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

Inward
Outward
Na + current
Ca 2+ L-type
current T-type
Transient I TO1
outward
current I TO2
I
Transient Ks
outward I Kr
current
I Kur
I C or I Kp
Inward rectifier, I K1
Pacemaker current, I I1
Na + -Ca 2+ exchange
Na + , K + -ATPase
1
(termed I TO
), 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 Ca 2+ channels, are balanced by outward, repolarizing currents
primarily through K + (“delayed-rectifier”) channels. Delayed-rectifier
currents (collectively termed I K
) increase with time, whereas Ca 2+
currents inactivate (and so decrease with time); as a result, cardiac
cells repolarize (phase 3) several hundred milliseconds after the initial
Na + channel opening. Mutations in the genes encoding repolarizing
K + channels are responsible for the most common forms of
the congenital long QT syndrome (Nerbonne and Kass, 2005).
Identification of these specific channels has allowed more precise
characterization of the pharmacologic effects of anti-arrhythmic
drugs. A common mechanism whereby drugs prolong cardiac action
potentials and provoke arrhythmias is inhibition of a specific
2
0 3
4
200 msec Primary gene
SCN5A
(4-AP-sensitive)
(Ca 2+ -activated)
CACNA1C
CACNA1H
KCND2/KCND3
KCNQ1/KCNE1
KCNH2(HERS)
KCNA5
KCNJ2
HCN4
NCX
ATP1A/ATP1B
group
Figure 29–3. The relationship between an action potential from
the conducting system and the time course of the currents that
generate it. The current magnitudes are not to scale; the Na + current
is ordinarily 50 times larger than any other current, although
the portion that persists into the plateau (phase 2) is small.
Multiple types of Ca 2+ current, transient outward current (I TO
),
and delayed rectifier (I K
) have been identified. Each represents a
different channel protein, usually associated with ancillary
(function-modifying) subunits. 4-AP (4-aminopyridine) is a
widely used in vitro blocker of K + channels. I TO2
may be a Cl –
current in some species. Components of I K
have been separated on
the basis of how rapidly they activate: slowly (I Ks
), rapidly (I Kr
),
or ultra-rapidly (I Kur
). The voltage-activated, time-independent
current may be carried by Cl – (I Cl
) or K + (I Kp
, p for plateau). The
genes encoding the major pore-forming proteins have been
cloned for most of the channels shown here and are included in
the right-hand column. The righthand column lists the primary
genes that code for the various ion channels and transporters.
delayed-rectifier current, I Kr
, 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; understanding these structural constraints is an important
first step to designing drugs lacking I Kr
-blocking properties
(Mitcheson et al., 2000). Avoiding I Kr
/HERG channel block has
become a major issue in the development of new anti-arrhythmic
drugs (Roden, 2004).
Action Potential Heterogeneity
in the Heart
The diversity of action potentials seen throughout different regions
of the heart plays a role in understanding the pharmacologic profiles
of anti-arrhythmic drugs. This general description of the action
potential and the currents that underlie it must be modified for certain
cell types (Figure 29–4), primarily due to variability in the
expression of ion channels and electrogenic ion transport pumps.
In the ventricle, action potential duration (APD) and shape vary
across the wall of each chamber, as well as apico-basally (Figure
29–4). In the neighboring His–Purkinje system, action potentials
are characterized by a more hyperpolarized plateau potential and
prolongation of the action potential due to divergent ion channel
expression and differences in intercellular Ca 2+ handling (Dun and
Boyden, 2008). Atrial cells have short action potentials, probably
because I TO
is larger, and an additional repolarizing K + current, activated
by the neurotransmitter 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,
and depolarization is achieved by the movement of Ca 2+
across the membrane. 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. Several ionic channels
and transport pumps underlie pacemaker currents in the heart.
One of the pacemaking currents responsible for this automaticity is
generated via specialized K + channels, the hyperpolarizationactivated
cyclic nucleotide-gated (HCN) channels that are permeable
to both potassium and sodium (Cohen and Robinson, 2006).
Another major mechanism responsible for automaticity is the repetitive
spontaneous Ca 2+ release from the sarcoplasmic reticulum
(SR), a specialized endoplasmic reticulum found in striated muscle
cells (Vinogradova and Lakatta, 2009). The rise in cytosolic
Ca 2+ causes membrane depolarizations when Ca 2+ is extruded from
the cell via the electrogenic Na-Ca exchanger (NCX). In addition,
sinus node cells lack inward rectifier K + currents that are primarily
responsible for protecting working myocardium against spontaneous
membrane depolarizations.
Molecular biologic and electrophysiologic techniques
have refined the description of ion channels important for the normal
functioning of cardiac cells and have identified channels that
may be particularly important under pathologic conditions. For
example, the transient outward and delayed-rectifier currents actually
result from multiple ion channel subtypes (Tseng and
Hoffman, 1989; Sanguinetti and Jurkiewicz, 1990) (Figure 29–3).
817
CHAPTER 29
ANTI-ARRHYTHMIC DRUGS