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

802 Mechanism of the Positive Inotropic Effect. With each cardiac
myocyte depolarization, Na + and Ca 2+ ions shift
into the intracellular space (Figure 28–5). Ca 2+ that
enters the cell via the L- type Ca 2+ channel during depolarization
triggers the release of stored intracellular Ca 2+
from the sarcoplasmic reticulum via the ryanodine
receptor (RyR). This Ca 2+ -induced Ca 2+ release increases
the level of cytosolic Ca 2+ available for interaction with
myocyte contractile proteins, ultimately increasing
myocardial contraction force. During myocyte repolarization
and relaxation, cellular Ca 2+ is re-sequestered by
the sarcoplasmic reticular Ca 2+ -ATPase and is removed
from the cell by the Na + Ca 2+ exchanger and, to a much
lesser extent, by the sarcolemmal Ca 2+ -ATPase.
Cardiac glycosides bind and inhibit the phosphorylated
(α subunit of the sarcolemmal Na + ,K + -
ATPase and thereby decreasing Na + extrusion and
increasing cytosolic [Na + ]. This decreases the transmembrane
Na + gradient that drives Na + −Ca 2+ exchange
during myocyte repolarization. As a consequence, less
Ca 2+ is removed from the cell and more Ca 2+ is accumulated
in the sarcoplasmic reticulum (SR) by
SERCA2. This increase in releasable Ca 2+ (from the
SR) is the mechanism by which cardiac glycosides
SECTION III
MODULATION OF CARDIOVASCULAR FUNCTION
Exterior
Interior
[Na + ] 0 = 140 mM, [K + ] 0 = 4 mM
[Na + ] i = 10 mM, [K + ] i = 150 mM
Ca 2+ Ca 2+ -
ATPase
PKA
PL
Ca 2+ RyR2
SR
PKA
SERCA2
Ca 2+
Ca 2+
PKA
L-type channel
Ca 2+ Ca 2+
NCX
NCX
(depolarized)
3Na + (polarized)
3 Na + 3 Na +
Na + , K +
ATPase
Na + channel
2K +
Na +
Figure 28–5. Sarcolemmal exchange of Na + and Ca 2+ during cell depolarization and repolarization. Na + and Ca 2+ enter the cardiac
myocyte via the Na + channel and the L- type Ca 2+ channel during each cycle of membrane depolarization, triggering the release,
through the ryanodine receptor (RyR), of larger amounts of Ca 2+ from internal stores in the sarcoplasmic reticulum (SR). The resulting
increase in intracellular Ca 2+ interacts with troponin C and activates interactions between actin and myosin that result in sarcomere
shortening. The electrochemical gradient for Na + across the sarcolemma is maintained by active transport of Na + out of the cell
by the sarcolemmal Na + ,K + -ATPase. The bulk of cytosolic Ca 2+ is pumped back into the SR by a Ca 2+ -ATPase, SERCA2. The remainder
is removed from the cell by either a sarcolemmal Ca 2+ -ATPase or a high- capacity Na + -Ca 2+ exchanger, NCX. NCX exchanges 3
Na + for every Ca 2+ , using the electrochemical potential of Na + to drive Ca 2+ extrusion. The direction of Na + -Ca 2+ exchange may reverse
briefly during depolarization, when the electrical gradient across the sarcolemma is transiently reversed. β adrenergic agonists and
PDE inhibitors, by increasing intracellular cyclic AMP levels, activate PKA, which phosphorylates phospholamban (PL), the α subunit
of the L- type Ca 2+ channel, and regulatory components of the RyR, as well as TnI, the inhibitory subunit of troponin (not shown).
As a result, the probabilities of opening of the L-type Ca 2+ channel and the RyR2 Ca 2+ channel are doubled; SERCA2 is uninhibited
and accumulates Ca 2+ into the SR faster, more avidly, and to a higher concentration; and relaxation occurs at slightly higher [Ca 2+ ] i
due to slightly reduced sensitivity of the troponin complex to Ca 2+ . The net effect of these phosphorylations is a positive inotropic effect:
a faster rate of tension development to a higher level of tension, followed by a faster rate of relaxation. ▲ indicates site of cardiac
glycoside binding. See the text for the mechanism of positive inotropic effect of cardiac glycosides.