Ganong's Review of Medical Physiology, 23rd Edition

CHAPTER 33

Cardiovascular Regulatory Mechanisms 565

ENDOTHELIN-1

In endothelial cells, the product of the endothelin-1 gene is
processed to a 39-amino-acid prohormone,
big endothelin-1,
which has about 1% of the activity of endothelin-1. The pro-
hormone is cleaved at a tryptophan-valine (Trp-Val) bond to
form endothelin-1 by
endothelin-converting enzyme.
Small
amounts of big endothelin-1 and endothelin-1 are secreted
into the blood, but for the most part, they are secreted locally
and act in a paracrine fashion.
Two different endothelin receptors have been cloned, both
of which are coupled via G proteins to phospholipase C (see
Chapter 2). The ET
A
receptor, which is specific for endothe-
lin-1, is found in many tissues and mediates the vasoconstric-
tion produced by endothelin-1. The ET
B
receptor responds to
all three endothelins, and is coupled to G
i

. It may mediate
vasodilation, and it appears to mediate the developmental
effects of the endothelins (see below).

REGULATION OF SECRETION

Endothelin-1 is not stored in secretory granules, and most reg-
ulatory factors alter the transcription of its gene, with changes
in secretion occurring promptly thereafter. Factors activating
and inhibiting the gene are summarized in Table 33–4.

CARDIOVASCULAR FUNCTIONS

As noted above, endothelin-1 appears to be primarily a para-

crine regulator of vascular tone. However, endothelin-1 is not

increased in hypertension, and in mice in which one allele of

the endothelin-1 gene is knocked out, blood pressure is actu-

ally elevated rather than reduced. The concentration of circu-

lating endothelin-1 is, however, elevated in congestive heart

failure and after myocardial infarction, so it may play a role in

the pathophysiology of these diseases.

OTHER FUNCTIONS OF ENDOTHELINS

Endothelin-1 is found in the brain and kidneys as well as the

endothelial cells. Endothelin-2 is produced primarily in the

kidneys and intestine. Endothelin-3 is present in the blood

and is found in high concentrations in the brain. It is also

found in the kidneys and gastrointestinal tract. In the brain,

endothelins are abundant and, in early life, are produced by

both astrocytes and neurons. They are found in the dorsal root

ganglia, ventral horn cells, the cortex, the hypothalamus, and

cerebellar Purkinje cells. They also play a role in regulating

transport across the blood–brain barrier. There are endothelin

receptors on mesangial cells (see Chapter 38), and the

polypeptide participates in tubuloglomerular feedback.

Mice that have both alleles of the endothelin-1 gene deleted

have severe craniofacial abnormalities and die of respiratory

failure at birth. They also have megacolon (Hirschsprung

FIGURE 33–10 Structure of human endothelins and one of
the snake venom sarafotoxins. The amino acid residues that differ
from endothelin-1 are indicated in pink.

L

Y

Y

T F

K T

H L I I W

C S C

E C D

K

D

M

L S S

C V Y F

Endothelin-1

H L I I W

C C

E C D

K

D

C V Y

Endothelin-3

M

F

D K

T S

H Q V I W

C C

E C D

K

D

C Y

Sarafotoxin b

W

L

H L I I W

C S C

E C D

K

D

S

S

C V Y F

Endothelin-2

TABLE 33–4 Regulation of endothelin-1

secretion via transcription of its gene.

Stimulators

Angiotensin II

Catecholamines

Growth factors

Hypoxia

Insulin

Oxidized LDL

HDL

Shear stress

Thrombin

Inhibitors

NO

ANP

PGE 2

Prostacyclin