5 4
CARDIOVASCULAR PHYSIOLOGY CONCEPTS
smooth muscle cells, where it activates gua-
nylyl cyclase, increases cGMP formation, and
causes smooth muscle relaxation. The precise
mechanisms by which cGMP relaxes vascular
smooth muscle are unclear; however, cGMP
can
activate
a
cGMP-dependent
protein
kinase, inhibit calcium entry into the vascular
smooth muscle, activate K+
channels causing
cellular hyperpolarization, stimulate myosin
light chain phosphatase, and decrease IP3.
PROBLEM 3-2
Intracellular cAMP is degraded by a
phosphodiesterase enzyme. Milrinone, a
drug sometimes used in the treatment of
acute heart failure, is a phosphodiesterase
inhibitor that increases cardiac inotropy
and relaxes blood vessels by inhibiting
the degradation of cAMP. Explain why
an increase in cAMP in cardiac muscle
increases the force of contraction,
whereas an increase in cAMP in vascular
smooth muscle cells diminishes the force
of contraction.
Vascular Endothelial Cells
The vascular endothelium is a thin layer of
cells that line all blood vessels. Endothelial
cells are flat, single-nucleated, elongated cells
that are 0.2 to 2.0 pm thick and 1 to 20 pm
across (varying by vessel type). Depending
on the type of vessel (e.g., arteriole versus
capillary) and tissue location (e.g., renal glo-
merular versus skeletal muscle capillaries),
endothelial cells are joined together by differ-
ent types of intercellular junctions. Some of
these junctions are very tight (e.g., all arter-
ies and skeletal muscle capillaries), whereas
others have gaps between the cells (e.g.,
capillaries in spleen and bone marrow) that
enable blood cells to move in and out of the
capillary easily. See Chapter 8 for informa-
tion about different types of capillaries and
endothelium.
Endothelial cells have several important
functions, including
1. Serving as a barrier for the exchange
of
fluid,
electrolytes,
macromolecules,
and cells between the intravascular and
extravascular space (see Chapter 8)
2. Regulating
smooth
muscle
function
through the synthesis of several different
vasoactive substances, the most important
of which are NO, PGI2, and endothelin-1
3. Modulating platelet aggregation primarily
through biosynthesis of NO and PGI2
4. Modulating
leukocyte
adhesion
and
transendothelial migration
through
the
biosynthesis of NO and the expression of
surface adhesion molecules
Vascular
endothelial
cells
continuously
produce NO. This basal NO production can
be enhanced by (1) specific agonists (e.g., ace-
tylcholine, bradykinin) binding to endothelial
receptors; (2) increased shearing forces act-
ing on the endothelial surface (e.g., as occurs
with increased blood flow); and (3) cytokines
such as tumor necrosis factor and interleukins,
which are released by leukocytes during inflam-
mation and infection. NO, although very labile,
rapidly diffuses out of endothelial cells to cause
smooth muscle relaxation or inhibit platelet
aggregation in the blood. Both of these actions
of NO result from increased cGMP formation
(see Fig. 3.10). Endothelial NO also inhibits
the expression of adhesion molecules involved
in attaching leukocytes to the endothelial sur-
face. Therefore, endothelial-derived NO relaxes
smooth muscle, inhibits platelet function, and
inhibits inflammatory responses (Fig. 3.11).
Platelets
FIGURE 3.11 Endothelial cell (EC) produc-
tion of nitric oxide (A/O), prostacyclin (PG/2),
and endothelin-1 (ET-7) stimulates (+) or inhibits
(-) vascular smooth muscle (
VSM)
contraction,
platelet aggregation and adhesion, and leukocyte-
endothelial cell adhesion.
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