full issue - Association of Biotechnology and Pharmacy

Current Trends in Biotechnology and Pharmacy
Vol. 5 (3) 1251-1272 July 2011, ISSN 0973-8916 (Print), 2230-7303 (Online)
hypertension. A second alternative could be used
taking in consideration the advice of the World
Health Organization, which has been promoting
a rational use of traditional medicine as a source
of less expensive medical care (8).
Current pharmacotherapy of hypertension
consists mainly on the use of two strategies. The
first strategy is the application of a single drug
capable of interacting with molecular mediators
involved in the rennin-angiotensin system (9) and
the endothelin system (10); with adrenergic (11)
and urotensin II receptors (12); and with the atrial
natriuretic peptide (13). The second strategy
consists in the use of a “multi-target approach”
(14) focused on the simultaneous treatment of
more than one target involved in blood pressure
regulation and the development of the disease.
This second approach has been successfully
tested combining drugs capable of inhibiting the
activity of ACE and NEP; ECE and NEP; AT 1
and ET A
receptors (14).
From the group of drugs acting as
inhibitors of receptors involved in blood pressure
regulation, endothelin receptor antagonists have
been the most prominent group containing drugs
which were first found in nature (e.g.
microorganisms, plants); thus the present review
focuses on endothelin receptor as drug targets.
Pathophysiology of hypertension: the
endothelin system
Endothelins are a family of
vasoconstrictive peptides synthesized from larger
precursors and expressed in different tissues (15).
They consist of three isoforms, namely,
endothelin-1 (ET-1), endothelin-2 (ET-2) and
endothelin-3 (ET-3), being ET-1 the most widely
distributed, best studied, and most powerful (16).
ET-1 is synthesized in endothelial cells by means
of a specific endothelin-converting enzyme
(ECE) (15, 17). ET-1 appears to be the
predominant member of the family with direct
Catherina Caballero-George
1252
vascular effects, inotropic and mitogenic
properties; it influences homeostasis of salts and
water, alters central and peripheral sympathetic
activity and stimulates the renin-angiotensinaldosterone
system (10).
Generation of endothelins : The major site of
generation of ET-1 is in endothelial cells and to
a lesser extent in smooth muscle cells, the heart,
kidneys, posterior pituitary and central nervous
systems (10). The initial product of the human
endothelin-1 gene is preproendothelin-1 (212
amino acid peptide), which is then transformed
into proendothelin-1 by removal of a short
secretory sequence. Proendothelin-1 is further
cleaved by a furin-like enzyme generating big
endothelin-1 (38 amino acid peptide) (18). The
formation of mature ET-1 requires cleavage of
big endothelin-1 by one of several unique ECE.
Several forms of ECE have been identified to
have distinct roles and tissue distribution (10).
ECE-1 and ECE-2 are relatively selective for big
endothelin-1, having much less activity in
cleaving big endothelin-2 and big endothelin 3.
A third type of ECE was purified from bovine
iris and named ECE-3, which selectively cleaved
big endothelin-3 (15).
Endothelin receptors : Endogenous ET-1
contributes to maintenance of basal vascular tone
and blood pressure through activation of two G-
protein coupled receptors (GPCR), namely,
endothelin ET A
(ET A
) and endothelin ET B
(ET B
)
(19), the only two receptor subtypes identified
in mammalian species, as mediating the different
actions of endothelins (20). As a member of the
GPCR superfamily, the ET A
receptor has seven
hydrophobic membrane-spanning domains and
a relatively long extracellular N terminal (10). A
model for the ET-1/ET A
receptor interaction
showed that ET-1 docks principally at the
extracellular ends of the transmembrane domain
1 (TM1), TM2 and TM7 of the receptor as well
as the extracellular loop 1 (EXL1) and, to a lesser