Ganong's Review of Medical Physiology, 23rd Edition

564
SECTION VI
Cardiovascular Physiology

different stimuli act on the endothelial cells to produce
endo-
thelium-derived relaxing factor (EDRF),
a substance that is
now known to be
nitric oxide (NO).
NO is synthesized from
arginine (Figure 33–9) in a reaction catalyzed by nitric oxide
synthase (NO synthase, NOS). Three isoforms of NOS have
been identified: NOS 1, found in the nervous system; NOS 2,
found in macrophages and other immune cells; and NOS 3,
found in endothelial cells. NOS 1 and NOS 3 are activated by
agents that increase intracellular Ca
2+
concentrations, includ-
ing the vasodilators acetylcholine and bradykinin. The NOS in
immune cells is not activated by Ca
2+
but is induced by cyto-
kines. The NO that is formed in the endothelium diffuses to
smooth muscle cells, where it activates soluble guanylyl cy-
clase, producing cyclic 3,5-guanosine monophosphate (cG-
MP; see Figure 33–9), which in turn mediates the relaxation of
vascular smooth muscle. NO is inactivated by hemoglobin.
Adenosine, atrial natriuretic peptide (ANP), and histamine
via H
2
receptors produce relaxation of vascular smooth muscle
that is independent of the endothelium. However, acetylcho-
line, histamine via H
1
receptors, bradykinin, vasoactive intesti-
nal peptide (VIP), substance P, and some other polypeptides
act via the endothelium, and various vasoconstrictors that act
directly on vascular smooth muscle would produce much
greater constriction if their effects were not limited by their
ability simultaneously to cause release of NO. When flow to a
tissue is suddenly increased by arteriolar dilation, the large
arteries to the tissue also dilate. This flow-induced dilation is
due to local release of NO. Products of platelet aggregation also
cause release of NO, and the resulting vasodilation helps keep
blood vessels with an intact endothelium patent. This is in
contrast to injured blood vessels, where the endothelium is

damaged at the site of injury and platelets therefore aggregate

and produce vasoconstriction (see Chapter 32).

Further evidence for a physiologic role of NO is the obser-

vation that mice lacking NOS 3 are hypertensive. This sug-

gests that tonic release of NO is necessary to maintain normal

blood pressure.

NO is also involved in vascular remodeling and angiogene-

sis, and NO may be involved in the pathogenesis of athero-

sclerosis. It is interesting in this regard that some patients with

heart transplants develop an accelerated form of atherosclero-

sis in the vessels of the transplant, and there is reason to

believe that this is triggered by endothelial damage. Nitroglyc-

erin and other nitrovasodilators that are of great value in the

treatment of angina act by stimulating guanylyl cyclase in the

same manner as NO.

Penile erection is also produced by release of NO, with con-

sequent vasodilation and engorgement of the corpora caver-

nosa (see Chapter 25). This accounts for the efficacy of drugs

such as Viagra, which slow the breakdown of cGMP.

OTHER FUNCTIONS OF NO

NO is present in the brain and, acting via cGMP, it is impor-

tant in brain function (see Chapter 7). It is necessary for the

antimicrobial and cytotoxic activity of various inflammatory

cells, although the net effect of NO in inflammation and tissue

injury depends on the amount and kinetics of release, which in

turn may depend on the specific NOS isoform involved. In the

gastrointestinal tract, it is important in the relaxation of

smooth muscle. Other functions of NO are mentioned in oth-

er parts of this book.

CARBON MONOXIDE

The production of carbon monoxide (CO) from heme is

shown in Figure 29–4. HO2, the enzyme that catalyzes the re-

action, is present in cardiovascular tissues, and there is grow-

ing evidence that CO as well as NO produces local dilation in

blood vessels. Interestingly, hydrogen sulfide is likewise

emerging as a third gaseotransmitter that regulates vascular

tone, although the relative roles of NO, CO, and H

2

S have yet

to be established.

ENDOTHELINS

Endothelial cells also produce

endothelin-1,

one of the most

potent vasoconstrictor agents yet isolated. Endothelin-1 (ET-

1), endothelin-2 (ET-2), and endothelin-3 (ET-3) are the

members of a family of three similar 21-amino-acid polypep-

tides (Figure 33–10). Each is encoded by a different gene. The

unique structure of the endothelins resembles that of the sa-

rafotoxins, polypeptides found in the venom of a snake, the

Israeli burrowing asp.

FIGURE 33–9
Synthesis of NO from arginine in endothelial
cells and its action via stimulation of soluble guanylyl cyclase and
generation of cGMP to produce relaxation in vascular smooth
muscle cells.
The endothelial form of nitric oxide synthase (NOS) is ac-
tivated by increased intracellular Ca
2+
concentration, and an increase
is produced by acetylcholine (Ach), bradykinin, or shear stress acting
on the cell membrane. Thiol, tetrahydrobiopterin, FAD, and FMN are
requisite cofactors.

Ach

Bradykinin

Shear

stress

Ca^2 + NOS

L-Arginine+ O 2 + NADPH

Citruline+ NO + NADP

Thiol

Tetrahydro-

biopterin

FAD

FMN

GTP

cGMP

Smooth muscle relaxation

Soluble

guanylyl

cyclase