48
CARDIOVASCULAR PHYSIOLOGY CONCEPTS
sensitivity of TN-C, thereby increasing cal-
cium
binding.
The mechanism
by which
changes in length increase calcium affinity by
TN-C is unknown.
MYOSIN ATPASE ACTIVITY
The myosin heads have sites (myosin light
chains) that can be phosphorylated by the
enzyme myosin light chain kinase (Fig. 3.5,
site 4). Increased cAMP is known to be asso-
ciated with increased phosphorylation of the
myosin heads, which may increase inotropy.
The physiologic significance of this mecha-
nism, however, is uncertain.
CALCIUM UPTAKE BY SARCOPLASMIC
RETICULUM
In addition to influencing relaxation, increas-
ing calcium transport into the sarcoplasmic
reticulum by the SERCA pump can indirectly
increase the amount of calcium released by the
sarcoplasmic reticulum (Fig. 3.5, site 5). PK-A
phosphorylation
of phospholamban, which
removes the inhibitory effect of phospholamban
on SERCA, increases the rate of calcium trans-
port into the sarcoplasmic reticulum. SERCA
activity can also be stimulated by increased
intracellular calcium caused by increased cal-
cium entry into the cell or decreased cellular
efflux. Enhanced sequestering of calcium by
the sarcoplasmic reticulum increases subse-
quent release of calcium by the sarcoplasmic
reticulum, thereby increasing inotropy Because
the SERCA pump requires ATP, hypoxic con-
ditions that reduce ATP production by the cell
can diminish the pump activity, thereby reduc-
ing subsequent release of calcium by the sarco-
plasmic reticulum and decreasing inotropy.
REGULATION OF CALCIUM EFFLUX
FROM THE MYOCYTE
The final mechanisms that can modulate inot-
ropy are the sarcolemmal Na+
/Ca++
exchange
pump and the ATP-dependent calcium pump
(Fig. 3.5, site 6). As described in Chapter 2,
these pumps transport calcium out of the cell,
thereby preventing the cell from becoming
overloaded with calcium. If calcium extrusion
is inhibited, the rise in intracellular calcium
can increase inotropy because more calcium
is available to be taken up by the sarcoplasmic
reticulum and subsequently released.
Digoxin
and
related
cardiac
glycosides
inhibit the Na+
/K+-ATPase, which increases
intracellular Na+ (see Chapter 2). This leads
to an increase in intracellular Ca++
through the
Na+
/Ca++
exchange pump, leading to enhanced
inotropy Cellular hypoxia also decreases the
activity of the Na+
/K+-ATPase pump, as well as
the Ca++-ATPase pump, by reducing ATP avail-
ability. This leads to calcium accumulation in
the cell; however, inotropy is not increased, in
part, because the lack of ATP decreases myo-
sin ATPase activity.
Regulation of Relaxation
(Lusitropy)
The rate of myocyte relaxation (lusitropy) is
determined by the ability of the cell to rap-
idly reduce the intracellular concentration
of
calcium
following
its
release
by
the
sarcoplasmic reticulum.
This reduction in
intracellular calcium causes calcium that is
bound to TN-C to be released, thereby permit-
ting the troponin-tropomyosin complex to
resume its resting, inactivated conformation.
Several intracellular mechanisms help to
regulate lusitropy, most of which influence
intracellular calcium concentrations.
1. The rate at which calcium enters the cell
at rest and during action potentials influ-
ences intracellular concentrations. Under
some pathologic conditions (e.g., myo-
cardial ischemia), the cell becomes more
permeable to calcium, leading to “calcium
overload,” which impairs relaxation.
2. The rate with which calcium leaves the cell
through the sarcolemmal calcium ATPase
pump and the Na+
/Ca++
exchange pump
(see Chapter 2) affects intracellular concen-
trations. Inhibiting these transport systems
can cause intracellular calcium concen-
trations to increase sufficiently to impair
relaxation.
3. The activity of the SERCA pump, which
pumps calcium back into the sarcoplasmic
reticulum, has a major role in determining
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