECG. Due to the aforementioned heterogeneity in
ventricular APDs, the T wave of the ECG, which represents ventricular
repolarization, is broader than the QRS complex and of opposite
polarity to what one would expect if repolarization directly
followed activation.
The ECG can be used as a rough guide to some cellular properties
of cardiac tissue (Figure 29–4):
• Heart rate reflects sinus node automaticity.
• PR-interval duration reflects AV nodal conduction time.
• QRS duration reflects conduction time in the ventricle.
• The QT interval is a measure of ventricular APD.
Refractoriness and Conduction Failure
In atrial, ventricular, and His–Purkinje cells, if a single action potential
is restimulated very early during the plateau, no Na + channels
are available to open, so no inward current results, and no action
potential is generated: At this point, the cell is termed refractory
(Figure 29–5). On the other hand, if a stimulus occurs after the cell
has repolarized completely, Na + channels have recovered from inactivation,
and a normal Na + channel–dependent upstroke results with
the same amplitude as the previous upstroke (Figure 29–5A). When
a stimulus occurs during phase 3 of the action potential, the
upstroke of the premature action potential is slower and of smaller
magnitude. The magnitude depends on the number of Na + channels
that have recovered from inactivation (Figure 29–5B). The recovery
from inactivation is faster at more hyperpolarized membrane potentials.
Thus, refractoriness is determined by the voltage-dependent
recovery of Na + channels from inactivation. Refractoriness frequently
is measured by assessing whether premature stimuli applied
to tissue preparations (or the whole heart) result in propagated
impulses. Although the magnitude of the Na + current is one major
determinant of propagation of premature beats, cellular geometry
also is important in multicellular preparations. Propagation from
cell to cell requires current flow from the first site of activation and
consequently can fail if inward current is insufficient to drive activation
in many neighboring cells. The effective refractory period
(ERP) is the longest interval at which a premature stimulus fails to
generate a propagated response and often is used to describe drug
effects in intact tissue.
A
B
mV
% OF Na + CHANNELS
(recovered from inactivation)
40
0
–40
–80
100
80
60
40
20
rest
drug
open
inactivated
drug-free
0
–100 –80 –60 –40
TRANSMEMBRANE
POTENTIAL (mV)
The situation is different in tissue whose depolarization is
largely controlled by Ca 2+ channel current such as the AV node. As
Ca 2+ channels have a slower recovery from inactivation, these tissues
often are referred to as slow response, in contrast to fast response in
the remaining cardiac tissues (Figure 29–5C). Even after a Ca 2+
channel–dependent action potential has repolarized to its initial resting
potential, not all Ca 2+ channels are available for re-excitation.
Therefore, an extra stimulus applied shortly after repolarization is
complete and generates a reduced Ca 2+ current, which may propagate
slowly to adjacent cells prior to extinction. An extra stimulus
applied later will result in a larger Ca 2+ current and faster propagation.
Thus, in Ca 2+ 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 prolonged
and propagation occurs slowly. Conduction that exhibits such
dependence on the timing of premature stimuli is termed decremental.
Slow conduction in the heart, a critical factor in the genesis of
re-entrant arrhythmias (see next section), 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
(Figure 29–5B).
C
= stimulus
Figure 29–5. Qualitative differences in responses of nodal and
conducting tissues to premature stimuli. A. With a very early premature
stimulus (black arrow) in ventricular myocardium, all
Na + channels still are in the inactivated state, and no upstroke
results. As the action potential repolarizes, Na + channels recover
from the inactivated to the resting state, from which opening can
occur. The phase 0 upstroke slope of the premature action potentials
(purple) are greater with later stimuli because recovery from
inactivation is voltage dependent. B. The relationship between
transmembrane potential and degree of recovery of Na + channels
from inactivation. The dotted line indicates 25% recovery.
Most Na + channel–blocking drugs shift this relationship to the
left. C. In nodal tissues, premature stimuli delivered even after
full repolarization of the action potential are depressed; recovery
from inactivation is time dependent.
819
CHAPTER 29
ANTI-ARRHYTHMIC DRUGS