46
CARDIOVASCULAR PHYSIOLOGY CONCEPTS
6
■ FIGURE 3.5 Intracellular mechanisms regulating inotropy. Inotropy can be increased by increasing
Ca++ influx through L-type Ca++ channels (site 1); increasing release of Ca++ by the sarcoplasmic reticulum
(
SR
) (site 2); increasing troponin-C
(TN-C)
affinity for Ca++ (site 3); increasing myosin-ATPase activity
through phosphorylation of myosin heads (site 4); increasing sarcoendoplasmic reticulum calcium ATPase
(SERCA)
activity by phosphorylation of phospholamban (site 5); or inhibiting Ca++ efflux across the
sarcolemma (site 6).
into the cell through L-type calcium channels;
(2)
calcium release by the sarcoplasmic reticu-
lum; (3) calcium binding to TN-C; (4) myosin
phosphorylation; (5) SERCA activity; and (6)
calcium efflux across the sarcolemma.
CALCIUM ENTRY INTO MYOCYTES
The amount of calcium that enters the cell
during depolarization (Fig. 3.5, site
1) is
regulated largely by phosphorylation of the
L-type calcium channel. The primary mech-
anism
for
this
regulation
involves
cyclic
adenosine monophosphate (cAMP), the for-
mation of which is coupled to ß-adrenocep-
tors (Fig. 3.6). Norepinephrine released by
sympathetic nerves, or circulating epineph-
rine released by the adrenal glands, binds
primarily to ß1-adrenoceptors located on the
sarcolemma. This receptor is coupled to a
specific guanine nucleotide-binding regula-
tory protein (stimulatory G-protein; Gs-pro-
tein), that activates adenylyl cyclase, which
in turn hydrolyzes ATP to cAMP. The cAMP
acts as a second messenger to activate protein
kinase A (cAMP-dependent protein kinase,
PK-A), which is capable of phosphorylating
different sites within the cell. One important
site of phosphorylation is the L-type calcium
channel. Phosphorylation increases the per-
meability of the channel to calcium, thereby
increasing
calcium
influx
during
action
potentials. This increase in trigger calcium
enhances calcium release by the sarcoplasmic
reticulum, thereby increasing inotropy. There-
fore, norepinephrine and epinephrine are pos-
itive inotropic agents.
Another G-protein, the inhibitory G-protein
(Gi-protein), inhibits adenylyl
cyclase and
decreases intracellular cAMP. Therefore, acti-
vation of this pathway decreases inotropy. This
pathway is coupled to muscarinic receptors
(M2) that bind acetylcholine released by para-
sympathetic (vagal) nerves within the heart.
Adenosine receptors (A1) also are coupled to
the Gi-protein. Therefore, acetylcholine and
adenosine are negative inotropic agents.
CALCIUM RELEASE BY THE
SARCOPLASMIC RETICULUM
Enhanced calcium release by the sarcoplasmic
reticulum also can increase inotropy (Fig. 3.5,
site 2). During P-adrenoceptor and cAMP
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