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(Circulation. 1998;98:2065-2073.)
© 1998 American Heart Association, Inc.
Basic Science Reports |
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
From the Department of Cardiovascular Medicine, Kyoto University Graduate School of Medicine, Kyoto, Japan.
Correspondence to Yasuki Kihara, MD, PhD, Department of Cardiovascular Medicine, Kyoto University Graduate School of Medicine, 54 Shogoin Kawahara-cho, Sakyo-ku, Kyoto 606-8507, Japan. E-mail kihara{at}kuhp.kyoto-u.ac.jp
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Abstract |
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 Top Abstract IntroductionMethodsResultsDiscussionReferences |
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Background—To investigate whether endogenous ET-1 participates in an adaptive process of left ventricular hypertrophy (LVH) or a maladaptive process from LVH to congestive heart failure (CHF), we used a Dahl salt-sensitive (DS) rat model, in which systemic hypertension caused compensated concentric LVH at the age of 11 weeks followed by marked LV dilatation and global hypokinesis at the age of 17 weeks.
Methods and Results—By specific sandwich enzyme immunoassay,
serum and myocardial ET-1 levels at the LVH stage were not elevated
compared with age-matched Dahl salt-resistant (DR) rats,
despite the marked increase of LV/body weight ratio (LV/BW). However,
at the CHF stage, serum and LV ET-1 levels increased by 3.8-fold and
5.4-fold, respectively. LV ET-1 contents had close relationships with
the fractional shortening (r=0.763) and the
systolic wall stress (r=0.858) measured by in
vivo transthoracic echocardiography.
Immunohistochemistry demonstrated that the remarkably increased ET-1 in
LV is located mainly in cardiomyocytes. By competitive
reverse transcriptase–polymerase chain reaction, LV prepro-ET-1 mRNA
levels increased by 4.1-fold in CHF rats. We randomized 11-week-old LVH
rats to chronic treatment with the endothelin receptor
antagonist bosentan (Bos, 100 mg ·
kg-1 · d-1, n=14), the
1-receptor antagonist doxazosin (Dox, 1
mg · kg-1 · d-1, n=12), or
vehicle (Cont, n=14). Bos treatment did not alter the LV geometry and
function at 15 weeks; however, it attenuated the decrease of LV
fractional shortening by 51% (P<0.01) without reducing
the LV/BW at 17 weeks. Conversely, Dox, which decreased the blood
pressure to the same extent as Bos, did not affect the progression of
LV dysfunction. Bos (93%; P<0.0001 versus Cont) but
not Dox (42%; P=0.8465 versus Cont) ameliorated the
survival rate at 17 weeks (Cont; 36%).
Conclusions—The accelerated myocardial synthesis of ET-1 contributes directly to LV contractile dysfunction during the transition from LVH to CHF. Unelevated levels of LV ET-1 at the established LVH stage and lack of effects on LV mass by chronic bosentan treatment suggest that myocardial growth is mediated through alternative pathways. These studies indicate that chronic ET antagonism may provide an additional strategy for heart failure therapy in humans.
Key Words: endothelin • heart failure • hypertrophy • remodeling • hypertension
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Introduction |
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TopAbstractIntroductionMethodsResultsDiscussionReferences |
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Endothelin-1 (ET-1) is a potent vasoconstrictor peptide originally isolated from the supernatants of cultured endothelial cells.1 2 It exerts its effects through stimulation of specific receptors, ETA and ETB receptors, widely distributed in the cardiovascular system.3 4 The plasma levels of ET-1 are elevated in various pathophysiological states, ie, hypertension, atherosclerosis, myocardial infarction, and congestive heart failure (CHF).5 The elevated levels of ET-1 in heart failure are closely associated with the extent of pulmonary hypertension.6 In this state, acute administration of endothelin receptor blocker reduced vascular resistance and improved overall left ventricular (LV) performance.7 8 These findings suggest that ET-1 plays a pathophysiological role in heart failure as a circulating hormone.
In addition to its action as a systemic hormone, ET-1 has a number of actions as a local factor. ET-1 mediates load-induced hypertrophy in cultured neonatal cardiac myocytes as an autocrine factor. Previous studies reported that the expression of ET-1 in the heart is accelerated after pressure overload and myocardial infarction and that chronic administration of an ET receptor antagonist improved the survival and hemodynamics in heart failure.9 10 11 However, several questions remain to be defined with regard to the local roles of ET-1. First, because no precise serial evaluation of the LV function has been performed, it is unclear at present whether the elevation of cardiac ET-1 levels occurs even in the hypertrophied heart with normal systolic function or in association with the deterioration of systolic function. Second, how an ET blocker prevents the development of heart failure is unclear. Specifically, it is unknown whether beneficial effects of ET blockers are mediated by suppressing cardiac growth such as ACE inhibitors or by other mechanisms.
To address these questions, we used the Dahl salt-sensitive (DS) rat. In this rat under a high-salt diet, systemic hypertension induces compensated concentric LV hypertrophy (LVH) at the age of 11 weeks, which is followed by marked LV dilatation and global hypokinesis (CHF) at the age of 16 to 18 weeks. Our previous studies clearly distinguished these 2 states in in vivo as well as in vitro studies.12 13 Thus, we investigated the role of endogenous ET-1 in the transition from LVH to CHF using this animal model.
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Methods |
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TopAbstractIntroductionMethodsResultsDiscussionReferences |
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Experimental Animals and In Vivo Assessment of LV Geometry and Function
Male inbred DS and Dahl salt-resistant (DR) rats obtained from Brookhaven National Laboratories, Upton, NY, were further bred and supplied by Eisai Co, Ltd (Tokyo, Japan).14 15 After weaning, the rats were fed a 0.3% NaCl (low-salt) diet until the age of 6 weeks, after which they were fed an 8% NaCl (high-salt) diet.
The systolic blood pressure (SBP) of each animal was measured on the day before euthanasia by a tail-cuff method. On the same day, LV dimensions and contractile function were evaluated in vivo by transthoracic echocardiography as previously reported in detail from our laboratory.12 We determined the LV end-diastolic diameter, end-systolic diameter, and diastolic posterior wall thickness, and the relative wall thickness, LV fractional shortening (FS), and end-systolic meridional wall stress were calculated from these measures.12
Measurement of Plasma and Myocardial ET-1 Levels
After pentobarbital anesthesia, blood was collected
in a polypropylene tube containing aprotinin (300 kallikrein-inhibiting
units/mL) and EDTA (2 mg/mL) and immediately centrifuged at
1800g for 15 minutes at 4°C. Plasma was stored at -80°C
until the time of assay. After the heart was excised, the atria were
trimmed off, and the right and left ventricles were rinsed in cold
physiological saline and homogenized
with a Polytron homogenizer for 30 seconds in 9 volumes
of 1 mol/L acetic acid containing 0.1% Triton-X, boiled for 7 minutes,
and centrifuged at 20 000g for 30 minutes at 4°C.
The supernatant was stored at -80°C until use.
ET-1 was extracted from the plasma and the supernatant of homogenized ventricular tissues according to the method of Kitamura et al16 and measured by means of the sandwich enzyme immunoassay (EIA) kit (Wako Pure Chemical) originally developed by Suzuki et al.17 This EIA for ET-1 could detect as little as 0.5 pg/mL of ET-1. The cross-reactivity with ET-3 or big ET-1 was <0.1%.
Immunohistochemical Staining for ET-1 in LV
The left ventricles of DS and DR rats were excised and then
fixed in 10% phosphate-buffered formalin solution for >24 hours. They
were embedded in paraffin and cut into 4-µm-thick sections. After
deparaffinization and hydration, they were immunostained
for ET-1 by an indirect immunoperoxidase method as described
previously.18 Briefly, the sections were
incubated with 0.3% hydrogen peroxide for 20 minutes to block
endogenous peroxidase activity, followed by further
incubation with normal goat serum for 30 minutes to block nonspecific
bindings. They were then incubated with ET-1 antiserum (Peninsula
Laboratories) at a final dilution of 1:40 for 16 hours at 4°C. In the
second step, they were treated with a 1:200 dilution of
peroxidase-conjugated goat anti-rabbit IgG (Jackson ImmunoResearch
Laboratories) for 45 minutes. Peroxidase activity was visualized by use
of diaminobenzidine and hydrogen peroxide. The sections were
counterstained with hematoxylin and evaluated microscopically. As a
control to check the specificity, the primary antibody was preincubated
with 1 µg ET-1 peptide (Peptide Institute) for 3 hours before
application to the slides.
Quantitative Reverse Transcriptase–Polymerase Chain Reaction for
Prepro-ET-1 mRNA
Total RNA was isolated from left ventricles by the acid
guanidinium thiocyanate–phenol-chloroform method. Quantitative reverse
transcriptase–polymerase chain reaction (RT-PCR) was carried out
essentially as described in detail
previously.19 20 After the synthesis of
first-strand cDNA, a constant amount of cDNA was amplified by PCR with
a serially diluted nonhomologous DNA fragment containing primer
template sequences as an internal control (PCR MIMIC Construction kit,
Clontech). To determine the exact amount of target mRNA species, the
internal control was diluted 2-fold. Sense primers (A) and antisense
primers (AS) for rat prepro-ET-1 and GAPDH were synthesized according
to the published cDNA sequences.21 22 The
sequences of the primers were as follows: prepro-ET-1 (A),
5'-GCTCCTGCTCCTCCTTGATG-3' (position: 158 to 177); prepro-ET-1 (AS),
5'-CTGGCTCTATGTAAGTCATGG-3' (637 to 657); GAPDH (A),
5'-TTGCCATCAACGACCCCTTC-3' (169 to 188); and GAPDH (AS),
5'-TTGTCATGGATGACCTTGGC-3' (558 to 577). These primers were designed to
cross introns to avoid the amplification of genomic DNA. PCR was
performed in a 50-µL reaction volume containing 200 µmol/L
dNTP, 40 µmol/L of each specific primer, 10 mmol/L
Tris-HCl, 50 mmol/L KCl, 1.5 mmol/L
MgCl2, 0.001% gelatin, 1.5 U Taq
polymerase (Takara), and 1 µCi [32P]dCTP
(Amersham). PCRs using ET-1 and GAPDH primers were carried out for 40
and 30 cycles (45 seconds at 94°C, 45 seconds at 55°C, 90 seconds
at 72°C), respectively. Under these conditions, linearity of the
amplification was confirmed. A portion of the PCR reaction product
was then resolved by electrophoresis on a 5% polyacrylamide
gel and analyzed with a FUJIX bioimaging analyzer BAS
2000. The molar ratio between the internal control and target was
calculated according to the formula target/internal
control=(IT/IC)x(CC/CT),
where IT and IC
represent the intensity of the PCR product from the target
and the internal control, respectively, and CT
and CC represent the dCTP content in the
PCR product from the target and the internal control,
respectively. The amount of target molecule was determined as
the point of an equal molar ratio between the internal control and the
target (Figure 1
). The amounts of ET-1
were divided by those of GAPDH to correct the efficiency of cDNA
synthesis.
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Assessment of Chronic Effects by Bosentan and Doxazosin
Eleven-week-old LVH-DS rats with compensatory LV
hypertrophy were randomly subjected to treatment with
either bosentan, a mixed ETA and
ETB receptor antagonist (F.
Hoffmann-La Roche, Ltd)23 24 (Bos group, 100
mg · kg-1 ·
d-1, n=14); doxazosin, an
1-receptor antagonist (Dox group,
1 mg · kg-1 ·
d-1, n=12); or vehicle (Cont group, n=14). Each
drug was suspended in 5% gum arabic and injected into the stomach by
gastric gavage once a day. The dosage of bosentan 100 mg ·
kg-1 · d-1 was
selected because in our preliminary studies, (1) it reduced the blood
pressure of the CHF rats the most effectively among doses between 30
and 200 mg · kg-1 ·
d-1 (n=3 in each group; 30, 100, and 200 mg
· kg-1 · d-1
groups) and (2) chronic treatment of the LVH rats by this dosage
significantly blunted the coronary vasoconstriction by
exogenous ET-1 administration up to 10-10 mol/L
in the isolated Langendorff setting (n=4). The dosage of doxazosin 1
mg · kg-1 ·
d-1 was selected because it decreased the SBP to
the same extent as bosentan throughout the course of the experiment in
a preliminary study. So we evaluated the effects of bosentan on the
cardiac remodeling and function independent of its systemic hypotensive
effect by comparing them with the effects of doxazosin.
Animals were monitored and deaths were recorded every day.
Survival after 15 weeks was analyzed by the standard
Kaplan-Meier analysis with log-rank test and
2 analysis. Body weights and in vivo
blood pressures were measured biweekly. Serial echocardiograms were
recorded at 11, 15, and 17 weeks. LV mass was calculated from the
following equation25: LV mass
(g)=1.05x[(EDD+2xPWT)3-EDD3],
where EDD is end-diastolic diameter and PWT is
diastolic posterior wall thickness. We previously
demonstrated that the calculated LV mass shows a linear correlation
with postmortem LV weight (r=0.948, P<0.001,
echocardiographic LV mass=0.900xpostmortem LV
weight+0.017 g).12
Statistical Analysis
The results are expressed as mean±SEM. Statistical comparisons
between 2 groups were performed by unpaired Student's t
test. Relationships between 2 variables were tested by linear
regression analysis. The main effects of the drugs were tested
by 2-factor ANOVA for repeated measures, and differences at specific
time points between the groups were assessed by 1-factor ANOVA with
post hoc comparisons by Fisher's protected least significant
difference test. In all tests, a value of P<0.05 was
considered statistically significant.
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Results |
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TopAbstractIntroductionMethodsResultsDiscussionReferences |
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We performed 2 series of experiments. In experiment 1, animals were killed at 11 and 17 weeks and the levels of ET-1 peptide and mRNA were determined. In experiment 2, 11-week-old LVH-DS rats with compensatory LV hypertrophy were randomly subjected to oral treatment with either bosentan (Bos, 100 mg · kg-1 · d-1), doxazosin (Dox, 1 mg · kg-1 · d-1), or vehicle (Cont).
Experiment 1
SBP, Heart Weight, and Echocardiography
SBP and heart weight are presented in Table 1. DS rats fed a high-salt diet
developed systemic hypertension (>220 mm Hg) at 11 weeks, which
continued until the CHF period. At 11 weeks, DS rats showed marked LVH.
The ratio of LV mass to body weight (LV/BW) was 50% greater in DS rats
than in age-matched DR rats. At 17 weeks, DS rats showed labored
respiration and loss of activity. Autopsy of these rats revealed
massive pulmonary congestion. The LV/BW increased further at 17
weeks. The right ventricle (RV)/BW ratio also increased (>0.8),
consistent with the existence of pulmonary congestion
and elevated LV diastolic pressure.26
Echocardiographic data are summarized in Table 2. In LVH-DS (11 weeks), the wall
thickness was 24% greater than in age-matched DR and the relative wall
thickness of DS reached 0.61, indicating LV concentric
hypertrophy. LV FS tended to be higher in DS than in DR.
Thus, the wall stress was within the normal range, implying an
established mechanical compensation for the increased afterload.
However, in CHF-DS (17 weeks), the FS decreased and the chamber
diameter increased. The wall stress was 3.5 times greater in CHF-DS
than in age-matched DR. These findings are consistent with our
previous report12 and show that the transition
from compensatory pressure-overloaded hypertrophy to heart
failure occurs between 11 and 17 weeks in this animal model.
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Plasma and Myocardial Endothelin-1 Concentrations and
Echocardiographic Correlates
Plasma, RV, and LV ET-1 levels are illustrated in Figure 2. The levels in LVH-DS did not differ
from those in age-matched DR rats. By contrast, plasma ET-1 levels in
CHF-DS were 3.8-fold higher than those in 17-week-old DR rats. The RV
and LV ET-1 levels at 17 weeks were 2.6-fold (P<0.01) and
5.4-fold (P<0.01) higher, respectively, in DS (RV,
1551±154 pg/g tissue; LV, 2123±411 pg/g tissue) than in DR (RV,
595±29 pg/g tissue; LV, 395±16 pg/g tissue). Figure 3A and 3B illustrates correlations
between LV ET-1 concentrations and in vivo measured
echocardiographic data. LV ET-1 contents had a
significant negative correlation with LV FS (r=0.763,
P<0.01) and a strong positive correlation with LV
systolic wall stress (r=0.858, P<0.01).
Plasma ET-1 levels had a significant but weaker relationship with LV FS
(r=0.586, P<0.01) and LV systolic wall
stress (r=0.651, P<0.01) than LV ET-1 levels.
Figure 3C illustrates correlations between LV ET-1 contents and LV/BW.
Despite a 57% increase of LV/BW in LVH-DS rats compared with DR, LV
ET-1 had no significant difference between DR and LVH-DS rats
(1.3-fold, P=NS). By contrast, LV/BW increased 39% from LVH
to CHF-DS, which was associated with a 4.6-fold increase in LV ET-1
levels (P<0.01). Thus, the increase in LV/BW was not
proportionate to that in LV ET-1 concentrations.
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Immunohistochemical Detection of ET-1 in the LV Myocardium
Strong positive signals for ET-1 were widely distributed within
the LV myocardium of CHF-DS (Figure 4A, brown). The specificity of the
immunostaining was confirmed when the signals were
completely abolished by preincubation of the primary antibody with the
excess of synthetic ET-1 (Figure 4B). The ET-1 staining intensity in
cardiac myocytes was much higher in CHF-DS (Figure 4A) than in
17-week-old DR (Figure 4C). The interstitial cells and the
endothelial and smooth muscle cells of the
intramyocardial coronary arteries showed modest staining for
ET-1, and the intensity did not differ between DS and DR.
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Measurement of Cardiac Prepro-ET-1 mRNA
The levels of prepro-ET-1 mRNA in the LV myocardium
are illustrated in Figure 5. In LVH-DS,
the levels did not differ from those in the age-matched DR rats.
However, at the CHF stage, the levels were 4.1-fold higher in DS than
in DR rats. Thus, ET-1 mRNA and peptide levels changed in parallel,
indicating that the remarkably upregulated expression of the myocardial
ET-1 during the transition from LVH to CHF is mediated, at least in
part, at the pretranslational level.
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Experiment 2
SBP and Echocardiographic Changes
There was a slight but significant difference in SBP between
the Cont and Bos groups, as illustrated in Figure 6A. Bos
showed 9 and 10 mm Hg lower SBP at 13 and 15 weeks, respectively
(P<0.05). Doxazosin of 1 mg ·
kg-1 · d-1
decreased SBP to the same extent as bosentan throughout the course of
the experiment. Figure 6B, 6C, and 6D shows changes of LVFS, LV
systolic wall stress, and LV/BW, respectively (Table 3). Until
15 weeks, these 3 parameters did not differ among the 3
groups. After that period, however, bosentan attenuated both the
increase of LV systolic wall stress and the decrease of LV FS
(LV FS change: Cont, -10.9%/wk; Dox, -11.3%/wk; Bos, -3.5%/wk).
At 17 weeks, the systolic stress was much lower in Bos
(106±8.2 g/cm2; P<0.01) than in Cont
(179±16 g/cm2) or Dox (160±15
g/cm2). The LV FS at 17 weeks was higher
(P<0.01) in Bos (41.6±2.3%) than in Cont (27.4±1.9%) or
in Dox (26.7±2.0%). In contrast, the LV/BW did not differ among Cont
(4.15±0.17 mg/g), Dox (4.20±0.18 mg/g), and Bos (4.14±0.23 mg/g).
Thus, chronic ET receptor blockade attenuated the progression of LV
dysfunction and remodeling without reducing the LV mass. These effects
were independent of its afterload reduction.
|
), doxazosin-treated
group (Dox, n=12; 
), and bosentan-treated group (Bos, n=14; 
).
Vertical axes denote LV FS in B, LV systolic wall stress in C,
and estimated LV/BW in D. Values are expressed as mean±SEM.
*P<0.01 vs age-matched control rats.
#P<0.01 vs age-matched doxazosin-treated rats.
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Survival Rate
All rats of the Cont and Dox groups died of pulmonary
congestion with LV dysfunction between 15 and 19 weeks (mean±SEM,
16.7±0.3 and 16.5±0.3 weeks, respectively) (Figure 7). By contrast, the longest survival in
Bos was 22.7 weeks (mean±SEM, 19.3±0.4 weeks). The survival rate at
17 weeks was 93% in Bos, 42% in Dox, and 36% in Cont. The
Kaplan-Meier survival analysis demonstrated a significant
improvement of survival in the Bos compared with the Cont or Dox group
(P<0.0001). There was no difference in survival between
Cont and Dox groups (P=0.555).
|
), and bosentan-treated group
(Bos, n=14; |
Discussion |
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TopAbstractIntroductionMethodsResultsDiscussionReferences |
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To investigate the role of endogenous ET-1 in the transition from compensated LVH to CHF, we used a DS rat model. In this model with a high-salt diet, systemic hypertension resulted in established LVH at the age of 11 weeks, which was followed by marked LV dilatation and global hypokinesis (CHF) at the age of 17 weeks. We found that at the established LVH stage, the cardiac ET-1 system was not activated, but along with the transition to failure, it showed a remarkable activation. The activation was not parallel to the progression of LV hypertrophy but rather to the deterioration of LV systolic function. The immunohistochemical study revealed that myocytes were involved in the activated ET-1 system in the ventricular myocardium. Furthermore, chronic ET receptor blockade with bosentan directly attenuated the progression of LV dysfunction and improved the survival from CHF in a manner independent of the progression of LV hypertrophy. The present results for the first time clarified the critical role of the local ET system in the progression of contractile dysfunction and ventricular remodeling during the transition from LVH to CHF.
Cardiac ET-1 System Is Not Activated in Compensated
Hypertrophy
ET-1 is a growth-promoting peptide able to induce
hypertrophy in cultured neonatal cardiac
myocytes.4 Stimulation with
angiotensin II or stretch induces the expression of ET-1 in
cultured neonatal cardiac myocytes, and ETA
receptor antagonist can block the hypertrophy
evoked by these stimuli.27 28 These findings
suggest a possible role of ET-1 as an autocrine factor for
hypertrophy in these culture systems. In
hypertrophy evoked by an acute aortic banding procedure or
by chronic norepinephrine administration, ET-1 peptide and
prepro-ET-1 mRNA levels in LV were increased.6 7
In those studies, however, precise and serial evaluation of LV function
was not performed. Therefore, it is unclear at present whether the
cardiac ET system is activated even in hypertrophied hearts
with normal systolic function. We demonstrated that Dahl
salt-sensitive rats at 11 weeks had a marked increase of LV mass with
normal LV systolic wall stress, indicating an established
compensated hypertrophy against increased afterload. The
serum and myocardial ET-1 peptide and mRNA levels in DS rats did not
differ from those in the age-matched DR rats. Our findings are
compatible with the report by Thibault et al29
that in 17-week-old spontaneously hypertensive rats (SHRs), serum and
myocardial ET-1 levels were not increased compared with those in the
age-matched Wistar-Kyoto rats. Although the possibility still exists
that even basal levels of ET-1 in myocardium contribute to
the development of compensated LVH, Li and
Schiffrin30 reported that chronic treatment of
12-week-old SHRs with bosentan for 4 weeks did not block cardiac
hypertrophy. In the present study, bosentan did not
affect the progress of LV hypertrophy. These results
suggest that myocardial growth at the compensated stage is mediated
through alternative pathways.
ET-1 Activation During Transition to CHF
In human CHF, it has been demonstrated that the increase of
circulating ET-1 levels correlates with functional class and
alterations in hemodynamics.31 32
The present study demonstrated that plasma and myocardial ET-1
levels increased de novo during the transition from LVH to CHF. In the
LV myocardium of the CHF-DS rats, ET-1 immunoreactivity
resided mainly in cardiomyocytes. The increase in ET-1
peptide levels was associated with a concomitant increase in the
prepro-ET-1 mRNA levels. These findings demonstrate that cardiac
synthesis of ET-1 is accelerated during the transition from LVH to CHF.
In addition, although these data do not rule out a possible
contribution of other organs to the increased levels of ET-1 in plasma,
they suggest that the heart is one of the main sources for plasma ET-1
in CHF.
Bosentan Preserved LV Systolic Function During the
Transition to CHF
LV ET-1 levels had close relationships with such LV functional
measures as systolic wall stress and FS. To clarify whether the
increased levels of LV ET-1 represent merely a marker of LV
dysfunction or a direct contributor to LV systolic dysfunction
during the transition from LVH to CHF, we examined chronic effects of
endothelin receptor blockade. We showed that chronic treatment with
bosentan attenuated the progression of LV dysfunction and decreased the
mortality rate. At 17 weeks, the systolic wall stress of
bosentan-treated animals was 41% lower than that of vehicle-treated
rats. Although chronic treatment with doxazosin reduced the blood
pressure to the same level as that with bosentan, it failed to improve
the wall stress, indicating the minor contribution of the afterload
reduction to the preserved LV function by bosentan. Thus, the chronic
bosentan treatment beneficially altered the process of LV remodeling.
These findings suggest that the accelerated expression of cardiac ET-1
contributes to LV systolic dysfunction and remodeling during
the transition from LVH to CHF.
Bosentan Did Not Block Myocardial Growth
ACE inhibitors are now considered one of the basic
pharmacological tools in the treatment of CHF. Litwin et
al33 showed that chronic ACE inhibition
attenuates the transition from LVH to CHF in an aortic-banding model.
In their study, an ACE inhibitor blunted the increase of LV
mass and maintained smaller a LV cavity, which resulted in an
improvement of both systolic and diastolic
function. Hence, in ACE inhibition, the suppression of LV growth
appears to play a central and key role. By contrast, our data
demonstrated that the ET receptor blockade by bosentan preserved the LV
systolic function but did not suppress the further increase in
LV mass from LVH to CHF. LV ET-1 levels and the degree of cardiac
hypertrophy did not correlate. These findings suggest that
myocardial growth was mediated primarily through alternative pathways
and that local ET-1 systems regulated LV function by distinct
mechanisms during the transition from LVH to CHF. Two independent
reports showed that acute administration of ET receptor blocker in
addition to ACE inhibitors resulted in synergistic
hemodynamic improvement in heart failure of rats and
humans.34 35 Therefore, endothelin blockers can
be additive therapeutic agents in patients already receiving medical
treatment with ACE inhibitors.
Possible Mechanisms That Mediate Beneficial Effects of
Bosentan
The mechanisms by which chronic endothelin receptor blockade
ameliorated LV function during the transition to CHF without reducing
LV mass should be discussed. At the CHF stage, plasma ET-1 levels were
significantly elevated in DS compared with DR rats, which may have
contributed to the increased afterload. Chronic treatment with bosentan
decreased the SBP by 5% at 17 weeks. However, from the results of the
doxazosin study, ie, that doxazosin at the same SBP level as the
bosentan group did not affect the progression of LV dysfunction or
improve survival, we conclude that bosentan directly modulated cardiac
function in a manner independent of the level of afterload.
Furthermore, LV ET-1 contents rather than plasma ET-1 levels had a
closer relationship with LV systolic dysfunction, supporting
the idea that local ET-1 in the heart directly regulates the LV
function.
This raises the question of how local ET-1 deteriorates cardiac function. We have previously reported that substantial activation of the ß-adrenergic system with a substantial increase in the inhibitory G-coupled protein (Gi) occurs during the transition to heart failure in this animal model.13 36 In contrast to the finding that ET-1 has a positive inotropic action on heart muscle cells in a normal condition,37 Ono et al38 demonstrated that under the ß-adrenergic stimulatory condition, ET-1 exerted a negative inotropic effect on isolated myocytes through a Gi-mediated pathway. These findings suggest that long-term activation of endothelin and the sympathetic nervous system in CHF adversely affects the myocardial function synergistically. In addition, it has been reported that ET-1 represses forskolin-induced increase of cAMP in cardiac myocytes in vitro.39 Thus, ET-1 might be involved in the depletion of cAMP in the failing myocardium. Hartong et al40 recently reported that treatment of neonatal myocytes with ET-1 led to a decrease in sarcoplasmic reticulum Ca2+-ATPase mRNA levels. Other studies have reported that ET-1 activation may directly exert cytotoxic or cell damage effects.41 In this model, the progression of LV dysfunction is in part related to alterations in excitation-contraction coupling, as we showed previously.42 It is possible that chronic ET-1 blockade might improve the impaired excitation-contraction coupling directly, resulting in an attenuation of the progression in LV dysfunction. In any event, unraveling how chronic accumulation of ET-1 in cardiac myocytes deteriorates function may provide further insight into the mechanisms mediating the development of heart failure. Finally, our findings suggest that ET antagonism provides a promising strategy for chronic heart failure therapy in humans.
|
Acknowledgments |
|---|
This work was supported in part by grants-in-aid from the Ministry of Education, Science, and Culture, Japan (A0-1, 06454291, and 07557343) and research grants from the Ministry of Health and Welfare, Japan (5A-2, 7A-2, and 7A-4). We thank W. Hayashida, MD, PhD, for his valuable suggestions on the manuscript. Bosentan was graciously supplied by F. Hoffmann-La Roche Ltd, Basel, Switzerland.
|
Footnotes |
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Guest editor for this article was Joseph Loscalzo, MD, PhD, Boston University Medical Center, Boston, Mass.
Received April 21, 1998; revision received June 1, 1998; accepted June 16, 1998.
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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 noble potent vasoconstrictor peptide produced by vascular endothelial cells. Nature. 1988;332:411–415.[Medline] [Order article via Infotrieve]
2. Battistini B, Chailler P, Dorleans JP, Briere N, Sirosis P. Growth regulatory properties of endothelins. Peptides. 1993;14:385–399.[Medline] [Order article via Infotrieve]
3. Komuro I, Kurihara H, Sugiyama T, Yoshizumi M, Takaku F, Yazaki Y. Endothelin stimulates c-fos and c-myc expression and proliferation of vascular smooth muscle cells. FEBS Lett. 1988;238:249–252.[Medline] [Order article via Infotrieve]
4.
Ito H, Hirata Y, Hiroe M, Tsujino M, Adachi S,
Takamoto T, Nitta M, Taniguchi K, Marumo F. Endothelin-1 induces
hypertrophy with enhanced expression of muscle-specific
genes in cultured neonatal rat cardiomyocytes. Circ
Res. 1991;69:209–215.
5. Haynes WG, Webb DJ. The endothelin family of peptides: local hormones with diverse roles in health and disease? Clin Sci. 1993;84:485–500.[Medline] [Order article via Infotrieve]
6.
Cody RJ, Hass GJ, Binkley PF, Capers Q, Kelley R.
Plasma endothelin correlates with extent of pulmonary
hypertension in patients with chronic congestive heart failure.
Circulation. 1992;85:504–507.
7.
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;94:779–784.
8. 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]
9.
Ito H, Hiroe M, Hirata Y, Fujisaki H, Adachi S,
Akimoto H, Ohta Y, Marumo F. Endothelin ETA
receptor antagonist blocks cardiac hypertrophy
provoked by hemodynamic overload.
Circulation. 1994;89:2198–2203.
10.
Kaddoura S, Firth JD, Boheler KR, Sugden PH,
Poole-Wilson PA. Endothelin-1 is involved in
norepinephrine-induced ventricular
hypertrophy in vivo. Circulation. 1996;93:2068–2079.
11. Sakai S, Miyauchi T, Kobayashi M, 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]
12.
Inoko M, Kihara Y, Morii I, Fujiwara H, Sasayama S.
Transition from compensatory hypertrophy to dilated,
failing left ventricles in Dahl salt-sensitive rats. Am J
Physiol. 1994;267:H2471–H2482.
13. Inoko M, Kihara Y, Sasayama S. Neurohumoral factors during transition from left ventricular hypertrophy to failure in Dahl salt-sensitive rats. Biochem Biophys Res Commun. 1995;206:814–820.[Medline] [Order article via Infotrieve]
14. Dahl LK, Heine MA, Tassinari L. Role of genetic factors in susceptibility to experimental hypertension due to chronic excess salt ingestion. Nature. 1962;194:480–482.[Medline] [Order article via Infotrieve]
15. Iwai J, Heine MA. Dahl salt-sensitive rats and human essential hypertension. J Hypertens. 1986;4(suppl):S29–S31.
16. Kitamura K, Tanaka J, Kato T, Ogawa T, Eto T, Tanaka K. Immunoreactive endothelin in rat kidney inner medulla: marked decrease in spontaneously hypertensive rats. Biochem Biophys Res Commun. 1989;156:1182–1186.
17. Suzuki N, Matsumoto H, Kitada C, Masaki T, Tsujino M. A sensitive sandwich-enzyme immunoassay for human endothelin. J Immunol Methods. 1989;118:245–250.[Medline] [Order article via Infotrieve]
18.
Hasegawa K, Fujiwara H, Doyama K, Miyamae M, Fujiwara
T, Suga S, Mukoyama M, Nakao K, Imura H, Sasayama S.
Ventricular expression of brain natriuretic
peptide in hypertrophic cardiomyopathy.
Circulation. 1993;88:372–380.
19.
Shioi T, Matumori A, Sasayama S. Persistent expression
of cytokine in the chronic stage of viral myocarditis in mice.
Circulation. 1996;94:2930–2937.
20.
Nadeau KC, Azuma H, Tilney NL. Sequential
cytokine dynamics in chronic rejection of rat renal allograft:
roles for cytokines RANTES and MCP-1. Proc Natl Acad Sci
U S A. 1995;92:8729–8733.
21.
Wang X, Douglas SA, Louden C, Vickery-Clark LM,
Feuerstein GZ, Ohlstein EH. Expression of endothelin-1, endothelin-3,
endothelin-converting enzyme-1, and endothelin-A and endothelin-B
receptor mRNA after angioplasty-induced neointimal
formation in the rat. Circ Res. 1996;78:322–328.
22.
Fort P, Marty L, Piechaczyk M, el Sabrouty S, Dani C,
Jeanteuer P, Blanchard JM. Various rat adult tissues express only one
major mRNA species from the
glyceraldehyde-3-phosphate-dehydrogenase multigenic
family. Nucleic Acids Res. 1985;13:1431–1442.
23.
Clozel M, Breu V, Gray GA, Kalina B, Löffler BM,
Burri K, Cassal JM, Hirth G, Müller M, Neidhart W, Ramuz H.
Pharmacological characterization of bosentan, a new potent orally
active nonpeptide endothelin receptor antagonist.
J Pharmacol Exp Ther. 1994;270:228–235.
24.
Mulder M, Richard V, Derumeaux G, Hogie M, Henry JP,
Lallemand F, Compagnon P, Mace B, Comoy E, Letac B, Thuillez C. Role of
endogenous endothelin in chronic heart failure: effect of
long-term treatment with an endothelin antagonist on
survival, hemodynamics, and cardiac remodeling.
Circulation. 1997;96:1976–1982.
25.
Troy BL, Pombo J, Rackley CE. Measurement of left
ventricular wall thickness and mass by
echocardiography. Circulation. 1972;45:602–611.
26.
Pfeffer MA, Pfeffer JM, Fishbein MC, Fletcher PJ,
Spadaro J, Kloner RA, Braunwald E. Myocardial infarct size and
ventricular function in rats. Circ Res. 1979;44:503–512.
27. Ito H, Hirata Y, Adachi M, Tanaka M, Tsujino A, Koike A, Nogami F, Marumo F, Hiroe M. Endothelin-1 is an autocrine/paracrine factor in the mechanism of angiotensin II-induced hypertrophy in cultured rat cardiomyocytes. J Clin Invest. 1993;92:398–403.
28.
Yamazaki T, Komuro I, Kudoh S, Zou Y, Shiojima I, Hiroi
Y, Mizuno T, Maemura K, Kurihara H, Aikawa R, Tanaka H, Yazaki Y.
Endothelin-1 is involved in mechanical stress-induced
cardiomyocyte hypertrophy. J Biol
Chem. 1996;271:3221–3228.
29. Thibault G, Arguin C, Garcia R. Cardiac endothelin-1 content and receptor subtype in spontaneously hypertensive rats. J Mol Cell Cardiol. 1995;27:2327–2336.[Medline] [Order article via Infotrieve]
30.
Li JS, Schiffrin L. Effect of chronic treatment of
adult spontaneously hypertensive rats with an endothelin receptor
antagonist. Hypertension. 1995;25:495–500.
31. Hiroe M, Hirata Y, Fujita N, Umezawa S, Ito H, Tsujino M, Koike A, Nogami A, Takamoto T, Marumo F. Plasma endothelin-1 levels in idiopathic dilated cardiomyopathy. Am Heart J. 1991;68:1114–1115.
32.
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.
33.
Litwin SE, Katz SE, Weinberg EO, Lorell BH, Aurigemma
GP, Douglas PS. Serial echocardiographic-doppler
assessment of left ventricular geometry and function in
rats with pressure-overload hypertrophy.
Circulation. 1995;91:2642–2654.
34.
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.
Circulation. 1994;90:2510–2518.
35.
Love MP, Haynes WG, Gray GA, Webb DJ, McMurray JJV.
Vasodilator effects of endothelin-converting enzyme inhibition and
endothelin ETA receptor blockade in chronic heart
failure patients treated with ACE inhibitors.
Circulation. 1996;94:2131–2137.
36. Kihara Y, Murakami T, Tomita T, Inoko M, Sasayama S. Transition to overt heart failure in Dahl salt-sensitive rats is preceded by G-protein-mediated ß-adrenergic desensitization. Pathophysiology. 1994;1(Suppl):306. Abstract.
37. Kelly RA, Eid H, Krämer BK, O'Neill M, Liang BT, Reers M, Smith TW. Endothelin enhances the contractile responsiveness of adult rat ventricular myocytes to calcium by a pertussis toxin-sensitive pathway. J Clin Invest. 1990;86:1164–1171.
38. Ono K, Tsujimoto G, Sakamoto A, Eto K, Masaki T, Ozaki Y, Satake M. Endothelin-A receptor mediates cardiac inhibition by regulating calcium and potassium currents. Nature. 1994;370:301–304.[Medline] [Order article via Infotrieve]
39. Jones LG. Inhibition of cyclic AMP accumulation by endothelin is pertussis toxin sensitive and calcium independent in isolated adult feline cardiac myocytes. Life Sci. 1996;58:115–123.[Medline] [Order article via Infotrieve]
40. Hartong R, Villarreal FJ, Giordano F, Hilal Dandan R, McDonough PM, Dillmann WH. Phorbol myristate acetate-induced hypertrophy of neonatal rat cardiac myocytes is associated with decreased sarcoplasmic reticulum Ca2+ ATPase gene expression and calcium reuptake. J Mol Cell Cardiol. 1996;28:2467–2477.[Medline] [Order article via Infotrieve]
41. Prasad MR. Endothelin stimulates degradation of phospholipids in isolated rat hearts. Biochem Biophys Res Commun. 1991;174:952–957.[Medline] [Order article via Infotrieve]
42. Kihara Y, Inoko M, Sasayama S. Changes of myocardial contractile state and the intracellular calcium transients during transitions to heart failure: studies in Dahl rat heart failure model. J Cardiac Failure. 1996;2:S113–S120.[Medline] [Order article via Infotrieve]
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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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|
|
|
|
 |
|
 T. Kakita, K. Hasegawa, E. Iwai-Kanai, S. Adachi, T. Morimoto, H. Wada, T. Kawamura, T. Yanazume, and S. Sasayama Calcineurin Pathway Is Required for Endothelin-1-Mediated Protection Against Oxidant Stress-Induced Apoptosis in Cardiac Myocytes Circ. Res., June 22, 2001; 88(12): 1239 - 1246. [Abstract] [Full Text] [PDF]
|
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