From the Departments of Medicine, Montreal Heart Institute (S.P., J.D.),
Montreal, Quebec, and St Michael's Hospital (D.J.S.), Toronto, Ontario,
Canada.
Correspondence to Dr J. Dupuis, Research Center, Montreal Heart Institute, 5000 Belanger St E, Montreal, Quebec, Canada H1T 1C8. E-mail dupuisj{at}icm.umontreal.ca
Methods and Results—Three weeks after MCT injection, PH was
associated with an increase in right ventricular pressure
(from 27.4±0.9 to 66.6±4.1 mm Hg) and a decrease in
endothelium-independent vasodilation in response to
sodium nitroprusside (10-10 to 10-5
mol/L
Conclusions—MCT PH is associated with a reduced smooth muscle
responsiveness to NO but a maintained
endothelium-dependent vasodilatory potency. Long-term
ETA antagonist therapy not only restores smooth
muscle responsiveness to NO but also increases
endothelium-dependent dilation in response to
acetylcholine. This mechanism may contribute to the therapeutic benefit
of ETA antagonists in PH.
The pulmonary circulation is an important site for both
clearance and production of the potent vasoconstrictor peptide
ET-1.1 2 ET-1 levels correlate closely with the
severity of PH of various etiologies3 4 with an
increase in local ET-1 expression.5 Long-term
therapy with specific ETA receptor
antagonists reduces the development of PH and right
ventricular hypertrophy in both hypoxic and
MCT-treated rats6 7 8 with beneficial effects on
pulmonary vascular remodeling.6 In the
rat myocardial infarction model, PH caused by congestive heart failure
is also ameliorated by long-term application of the specific
ETA antagonist
BQ-123.9
The mechanism involved in the therapeutic benefits of long-term
ETA antagonist therapy in PH has not
been studied. The lungs are also rich in ETB
receptors, located predominantly on the vascular
endothelium10; stimulation of
this receptor by ET-1 causes vasodilation through the release of NO and
prostacyclin. Inhibition of NOS has been shown to unmask the tonic
pressor influence ET-1 in vivo.11 In addition to
direct effects through the blockade of the smooth muscle
ETA receptor, ETA
antagonists theoretically could indirectly modulate
endothelial reactivity through unopposed stimulation of
the ETB receptor by persistently elevated
circulating levels of ET-1. This hypothesis is consistent with
the recently described increase in pulmonary pressure by the
ETB antagonist RES-701–1 in beagles
with dehydromonocrotaline-induced PH (control animals showed no
variation).12 Some undefined interactions between
the L-arginine–NO pathway and the ET system may be
favorably altered by ETA antagonist
therapy. Such an interaction has been demonstrated in the systemic
circulation, in which long-term ETA receptor
blockade in angiotensin II–induced hypertension was
associated with improved endothelium-dependent
relaxation to ACh.13
This study was designed to evaluate the effects of long-term therapy
with the specific ETA antagonist
LU14 on the endothelium-dependent
and -independent pulmonary vascular reactivity of rats with
MCT-induced PH.
Experimental Protocol
A midline sternotomy was performed to expose the heart and lungs, and
the pulmonary artery was cannulated through an incision in the
right ventricle. Another cannula was inserted into the left atrium
through an incision in the left ventricle to collect the effluent from
the lungs. The lungs perfusion was initiated by slow infusion (2.0
mL/min) of Krebs' solution composed of (in mmol/L): NaCl 120,
NaHCO3 25, KCl 4.7,
KH2PO4 1.18,
MgSO4 1.17, CaCl2 2.5, and
glucose 5.5. The Krebs' solution was bubbled with 95%
O2/5% CO2 to maintain pH
7.4. The lungs then were rapidly isolated and suspended in a warmed
(37°C) water-jacketed chamber to be perfused in a recirculating
fashion with Krebs' solution supplemented with albumin (3%)
at 37°C. The pulmonary flow was continuously measured with a
Transonic flow probe connected to a Transonic flowmeter (Model 208) and
put on the circuit proximal to the pulmonary cannula.
Evaluation of Pulmonary Vasodilations
Evaluation of NO Activity
Samples were assayed in duplicate to measure the conversion of
[14C]L-arginine to
[14C]L-citrulline; 20 µL
supernatant was incubated in 100 µL NOS activity buffer (50
mmol/L KH2PO4, 1.2
mmol/L MgCl2, 0.24 mmol/L
CaCl2, 50 mmol/L valine, 1 mmol/L
L-citrulline, 0.1 mmol/L NADPH, 18 µmol/L
L-arginine, 30 µmol/L BH4, 10
58 mol/L FAD, and 2 58 mol/L
[U-14C]L-arginine [100 µCi/mL,
0.313 mmol/mL] to measure total NOS activity and in the presence
of either 24 mmol/L EGTA [for inducible NOS activity] and
24 mmol/L EGTA plus 24 mmol/L L-NAME [no
activity]). Samples were incubated for 60 minutes at 37°C. After
incubation, the reaction was terminated with the addition of 750 µL
cold stop buffer (50 mmol/L HEPES, 5 mmol/L EDTA, pH 5.5).
The samples were applied to a 1-mL column of Dowex AG 50W-X8
(Na+ form) and then eluted with 4 mL Stop buffer.
[14C]L-Citrulline in the eluent was
measured with liquid scintillation spectroscopy and expressed as
pmol · mg of protein-1 ·
min-1.
Drugs
Statistical Analysis
The effects of the ETA
antagonist LU on right ventricular
systolic pressure in control and MCT-treated rats are
presented in Figure 1
Effect of LU on Pulmonary
Endothelium-Independent Vasodilation
LU therapy did not significantly modify the vasodilation curve in
response to SNP in control rat lungs (Emax,
10.1±1.0 mm Hg) but significantly improved it
(P<0.05) after MCT administration, increasing the
Emax value to 5.6±0.6 mm Hg.
In both LU-treated groups, the -log EC50 values
of SNP that induced pulmonary vasodilation were significantly
(P<0.01) increased (control, 8.3±0.1; MCT, 8.6±0.2)
compared with groups not treated with LU (control, 7.7±0.1; MCT,
7.7±0.1) (Table
Effect of LU on Pulmonary
Endothelium-Dependent Vasodilation
The responses to A23187 (10-9 to
10-7 mol/L) did not differ
significantly among the four groups, although at lower concentrations,
higher vasodilations were induced in lungs from MCT-treated rats that
received LU (Figure 2C
Effect of LU on Pulmonary NO Activity
Endothelium-Dependent and -Independent Vasodilation
in MCT-Induced PH
Pulmonary vascular rings taken from patients with chronic
obstructive pulmonary disease exhibit reduced basal and
receptor-mediated endothelium-dependent dilation but
preserved responses to the EDNO donor SNP.26 The
magnitude of impairment in endothelium-dependent
dilation correlates with the severity of intimal
hypertrophy and the degree of
hypoxia,26 suggesting a link between
endothelial dysfunction and disease severity.
Similarly, pulmonary arterial rings taken from
patients with Eisenmenger's syndrome have a reduced response to ACh,
even exhibiting paradoxical vasoconstriction at higher
concentrations.27 Although these observations in
large conduit pulmonary arteries are consistent with
animal data in similar preparations, there is no general agreement on
the pathophysiological role of NO in human PH.
Indeed, some have reported a decrease in pulmonary cNOS
expression by in situ hybridization,5 whereas
another group reported an increase in cNOS immunoreactivity in the
pulmonary vascular endothelium of patients with
PH.28 Our study in isolated rat lungs with
MCT-induced PH supports an emerging pattern in animal models that
suggests increases in NOS in the smaller resistance vessels, likely as
a mechanism of compensation while endothelium-dependent
dilation in larger pulmonary arteries appears to be reduced.
The limited data available from human studies are not incompatible with
a similar interpretation. More functional human studies with various
forms and severities of PH are needed to clarify this issue.
Effect of Chronic ETA Blockade on
Endothelium-Dependent and -Independent
Vasodilation
In the control rats, long-term therapy with the specific
ETA antagonist
LU14 did not modify the vasodilator response to
SNP. In MCT-treated rats, however, LU therapy strongly potentiated the
response to this agonist. Endothelium-independent
dilation in response to SNP was markedly improved by LU therapy with an
increase in the Emax value as well as a reduction
in the EC50 value. Long-term therapy with
ETA antagonists can reduce
MCT-induced and hypoxic pulmonary artery medial
hypertrophy,6 29 so part of this
improvement could easily be attributed to beneficial remodeling of the
pulmonary arteries. However, we have previously shown that LU
does not reduce pulmonary medial hypertrophy in
arteries of 50- to 150-mm diameter,8 suggesting
other mechanisms may be more important. Consequently, reduced basal
vessel tone may also contribute to this improvement because MCT induces
early pulmonary hyperresponsiveness to various
vasoconstrictors.16 31
The mechanisms by which LU could improve EDNO-dependent dilation are
not well established. We measured whole lung cNOS and iNOS activities,
which were unaffected by LU therapy. The receptor-independent ionophore
A23187 tended to show a lower-threshold concentration response in
MCT-treated animals but no differences in the
EC50 and Emax values.
Together, these results suggest LU therapy did not modify the maximal
capacity of the pulmonary vasculature to generate NO from
L-arginine. It, however, greatly increased
receptor-dependent NO release by ACh in MCT-treated animals with a net
tendency for an increase even in the control animals. These suggests an
upregulation or increased sensitivity of the
endothelial ACh receptor in the pulmonary
circulation. Our findings are consistent with those of d'Uscio
et al13 showing that long-term
ETA antagonist therapy improved
ACh-dependent dilation in the aortas of rats with
angiotensin II–induced systemic hypertension.
The present study, in isolated lungs, has the advantage of being an
evaluation of the functional behavior of the whole pulmonary
circulation (including large and small vessels) with good control on
concentrations of the pharmacological agents used and without effects
of variables such as heart rate and systemic pressure. The lungs
were preconstricted as needed with U46619 to obtain similarly elevated
perfusion pressures of
In conclusion, we demonstrated that EDNO-dependent dilation is
maintained in MCT-induced PH and SNP dilator potency is greatly
reduced. Long-term ETA antagonist
therapy improves PH in this model and improves pulmonary
vascular reactivity by increasing both
endothelium-independent dilation in response to SNP and
EDNO-dependent dilation in response to ACh. These findings demonstrate
that the ETA receptor contributes to the
development of PH and to alterations of pulmonary vascular
reactivity during sustained elevation of the pulmonary pressure
and support the development of ETA
antagonists for the therapy of PH.
Received August 14, 1997;
revision received November 21, 1997;
accepted December 22, 1997.
© 1998 American Heart Association, Inc.
Basic Science Reports
EndothelinA Receptor Blockade Improves Nitric Oxide–Mediated Vasodilation in Monocrotaline-Induced Pulmonary Hypertension
Abstract
Top
Abstract
Introduction
Methods
Results
Discussion
References
Background—Nitric oxide (NO) and
endothelin (ET) have been implicated in the pathogenesis of
pulmonary hypertension (PH). Chronic ETA
antagonist therapy reduces PH in monocrotaline
(MCT)-treated rats. Interactions between the L-arginine–NO
pathway and the ET system have been described. We therefore studied the
effect of long-term treatment with an oral ETA
antagonist (LU 135252) on NO-related vasodilation in
isolated lungs from control rats and rats with MCT-induced PH. 
Emax, from 11.1±0.9 to 2.7±0.3
mm Hg). Endothelium-dependent vasodilation in response
to acetylcholine (10-9 to 10-4
mol/L) and the calcium ionophore A23187 (10-9
to 10-7 mol/L) remained unaffected. Treatment
with LU 135252 did not significantly affect the
endothelium-dependent and -independent vasodilations in
control rats. However, in MCT-treated rats, LU 135252 therapy
significantly reduced right ventricular pressure
(39.7±2.1 mm Hg), potentiated acetylcholine-induced
vasodilatation (Emax, from 1.6±0.2 to 3.7±0.4
mm Hg), and improved the responses to sodium nitroprusside
(Emax, from 2.7±0.3 to 5.6±0.6 mm Hg). LU 135252
did not significantly alter the non–receptor-mediated
endothelium-dependent vasodilation to A23187 or
pulmonary constitutive NO synthase activity.
Key Words: endothelin • pulmonary heart disease • endothelium • drugs
Introduction
Top
Abstract
Introduction
Methods
Results
Discussion
References
Pulmonary
hypertension is associated with vascular endothelial
cell metabolic alterations that may contribute to the
pathogenic process. Among these, potential modifications in the
L-arginine–NO pathway and the ET system have generated
much attention not only because of their vascular tone–modulating
properties but also because of their potential role in vascular wall
remodeling.
Methods
Top
Abstract
Introduction
Methods
Results
Discussion
References
Experiments were carried out on 9-week-old male Sprague-Dawley
rats weighing 275 to 375 g (Charles River), which were randomly
assigned to receive an intraperitoneal injection of
either 0.5 mL of 0.9% saline or 0.5 mL 60 mg/kg MCT followed by daily
oral gavage with either 1 mL of 0.9% saline or 50 mg/kg LU starting 48
hours before the intraperitoneal injection and
subsequently for 3 weeks. This dosage regimen of LU has previously been
shown effective in prevention of PH in this
model.8 This protocol resulted in the creation of
four groups: control+saline (n=18), control+LU (n=16), MCT+saline
(n=17), and MCT+LU (n=15). The MCT was dissolved in 1.0 N HCl, and pH
was adjusted to 7.4 with 0.5 N NaOH. The compound LU (Knoll AG) was
dissolved in 1.0 N NaOH, and pH was adjusted to 7.4 with 0.5 N
HCl.
Twenty-four hours after the last gavage, rats were
anesthetized with sodium pentobarbital (50 mg/kg IP) followed
by 2000 U heparin IP (Sigma Chemical). After stable
anesthesia was obtained, the left carotid artery was
isolated and incised, and a polyethylene catheter (PE 50; 0.97-mm OD,
0.58-mm ID) was inserted to record arterial pressure. A
second catheter (0.97-mm OD, 0.58-mm ID) was advanced into the right
ventricle through the right jugular vein for measurement of right
ventricular pressure. The position of the catheter was
guided by the shape of the pressure tracing displayed on an
oscilloscope. The arterial and right
ventricular pressures were measured with a polygraph and
recorded (model TA4000; Gould). The trachea was cannulated with a
tubing connected to a rodent ventilator (Harvard Apparatus)
and ventilated with room air with a tidal volume of 1 mL and 2 cm
H2O positive end-expiratory pressure.
After a 10-minute period of stabilization, a cumulative
concentration-response curve was performed with ACh, SNP, or ionophore
A23187. In the control+saline, control+LU, and MCT+LU groups, the lungs
were perfused at an average constant flow rate of 9.23±0.03 mL/min. In
these groups, incremental aliquots of thromboxane analog
U46619 were injected into the perfusion circuit to increase the
baseline perfusion pressure to 15.2±0.4 mm Hg. In the MCT+saline
group, a similar perfusion pressure of 15.0±0.7 mm Hg was
reached with a slightly lower constant flow rate of 7.3±0.3 mL/min and
without the addition of U46619. The total pulmonary pressure
was increased to a similar degree in all groups, but a significantly
lower concentration of U46619 was required in lungs from MCT-treated
rats that received LU (0.80±0.12x10-7
mol/L) than in lungs from both control groups
(1.78±0.09x10-7 mol/L)
(P<0.01). Once the perfusion pressure had reached a
plateau, lungs were vasodilated with ACh, SNP, or ionophore A23187 to
obtain a cumulative concentration-response curve. Only one
concentration-vasodilation curve was obtained for each lung.
Tissue samples were homogenized using a 3:1 vol of
homogenizing buffer (10 mmol/L HEPES, 0.32
mmol/L sucrose, 0.1 mmol/L EDTA, 1 mmol/L dithiothreitol, 10
µg/mL leupeptin, 2 µg/µL aprotinin, 1 mg/mL phenylmethylsulfonyl
fluoride, final pH 7.2). The homogenized samples
were centrifuged at 12 000 rpm at 4°C for 15 minutes, and
the supernatants were removed and placed on ice.
U46619 and ionophore A23187 (Sigma Chemical) were dissolved in
95% ethanol and stored at -20°C. ACh and SNP (Sigma Chemical) were
dissolved in saline and kept in stock solution (-20°C) at a
concentration of 10-4 and
10-5 mol/L, respectively.
Differences in concentration-response curves between groups were
evaluated with a repeated measures ANOVA followed by a multiple-group
comparison. Right ventricular pressures, cNOS activities,
Emax values, and -log EC50
values were compared with the use of an ANOVA followed by multiple
group comparisons with the use of the Bonferroni correction.
EC50 and Emax values were
obtained with the use of a five-parameters logistic
function with SigmaPlot curve-fitting software. All values were
expressed as mean±SEM unless specified otherwise. Statistical
significance was assumed at a level of P<0.05.
Results
Top
Abstract
Introduction
Methods
Results
Discussion
References
Effect of LU on Right Ventricular and Systemic
Pressures
. Right
ventricular pressure in MCT-treated rats (66.6±4.1
mm Hg) was significantly (P<0.01) higher than that in
control rats (27.4±0.9 mm Hg). LU therapy did not
affect right ventricular pressure in control rats but
markedly decreased it after MCT to 39.7±2.1 mm Hg
(P<0.01). The mean systemic arterial pressures
were not significantly affected in all four groups: control+saline
(106.9±6.2 mm Hg), control+LU (106.7±3.6 mm Hg),
MCT+saline (100.1±4.0 mm Hg), and MCT+LU (105.6±3.8
mm Hg).
View larger version (25K):
[in a new window]
Figure 1. Effect of LU on the right ventricular
pressure (RVP) in control and MCT-treated rats. Measurements were
obtained 3 weeks after MCT injection. Oral administration of LU was
started 2 days before the injection of MCT and continued until 24 hours
before the experiment. Values are mean±SEM. **P<0.01
versus control+saline. 
P<0.01 versus
MCT+saline.
SNP (10-10 to
10-5 mol/L) induced a cumulative
concentration-dependent vasodilation in isolated perfused lungs (Figure 2A). The response was markedly lowered
with MCT with an Emax value of 2.7±0.3
mm Hg compared with 11.1±0.9 mm Hg in control rats
(P<0.01).
View larger version (18K):
[in a new window]
Figure 2. Effect of LU on the concentration-response curves
to SNP (10-10 to 10-5
molL), ACh (10-9 to 10-4
molL), and ionophore A23187 (10-9 to
10-7 molL) in isolated perfused lungs from
control and MCT-treated rats. Values are mean±SEM.
**P<0.01, *P<0.05 versus
control+saline. P<0.01, 
P<0.05
versus MCT+saline.).
View this table:
[in a new window]
Table 1. Effect of LU on Agonist Sensitivity and Maximal Responses in
PH
ACh (10-9 to 10-4
mol/L) and calcium ionophore A23187
(10-9 to 10-7
mol/L) induced concentration-dependent vasodilations in
isolated rat lungs (Figure 2
). ACh-induced vasodilation in MCT rat
lungs was not significantly different from that in control rat lungs
(Figure 2B). The Emax values for ACh were
1.6±0.2 and 2.1±0.2 mm Hg in MCT-treated and control rat lungs,
respectively (P=0.25). LU therapy did not significantly
modify the concentration-response curve in control rats, although it
tended to improve the response with a greater
Emax value (2.6±0.1 mm Hg). Half-maximal
responses were not significantly different, with -log
EC50 values of 6.7±0.2 and 6.5±0.5 in lungs
from control rats not treated and treated with LU, respectively
(Table). Lungs from MCT-treated rats that received LU showed a
significant (P<0.01) improvement in pulmonary
vasodilation in response to ACh with a higher
Emax value (3.7±0.4 mm Hg). The -log
EC50 values for ACh were 6.8±0.3 and 8.4±0.6
(P<0.05) in lungs from MCT-treated rats and MCT-treated
rats that received with LU, respectively (Table). and Table).
The cNOS activities did not differ significantly between control
(NaCl, 0.357±0.081 pmol · mg of
protein-1 · min-1;
LU, 0.428±0.127 pmol · mg of
protein-1 · min-1)
and MCT-treated rats (NaCl, 0.427±0.144
protein-1 · min-1;
LU, 0.356±0.169 pmol · mg of
protein-1 ·
min-1). Similarly, iNOS activity did not vary
between groups and was at the limit of detection of the assay with an
overall mean of 0.017±0.043 pmol · mg of
protein-1 ·
min-1.
Discussion
Top
Abstract
Introduction
Methods
Results
Discussion
References
The major findings of this study are that (1) although
endothelium-independent dilation in response to SNP is
reduced in MCT-induced PH, EDNO-dependent dilation is preserved and (2)
long-term therapy with the ETA
antagonist LU improved PH and both
endothelium-independent dilation in response to SNP and
EDNO-dependent dilation in response to ACh.
The results of the present study confirm that MCT-induced
hypertensive rats have a marked reduction in SNP-induced
pulmonary vasodilation. This suggests a reduced responsiveness
of the pulmonary vasculature to NO due to either an increase in
basal tone or abnormal vascular remodeling.15
Although it has been convincingly demonstrated that the response of the
hypertensive pulmonary circulation to EDNO donors such as SNP
is attenuated,16 17 18 19 20 studies of the
endogenous endothelial production
of NO have yielded conflicting results. Studies in isolated
pulmonary arteries from hypoxic19 and
MCT-treated pulmonary hypertensive
rats16 20 have shown reduced responsiveness to
the endothelium-dependent vasodilators, including ACh
and A23187, whereas others have suggested an increased basal NO
production in the latter model.15 In
intact chronically hypoxic lungs, some have observed a maintained basal
and agonist-stimulated endothelial NO
activity,21 whereas others have found that both
were increased.22 Responsiveness to ACh also is
maintained in isolated lungs from rats with severe MCT-induced
PH.23 A mild selective increase in the total
pulmonary vasodilatory response to the EDNO-dependent agonist
arginine vasopressin and unchanged response to the calcium ionophore
ionomycin was observed in isolated lungs from MCT-treated
rats.24 We found a mild nonsignificant decrease
in the response to ACh and no variation in the response to A23187 in
MCT-treated rats. We also measured cNOS activity in whole lung
homogenates and found it to be unaffected by PH. Although
this is consistent with our results, it may not be an adequate
reflection of local vascular NO activity. Resta et
al24 demonstrated an increase in
arterial but not venous cNOS with immunocytochemistry in
MCT rats. Our results combined with the above studies consequently
confirm that although endothelium-dependent dilation
may be attenuated in large isolated pulmonary arteries, it is
not significantly affected by MCT-induced PH when intact lungs are
evaluated. This is consistent with the previously observed
enhancement of vasoconstriction by NOS inhibitors in the
hypoxic25 and MCT-induced
hypertensive15 pulmonary circulation.
Long-term treatment of MCT-treated rats with an
ETA receptor antagonist reduces the
increase in right ventricular pressure and
hypertrophy.6 8 Similar beneficial
effects have been shown in chronically hypoxic
rats29 as well as on the right
ventricular function and hemodynamics of
the rats after myocardial infarction.30 Because
of the previously shown interactions between the
L-arginine/NO pathway and the ET
system,11 12 13 we hypothesized that long-term
ETA blockade may improve not only
endothelium-independent but also
endothelium-dependent dilation in the MCT-induced
hypertensive rats. 
15 mm Hg. U46619 was not needed for the
MCT+saline group, whereas an intermediate dose was needed for the
MCT+LU group. This methodology has the advantage of comparing all
groups with a similar baseline vascular tone, but we cannot exclude
that the various doses of U46619 may have altered the reactivity to the
various agonists that were used. Indeed, a greater dose of U46619 would
favor a greater active and reversible component of vascular tone.
Preconstriction was not used in the MCT+saline group because
hydrostatic pulmonary edema would invariably develop after
infusion of this constrictor. However, the observation that despite
greater active pharmacological preconstriction the response to the
endothelium-dependent dilator calcium ionophore was
similar and the response to ACh was less in the control+saline group
than in the MCT+LU groups strengthens our conclusion.
Selected Abbreviations and Acronyms
ACh
=
acetylcholine
cNOS
=
constitutive nitric oxide synthase
EDNO
=
endothelium-derived nitric oxide
ET
=
endothelin
LU
=
LU 135252
MCT
=
monocrotaline
NO
=
nitric oxide
NOS
=
nitric oxide synthase
PH
=
pulmonary hypertension
SNP
=
sodium nitroprusside
Acknowledgments
This work was supported by the Medical Research Council of
Canada, Quebec Heart and Stroke Foundation, and Fonds de Recherche de
l'Institut de Cardiologie de Montréal. Dr Dupuis is a scholar
from the Fonds de la Recherche en Santé du Québec. LU was a
gift from Dr M. Kirchengast (Knoll AG).
Footnotes
Guest editor for this article was Wilson S. Colucci, MD, Boston Medical Center, Boston, Mass.
References
Top
Abstract
Introduction
Methods
Results
Discussion
References
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J. E. Jones, L. Mendes, M. A. Rudd, G. Russo, J. Loscalzo, and Y.-Y. Zhang Serial noninvasive assessment of progressive pulmonary hypertension in a rat model Am J Physiol Heart Circ Physiol, July 1, 2002; 283(1): H364 - H371. [Abstract] [Full Text] [PDF]
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J.-F. Jasmin, M. Lucas, P. Cernacek, and J. Dupuis Effectiveness of a Nonselective ETA/B and a Selective ETA Antagonist in Rats With Monocrotaline-Induced Pulmonary Hypertension Circulation, January 16, 2001; 103(2): 314 - 318. [Abstract] [Full Text] [PDF]
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C. Veyssier-Belot and P. Cacoub Role of endothelial and smooth muscle cells in the physiopathology and treatment management of pulmonary hypertension Cardiovasc Res, November 1, 1999; 44(2): 274 - 282. [Abstract] [Full Text] [PDF]
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B Prendergast, D E Newby, L E Wilson, D J Webb, and P S Mankad Early therapeutic experience with the endothelin antagonist BQ-123 in pulmonary hypertension after congenital heart surgery Heart, October 1, 1999; 82(4): 505 - 508. [Abstract] [Full Text] [PDF]
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A. Y. Saadjian, F. Paganelli, M. L. Reynaud Gaubert, S. Levy, and R. P. Guieu Adenosine plasma concentration in pulmonary hypertension Cardiovasc Res, July 1, 1999; 43(1): 228 - 236. [Abstract] [Full Text] [PDF]
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