Paracrine Control of Blood Vessel Function: Role of the Endothelins 
residue endothelins are produced via a formerly 
unknown type of proteolytic processing. Biologi- 
cally inactive intermediates of approximately 40 
amino acids, called big endothelins, are first cut 
out from the prepro-proteins. Their carboxyl- 
terminal half is then sheared off to produce the 
amino-terminal active peptides. 
'This unusual endoproteolytic activation is cata- 
lyzed by a novel membrane-bound metallopro- 
tease called endothelin-converting enzyme. This 
unique enzyme is sensitive to the metallopro- 
tease inhibitor phosphoramidon and is distinct 
from any other protease know^n. Since big ET-1 is 
at least 100-200 times less active than mature 
ET-1 in constricting vascular smooth muscle 
strips, the converting enzyme is essential in pro- 
ducing the potent vasoconstrictive agent. There- 
fore the enzyme could also be an important target 
for pharmacological intervention in the endothe- 
lin system. If one could develop an inhibitor of 
endothelin-converting enzyme, it could possibly 
be used as a novel class of vasodilatory drug. 
Apart from their potent and long-lasting vaso- 
constrictor/pressor activities, endothelins pos- 
sess a wide spectrum of nonvascular actions in 
various tissues. Furthermore, two distinct sub- 
types of endothelin receptors (called ET^ and 
ETg) with different selectivities to the three iso- 
peptides have been pharmacologically demon- 
strated and molecularly cloned by us and other 
researchers. In keeping with the wide spectrum 
of endothelin action, the two receptors are ex- 
pressed in a variety of vascular and nonvascular 
tissues. 
The observation that many endothelin-produc- 
ing tissues also express one or more subtypes of 
endothelin receptors suggests the importance of 
the peptide family as locally acting mediators 
(paracrine and/or autocrine) rather than circu- 
lating agents. The idea is further supported by 
several lines of evidence. For example, clearance 
of endothelins from the circulation is extremely 
rapid, with an initial half-life of less than 2-3 
min; plasma concentration of immunoreactive 
ET-1 is well below the threshold concentration 
for pharmacological actions; and circulating en- 
dothelins are capable of inducing the release of 
vasodilator substances such as nitric oxide and 
prostacyclin via the receptors on the endothelial 
cells, thereby limiting their own vasoconstrictor 
actions. 
Increased plasma concentrations of FT- 1 have 
been reported in patients with various disease 
states, including vasospasm and hypertension, 
where abnormal vasomotor function is impli- 
cated. Moreover, in animal models of certain vas- 
cular disorders, such as acute myocardial infarc- 
tion, cerebral vasospasm, and acute ischemic 
renal failure, treatment with antiendothelin 
neutralizing antibody significantly ameliorates 
the abnormal vasoconstriction seen in these 
conditions. 
It is hoped that further insight into the physio- 
logical and pathobiological roles of this complex 
system of peptidic mediators will be gained in 
the near future with the development of endothe- 
lin receptor antagonists, inhibitors of endothelin- 
converting enzyme, and mice deficient in en- 
dothelin/endothelin receptors. This may lead to 
a new level of understanding of how cardiovascu- 
lar homeostasis is maintained via local communi- 
cation between cells of blood vessel walls in 
health and disease. 
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