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

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SA node
Atrium
AV node
Purkinje fiber
Endocardium
Mid-myocardium
Septum
RV
LV
Apex
Epicardium
SECTION III
P
R
400 msec
T
MODULATION OF CARDIOVASCULAR FUNCTION
Q
S
QT
Figure 29–4. Normal impulse propagation. A schematic of the human heart with example action potentials from different regions of
the heart (top) for a normal beat and their corresponding contributions to the macroscopic ECG (bottom). AV, atrioventricular; LV, left
ventricle; RV, right ventricle; SA, sinoatrial. (Used with permission from The Am Physiol Soc. Nerbonne and Kass, Physiol Rev, 2005.)
The acetylcholine-evoked hyperpolarization results from activation
of a K + channel formed by hetero-oligomerization of multiple, distinct
channel proteins (Krapivinsky et al., 1995). The understanding
that molecularly diverse entities subserve regulation of the cardiac
action potential is important because drugs may target one channel
subtype selectively. Furthermore, ancillary function-modifying proteins
(the products of diverse genes) have been identified for most
ion channels.
Maintenance of Intracellular Ion
Homeostasis
With each action potential, the cell interior gains Na + ions and loses
K + ions. An ATP-requiring Na + –K + exchange mechanism, or pump,
is activated in most cells to maintain intracellular homeostasis. This
Na + ,K + -ATPase extrudes three Na + ions for every two 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, basal intracellular Ca 2+ is maintained at very low
levels (100 nM). In cardiac myocytes, the entry of Ca 2+ during each
action potential through L-type Ca 2+ channels is a signal to the sarcoplasmic
reticulum to release its Ca 2+ stores. The efflux of Ca 2+ from
the sarcoplasmic reticulum occurs through ryanodine-receptor
(RyR2) Ca 2+ release channels, and the resulting increase in intracellular
Ca 2+ subsequently triggers Ca 2+ -dependent contractile processes
(= excitation-contraction coupling). Removal of intracellular Ca 2+
occurs by both Ca 2+ -ATPase (which moves Ca 2+ ions back into the
sarcoplasmic reticulum) and NCX, which exchanges three Na + ions
from the exterior for each Ca 2+ ion extruded. Abnormal regulation of
intracellular Ca 2+ is increasingly well described in heart failure and
contributes to arrhythmias in this setting. Furthermore, mutations that
disrupt the normal activity of the RyR2 channels and the cardiac isoform
of calsequestrin have been linked to catecholaminergic polymorphic
ventricular tachycardia (CPVT), thereby demonstrating a
direct link between spontaneous sarcoplasmic reticulum Ca 2+ release
and cardiac arrhythmias (Mohamed et al., 2007). Inhibiting RyR2
channels with flecainide appears to prevent CPVT in mouse models
and in humans (Watanabe et al., 2009). Thus, in both CPVT and heart
disease, the cardiac ryanodine receptor has become an intriguing target
for future anti-arrhythmic drug therapies.
Impulse Propagation
and the Electrocardiogram
Normal cardiac impulses originate in the sinus node. Impulse propagation
in the heart depends on two factors: the magnitude of the
depolarizing current (usually Na + current) and the geometry of
cell–cell electrical connections. Cardiac cells are relatively long and
thin and well coupled through specialized gap junction proteins at
their ends, whereas lateral (“transverse”) gap junctions are sparser.