not increased by Gq-proteins linked to
o^-adrenoceptors, and fi-adrenoceptors
in the heart are not coupled to IP3;
however, IP3 may increase in the heart
because norepinephrine also binds to
cardiac o^-adrenoceptors.
The correct answer is “d” because endo-
thelial-derived nitric oxide normally
inhibits platelet aggregation and clot for-
mation; therefore, decreased nitric oxide
production can lead to clot formation.
Choice “a” is incorrect because the pro-
duction of nitric oxide and prostacyclin
are decreased when the endothelium is
damaged or dysfunctional. Choice “b” is
incorrect because decreased endothelial
cGMP does not affect platelet function.
Choice “c” is incorrect because dysfunc-
tional endothelium results in decreased
prostacyclin production.
Sympathetic nerve stimulation releases nor-
epinephrine, which binds to Pj-adrenoceptors
and a i -adrenoceptors found on cardiac myo-
cytes. P1-adrenoceptor activation stimulates
cAMP production through the Gs-protein.
cAMP production activates protein kinase A
(PK-A), which phosphorylâtes L-type calcium
channels, leading to an increase in calcium
influx during the action potential. Increased
calcium influx triggers increased calcium
release by the sarcoplasmic reticulum, lead-
ing to increased calcium binding by TN-C.
Calcium binding increases myosin ATPase
activity and force generation. PK-A also
phosphorylâtes phospholamban and removes
its inhibition of SERCA, which leads to
increased calcium reuptake by the sarcoplas-
mic reticulum and increases the rate of relax-
ation, or lusitropy. Increased calcium within
the sarcoplasmic reticulum subsequently
enhances the release of calcium from the
sarcoplasmic reticulum. In addition, PK-A
may phosphorylate sites on the sarcoplasmic
reticulum to enhance calcium release. PK-A
phosphorylation of TN-I also may contrib-
ute to enhanced lusitropy by altering TN-C
affinity for calcium. Although physiologically
less important than the [^-adrenoceptor-Gs
protein pathway, norepinephrine binding to
a i -adrenoceptors increases the formation of
IP3 via Gq-protein and phospholipase C acti-
vation, which stimulates the release of calci-
um from the sarcoplasmic reticulum, leading
to an increase in inotropy.
Increasing cAMP in the heart activates pro-
tein kinase A, which phosphorylâtes differ-
ent sites within the cells (see the answer to
Problem 3-1). Phosphorylation enhances
calcium influx into the cell and calcium
release by the sarcoplasmic reticulum, lead-
ing to an increase in inotropy. In vascular
smooth muscle, myosin light chain kinase,
when activated by calcium-calmodulin,
phosphorylâtes myosin light chains to
stimulate smooth muscle contraction. cAMP
inhibits myosin light chain kinase; therefore,
an increase in cAMP by a phosphodiester-
ase inhibitor such as milrinone inhibits the
myosin light chain kinase, thereby reducing
smooth muscle contraction.
Acetylcholine has two effects on blood
vessels. When acetylcholine hinds to M2
receptors on the vascular endothelium, it
stimulates the formation of nitric oxide
(NO) by NO synthase. The NO can then
diffuse from the endothelial cell into the
adjacent smooth muscle cells, where it
activates guanylyl cyclase to form cGMP.
Increased cGMP relaxes vascular smooth
muscle cells by inhibiting calcium entry
into the cell and by other mechanisms.
Acetylcholine, however, also can bind
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