CHAPTER 3 • CELLULAR STRUCTURE AND FUNCTION
49
intracellular calcium concentrations. Lusi-
tropy can be increased by increasing SERCA
activity through phosphorylation of phos-
pholamban, a regulatory protein associated
with SERCA. Phosphorylation of phos-
pholamban removes its inhibitory effect
on SERCA. This is a normal physiologic
mechanism in response to ff-adrenoceptor
stimulation, which increases cAMP and
PK-A, the latter of which phosphorylâtes
phospholamban. Impairment of the activ-
ity of the SERCA pump, as occurs in some
forms of heart failure, causes intracellular
calcium concentrations to rise, leading to
impaired relaxation.
4. The binding affinity of TN-C for calcium
also influences lusitropy. Calcium binding
to TN-C can be modulated by PK-A phos-
phorylation of TN-I. This increases calcium
dissociation from TN-C, thereby increas-
ing relaxation. The increased lusitropy
caused
by
P-adrenoceptor
stimulation
may be partly related to TN-I phospho-
rylation. Some drugs used to increase the
force of contraction (inotropic drugs) do
so by increasing TN-C affinity for calcium.
Although this may increase inotropy, it also
may lead to reduced lusitropy because the
calcium is more tightly bound to the TN-C.
PROBLEM 3-1
Describe the mechanisms by which
norepinephrine, after being released by
sympathetic nerve activation, increases
myocardial inotropy and lusitropy. Note
that norepinephrine primarily binds to
^-adrenoceptors, although it also can
bind to cq-adrenoceptors.
Cardiac Myocyte Metabolism
The maintenance of ionic pumps and other
transport systems in living cells requires
significant amounts of energy, primarily in
the form of ATP. Cardiac myocytes have an
exceptionally high metabolic rate because
their primary function is to contract repeti-
tively. Unlike skeletal muscle, in which con-
traction is often intermittent and relatively
short, cardiac muscle contracts one to three
times per second throughout life. Repetitive
cycles of contraction and relaxation require
an enormous amount of ATP, which the heart
must produce aerobically. This is why car-
diac myocytes contain such large numbers of
mitochondria. In the absence of oxygen, myo-
cytes can contract for no more than a minute.
Unlike some types of skeletal muscle fibers
(e.g., fast twitch, glycolytic), cardiac myo-
cytes have only a limited anaerobic capacity
for meeting ATP requirements. This limited
anaerobic capacity coupled with a high use
of ATP explains why cellular ATP concentra-
tions fall and contractions weaken so rapidly
under hypoxic conditions.
Unlike many other cells in the body, car-
diac myocytes can use a variety of substrates
to regenerate ATP oxidatively. For example, in
an overnight fasted state, the heart uses pri-
marily fatty acids (-60%) and carbohydrates
(-40%). Following a high-carbohydrate meal,
the heart can adapt to using carbohydrates
(primarily glucose) almost exclusively. Lac-
tate can be used in place of glucose, and it
becomes an important substrate during exer-
cise when circulating concentrations of lac-
tate increase. The heart also can use amino
acids and ketones (e.g., acetoacetate) instead
of fatty acids.
Myocyte ATP use and oxygen consumption
increase dramatically when the frequency of
contraction (i.e., heart rate) and the force of
contraction are increased. Under these condi-
tions, more oxygen must be delivered to the
heart by the coronary circulation to support
myocyte metabolic demands. As Chapter 8 dis-
cusses, biochemical signals from the myocytes
dilate the coronary blood vessels to supply addi-
tional blood flow and oxygen to meet greater
oxygen demands. This ensures that the heart is
able to generate ATP by aerobic mechanisms.
VASCULAR STRUCTURE
AND FUNCTION
Large blood vessels, both arterial and venous,
are composed of three layers—intima, media,
and adventitia (Fig. 3.7). The intima, or
innermost layer, is composed of a single layer
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