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Abstract
The endothelin system has been extensively studied
over the last several years. It is clear that endothelin-1
(ET-1) is a key mediator in pulmonary vascular biology
and physiology. Abnormal increases in ET-1 production
and decreased pulmonary clearance appear to play a major
pathogenetic and perpetuating role in the pulmonary hypertensive
process, through their vasconstrictive, smooth muscle
cell proliferative and profibrotic effects. The degree
of overexpression of ET-1 may correlate with the severity
of pulmonary hypertension (PH). Advances in understanding
the role of ET-1 in pul-monary hypertension have driven
the development of endo-thelin receptor antagonists. One
such agent, bosentan (Tracleer), is FDA approved for pulmonary
arterial hyperten-sion. Bosentan was approved following
two randomized, placebo controlled, double-blind studies
that both showed marked improvement in exercise capacity
after treatment with bosen-tan.The beneficial effects
of bosentan appear to be sustained in most patients followed
for as long as 22 months. Other uses for endothelin receptor
antagonists are being examined, such as in combination
with epoprostenol (Flolan) or in pedi-atric PH patients.
One of the most exciting developments in the treatment
of pulmonary arterial hypertension in recent years is
the approval of the first oral agent specifically indicated
for the treatment of pulmonary hypertension, the dual
endothelin receptor antagonist bosentan. This article
will review the importance of the endothelin system in
pulmonary arterial hypertension and the role of inhibiting
this system as a treatment modality in pulmonary arterial
hypertension.
Biology of ET-1
ET-1 is a 21-amino acid peptide discovered in 1988. ET-1
is produced in high concentrations within human lung.1,2
High-affinity binding sites for ET-1 are found throughout
the lung parenchyma, predominantly on small pulmonary
arteries and
arterioles, but also on bronchial smooth muscle.3 Two
receptor subtypes, ETA and ETB, have been described; the
propor-tion and distribution of these subtypes vary among
species. In human pulmonary artery, the ETA receptor subtype
appears to
be most predominant.4 At the capillary level, both ETA
(30%) and ETB (70%) receptors are found.5 In addition
to being the predominant producer of ET-1, the human lung
appears to clear ET-1, under normal conditions.6 Thus,
there is no net arteriovenous difference in ET-1 levels.
The biologic and physiologic effects of ET-1 are varied.
ET-1 is the most potent
 |
| Fig.
1—Illustration of the actions of endothelin-1
(ET-1) on vascular smooth muscle cells. In addition
to contraction, ET-1 can mediate smooth muscle cell
relaxation through release of PG2 and nitric oxide
(NO). AVP = argenine vasopressin; EDHF, endothelin-derived
hyperplarizing factor. |
known endogenous asoconstrictor. Although it was previously
thought that vasoconstriction was mediated only through
the ETA receptor, it appears that both receptor subtypes
can mediate the pressor response.7 At lower levels, ET-1
does exert a mild vasodilator effect, mediat-ed by the
ETB receptor through release of the vasodilating substances
prostacyclin and nitric oxide.8 An illustration of the
actions of ET-1 on vascular smooth muscle is shown in
Figure 1.
In addition to its effect on vascular tone, ET-1 is known
to be a smooth muscle mitogen and a proinflammatory mediator
with marked profibrotic effects. These effects may, in
fact, be of importance when the contribution of ET-1 to
the pathogenesis and progression of pulmonary arterial
hypertension (PAH) is considered.
Abnormalities in the Endothelin
System in Pulmonary Hypertension
Numerous studies have confirmed the prominent
role of abnormalities in ET-1 in the pulmonary hypertensive
process. Patients with primary pulmonary hypertension
(PPH) have been shown to have elevated circulating levels
of ET-1, with higher arterial than venous levels, suggesting
increased pulmonary production.9 Some investigators have
found that levels of ET-1 correlate with the severity
of pulmonary hypertension.
 |
Fig. 2—In primary pulmonary
hypertension a high expression of endothelin-1 (ET-1)
has been demonstrated in the plexiform lesions
(neoplastic-like outgrowth of endothelial cells in
the pulmonary arteri-oles) of the lung. In this photograph
the ET-1 expression is shown by the brownish staining.
The levels of ET-1 were found to correlate with disease
severity. |
Immunostaining studies have demonstrated increased expression
of ET-1 in the muscular pulmonary arteries of PPH patients
as well as in the plexiform lesions often seen in this
disease (Figure 2).10 The degree of immunoreactivity
in these vessels has been found to correlate with the
pulmonary vascular resistance. Treatment of PPH with epoprostenol
has been shown to decrease the production of ET-1, suggesting
improvement in endothelial function. 11
Although less studied in other forms of PAH, increased
ET-1 levels have been noted in patients with PH associated
with systemic lupus erythematosus (SLE)12 and scleroderma
13 as well as congenital heart disease-associated PAH.14
Other forms of pulmonary hypertension have also been associated
with ET-1 increases. For example, Cody et al found high
plasma ET-1 levels in patients with congestive heart failure.15
In addition, PH due to chronic hypoxic lung disease, notably
COPD 16 and interstitial pulmonary fibrosis (IPF), has
also been reported. In IPF, Giaid and coworkers found
increased expression of ET-1 in airway epithelium and
type II pneumocytes compared with controls.2 In IPF patients
with PH, increased ET-1 and mRNA were present in endothelial
cells. Finally, in the pulmonary vasculopathy that develops
in association with chronic pulmonary arterial obstruction,
increased ET-1 immunoreactivity has been noted in an animal
model of
pulmonary embolism.17 Notably, postobstructive pulmonary
vasculopathic changes were inhibited by the dual receptor
antagonist bosentan.
Endothelin Receptor Antagonists
Because of the clear importance of ET-1 in the spectrum
of pulmonary hypertensive disorders, the potential use
of endothelin antagonists is obvious. The dual receptor
antagonist bosentan has received the most study. Both
intravenous and orally active endothelin receptor antagonists
have been devel-oped. Oral bosentan has been studied in
two randomized, placebo-controlled, double blind studies.
 |
| Fig. 3—Effects of 12
weeks of bosentan on WHO functional class. Several
bosentan-treated patients had improved functional
class while 18% of placebo-treated patients deteriorated
to class IV during the study period. |
The first study enrolled 32 patients with either PPH
or PAH associated with scleroderma.18 Patients were all
in mod-ified New York Heart Association functional class
III at the onset of the study. Patients had been maximally
treated and were stable on conventional therapy, including
calcium chan-nel antagonists and diuretics. Two thirds
of patients received 62.5 mg of bosentan for 4 weeks followed
by 125 mg of bosentan for 8 weeks. One third received
placebo. The primary efficacy endpoint was a 6-minute
walk distance. Patients receiving bosentan walked an average
of 70 meters farther after 12 weeks (Figure 3)
while placebo patients had a decline in walk distance.
In addition, bosentan-treated patients had improvements
in dyspnea score and functional class (Figure 4)
compared with placebo patients. Pulmonary hemodynamic
measurements revealed decreases in pulmonary arterial
pressure and pulmonary vascular resistance and increase
in cardiac output after 12 weeks of bosentan, com-pared
with worsening of pulmonary hemodynamics in placebo patients.
All these changes in treated patients were highly significant
compared with placebo.
 |
| Fig. 4—Six-minute
walk distance in patients treated with 125 mg bosentan
vs placebo. Walk distance improved by 70 meters in
treated patients vs a decline in walk distance in
placebo patients. |
In this study the only significant adverse effect noted
was an increase in hepatic transaminases in 2 patients
treated with bosentan. These abnormalities, however, resolved
with either discontinuation or dose reduction. On the
basis of the results of this pilot study, a large study
(BREATHE-1) was conducted. In BREATHE-1, 213 patients
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