importance is far less than that of adeno-
sine, potassium, and nitric oxide in regu-
lating skeletal muscle blood flow.
3. Carbon dioxide formation increases during
states of increased oxidative metabolism.
CO2 concentrations in the tissue and vascu-
lature can also increase when blood flow is
reduced, which reduces the washout of CO2.
As a gas, CO2 readily diffuses from parenchy-
mal cells to the vascular smooth muscle of
blood vessels, where it causes vasodilation.
Considerable evidence indicates that CO2
plays a significant role in regulating cerebral
blood flow through the formation of H+.
4. Hydrogen ion increases through the bicar-
bonate buffer system when CO2 increases.
Hydrogen ion also increases during states of
increased anaerobic metabolism (e.g., during
ischemia or hypoxia) when acid metabolites
such as lactic acid are produced. Increased
H+ causes local vasodilation, particularly in
the cerebral circulation.
5. Potassium ion is released by contracting
cardiac and skeletal muscle. Muscle contrac-
tion is initiated by membrane depolariza-
tion, which results from a cellular influx of
Na+ and an efflux of K+. Normally, the Na+/
K+-ATPase pump is able to restore the ionic
gradients (see
Chapter 2); however,
pump does not keep up with rapid depolari-
zations (i.e., there is a time lag) during mus-
cle contractions, and a small amount of K+
accumulates in the extracellular space. Small
increases in extracellular K+ around blood
vessels cause hyperpolarization of the vascu-
lar smooth muscle cells, possibly by stimu-
lating the electrogenic Na+/K+-ATPase pump
increasing K+
potassium channels. Hyperpolarization leads
to smooth muscle relaxation. Potassium ion
appears to play a role in causing the increase
in blood flow in contracting skeletal muscle.
6. Oxygen levels
sel wall, and surrounding tissue are also
important in local regulation of blood flow.
Decreased tissue partial pressure of oxygen
(PO2) resulting from reduced oxygen sup-
ply or increased oxygen utilization by tis-
sues causes vasodilation. Hypoxia-induced
vasodilation may be direct (inadequate O2
to sustain smooth muscle contraction) or
indirect via the production of vasodilator
metabolites (e.g., adenosine, lactic acid,
H+). Although hypoxia causes vasodilation
in nearly all vascular beds, there is a nota-
ble exception—it causes vasoconstriction
in the pulmonary circulation.
7. Osmolarity changes in the blood and in
the tissue interstitium have been impli-
cated in local blood flow regulation. It is
well known that intra-arterial infusions
of hyperosmolar solutions can produce
vasodilation. The molecules making up the
hyperosmolar solution need not be vasoac-
tive. Tissue ischemia and increased meta-
bolic activity raise the osmolarity of the
tissue interstitial fluid and venous blood.
Therefore, it has been suggested that non-
specific changes in osmolarity may play a
role in the regulation of blood flow.
Several tissue factors involved in regulating
blood flow are not directly coupled to tissue
These include paracrine hor-
mones such as histamine, bradykinin, and
products of arachidonic acid (eicosanoids).
Histamine, released by tissue mast cells in
response to injury, inflammation, and aller-
gic responses, causes arteriolar vasodilation,
venous constriction in some vascular beds,
and increased capillary permeability. Both H1
and H2 histamine receptors are involved in
the vascular effects of histamine. Bradykinin
is formed from the action of kallikrein (a pro-
teolytic enzyme) acting on alpha2-globulin
(kininogen), which is found in blood and
tissues. Like histamine, bradykinin is a pow-
erful dilator of arterioles. It acts on vascular
bradykinin receptors, which stimulate nitric
oxide formation by the vascular endothelium,
thereby producing vasodilation. In addition,
tion, which produces vasodilation. One of
the enzymes responsible for breaking down
bradykinin is angiotensin-converting enzyme
(ACE) (see Chapter 6, Fig. 6.11). Therefore,
drugs that inhibit ACE not only decrease
angiotensin II but also increase bradykinin,
which is believed to be partly responsible for
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