Ganong's Review of Medical Physiology, 23rd Edition

D
D
D
D
M
L
K
T
K
K
K
K
L
W
Y
M
C L Y
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.
ENDOTHELIN-1
E
E
E
E
S
S
T
D
S
F
C S
C V Y F
S
C
C V Y
K
C S
C V Y F
C
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 prohormone
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 endothelin-1,
is found in many tissues and mediates the vasoconstriction
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
T
S
Y
F
C
C
C
C
H L D I I
Endothelin-1 is not stored in secretory granules, and most regulatory
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.
C
C
C
C
Endothelin-1
Endothelin-2
D
H L I I
Endothelin-3
H L D I I
Sarafotoxin b
H Q D V I
W
W
W
W
CHAPTER 33 Cardiovascular Regulatory Mechanisms 565
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
CARDIOVASCULAR FUNCTIONS
As noted above, endothelin-1 appears to be primarily a paracrine
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 actually
elevated rather than reduced. The concentration of circulating
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