(Circulation. 1997;96:1976-1982.)
© 1997 American Heart Association, Inc.
Articles |
Role of Endogenous Endothelin in Chronic Heart Failure
Effect of Long-term Treatment With an Endothelin Antagonist on Survival, Hemodynamics, and Cardiac Remodeling
From VACOMED, Departments of Pharmacology (IFRMP 23) (P.M., V.R., M.H., J.P.H., F.L., P.C., E.C., C.T.), Cardiology (G.D., B.L.), and Histology (B.M.), Rouen University Medical School and Rouen University Hospital, France.
Correspondence to Christian Thuillez, Service de Pharmacologie, Hôpital de Bois Guillaume, CHU de Rouen, 76031 Rouen Cedex, France. E-mail Christian.Thuillez{at}chu-rouen.fr
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Abstract |
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Background Plasma levels of the vasoconstrictor peptide endothelin (ET) are increased in chronic heart failure (CHF), and ET levels are a major predictor of mortality in this disease. Thus, ET may play a deleterious role in CHF. The purpose of this study was to assess the effects of chronic treatment with the ET receptor antagonist bosentan in a rat model of CHF.
Methods and Results Rats were subjected to coronary artery ligation and were treated for 2 or 9 months with placebo or bosentan (30 or 100 mg · kg-1 · d-1). Bosentan 100 mg · kg-1 markedly increased survival (after 9 months: untreated, 47%; bosentan, 65%; P<.01). Throughout the 9-month treatment period, bosentan significantly reduced arterial pressure and heart rate. After 2 or 9 months of treatment, the ET antagonist reduced central venous pressure and left ventricular (LV) end-diastolic pressure as well as plasma catecholamines, urinary cGMP, and LV ventricular collagen density. Bosentan also reduced LV dilatation (evidenced at 2 months by a shift in the pressure/volume relationship ex vivo). Echocardiographic studies performed after 2 months showed that the ET antagonist reduced hypertrophy and increased contractility of the noninfarcted LV wall. The lower dose of bosentan (30 mg · kg-1), which had no major hemodynamic or structural effects, also had no effect on survival.
Conclusions Long-term treatment with an ET antagonist markedly increases survival in this rat model of CHF. This increase in survival is associated with decreases in both preload and afterload and an increase in cardiac output as well as decreased LV hypertrophy, LV dilatation, and cardiac fibrosis. Thus, chronic treatment with ET antagonists such as bosentan might be beneficial in human CHF and might increase long-term survival in this disease.
Key Words: echocardiograph • endothelin • heart failure • survival
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Introduction |
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Vascular endothelial cells synthesize various vasoactive substances, including the 21-amino-acid vasoconstrictor peptide ET.1 Plasma concentrations of ET are increased in experimental2 3 4 and human5 6 7 8 CHF. CHF may also upregulate ET receptors9 and increase vascular responsiveness to ET.10 Given the marked vasoconstrictor properties of ET, this peptide may contribute to the increased peripheral tone seen in heart failure. Moreover, plasma levels of ET are a major predictor of mortality after myocardial infarction.11 Thus, on the basis of these observations, it has been suggested that ET may play a role in the long-term pathophysiological changes induced by CHF and that ET antagonists may be useful therapeutic agents in this disease.
Recently, several antagonists of ET receptors have become available, allowing us to investigate the role of endogenous ET in physiological and pathophysiological situations such as heart failure. Indeed, acute administration of ET antagonists exerts favorable hemodynamic effects in rat12 13 or dog14 models of heart failure as well as in humans.15 A recent study suggested that BQ-123, a peptidic ETA antagonist, might improve survival in CHF.16 However, this study was performed with a small number of rats and a short duration of CHF (3 months). Whether long-term treatment with ET antagonists exerts beneficial hemodynamic and cardiovascular effects and affects survival in CHF is not known. Such long-term studies appear to be essential before we can draw conclusions on the therapeutic potential of ET antagonists in this disease.17
Thus, the goal of the present study was to assess whether chronic treatment with bosentan, a nonpeptidic, orally active ETA-ETB antagonist,18 affects survival, systemic and cardiac hemodynamics, and cardiac remodeling in a rat model of CHF.
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Methods |
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Experimental Design
Myocardial infarction was produced in 10-week-old male Wistar rats (Charles River, France) by left coronary artery ligation. The surgical procedure used was developed in our laboratory to induce a lower postoperative mortality compared with the "classic" technique.19 Thus, animals were anesthetized with 50 mg · kg-1 sodium methohexital IP. The animals were intubated with a small metal cannula and mechanically ventilated with room air by use of a small rodent ventilator (Apelex) at a rate of 60 cycles per minute and a tidal volume of 1 mL/100 g body wt. An ECG was obtained with standard limb electrodes and was monitored continuously on a Gould Windowgraph recorder. A left thoracotomy was performed, and the heart was exposed. A 6-0 polypropylene suture was passed around the proximal left coronary artery. Sham-operated rats were subjected to the same protocol, except that the snare was not tied. Fifteen minutes after occlusion, the chest was closed in three layers (ribs, muscles, and skin) with polyester sutures. A plastic catheter connected to a 5-mL syringe was placed in the chest before sewing and was used to remove air from the chest after closure. The animals were allowed to recover from anesthesia (usually within 30 minutes), after which they were returned to their cages and left 5 per cage. With this method, the 24-hour mortality rates were 18% and 15% in the infarction groups from studies 1 and 2, respectively.
Seven days after ligation, infarcted rats were randomized to receive either placebo (untreated) or bosentan (30 or 100 mg · kg-1 · d-1). Treatments were given as food additives. Rats were weighed every week, and their food intake was measured to allow adjustment of the drug concentrations in the chow. Treatments lasted either 2 months or 9 months before euthanasia.
Nine-Month Study
In the 9-month study, two different protocols were performed. In
the first protocol (low-dose bosentan), infarcted rats were either
untreated (n=53) or treated with bosentan (30 mg ·
kg-1 · d-1;
n=52). Twelve sham-operated rats were used as controls. However,
because this study turned out essentially negative, a second protocol
was performed to test the effect of a higher dose of bosentan. In this
latter study, infarcted rats were either untreated (n=51) or treated
with bosentan (100 mg · kg-1 ·
d-1; n=52). Eleven sham-operated rats were
used as controls.
Two-Month Study
Although we assessed the effect of the ET antagonist
on cardiac hemodynamics and cardiac structural changes
after 9 months of treatment, interpretation of the results obtained
after 9 months is rendered difficult by the fact that mortality causes
a selection of animals with only moderate cardiac dysfunction,
especially in the untreated group. Thus, to avoid this experimental
bias, we performed studies on an additional series of rats that were
killed after 2 months of treatment, ie, before any significant
mortality had occurred.
The 2-month study consisted of one single protocol. Because this study did not include assessment of survival, the number of animals in each group was lower than that of the 9-month studies. Thus, 34 infarcted rats were used: they were either untreated (n=10) or treated with bosentan 30 mg · kg-1 (n=12) or 100 mg · kg-1 (n=12). Eight sham-operated rats were used as controls.
Survival
Survival rate was assessed in the two 9-month protocols. During
the treatment period, cages were inspected daily for deceased animals
to calculate survival time. All deceased rats were examined for signs
of infection, then the heart was removed and fixed in Bouin's solution
for subsequent determination of infarct size.
Hemodynamic Measurements
Body weight, systolic blood pressure (plethysmography),
and heart rate were determined in conscious rats from the 9-month
studies just before the start of the treatment (ie, 7 days after the
surgical procedure) and after 1, 3, 6, and 9 months of treatment.
At the end of the studies (either 2 months or 9 months), the surviving rats were anesthetized with pentobarbital (50 mg · kg-1 IP). The right carotid artery and the right external jugular vein were cannulated with micromanometer-tipped catheters (SPR 407, Millar Instruments) advanced into the aorta and thoracic vena cava, respectively, for the recording of arterial pressure and CVP. The aortic catheter was then advanced into the LV for the recording of LV pressure and its maximal rate of rise (dP/dtmax). All tracings were recorded on a physiological recorder (Windowgraph, Gould).
In addition, the pressor effects of bolus intravenous injections of ET-1 (1 nmol · kg-1) or big ET-1 (1 nmol · kg-1) were assessed in randomly selected subgroups of rats.
Measurement of Plasma Catecholamines and Plasma
ET-1
Two weeks before completion of the study, the surviving
animals were anesthetized with ether, and venous blood samples
(1.25 mL) were collected in prechilled tubes containing EDTA (10
mmol · L-1 final concentration). Tubes
were immediately centrifuged at 3000g for 8 minutes
and stored at -80°C for determination of plasma
catecholamines (high-performance liquid
chromatography) and plasma ET
(radioimmunoassay).20
LV Pressure/Volume Relationship
LV pressure/volume relationships were assessed in rats from the
2-month study as described previously.21 At the completion
of the hemodynamic measurements, the heart was arrested
by intravenous injection of KCl. The heart was taken out,
and a double-lumen catheter was introduced into the LV through the
aorta. A snare was tied around the atrioventricular
groove to isolate the left atrium from the LV. Saline solution was
perfused at the rate of 0.68 mL/min while
intraventricular pressure was
simultaneously recorded with a transducer connected to
a recorder. When the pressure increased to 40 mm Hg, the
infusion was stopped.
Echocardiographic Studies
Transthoracic Doppler
echocardiographic studies were performed in rats from
the 2-month study. For this purpose, rats were anesthetized
with methohexital, the chest was shaved, and echocardiograms were
performed with an echocardiographic system equipped
with a 7-MHz transducer (Acuson 128 XP/10C), as described
previously.22 Briefly, a two-dimensional short-axis view
of the LV was obtained at the level of the papillary muscle to
record M-mode tracings. Tracings were analyzed on-line with
a commercially available on-line analysis system (Acuson).
Anterior and posterior end-diastolic and
end-systolic wall thicknesses and LV diameters were measured by
the American Society of Echocardiology leading-edge
method from at least three consecutive cardiac cycles.23
LV fractional shortening was calculated as the ratio of (LV
diastolic diameter minus LV systolic diameter)/LV
diastolic diameter.23 Measurements were
performed by a single observer (G.D.) blinded to prior results and
treatment groups. Our preliminary experiments showed that these
techniques showed good intraobserver variability and that the
echocardiographic evaluation of cardiac dimensions and
infarct size correlated well with histological
measurements (data not shown).
Urinary cGMP
The day before euthanasia, rats were placed in
metabolic cages for collection of 24-hour urine samples.
Samples were frozen at -80°C. Urinary cGMP was measured by enzyme
immunoassay. Concentrations of cGMP were then normalized to urinary
creatinine levels.
Cardiac Morphometry
Morphometric analyses were performed as described
previously.24 25 The atria and ventricles were weighed
separately, and the LV was immersed in Bouin's fixative solution.
After fixation, the heart was cut perpendicular to the apex-to-base
axis into three sections of approximately identical thicknesses.
Sections were dehydrated and embedded in paraffin. From these sections,
histological slices 3 µm thick were obtained and
stained with Sirius red.
For the measurement of infarct size, slices were placed under a videomicroscope (Microwatcher VS-30H, Mitsubishi Kasei Coop) with a x20 lens. The endocardial and epicardial circumferences of the infarcted tissue and of the LV were determined with image analysis software (Cyberview, Cervus International). Infarct size was calculated as (endocardial+epicardial circumference of the infarcted tissue)/(endocardial+epicardial circumference of the LV) and expressed as a percentage.
For the measurement of cardiac collagen density, slides stained with Sirius red were enlarged 500 times with a microscope connected to the same image analysis system. Collagen density was then calculated as the surface occupied by collagen/the surface of the image. Perivascular collagen was excluded from this measurement. It has been shown that total volume fraction, as determined by this morphometric approach, is closely related to hydroxyproline concentration of the ventricle.26
Statistical Analysis
All results except survival are given as mean±SEM. Comparison
of survival in untreated and treated CHF rats was performed by the
Mantel procedure.27 Differences between values obtained at
2 or 9 months were evaluated by ANOVA, followed, if ANOVA revealed
significant differences, by Tukey's test for multiple comparisons.
Pressure-volume relationships were compared by repeated-measures ANOVA.
Differences were considered significant at the level of
P<.05.
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Results |
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Survival and Infarct Size
During the 9-month study period, none of the sham animals died. Fig 1
illustrates the survival curves in
CHF rats. Survival at 9 months was similar in the two control groups
(44% and 47% in studies 1 and 2, respectively). In the second study,
however, early (ie, <2 months) mortality was higher than in study 1.
Indeed, after 2 months, survival was 96% and 85% in untreated rats
from studies 1 and 2, respectively.
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Compared with untreated (control) rats, bosentan at the dose of 30 mg · kg-1 · d-1 did not affect survival at any time. Indeed, at 9 months, survival was 44% in untreated rats and 43% in bosentan-treated rats (P=NS versus untreated). In contrast, bosentan 100 mg · kg-1 markedly increased survival, and this was significant at all times starting after 2 months. After 9 months, survival was 47% in untreated rats and 65% in rats treated with bosentan 100 mg · kg-1 (P<.01 versus untreated).
These differences in survival could not be due to differences in infarct size, because infarct size (including both animals that died spontaneously and animals killed after 9 months) was 38±1%, 38±2%, and 36±1% of the LV in untreated, bosentan 30 mg · kg-1, and bosentan 100 mg · kg-1, respectively.
Hemodynamic Measurements in Conscious Rats
Fig 2 shows the evolution of
systolic blood pressure and heart rate in the surviving rats
from the 9-month studies. Because the values of systolic
pressure and heart rate were not different in the two studies at any
time, the values were pooled.
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Systolic pressure in untreated CHF rats was always significantly lower than that of sham-operated animals, whereas heart rate was not affected. Bosentan 30 mg · kg-1 did not affect blood pressure or heart rate during the first 6 months, although it induced a small decrease in blood pressure after 9 months. In contrast, bosentan 100 mg · kg-1 significantly reduced both systolic pressure and heart rate, and this was significant after 3, 6, and 9 months of treatment.
Pressor Responses to ET-1 and Big ET-1
Fig 3 illustrates the effects on
mean arterial pressure of intravenous
administration of ET-1 (1 nmol · kg-1)
and big ET-1 (1 nmol · kg-1) in rats
anesthetized after 2 or 9 months. In the sham and untreated CHF
groups, data obtained at 9 months in protocols 1 and 2 were not
different and were pooled. Compared with sham-operated animals, CHF did
not modify the response to ET-1 or big ET-1 at either 2 or 9 months.
Bosentan markedly reduced the pressor responses to ET-1 and big ET-1.
Moreover, these inhibitory effects were more pronounced at
the dose of 100 mg · kg-1 than at 30
mg · kg-1, except for the response to
ET-1 at 9 months, which was inhibited to the same extent by the 2
doses.
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Neurohumoral Assessments
Fig 4 shows plasma ET-1, plasma
norepinephrine, and urinary cGMP measured after 2 and 9
months.
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Compared with sham-operated animals, CHF was not associated with a significant increase in the plasma levels of ET-1. Bosentan 30 mg · kg-1 did not affect ET-1 levels at 2 months and induced a small, nonsignificant increase in ET-1 at 9 months. In contrast, bosentan 100 mg · kg-1 significantly increased ET-1 levels after both 2 and 9 months of treatment. This increase, however, appeared less marked after 9 months than after 2 months.
Plasma norepinephrine levels were higher at 9 months than at 2 months in all groups. After both 2 and 9 months, compared with sham-operated animals, CHF was associated with significant increases in plasma norepinephrine, which were completely prevented by bosentan 100 mg · kg-1. In contrast, the lower dose of bosentan had no effect on norepinephrine levels.
Compared with sham-operated animals, CHF was associated with significant increases in urinary cGMP at both 2 and 9 months. Bosentan 30 mg · kg-1 did not affect cGMP levels at 2 months but significantly reduced these levels at 9 months. Bosentan 100 mg · kg-1 prevented the CHF-induced increase in cGMP at both 2 and 9 months.
Cardiac Hemodynamics
Fig 5 shows LV systolic
pressure, CVP, LVEDP, and LV dP/dt measured in anesthetized
animals after 2 or 9 months of treatment. Hemodynamic
data obtained in the two studies at 9 months in the sham and untreated
CHF groups were not different and were pooled.
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After 2 and 9 months, compared with sham-operated animals, CHF significantly decreased LV systolic pressure and dP/dt and increased CVP and LVEDP. In untreated CHF rats, however, CVP and LVEDP were lower after 9 months than after 2 months, whereas LV pressure and dP/dt were similar.
After 2 months of treatment, compared with untreated CHF rats, bosentan 100 mg · kg-1 (but not 30 mg · kg-1) reduced LV pressure and also markedly reduced both CVP and LVEDP without affecting dP/dt. Bosentan 100 mg · kg-1 also significantly reduced LVEDP after 9 months of treatment but did not significantly affect CVP at this time, probably because of the modest increase in CVP observed in untreated CHF rats.
LV Collagen Content
LV collagen density increased significantly between 2 and 9 months
in both sham-operated and untreated CHF rats. After 2 and 9 months,
compared with sham-operated rats, CHF was associated with significant
increases in LV collagen density (2 months: sham, 2.10±0.05%; CHF,
2.29±0.04%; P<.05; 9 months: sham, 2.02±0.23%; CHF,
3.49±0.19%; P<.05). At the dose of 30 mg ·
kg-1, bosentan also did not affect collagen
density at either 2 or 9 months (2 months, 2.22±0.08%; 9 months,
3.39±0.09%). In contrast, at the dose of 100 mg ·
kg-1, bosentan significantly reduced collagen
density at both 2 months (2.09±0.09%; P<.05 versus
untreated CHF) and 9 months (2.18±0.06%; P<.05 versus
untreated CHF).
Cardiac Volume-Pressure Relationships
Fig 6 shows cardiac volume-pressure
relationships obtained in vitro after 2 months. Compared with
sham-operated animals, the relationship was significantly shifted to
the right by CHF, suggesting LV dilatation. Bosentan 100 mg ·
kg-1 (but not the lower dose) shifted the
relationship to the left (P<.05).
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Echocardiography
Results from the echocardiographic studies
performed at 2 months are summarized in the
Table. Besides the expected marked
increase in end-diastolic and end-systolic LV
diameters, CHF induced a significant increase in thickness of the
noninfarcted wall, associated with a decreased percent thickening. CHF
also markedly increased wall-thinning ratio and LV fractional
shortening. Bosentan 30 mg · kg-1 did
not modify any of those parameters. In contrast, the higher
dose of the ET antagonist (100 mg ·
kg-1) significantly decreased anterior wall
thickness as well as wall-thinning ratio and increased percent
thickening without affecting LV fractional shortening. The higher dose
of bosentan also induced a small, nonsignificant decrease in LV
diameters.
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Discussion |
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The main result of the present study is that the ET antagonist bosentan markedly increased long-term survival in a rat model of CHF. Bosentan also reduced blood pressure and heart rate throughout the 9-month treatment period. In addition, after 2 or 9 months of treatment, the ET antagonist (1) reduced LVEDP and CVP and increased contractility of the noninfarcted LV without affecting LV dP/dt, (2) reduced hypertrophy and fibrosis of the noninfarcted LV as well as LV dilatation, and (3) reduced plasma catecholamines and urinary cGMP.
The main result of our study is that long-term treatment with an ET antagonist markedly increased survival. Indeed, survival was 47% in untreated CHF rats and 65% in CHF rats treated with bosentan 100 mg · kg-1 · d-1. This effect on survival was similar to that induced by an ACE inhibitor in the same experimental conditions.19 Although Sakai et al13 showed a beneficial effect of a short-term treatment with an ET antagonist, our study is the first to describe the effect of long-term treatment with ET antagonists on survival in CHF.
Our experiments were performed in a context of moderate cardiac failure, as evidenced by the moderate increase in LVEDP and the lower mortality obtained in our model compared with previous studies.24 25 28 This could be explained by the size of the infarcts, involving on average 35% to 40% of the LV, which thus could be considered moderate to large28 and could be due in part to the modifications we introduced in the technique used to induce coronary artery ligation, compared with the method initially described by Pfeffer et al.29 Whether the presence of larger infarcts and thus of more severe cardiac dysfunction would have affected the outcome of the present study (as in the case of ACE inhibitors, which are less effective in severe than in moderate dysfunction) is not known and requires further investigation.
Chronic treatment with the high dose of bosentan significantly reduced arterial blood pressure throughout the 9-month treatment period. Using a rat model of CHF, Teerlink et al12 showed that acute administration of bosentan induced a small (3 to 5 mm Hg) decrease in arterial blood pressure. Acute lowering of blood pressure has also been reported with ET antagonists in humans with CHF.15 However, to the best of our knowledge, our study is the first to assess the long-term hemodynamic effects of ET antagonists. Thus, our data suggest that ET is indeed involved in the maintenance of arterial blood pressure in CHF.
In parallel to the decrease in blood pressure, we also found that the high dose of bosentan significantly decreased heart rate throughout the 9-month treatment period. This decrease in heart rate could contribute to the overall beneficial effect of the ET antagonist in our model, especially in the marked effect on survival. Such a decrease in heart rate was not observed after acute administration of bosentan in rats with CHF.12 This decrease in heart rate could be the consequence of the inhibition of the positive chronotropic effects that have been described in vitro at low doses of ET.30 31 Another likely explanation is that the chronic decrease in heart rate is the consequence of the lesser sympathetic stimulation in treated rats. Indeed, the high dose of the ET antagonist completely prevented the CHF-induced increase in plasma catecholamines. This could be due either to an inhibition of an ET-1 induced increase in sympathetic tone or catecholamine release32 or to a lesser sympathetic stimulation secondary to the improved hemodynamic status.
Finally, bosentan also decreased an index of cardiac preload, ie, CVP. Although we have not measured any index of venous tone in our study, this probably reflects a venous vasodilatation, because ET is a potent venous constrictor.33
With regard to cardiac structure, we found that the ET antagonist reduced LV hypertrophy and fibrosis and also induced a moderate decrease in LV dilatation, in agreement with previous results.16 This could be due to blockade of the ET receptors present on the myocardium34 and/or to the hemodynamic effects of the ET antagonist. These effects on LV hypertrophy and dilatation, as well as on LV fibrosis, may also contribute to the increased survival.
In our experiments, we did not detect a significant increase in plasma ET-1 after 2 or 9 months of CHF. This is not in agreement with most experimental and clinical studies, in which plasma levels of ET-1 are increased after CHF. This could be partly explained by the selection, as a result of mortality, of animals with moderate cardiac dysfunction (in the case of the 9-month study), or by the fact that previous experiments may have involved larger infarcts and possibly more severe cardiac dysfunction.
In contrast, we found that bosentan dose-dependently increased plasma levels of ET-1. Such an increase has already been described after short-term administration and could be due to a compensatory activation of the ET system after chronic blockade or to the blockade of endothelial ETB receptors, which could play a role in the clearance of circulating ET.35 It should be noted, however, that the effect of bosentan on plasma levels of ET-1 decreases with time and is less marked after 9 months than after 2 months of treatment. Moreover, the twofold to threefold increase in plasma ET after bosentan observed in the present study is much lower than that previously reported after short-term administration of the ET antagonist in a dog model of CHF (>10-fold).14 In any case, the exact biological relevance of such an increase in plasma levels of ET is not clear, because this peptide is released mainly abluminally and thus may act only as a local hormone.17
Our results were obtained with a mixed antagonist of ETA and ETB receptors, whereas other studies were performed with selective ETA antagonists.13 In theory, specific blockade of ETA receptors would have the advantage of maintaining ETB-mediated, endothelium-dependent vasodilatation and possibly of inducing a smaller increase in plasma levels of ET. However, it is important to note that ETB receptors are also present on smooth muscle cells and induce vasoconstriction.36 Indeed, the ET-induced contraction of isolated human arteries is inhibited more markedly by mixed ETA-ETB antagonists than by selective ETA antagonists.37 ETB receptors may also mediate hypertrophic signals and, as mentioned above, may also be involved in the ET-induced synthesis of collagen by cardiac fibroblasts.38 Moreover, the vasoconstriction induced by sarafotoxin S6c (an ETB agonist) is increased in humans with CHF compared with control subjects, suggesting that vascular smooth muscle (constricting) ETB receptors are upregulated in human heart failure.39 Similar results were also obtained at the level of the coronary circulation in dogs with CHF.9 Whether the use of a specific ETA antagonist would have led to different results is not known and cannot be answered from the present study.
In conclusion, our experiments, performed in a rat model of CHF, show that long-term treatment with an ET antagonist markedly increases survival in this rat model of CHF. This increase in survival may be the consequence of the observed marked beneficial hemodynamic and cardiac structural effects, characterized by decreases in both preload and afterload and an increase in cardiac output, as well as decreased LV hypertrophy and LV dilatation and cardiac fibrosis. Thus, chronic treatment with ET antagonists such as bosentan might be beneficial in human CHF and might increase long-term survival in this disease.
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Selected Abbreviations and Acronyms |
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Acknowledgments |
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The authors thank Eliane Abdelhouab for her excellent technical assistance, Dr Martine Clozel for providing bosentan, and Dr Bernd-Michael Löffler for the endothelin assays.
Received December 31, 1996; revision received March 26, 1997; accepted April 12, 1997.
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References |
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TopAbstractIntroductionMethodsResultsDiscussionReferences |
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1. Yanagisawa M, Kurihara H, Kimura S, Tomobe Y, Kobayashi M, Mitsui Y, Yazaki Y, Goto K, Masaki T. A novel potent vasoconstrictor peptide produced by vascular endothelial cells. Nature. 1988;332:411-415.[Medline] [Order article via Infotrieve]
2.
Cavero PG, Miller WL, Heublein DM, Margulies KB,
Burnett JC Jr. Endothelin in experimental congestive heart failure in
the anesthetized dog. Am J Physiol. 1990;259:F312-F317.
3.
Margulies KB, Hildebrand FL Jr, Lerman A, Perrella MA,
Burnett JC Jr. Increased endothelin in experimental heart failure.
Circulation. 1990;82:2226-2230.
4.
Underwood RD, Aarhus LL, Heublein DM, Burnett JC Jr.
Endothelin in thoracic inferior vena cava constriction
model of heart failure. Am J Physiol. 1992;263:H951-H955.
5. Lerman A, Kubo SH, Tschumperlin LK, Burnett JC Jr. Plasma endothelin concentrations in humans with end-stage heart failure and after heart transplantation. J Am Coll Cardiol. 1992;20:849-853.[Abstract]
6.
McMurray JJ, Ray SG, Abdullah I, Dargie HJ, Morton
JJ. Plasma endothelin in chronic heart failure.
Circulation. 1992;85:1374-1379.
7.
Stewart DJ, Cernacek P, Costello KB, Rouleau
JL. Elevated endothelin-1 in heart failure and loss of normal
response to postural change. Circulation. 1992;85:510-517.
8.
Wei CM, Lerman A, Rodeheffer RJ, McGregor CG, Brandt
RR, Wright S, Heublein DM, Kao PC, Edwards WD, Burnett JC Jr.
Endothelin in human congestive heart failure. Circulation. 1994;89:1580-1586.
9.
Cannan CR, Burnett JC Jr, Lerman A. Enhanced
coronary vasoconstriction to endothelin-B–receptor activation
in experimental chronic heart failure. Circulation. 1996;93:646-651.
10. Noll G, Tschudi M, Novosel D, Lüscher TF. Activation of the L-arginine/nitric oxide pathway and endothelin-1 in experimental heart failure. J Cardiovasc Pharmacol. 1994;23:916-921.[Medline] [Order article via Infotrieve]
11.
Omland T, Lie RT, Aakvaag A, Aarsland T, Dickstein
K. Plasma endothelin determination as a prognostic indicator of
1-year mortality after acute myocardial infarction.
Circulation. 1994;89:1573-1579.
12.
Teerlink JR, Löffler BM, Hess P, Maire JP, Clozel
M, Clozel JP. Role of endothelin in the maintenance of
blood pressure in conscious rats with chronic heart failure: acute
effects of the endothelin receptor antagonist Ro 47-0203
(bosentan). Circulation. 1994;90:2510-2518.
13.
Sakai S, Miyauchi T, Sakurai T, Kasuya Y, Ihara M,
Yamaguchi I, Goto K, Sugishita Y. Endogenous
endothelin-1 participates in the maintenance of cardiac
function in rats with congestive heart failure: marked increase in
endothelin-1 production in the failing heart.
Circulation. 1996;93:1214-1222.
14.
Shimoyama H, Sabbah HN, Borzak S, Tanimura M,
Shevlyagin S, Scicli G, Goldstein S. Short-term
hemodynamic effects of endothelin receptor blockade in
dogs with chronic heart failure. Circulation. 1996;94:779-785.
15. Kiowski W, Sutsch G, Hunziker P, Muller P, Kim J, Oechslin E, Schmitt R, Jones R, Bertel O. Evidence for endothelin-1-mediated vasoconstriction in severe chronic heart failure. Lancet. 1995;346:732-736.[Medline] [Order article via Infotrieve]
16. Sakai S, Miyauchi T, Kobayashi M, Yamaguchi I, Goto K, Sugishita Y. Inhibition of myocardial endothelin pathway improves long term survival in heart failure. Nature. 1996;384:353-355.[Medline] [Order article via Infotrieve]
17.
Cohn JN. Is there a role for endothelin in the
natural history of heart failure? Circulation. 1996;94:604-606.
18.
Clozel M, Breu V, Gray GA, Kalina B, Löffler B,
Burri K, Cassal J, Hirth G, Müller M, Neidhart W, Ramuz H.
Pharmacological characterization of bosentan, a new potent orally
active non-peptide endothelin receptor antagonist.
J Pharmacol Exp Ther. 1994;270:228-235.
19. Mulder P, Richard V, Compagnon P, Henry JP, Lallemand F, Clozel JP, Koen R, Macé B, Thuillez C. Increased survival after chronic treatment with mibefradil, a selective T channels calcium antagonist, in heart failure. J Am Coll Cardiol. 1997;29:416-421.[Abstract]
20. Löffler B, Maire JP. Radioimmunological determination of endothelin peptides in human plasma: a methodological approach. Endothelium. 1994;1:273-286.
21.
Fletcher PJ, Pfeffer MA, Pfeffer JM, Braunwald
E. Left ventricular diastolic
pressure-volume relations in rats with healed myocardial infarction:
effects on systolic function. Circ Res. 1981;49:618-626.
22.
Litwin SE, Katz SE, Morgan JP, Douglas PS.
Serial echocardiographic assessment of left
ventricular geometry and function after large myocardial
infarction in the rat. Circulation. 1994;89:345-354.
23.
Sahn DJ, DeMaria A, Kisslo J, Weyman A.
Recommendations regarding quantitation in M-mode
echocardiography: results of a survey of
echocardiographic measurements.
Circulation. 1978;58:1072-1083.
24.
Mulder P, Elfertak L, Richard V, Compagnon P, Devaux B,
Henry JP, Scalbert E, Desché P, Macé B, Thuillez C.
Peripheral artery structure and endothelial
function in heart failure: effect of ACE inhibition.
Am J Physiol. 1996;271:H469-H477.
25.
Mulder P, Devaux B, Richard V, Henry JP, Wimart MC,
Thibout E, Macé B, Thuillez C. Early vs delayed
angiotensin converting enzyme inhibition in experimental
chronic heart failure: effects on survival,
hemodynamics and cardiovascular
remodeling. Circulation. 1997;95:1314-1319.
26.
Weber KT, Janicki JS, Schroff SG, Pick R, Chen RM,
Bashey RI. Collagen remodeling of the pressure-overloaded,
hypertrophied nonhuman primate myocardium.
Circ Res. 1988;62:757-765.
27. Mantel N. Chi-square tests with one degree of freedom: extension of the Mantel-Haenszel procedure. J Am Stat Assoc. 1963;58:690-700.
28. Pfeffer MA, Pfeffer JM, Steinberg C, Finn P. Survival after an experimental myocardial infarction: beneficial effects of long-term therapy with captopril. Circ Res. 1985;72:406-412.
29.
Pfeffer MA, Pfeffer JM, Fishbein MC, Fletcher PJ,
Sparado J, Kloner RA, Braunwald E. Myocardial infarct size and
ventricular function in rats. Circ Res. 1979;44:503-512.
30. Ishikawa T, Yanagisawa M, Kimura S, Goto K, Masaki T. Positive chronotropic effects of endothelin, a novel endothelium-derived vasoconstrictor peptide. Pflugers Arch. 1988;413:108-110.[Medline] [Order article via Infotrieve]
31.
Ono K, Eto K, Sakamoto A, Masaki T, Shibata K, Sada T,
Hashimoto K. Negative chronotropic effect of endothelin 1
mediated through ETA receptors in guinea pig atria.
Circ Res. 1995;76:284-292.
32. Boarder MR, Marriott DB. Endothelin-1 stimulation of noradrenaline and adrenaline release from adrenal chromaffin cells. Biochem Pharmacol. 1991;41:521-526.[Medline] [Order article via Infotrieve]
33.
Lüscher TF, Yang Z, Von Segesser L, Stulz P,
Boulanger C, Siebenmann R, Turina M, Buhler F. Interaction
between endothelin-1 and endothelium-derived relaxing
factor in human arteries and veins. Circ Res. 1990;66:1088-1094.
34.
Ishikawa T, Li L, Shinmi O, Kimura S, Yanagisawa M,
Goto K, Masaki T. Characteristics of binding of endothelin-1 and
endothelin-3 to rat hearts: developmental changes in mechanical
responses and receptor subtypes. Circ Res. 1991;69:918-926.
35. Fukuroda T, Fujikawa T, Ozaki S, Ishiwaka K, Yano M, Nishikibe M. Clearance of circulation endothelin-1 by ETB receptors in rats. Biochem Biophys Res Commun. 1994;199:1461-1465.[Medline] [Order article via Infotrieve]
36. Clozel M, Gray GA, Breu V, Löffler BM. The endothelin ETB receptor mediates both vasodilatation and vasoconstriction in vivo. Biochem Biophys Res Commun. 1992;186:867-873.[Medline] [Order article via Infotrieve]
37.
Seo B, Oemar BS, Siebenmann R, von Segesser L,
Lüscher TF. ETA and ETB receptors
mediate contraction to endothelin-1 in human blood vessels.
Circulation. 1994;89:1203-1208.
38.
Guarda E, Katwa LC, Myers PR, Tyagi SC, Weber
KT. Effects of endothelin on collagen turnover in cardiac
fibroblasts. Cardiovasc Res. 1993;27:2130-2134.
39. Love M, Webb DJ. Vasodilator effects of endothelin-converting enzyme inhibition and endothelin ETA receptor blockade in chronic heart failure patients treated with ACE inhibitors. Circulation. 1996;95:2131-2137.
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|
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|
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|
|
|
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|
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|
|
|
|
|
|
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|
|
|
|
|
|
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|
|
|
|
|
|
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|
|
|
|
|
|
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|
|
|
|
|
|
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|
|
|
|
|
|
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|
|
|
|
 |
|
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|
|
|
|
 |
|
 C. Joffs, C. A. Walker, J. W. Hendrick, D. J. Fary, D. K. Almany, J. N. Davis, A. T. Goldberg, F. A. Crawford Jr, and F. G. Spinale Endothelin receptor subtype A blockade selectively reduces pulmonary pressure after cardiopulmonary bypass J. Thorac. Cardiovasc. Surg., August 1, 2001; 122(2): 365 - 370. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
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|
|
|
|
|
|
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|
|
|
|
|
|
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|
|
|
|
|
|
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|
|
|
|
|
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|
|
|
|
|
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|
|
|
|
|
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|
|
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R. Varin, P. Mulder, F. Tamion, V. Richard, J.-P. Henry, F. Lallemand, G. Lerebours, and C. Thuillez Improvement of Endothelial Function by Chronic Angiotensin-Converting Enzyme Inhibition in Heart Failure : Role of Nitric Oxide, Prostanoids, Oxidant Stress, and Bradykinin Circulation, July 18, 2000; 102(3): 351 - 356. [Abstract] [Full Text] [PDF]
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I. Hamanaka, Y. Saito, T. Nishikimi, T. Magaribuchi, S. Kamitani, K. Kuwahara, M. Ishikawa, Y. Miyamoto, M. Harada, E. Ogawa, et al. Effects of cardiotrophin-1 on hemodynamics and endocrine function of the heart Am J Physiol Heart Circ Physiol, July 1, 2000; 279(1): H388 - H396. [Abstract] [Full Text] [PDF]
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J. Bauersachs, D. Fraccarollo, P. Galuppo, J. Widder, and G. Ertl Endothelin-receptor blockade improves endothelial vasomotor dysfunction in heart failure Cardiovasc Res, July 1, 2000; 47(1): 142 - 149. [Abstract] [Full Text] [PDF]
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M. P Love, C. J Ferro, W. G Haynes, C. Plumpton, A. P Davenport, D. J Webb, and J. J.V McMurray Endothelin receptor antagonism in patients with chronic heart failure Cardiovasc Res, July 1, 2000; 47(1): 166 - 172. [Abstract] [Full Text] [PDF]
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M. M. Givertz, W. S. Colucci, T. H. LeJemtel, S. S. Gottlieb, J. M. Hare, M. T. Slawsky, C. V. Leier, E. Loh, J. M. Nicklas, and B. E. Lewis Acute Endothelin A Receptor Blockade Causes Selective Pulmonary Vasodilation in Patients With Chronic Heart Failure Circulation, June 27, 2000; 101(25): 2922 - 2927. [Abstract] [Full Text] [PDF]
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S. Sakai, T. Miyauchi, and I. Yamaguchi Long-Term Endothelin Receptor Antagonist Administration Improves Alterations in Expression of Various Cardiac Genes in Failing Myocardium of Rats With Heart Failure Circulation, June 20, 2000; 101(24): 2849 - 2853. [Abstract] [Full Text] [PDF]
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 A. Talbodec, N. Berkane, V. Blandin, J. P. Breittmayer, E. Ferrari, C. Frelin, and P. Vigne Aspirin and Sodium Salicylate Inhibit Endothelin ETA Receptors by an Allosteric Type of Mechanism Mol. Pharmacol., April 1, 2000; 57(4): 797 - 804. [Abstract] [Full Text]
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H. Kjekshus, O. A. Smiseth, R. Klinge, E. Oie, M. E. Hystad, and H. Attramadal Regulation of ET: pulmonary release of ET contributes to increased plasma ET levels and vasoconstriction in CHF Am J Physiol Heart Circ Physiol, April 1, 2000; 278(4): H1299 - H1310. [Abstract] [Full Text] [PDF]
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P. A. MacCarthy, R. Grocott-Mason, B. D. Prendergast, and A. M. Shah Contrasting Inotropic Effects of Endogenous Endothelin in the Normal and Failing Human Heart : Studies With an Intracoronary ETA Receptor Antagonist Circulation, January 18, 2000; 101(2): 142 - 147. [Abstract] [Full Text] [PDF]
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T. Mishima, M. Tanimura, G. Suzuki, A. Todor, V. G. Sharov, S. Goldstein, and H. N. Sabbah Effects of long-term therapy with bosentan on the progression of left ventricular dysfunction and remodeling in dogs with heart failure J. Am. Coll. Cardiol., January 1, 2000; 35(1): 222 - 229. [Abstract] [Full Text] [PDF]
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Z R Yousef, S R Redwood, and M S Marber Postinfarction left ventricular remodelling: where are the theories and trials leading us? Heart, January 1, 2000; 83(1): 76 - 80. [Full Text] [PDF]
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G. P. Rossi, M. Cesari, A. C. Pessina, B. Hocher, and I. George Endothelins and Cardiac Fibrosis • Response Hypertension, November 1, 1999; e1(5): . [Full Text]
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K. Ono, A. Matsumori, T. Shioi, Y. Furukawa, and S. Sasayama Contribution of Endothelin-1 to Myocardial Injury in a Murine Model of Myocarditis : Acute Effects of Bosentan, an Endothelin Receptor Antagonist Circulation, October 26, 1999; 100(17): 1823 - 1829. [Abstract] [Full Text] [PDF]
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F. Brunner Cardiac endothelin and big endothelin in right-heart hypertrophy due to monocrotaline-induced pulmonary hypertension in rat Cardiovasc Res, October 1, 1999; 44(1): 197 - 206. [Abstract] [Full Text] [PDF]
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 C. Lowbeer, A. Ottosson-Seeberger, S. A. Gustafsson, R. Norrman, J. Hulting, and A. Gutierrez Increased cardiac troponin T and endothelin-1 concentrations in dialysis patients may indicate heart disease Nephrol. Dial. Transplant., August 1, 1999; 14(8): 1948 - 1955. [Abstract] [Full Text] [PDF]
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G. P. Rossi, A. Sacchetto, M. Cesari, and A. C Pessina Interactions between endothelin-1 and the renin-angiotensin-aldosterone system Cardiovasc Res, August 1, 1999; 43(2): 300 - 307. [Abstract] [Full Text] [PDF]
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R. Varin, P. Mulder, V. Richard, F. Tamion, C. Devaux, J.-P. Henry, F. Lallemand, G. Lerebours, and C. Thuillez Exercise Improves Flow-Mediated Vasodilatation of Skeletal Muscle Arteries in Rats With Chronic Heart Failure : Role of Nitric Oxide, Prostanoids, and Oxidant Stress Circulation, June 8, 1999; 99(22): 2951 - 2957. [Abstract] [Full Text] [PDF]
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R. Yamauchi-Kohno, T. Miyauchi, T. Hoshino, T. Kobayashi, H. Aihara, S. Sakai, H. Yabana, K. Goto, Y. Sugishita, and S. Murata Role of Endothelin in Deterioration of Heart Failure Due to Cardiomyopathy in Hamsters : Increase in Endothelin-1 Production in the Heart and Beneficial Effect of Endothelin-A Receptor Antagonist on Survival and Cardiac Function Circulation, April 27, 1999; 99(16): 2171 - 2176. [Abstract] [Full Text] [PDF]
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B. Pieske, B. Beyermann, V. Breu, B. M. Loffler, K. Schlotthauer, L. S. Maier, S. Schmidt-Schweda, H. Just, and G. Hasenfuss Functional Effects of Endothelin and Regulation of Endothelin Receptors in Isolated Human Nonfailing and Failing Myocardium Circulation, April 13, 1999; 99(14): 1802 - 1809. [Abstract] [Full Text] [PDF]
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T. Kobayashi, T. Miyauchi, S. Sakai, M. Kobayashi, I. Yamaguchi, K. Goto, and Y. Sugishita Expression of endothelin-1, ETA and ETB receptors, and ECE and distribution of endothelin-1 in failing rat heart Am J Physiol Heart Circ Physiol, April 1, 1999; 276(4): H1197 - H1206. [Abstract] [Full Text] [PDF]
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B. Hocher, I. George, J. Rebstock, A. Bauch, A. Schwarz, H.-H. Neumayer, and C. Bauer Endothelin System–Dependent Cardiac Remodeling in Renovascular Hypertension Hypertension, March 1, 1999; 33(3): 816 - 822. [Abstract] [Full Text] [PDF]
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A. Wada, T. Tsutamoto, M. Ohnishi, M. Sawaki, D. Fukai, Y. Maeda, and M. Kinoshita Effects of a Specific Endothelin-Converting Enzyme Inhibitor on Cardiac, Renal, and Neurohumoral Functions in Congestive Heart Failure : Comparison of Effects With Those of Endothelin A Receptor Antagonism Circulation, February 2, 1999; 99(4): 570 - 577. [Abstract] [Full Text] [PDF]
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Y. Matsumura, N. Hashimoto, S. Taira, T. Kuro, R. Kitano, M. Ohkita, T. J. Opgenorth, and M. Takaoka Different Contributions of Endothelin-A and Endothelin-B Receptors in the Pathogenesis of Deoxycorticosterone Acetate–Salt–Induced Hypertension in Rats Hypertension, February 1, 1999; 33(2): 759 - 765. [Abstract] [Full Text] [PDF]
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G. Sutsch, W. Kiowski, X.-W. Yan, P. Hunziker, S. Christen, W. Strobel, J.-H. Kim, P. Rickenbacher, and O. Bertel Short-Term Oral Endothelin-Receptor Antagonist Therapy in Conventionally Treated Patients With Symptomatic Severe Chronic Heart Failure Circulation, November 24, 1998; 98(21): 2262 - 2268. [Abstract] [Full Text] [PDF]
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Q. T. Nguyen, P. Cernacek, A. Calderoni, D. J. Stewart, P. Picard, P. Sirois, M. White, and J. L. Rouleau Endothelin A Receptor Blockade Causes Adverse Left Ventricular Remodeling but Improves Pulmonary Artery Pressure After Infarction in the Rat Circulation, November 24, 1998; 98(21): 2323 - 2330. [Abstract] [Full Text] [PDF]
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Y. Iwanaga, Y. Kihara, K. Hasegawa, K. Inagaki, T. Yoneda, S. Kaburagi, M. Araki, and S. Sasayama Cardiac Endothelin-1 Plays a Critical Role in the Functional Deterioration of Left Ventricles During the Transition From Compensatory Hypertrophy to Congestive Heart Failure in Salt-Sensitive Hypertensive Rats Circulation, November 10, 1998; 98(19): 2065 - 2073. [Abstract] [Full Text] [PDF]
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E. Oie, R. Bjonerheim, H. K. Grogaard, H. Kongshaug, O. A. Smiseth, and H. Attramadal ET-receptor antagonism, myocardial gene expression, and ventricular remodeling during CHF in rats Am J Physiol Heart Circ Physiol, September 1, 1998; 275(3): H868 - H877. [Abstract] [Full Text] [PDF]
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B. Geny, F. Piquard, J. Lonsdorfer, and P. Haberey Endothelin and heart transplantation Cardiovasc Res, September 1, 1998; 39(3): 556 - 562. [Full Text] [PDF]
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R. Choussat, L. Hittinger, F. Barbe, G. Maistre, A. Carayon, B. Crozatier, and J. Su Acute effects of an endothelin-1 receptor antagonist bosentan at different stages of heart failure in conscious dogs Cardiovasc Res, September 1, 1998; 39(3): 580 - 588. [Abstract] [Full Text] [PDF]
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P. Mulder, V. Richard, F. Bouchart, G. Derumeaux, K. Munter, and C. Thuillez Selective ETA receptor blockade prevents left ventricular remodeling and deterioration of cardiac function in experimental heart failure Cardiovasc Res, September 1, 1998; 39(3): 600 - 608. [Abstract] [Full Text] [PDF]
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M. Ohnishi, A. Wada, T. Tsutamoto, D. Fukai, and M. Kinoshita Comparison of the acute effects of a selective endothelin ETA and a mixed ETA/ETB receptor antagonist in heart failure Cardiovasc Res, September 1, 1998; 39(3): 617 - 624. [Abstract] [Full Text] [PDF]
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T. Hoshino, R. Yamauchi, K. Kikkawa, H. Yabana, and S. Murata Pharmacological Profile of T-0201, a Highly Potent and Orally Active Endothelin Receptor Antagonist J. Pharmacol. Exp. Ther., August 1, 1998; 286(2): 643 - 649. [Abstract] [Full Text]
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