CHAPTER 33
Cardiovascular Regulatory Mechanisms 563vasoconstriction in humans, but there is little change in blood
pressure. Exposure to high concentrations of CO
2
is associ-
ated with marked cutaneous and cerebral vasodilation, but
vasoconstriction occurs elsewhere and usually there is a slow
rise in blood pressure.
LOCAL REGULATION
AUTOREGULATION
The capacity of tissues to regulate their own blood flow is re-
ferred to as
autoregulation.
Most vascular beds have an intrin-
sic capacity to compensate for moderate changes in perfusion
pressure by changes in vascular resistance, so that blood flow
remains relatively constant. This capacity is well developed in
the kidneys (see Chapter 38), but it has also been observed in
the mesentery, skeletal muscle, brain, liver, and myocardium.
It is probably due in part to the intrinsic contractile response of
smooth muscle to stretch
(myogenic theory of autoregula-
tion).
As the pressure rises, the blood vessels are distended and
the vascular smooth muscle fibers that surround the vessels
contract. If it is postulated that the muscle responds to the ten-
sion in the vessel wall, this theory could explain the greater de-
gree of contraction at higher pressures; the wall tension is
proportional to the distending pressure times the radius of the
vessel (law of Laplace; see Chapter 32), and the maintenance of
a given wall tension as the pressure rises would require a de-
crease in radius. Vasodilator substances tend to accumulate in
active tissues, and these “metabolites” also contribute to auto-
regulation
(metabolic theory of autoregulation).
When blood
flow decreases, they accumulate and the vessels dilate; when
blood flow increases, they tend to be washed away.
VASODILATOR METABOLITES
The metabolic changes that produce vasodilation include, in
most tissues, decreases in O
2
tension and pH. These changes
cause relaxation of the arterioles and precapillary sphincters.
A local fall in O
2
tension, in particular, can initiate a program
of vasodilatory gene expression secondary to production of
hypoxia-inducible factor-1
α
(HIF-1
α
), a transcription factor
with multiple targets. Increases in CO
2
tension and osmolality
also dilate the vessels. The direct dilator action of CO
2
is most
pronounced in the skin and brain. The neurally mediated
vasoconstrictor effects of systemic as opposed to local hypoxia
and hypercapnia have been discussed above. A rise in temper-
ature exerts a direct vasodilator effect, and the temperature
rise in active tissues (due to the heat of metabolism) may con-
tribute to the vasodilation. K
- is another substance that accu-
mulates locally, and has demonstrated dilator activity
secondary to the hyperpolarization of vascular smooth muscle
cells. Lactate may also contribute to the dilation. In injured tis-
sues, histamine released from damaged cells increases capil-
lary permeability. Thus, it is probably responsible for some of
the swelling in areas of inflammation. Adenosine may play a
vasodilator role in cardiac muscle but not in skeletal muscle. It
also inhibits the release of norepinephrine.LOCALIZED VASOCONSTRICTION
Injured arteries and arterioles constrict strongly. The constric-
tion appears to be due in part to the local liberation of seroto-
nin from platelets that stick to the vessel wall in the injured
area. Injured veins also constrict.
A drop in tissue temperature causes vasoconstriction, and
this local response to cold plays a part in temperature regula-
tion (see Chapter 18).SUBSTANCES SECRETED
BY THE ENDOTHELIUM
ENDOTHELIAL CELLS
As noted in Chapter 32, the endothelial cells constitute a large
and important tissue. They secrete many growth factors and va-
soactive substances. The vasoactive substances include prosta-
glandins and thromboxanes, nitric oxide, and endothelins.PROSTACYCLIN & THROMBOXANE A
2Prostacyclin is produced by endothelial cells and thrombox-
ane A
2
by platelets from their common precursor arachidonic
acid via the cyclooxygenase pathway. Thromboxane A
2
pro-
motes platelet aggregation and vasoconstriction, whereas
prostacyclin inhibits platelet aggregation and promotes vaso-
dilation. The balance between platelet thromboxane A
2
and
prostacyclin fosters localized platelet aggregation and conse-
quent clot formation (see Chapter 32) while preventing ex-
cessive extension of the clot and maintaining blood flow
around it.
The thromboxane A
2
–prostacyclin balance can be shifted
toward prostacyclin by administration of low doses of aspirin.
Aspirin produces irreversible inhibition of cyclooxygenase by
acetylating a serine residue in its active site. Obviously, this
reduces production of both thromboxane A
2
and prostacyclin.
However, endothelial cells produce new cyclooxygenase in a
matter of hours, whereas platelets cannot manufacture the
enzyme, and the level rises only as new platelets enter the circu-
lation. This is a slow process because platelets have a half-life of
about 4 days. Therefore, administration of small amounts of
aspirin for prolonged periods reduces clot formation and has
been shown to be of value in preventing myocardial infarctions,
unstable angina, transient ischemic attacks, and stroke.NITRIC OXIDE
A chance observation two decades ago led to the discovery
that the endothelium plays a key role in vasodilation. Many