Ganong's Review of Medical Physiology, 23rd Edition

CHAPTER 34

Circulation Through Special Regions 573

protein-bound forms and, in general, all proteins and polypep-
tides do not. The rapid passive penetration of CO
2
contrasts
with the regulated transcellular penetration of H

• and HCO
  3

and has physiologic significance in the regulation of respira-
tion (see Chapter 37).
Glucose is the major ultimate source of energy for nerve cells.
Its diffusion across the blood–brain barrier would be very slow,
but the rate of transport into the CSF is markedly enhanced by
the presence of specific transporters, including the glucose
transporter 1 (GLUT 1). The brain contains two forms of
GLUT 1: GLUT 1 55K and GLUT 1 45K. Both are encoded by
the same gene, but they differ in the extent to which they are
glycosylated. GLUT 1 55K is present in high concentration in
brain capillaries (Figure 34–6). Infants with congenital GLUT 1
deficiency develop low CSF glucose concentrations in the pres-
ence of normal plasma glucose, and they have seizures and
delayed development. In addition, transporters for thyroid hor-
mones; several organic acids; choline; nucleic acid precursors;
and neutral, basic, and acidic amino acids are present at the
blood–brain barrier.
A variety of drugs and peptides actually cross the cerebral
capillaries but are promptly transported back into the blood
by a multidrug nonspecific transporter in the apical mem-
branes of the endothelial cells. This
P-glycoprotein
is a mem-
ber of the family of adenosine triphosphate (ATP) binding
cassettes that transport various proteins and lipids across cell
membranes (see Chapter 2). In the absence of this transporter
in mice, much larger proportions of systemically adminis-
tered doses of various chemotherapeutic drugs, analgesics,
and opioid peptides are found in the brain than in controls. If
pharmacologic agents that inhibit this transporter can be
developed, they could be of value in the treatment of brain
tumors and other central nervous system (CNS) diseases in
which it is difficult to introduce adequate amounts of thera-
peutic agents into the brain.

CIRCUMVENTRICULAR ORGANS

When dyes that bind to proteins in the plasma are injected,

they stain many tissues but spare most of the brain. However,

four small areas in or near the brain stem do take up the stain.

These areas are (1) the

posterior pituitary

(neurohypophysis)

and the adjacent ventral part of the

median eminence

of the

hypothalamus, (2) the

area postrema,

(3) the

organum vas-

culosum of the lamina terminalis (OVLT,

supraoptic crest),

and (4) the

subfornical organ (SFO).

These areas are referred to collectively as the

circumventric-

ular organs

(Figure 34–7). All have fenestrated capillaries, and

because of their permeability they are said to be “outside the

blood–brain barrier.” Some of them function as

neurohemal

organs

; that is, areas in which polypeptides secreted by neu-

rons enter the circulation. Others contain receptors for many

different peptides and other substances, and function as

chemoreceptor zones in which substances in the circulating

blood can act to trigger changes in brain function without

penetrating the blood–brain barrier. For example, the area

postrema is a chemoreceptor trigger zone that initiates vomit-

ing in response to chemical changes in the plasma (see Chap-

ter 28). It is also concerned with cardiovascular control, and in

many species circulating angiotensin II acts on the area pos-

trema to produce a neurally mediated increase in blood pres-

sure. Angiotensin II also acts on the SFO and possibly on the

OVLT to increase water intake. In addition, it appears that the

OVLT is the site of the osmoreceptor controlling vasopressin

secretion (see Chapter 39), and evidence suggests that circulat-

ing interleukin-1 (IL-1) produces fever by acting here too.

The subcommissural organ (Figure 34–7) is closely associ-

ated with the pineal gland and histologically resembles the cir-

cumventricular organs. However, it does not have fenestrated

capillaries, is not highly permeable, and has no established

FIGURE 34–5
Penetration of urea into muscle, brain, spinal
cord, and CSF.
Urea was administered by constant infusion.

1.0

0.8

0.6

0.4

0.2

0

30 60 90 120 150 180

Min after start of infusion

TissuePlasma

concentration

Muscle

Brain

CSF

FIGURE 34–6

Localization of the various GLUT transporters

in the brain.

(Adapted from Maher F, Vannucci SJ, Simpson IA: Glucose

transporter proteins in brain. FASEB J 1994;8:1003.)

GLUT 3

GLUT 3

GLUT 1 55K

GLUT 1

55K GLUT 1

45K

GLUT 1 45K

GLUT 5

GLUT 5

Endothelial

cell

Astroglia

Neuron

Oligodendroglia

Microglia

Microvessel

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