contractile proteins. Any cellular mechanism
that ultimately alters myosin ATPase activity
generation and therefore can be considered
an inotropic mechanism. Most of the signal
transduction pathways
that regulate inot-
ropy involve Ca++
(see Chapter 3 for details).
Briefly, the following calcium-related intracel-
lular mechanisms play an important role in
regulating inotropy:
1. Increasing Ca++
influx across the sarco-
lemma during the action potential
2. Increasing the release of Ca++
by the sarco-
plasmic reticulum
3. Sensitizing troponin C to Ca++
Previous discussion focused on the independ-
ent effects of preload, afterload, and inotropy
on ventricular function; however, it is impor-
tant to understand that these determinants of
ventricular function are also interdependent.
For example, a change in preload leads to
secondary changes in afterload that can alter
the initial response to the change in preload.
Furthermore, a change in afterload leads to
changes in preload, and a change in inotropy
can alter both preload and afterload.
responses to a change in preload can be modi-
fied by secondary changes in afterload. Similar
to Figure 4.11, panel A of Figure 4.24 (solid
red loop) shows that the independent effect
of an increase in preload (EDV) is an increase
in SV (width of pressure-volume loop) with-
out a change in ESV However, because SV is
increased, cardiac output is increased, and
this will likely lead to an increase in arterial
pressure, which increases afterload. Further-
more, the increase in EDV increases ven-
tricular wall stress (see Equation 4-2), which
represents an increase in afterload. Therefore,
a change in preload is normally accompanied
by a secondary change in afterload. If after-
load increases when there is an increase in
preload (dashed red loop), then this will lead
to a small increase in ESV that will partially
attenuate the increase in SV brought about by
the increased preload as shown in Figure 4.24
(panel A). The increased preload still results
in an increase in SV, but the increase is less
than what would have occurred had the after-
load not increased.
An increase in afterload, as previously dis-
cussed, leads to a decrease in SV and an increase
in ESV as shown in Figure 4.24 (panel B,
solid red loop). However, because the ESV is
increased, changes in afterload produce sec-
ondary changes in preload (dashed red loop).
The increased ESV inside the ventricle is added
to the venous return, thereby increasing EDV.
After several beats, a steady state is achieved in
which the increase in ESV is greater than the
secondary increase in EDV so that the differ-
ence between the two—the SV—is decreased
(i.e., the width of the pressure-volume loop is
decreased). This increase in preload secondary
to an increase in afterload activates the Frank-
Starling mechanism, which partially compen-
sates for the reduction in SV caused by the
initial increase in afterload.
The direct, independent effects of an increase
inotropy are an increase in SV and a decrease in
ESV (Fig. 4.24, panel C, solid red line). How-
ever, the increased SV increases cardiac output
and arterial pressure, which increases afterload
on the ventricle (dashed red line). Increased
afterload tends to increase ESV, which par-
tially offsets the effects of increased inotropy
on ESV With a decrease in ESV from control,
less blood remains in the ventricle that can be
added to the venous return, so the EDV will
be smaller, although this will be partially off-
set by the tendency of the increased afterload
to increase EDV. After a new steady state is
reached following the increase in inotropy, the
net effect of these changes is an increase in SV,
which is accompanied by a reduction in ESV
and a smaller reduction in EDV
The interactions between preload, after-
load, and inotropy can also be visualized
In this figure, the left ventricle under con-
trol conditions has a SV of 60 mL at an
end-diastolic pressure (index of preload) of
about 8 mm Hg. Decreasing the afterload or
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