152
CARDIOVASCULAR PHYSIOLOGY CONCEPTS
the vasodilation accompanying ACE inhibi-
tion. Some arachidonic acid m etabolites such
as prostaglandin E2 (PGE2) are vasodilators,
whereas other eicosanoids such as PG F ,
thromboxanes, and leukotrienes are generally
vasoconstrictors. Drugs that block the forma-
tion of these eicosanoids (e.g., cyclooxyge-
nase inhibitors such as aspirin or ibuprofen)
alter vascular control by these substances.
Endothelial Factors
The vascular endothelium serves an important
paracrine role in the regulation of smooth mus-
cle tone and organ blood flow. As described in
Chapter 3, the vascular endothelium produces
vasoactive substances that have significant
effects on vascular smooth muscle. Circulat-
ing
(endocrine)
and
paracrine
hormones,
shearing forces, hypoxia, and many different
drugs can stimulate the formation and release
of endothelial substances (Fig. 7.2). Among
their many actions, two of these substances,
nitric oxide and prostacyclin, are powerful
Circulating Hormones
Paracrine Hormones
Shearing Forces
Hypoxia
■ FIGURE 7.2 Endothelial-derived vasoactive
factors. Nitric oxide (NO) formed by nitric oxide
synthase
(NOS)
acting on L-arginine
(L-arg),
endothelial-derived hyperpolarizing factor
(EDHF),
and prostacyclin
(PGI2)
derived from arachidonic
acid (AA) inhibit (-) smooth muscle contraction and
cause vasodilation. Endothelin-1
(ET-1)
formed by
endothelin-converting enzyme
(ECE)
causes smooth
muscle contraction (+). The formation and release of
these substances are influenced by circulating and
paracrine hormones, shearing forces acting on the
endothelium, hypoxia, and many different drugs.
vasodilators. In contrast, endothelin-1 is a
powerful vasoconstrictor.
Nitric
oxide
appears
to
be
the
most
important in terms of regulating blood flow
under normal physiologic conditions. Nitric
oxide is synthesized in the endothelium by
the action of a nitric oxide synthase (NO S)
enzyme on the amino acid, L-arginine. Nitric
oxide diffuses from the endothelial cell to
the sm ooth muscle cells where it binds to
and activates intracellular guanylyl cyclase
to form cGMP, which leads to sm ooth muscle
relaxation (see Chapter 3). If nitric oxide syn-
thesis is inhibited pharmacologically using
NOS inhibitors, vasoconstriction occurs in
most vascular beds. This demonstrates that
there normally is a basal release of nitric
oxide that inhibits vascular tone; therefore,
blocking nitric oxide formation leads to an
increase in tone.
Nitric oxide is involved in what is termed
flow-dependent vasodilation. Experimental
studies have shown that an increase in vessel
flow (actually an increase in shearing forces
acting on the vascular endothelium) stimu-
lates
endothelial
nitric
oxide
production,
which causes vasodilation. Flow-dependent
vasodilation is particularly important as a
mechanism
for
increasing coronary blood
flow when cardiac activity and metabolism
are increased. Impaired nitric oxide synthesis
or decreased bioavailability, as occurs during
coronary artery disease, limits the ability of
coronary blood flow to increase when cardiac
activity and oxygen demand are increased.
Other disorders such as hypertension, cer-
ebrovascular disease, and diabetes are asso-
ciated with impaired endothelial control of
vascular function as well.
Another endothelial factor is endothelial-
derived hyperpolarizing factor (EDHF). Some
substances
(e.g.,
acetylcholine,
bradykinin)
that stimulate nitric oxide production stimulate
EDHF as well. The identity of this factor is not
known for certain, but its release causes smooth
muscle hyperpolarization and relaxation.
Prostacyclin (PGI2) is formed from arachi-
donic acid and the cyclooxygenase enzyme
within
endothelial
cells.
This
paracrine
substance is a potent vasodilator in addition to
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