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U P D A T E A R T I C L E JIACM 2004; 5(1): 55-9
Endothelins and Endothelin Receptor Antagonists
Sidhartha Das*, TK Mishra**, C Satpathy***, SN Routray***
Abstract
Endothelin-1 is a 21 amino acid peptide and is the most potent vasoconstrictor and pressor substance known. Generated by vascularendothelial cells in response to a variety of chemical and mechanical signals, endothelin-1 contributes to the pathophysiology ofconditions associated with sustained vasoconstriction, such as hypertension and heart failure. The endothelin receptor antagonistswere until recently regarded as drugs of great potential in patients with heart failure. However, trials like REACH-1, ENABLE, andRITZ-4 have not found this group of drugs to be beneficial. In contrast, bosentan, a non-selective endothelin receptor antagonist,has been proved to improve functional class and increase the time to clinical worsening in patients with pulmonary arterialhypertension.
* Senior Consultant and Professor, PG Department of Medicine, ** Assistant Professor, *** Lecturer,Department of Cardiology, SCB Medical College, Cuttack-753 001, Orissa.
Introduction
The vascular endothelium has been shown to produce a
variety of vasoactive substances that are crucial for the
regulation of vascular tone, both in health and disease.
Yanagisawa et al, were the first to purify the sequence and
clone the 21 amino acid structure of endothelin (ET) and
its mRNA from the culture supernatant of porcine aortic
endothelial cells in 19881. The aim of the present article is
to outline the biology of endothelin system, endothelin
receptors, and review the role of the endothelin receptor
antagonists in various diseases.
Endothelin system
Endothelin is synthesised not only in the endothelium but
also in the brain, lung, kidney, and some circulating cells2.
The human genome holds three distinct endothelin
genes, encoding the closely related products ET-1, ET-2,
and ET-33. While there is evidence that endothelin-2 (ET-
2) may possibly function as a mediator in the kidney and
that endothelin-3 (ET-3) may act as a mediator in the gut
and nervous system, endothelin-1 (ET-1) is the major
isoform generated in blood vessels and appears to be of
greatest relevance4.
Currently, regulation of endothelin synthesis is thought
to be primarily at the level of gene transcription, with de
novo production and release occurring in response to
endothelial cell stimulation4. Factors acting at this level to
stimulate ET-1 synthesis include vasoactive hormones,
inflammatory mediators, vascular shear stress, and
hypoxia. In contrast, factors like nitric oxide, natriuretic
peptides, and dilator prostanoids serve to inhibit ET-1
generation5 (Figure-1).
The product of ET-1 gene transcription is
preproendothelin-1, which undergoes cleavage to
generate big endothelin-1. Subsequent conversion to the
mature, biologically active peptide, ET-1, occurs through
the action of endothelin converting enzyme (ECE). ET-1,
once formed, acts as a paracrine and autocrine mediator
rather than an endocrine hormone, and its secretion by
the endothelial cells is largely abluminal, i.e., toward the
adjacent vascular smooth muscle. The half life of ET-1 in
blood is short (4 - 7 minutes), with clearance via receptor
binding and metabolism in the lungs and kidneys6.
Endothelin receptors and its blockers
The endothelins act on two receptor subtypes ETA and
ETB. ET-1 has a similar binding affinity for ET
A and ET
B
receptor but has a much higher binding affinity for the
ETA receptor than ET-2. In contrast, ET-1 and ET-3 have
equal affinity for ETB receptor4. The ET
A receptor
predominates on vascular smooth muscle cells and is
responsible for causing vasoconstriction in both large and
small blood vessels. It is also the major subtype in the
heart. The ETB receptors are present in endothelial and
vascular smooth cells and is predominantly found in brain,
lung, kidney, and aorta. The ETB receptors on endothelial
cells modulate vasoconstriction in response to ET-1
through the production of nitric oxide and prostacyclin.
The ETB receptors, present on vascular smooth muscle cells,
56 Journal, Indian Academy of Clinical Medicine Vol. 5, No. 1 January-March, 2004
can mediate vasoconstriction.
The understanding of the function of endothelin receptor
has been aided by the advent of specific pharmacological
antagonists. These endothelin receptor antagonists can
be classified into non-selective and selective ones. The
non-selective antagonists act on both ETA and ET
B
receptors. These include bosentan, tezosentan, and Tak-
044. The selective antagonists act either on ETA receptor
or ETB receptor only. The selective ET
A receptor antagonists
are sitaxentan, darusentan, and BQ-123 whereas BQ-288
is a selective ETB receptor antagonist.
The biological activity of ET-1
ET-1 has potent and long lasting vasopressor activity and
helps regulate the arterial and venous tone9. Local
selective ETA receptor blockade in the fore-arm
vasculature of healthy volunteers substantially increases
forearm blood flow, suggesting that endogenous
generation of ET contributes to maintenance of basal
vascular tone in humans10.
ET-1 has potent inotropic effects in vitro, although its effect
on overall cardiac function is more difficult to assess.
Systemic infusion of ET-1 in healthy volunteers and
patients with heart failure causes cardiac output to fall11.
This may be a secondary effect due to potent peripheral
and coronary vasoconstriction, rather than a negative
inotropic effect of ET-1 on cardiac myocytes12. BQ-123, an
ETA selective antagonist, has been shown to reduce left
ventricular contractility in humans, but has no effect on
patients with dilated cardiomyopthy13. This suggests that
ET-1 has a positive inotropic effect in normal subjects, but
this effect is lost in the failing human heart. Onishi et al
have shown that elevated levels of plasma ET-1 in chronic
heart failure may directly impair cardiac contractility and
hence contribute to the functional impairment seen in
chronic heart failure14.
In addition to its direct arterial and vasoconstrictor and
neuroendocrine action, ET-1 has been shown to enhance
conversion of angiotensin I to angiotensin II15 and adrenal
synthesis of adrenaline16. It can also augment plasma renin
activity17. ET-1 may amplify vasoconstrictor reflexes and
be of pathophysiological relevance even when plasma ET-
1 concentration is not clearly elevated12. ET-1 can also
stimulate vascular smooth muscle proliferation and
cardiac hypertrophy and is consequently thought to have
a role in myocardial and vascular remodelling18.
Given the diversity of actions of ET-1, it has clearly a role in
the pathophysiology of cardiovascular disease and has
emerged as a novel therapeutic target in this area. In
subsequent sections, we will focus on the role of endothelin
system in various cardiovascular diseases and the impact of
the endothelin receptor antagonists on them.
Congestive heart failure (CHF)
CHF is a disease process characterised by impaired left
ventricular function, increased peripheral and pulmonary
vascular resistance, and sodium and water retention19. In
patients with CHF, circulating ET-1 is elevated and
correlates with symptoms20 and haemodynamic severity21.
The plasma level of ET-1 precursor, big ET-1 is a strong
independent predictor of death22. Parallel to ET-1, the ETA
receptors are up-regulated in the failing human heart23.
In contrast, the ETB receptors are down-regulated24. The
vasoconstrictor response to exogenous ET-1 is blunted in
CHF as compared with healthy subjects, both in the arterial
and venous arm of the circulation.
The mechanisms leading to increased ET-1 expression in
CHF remain incompletely understood. The main source
of ET-1 seems to be the pulmonary vascular bed in CHF25.
ET-1 production is modulated by baroreflexes. Decreased
shear stress caused by low cardiac output contributes to
the elevated ET-1 release. Down-regulation of lung ETB
receptors, which are involved in clearance of ET-1, further
contributes to elevated circulating levels of ET-1 in CHF26.
In addition, other neurohumoral systems activated in CHF,
such as angiotensin II and catecholamines, also stimulate
ET-1 production27.
Endothelin receptor antagonists and CHF
Beneficial role of neurohumoral inhibitors like angiotensin
converting enzyme (ACE) inhibitors and -blockersprompted investigators to assess the utility of endothelin
receptor antagonists in patients with CHF.
Infusion of the mixed ETA/B
antagonist, bosentan, has been
shown to improve systemic and pulmonary
haemodynamics in patients with CHF28.
Journal, Indian Academy of Clinical Medicine Vol. 5, No. 1 January-March, 2004 57
A clinical trial, REACH-1 (Research on Endothelin
Antagonists in Chronic Heart Failure) investigating the
long term effects of bosentan on clinical events in CHF
showed an improvement in symptoms29. Unfortunately,
the trial had to be stopped prematurely because of
elevation of liver transaminases.
The endothelin antagonism with Bosentan and Lowering
of Events (ENABLE) investigators studied 1,613 patients
with CHF and could not demonstrate any improvement
in mortality or hospitalisations due to heart failure30.
Results of RITZ-4 (Randomised Intravenous Tezosentan
Study) have been published recently31. Tezosentan,
another non-selective ETA/B
receptor antagonist, was tried
in patients with acute decompensated heart failure
associated with acute coronary syndrome. There was no
significant difference in deaths, worsening heart failure,
and recurrent ischaemia between the tezosentan group
when compared with the placebo group.
As the non-selective ETA/B
receptor antagonists proved to
be ineffective in patients with CHF, therapy with selective
ETA agent was tried. It was thought that as ET
B receptor
causes beneficial nitric oxide mediated vasodilation a
selective ETA receptor antagonist may be beneficial by
leaving ETB receptor untouched. However, in a study of
157 patients, the selective agent darusentan caused
haemodynamic improvement, but there was no
improvement in symptoms32. Rather, there was a trend
towards increased mortality.
The explanations for these negative results remain
speculative. It is possible that the dose administered in
RITZ-4 may have been too high and that the study
was relatively small and underpowered. More
likely benefits cannot be accrued by further
antagonising the neurohormonal system after
administration of b-blocker and ACE-inhibitor33.
Role of endothelin receptor antagonistsin hypertension
Human data on the role of endothelin in
hypertension is conflicting2. Systemic administration
of TAK 044, a non-selective ETA/B
receptor
antagonist has been shown to reduce systemic
vascular resistance and lower blood pressure4. The
potential additional benefits of the ET receptor
antagonists on atherogenesis, cardiac and vascular
hypertrophy, and progression of renal impairment
makes this group of drugs an attractive option as
antihypertensive agents. Research is going on in
this regard.
Role of endothelin receptor antagonistsin pulmonary arterial hypertension
Bosentan, an orally active non-selective
endothelin receptor antagonist, has been proved
to be effective in the treatment of pulmonary
arterial hypertension (PAH). The drug is now
approved in USA, Canada, and the European Union
countries for treatment of PAH associated with
Fig. 1 : Factors that alter endothelin-1 (ET-1) synthesis and the pathway for ET-1 generation.IL-1, interleukin-1; TGF-, transforming growth factor ; LDL, low density lipoprotein; ANP,BNP, CNP, atrial, brain and c-type natriuretic peptides, respectively.
58 Journal, Indian Academy of Clinical Medicine Vol. 5, No. 1 January-March, 2004
collagen disease like scleroderma4.
BREATH-1 (Bosentan : Randomised Trial of Endothelin
Receptor antagonist Therapy for Pulmonary Arterial
Hypertension) trial was a first large scale (n = 213), double
blind, placebo-controlled study of an orally active
endothelin receptor antagonist in PAH34. In BREATH-1, 16
weeks of bosentan therapy resulted in significant
symptomatic improvement in the overall population.
There was also significant increase in time to clinical
worsening. Favourable results were noted also in
combined end-points that included lung transplantation,
hospitalisation, and death. Headache was the most
common adverse effect, seen in 19%. Abnormal hepatic
function was noted in 9%.
At present BREATH-2 trial is in progress. This trial is
evaluating the effect of bosentan in combination with
intravenous epoprostenol in patients with severe PAH35.
Preliminary results from BREATH-3, a study of the
pharmacokinetics and tolerability of bosentan in
paediatric patients with PAH, appear positive35.
Thus, bosentan is definitely useful in patients having
primary pulmonary arterial hypertension or PAH
associated with collagen vascular disease like scleroderma.
The drug is well tolerated at dose of 125mg twice daily.
Future directions
Research is being done to assess the role of endothelins
and ET receptor antagonists in various diseases like
atherosclerosis, subarachnoid haemorrhage, and
proteinuric nephropathies. Though the selective ETA
receptor antagonist holds exciting promise, it may worsen
renal vasoconstriction. Moreover, the safety side of
endothelin receptor antagonists is yet to be fully
addressed. Inhibition of endothelin during embryogenesis
can be devastating.
Summary and conclusions
Endothelin-1 is a potent vasoconstricting agent that acts
as a local autocrine and paracrine mediator. ET is the most
potent and sustained vasoconstrictor and pressor
substance yet identified. Abnormalities of the endothelin
system occur in a range of diseases associated with
vasoconstriction, vasospasm, and vascular hypertrophy. ET
receptor antagonists were only till recently regarded as a
drug of great promise in patients with CHF. However, the
result of trial like REACH-1 has been disappointing in this
regard. Still, an orally active selective ETA receptor
antagonist may tilt the balance in favour of its use in CHF
patients.
Role of ET receptor antagonists in PAH (Primary or
secondary to collagen vascular disease) is fairly well
established. Now, bosentan is an approved ET receptor
antagonist for use in patients with PAH associated with
collagen diseases.
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A N N O U N C E M E N T
IACM Credentials Committee 2003-2004
1. VN Kaushal Chairman2. SK Sharma Convener3. Nitya Nand Ex-Officio Member4. KK Dang Member5. Ajay Kumar Member6. HK Aggarwal Member7. DP Agarwal Member8. MS Gupta Member