(Circulation. 1997;96:3963-3973.)
© 1997 American Heart Association, Inc.
Articles |
Chronic Endothelin Receptor Blockade Attenuates Progressive Ventricular Dilation and Improves Cardiac Function in Rats With Myocardial Infarction
Possible Involvement of Myocardial Endothelin System in Ventricular Remodeling
From the II. Medizinische Klinik, Fakultät für Klinische Medizin Mannheim der Universität Heidelberg, Germany.
Correspondence to Prof Dr Georg Ertl, II. Medizinische Klinik, Fakultät für Klinische Medizin Mannheim der Universität Heidelberg, Theodor-Kutzer Ufer 1–3, 68167 Mannheim, Germany.
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Abstract |
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Background Left ventricular dilatation after myocardial infarction is associated with impaired ventricular function and heart failure and has important implications for survival. The purpose of this study was to investigate the role of endothelin-1 (ET-1) in ventricular dilatation and the effects of chronic endothelin receptor blockade by a mixed ETA and ETB receptor blocker (bosentan) on the circulating and cardiac endothelin systems.
Methods and Results Three hours after coronary ligation or sham operation, bosentan (100 mg · kg body wt-1 · d-1) or placebo was given by gavage. Seven days and 8 weeks after surgery, hemodynamic and left ventricular volume studies were performed. Acute bosentan treatment (7 days) had no effects on hemodynamic parameters and early left ventricular dilatation. In the rats with large infarcts, chronic bosentan treatment (8 weeks) versus placebo reduced left ventricular systolic pressure (116±2 versus 125±3 mm Hg, P<.05) and arterial pressure (93±2 versus 103±3 mm Hg, P<.05), improved stroke volume index (0.69±0.06 versus 0.52±0.04 mL/kg, P<.05), and prevented in part the rightward shift of the pressure-volume curve. Chronic bosentan treatment also decreased ET-1 levels (390±33 versus 475±22 pg/g tissue, P<.05) and density of ET-1 receptors (262±24 versus 346±31 fmol/mg protein, P<.05) in left ventricular myocardium.
Conclusions In the present study, a mixed ETA and ETB receptor antagonist (bosentan) partially prevented left ventricular dilatation and improved hemodynamics, suggesting that endothelin plays a role in left ventricular remodeling after myocardial infarction. Supporting this hypothesis, we show inhibitory effects of bosentan on the peripheral and myocardial endothelin system.
Key Words: endothelin • myocardial infarction • receptors
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Introduction |
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Myocardial infarction activates compensatory mechanisms that act to maintain cardiac output and peripheral perfusion. These adaptive responses are the results of a complex interplay between hemodynamic, myocardial, and neurohormonal mechanisms.1,2 Hemodynamic and nonhemodynamic influences lead to left ventricular dilation that initially represents an adaptive mechanism to enhance cardiac pumping capability; progressive dilatation, however, may result in a worsening of cardiac performance.3-8 It has been assumed that the beneficial effects of ACE inhibitors in preventing progressive ventricular dilatation are mediated through the reduction of preload and afterload and perhaps specific interference with the cardiac renin-angiotensin system or bradykinin.9-15 Myocardial cell growth promoting effects of angiotensin II as inhibiting effects of bradykinin might contribute to remodeling of the heart and represent sites of action for ACE inhibitors. Because other factors may contribute to cardiac load and promote myocardial cell growth, it appears worthwhile to look for other principles potentially involved in remodeling after MI.
Experimental and clinical studies demonstrated an activation of the endothelin system, like that of the sympathetic and renin-angiotensin systems after MI.16-20 The vasoconstrictor actions of ET-1 and potential positive inotropic and chronotropic effects21-24 may affect the loading conditions of the infarcted heart and contribute to the development of ventricular dilatation and heart failure. Moreover, an increasing number of observations suggest the existence of a myocardial endothelin system and its possible involvement in the pathophysiology of cardiovascular diseases. The production of ET-1 and number of its binding sites are upregulated in the hypertrophied rat heart because of pressure overload25 and in the left ventricle of rats with chronic heart failure.26 The recent evidence that the selective ETA receptor antagonist BQ-123 improves long-term survival in rats with heart failure induced by coronary artery occlusion suggests that endothelin may play a role in myocardial failure.27
However, the role of circulating and cardiac endothelin systems is by far not completely understood in the pathophysiology of postinfarction ventricular dilatation, and no information is available on a right ventricular myocardial endothelin system. Structural left ventricular dilatation after MI is a dynamic time-dependent process involving the infarcted region and the residual viable myocardium.28,29 Ventricular enlargement in the early postinfarction phase is a consequence of thinning and dilatation of the infarct zone, which may progress in severity over time and reach a plateau at 7 days in rats30; in late phases, ventricular enlargement is generated by architectural rearrangements of surviving myocardium. Accordingly, this study investigates the possible involvement of ET-1 in ventricular dilatation by studying the effects of the mixed ETA and ETB receptor antagonist bosentan31 on left ventricular hemodynamics and volume in the acute (7-day) and chronic (8-week) myocardial infarct phases. In addition, we studied the effects of chronic endothelin receptor blockade on the circulating and cardiac endothelin systems and on left ventricular catecholamine content.
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Methods |
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MI, Study Protocols, and Dose-Response Data
Left coronary artery ligations were performed in adult female Wistar rats weighing 250 to 300 g (Charles River, Sulzfeld, Germany) by a previously described method.32 Briefly, under ether anesthesia, the thorax was opened, the heart exteriorized, and a ligature placed around the proximal left coronary artery. The heart was returned to its normal position and the thorax closed. Sham-operated rats were treated similarly except that the operative procedure did not produce a detectable MI. Surviving rats were randomly selected for bosentan or placebo treatment and maintained with free access to standard rat chow and water.
Bosentan (100 mg/kg body wt) was prepared fresh every day as a microsuspension in 5% arabic gum and administered by gavage daily for 7 days (acute effects) or 8 weeks (chronic effects), starting 3 hours after coronary artery ligation. After 7 days the animals were assigned to hemodynamic measurements and after 8 weeks were randomly selected for hemodynamic or biochemical study.
Dose-response curves for the effect of intravenous ET-1 on arterial blood pressure were constructed for various oral doses of bosentan. Four groups of six rats were studied. Group 1 was treated with vehicle (5% arabic gum) and groups 2, 3, and 4 with bosentan 30, 100, 200 mg/kg body wt, respectively. Six hours later, ET-1 (0.03 to 1 nmol/kg body wt IV) was injected in a cumulative manner. At 100 mg/kg body weight, bosentan significantly inhibited the pressor effect of ET-1 (0.03 to 0.3 nmol/kg body wt). Finally, in another experiment, the duration of the effect of bosentan was tested by measurement of the inhibition of ET-1 action 24 hours after its administration. At a dose of 100 mg/kg body wt administered by gavage, bosentan significantly inhibited the pressor effect of ET-1 (0.03 to 0.1 nmol/kg body wt) (P<.05, n=6). Hemodynamic measurements and sample collection for biochemical study were performed 36 hours after the last administration of bosentan.
Hemodynamic Measurements and Left
Ventricular Pressure-Volume Relationship
Hemodynamic studies were performed 7 days or 8
weeks after coronary artery ligation, as described by Pfeffer
et al.32 Rats were reanesthetized with
ether, tracheotomized, and ventilated. Saline-filled catheters (PE 50)
were advanced from the right carotid artery and jugular vein into the
left ventricle and right atrium, respectively, and connected via a
three-way stopcock to a Millar micromanometer and
Statham (P50) transducer. After measurements of left
ventricular pressure, the catheter was withdrawn to the
aorta and heart rate was calculated from arterial blood
pressure tracings. Left ventricular systolic and
end-diastolic pressures, mean arterial
pressure, and heart rate were measured under light ether
anesthesia and spontaneous respiration. During
positive-pressure ventilation and after midsternal thoracotomy, an
electromagnetic flow probe (2.5 mm ID; Statham, Inc) was placed
around the ascending aorta for continuous measurement of aortic blood
flow (cardiac output). Stroke volume was calculated as the ratio of
cardiac output and heart rate, and total peripheral
resistance was calculated as the ratio of the difference between mean
systemic and right atrial pressures and cardiac output. All
variables derived from aortic blood flow were corrected for body
weight. To assess the maximal flow-generating capacity of the heart,
warmed (39°C to 40°C) Tyrode's solution was infused into a femoral
vein at a rate of 40 mL · kg-1 ·
min-1 for 45 seconds or until maximal flow was
achieved. This infusion produces a rise in cardiac output to peak
values, followed by a plateau, despite further elevation of right
atrial pressure. Maximum cardiac performance was defined as
peak values of cardiac output and stroke volume during this infusion of
Tyrode's solution.
Passive pressure-volume curves of the left ventricle were obtained as previously described.10 The heart was arrested by potassium chloride, and a double-lumen catheter (PE 50 inside PE 200) was inserted into the left ventricle via the ascending aorta. The right ventricular free wall was incised to avoid fluid accumulation. The atrioventricular groove was ligated, and isotonic saline was infused at a rate of 0.76 mL/min via one lumen while intraventricular pressure was continuously recorded through the other lumen from negative pressure to 30 mm Hg. Three pressure-volume curves were obtained from each left ventricle within 10 minutes after cardiac arrest.
Biochemical Measurements
Sample Collection
Eight weeks after coronary artery ligation, under
anesthesia with sodium pentobarbital (50 mg/kg body
wt IP), a blood sample was collected from the abdominal aorta into a
chilled tube containing potassium EDTA (2 mg/mL blood). Plasma
was separated by centrifugation at 3000g for
10 minutes at 4°C and stored at -80°C. The heart was subsequently
removed, rinsed in ice-cold normal saline, and divided into right
ventricle and left ventricle, including septum. After infarct size
estimation, the scarred area was removed and the tissues were
separately weighed and rapidly frozen in liquid nitrogen and stored at
-80°C.
Tissue Homogenization
Tissue samples were thawed in ice-cold buffer (10%, wt/vol)
containing 50 mmol/L Tris/HCl (pH 7.4), cut into small
pieces, and homogenized with a glass Teflon
homogenizer. Each tissue homogenate was
divided into three aliquots for receptor binding assay and
analysis of ET-1 and catecholamine levels,
respectively. Tissue homogenate for the binding assay was
stored in liquid nitrogen until use. The aliquot for tissue ET-1
determination was quickly diluted 1:1 with ice-cold 2 mol/L
acetic acid, and the tissue homogenate for
catecholamine measurements was diluted 1:1 with ice-cold
0.4 mol/L perchloric acid containing dihydroxybenzylamine as
internal standard.
Plasma and Tissue ET-1
Plasma samples (500 µL) were applied to Sep-Pak C-18
cartridges (Waters Corp) previously washed with 3 mL methanol, 1 mL
methanol/water (90/10, vol/vol), and 4 mL
methanol/water (5/95, vol/vol). After application of the
sample, the cartridge was washed with 10 mL methanol/water
(5/95, vol/vol), and the peptides were eluted with 1.5 mL
methanol/water (90/10, vol/vol) and 0.5 mL
methanol/water/acetic acid (90/9/1 vol/vol/vol).
The eluate was dried at 30°C under reduced pressure, reconstituted in
250 µL assay buffer, and subjected to radioimmunoassay. The recovery
of the extraction procedure was >85%, as determined by addition of
synthetic ET-1 to plasma. Data were not corrected for extraction
recovery. Radioimmunoassay was carried out with
125I-labeled ET-1 (DuPont NEN) at a concentration
of 4 pg (6000 cpm per tube). A standard curve was constructed by
dilution of synthetic ET-1 (Sigma Chemical Co) from 8 to 0.125 pg per
tube. Rabbit ET-1 antiserum (RAS 6901, Peninsula Laboratories Europe,
Ltd) was incubated with standard or sample for 20 hours at 4°C;
125I-ET-1 was added for a subsequent 20 hours of
incubation at 4°C. Bound counts were separated by precipitation at
25°C for 2 hours with goat antirabbit IgG serum (GARGG-500,
Peninsula) in conjunction with pretitered normal rabbit serum (NRS-500,
Peninsula). After centrifugation at 2000g
for 20 minutes at 4°C, the free fraction was aspirated and the
pellets were counted in a gamma counter. The detection limit of the
assay was 0.2 pg per tube. The anti–ET-1 serum showed cross-reactivity
of <7% with ET-3.
Cardiac tissues, which were placed in 1 mol/L acetic acid, were immediately rehomogenized and boiled for 10 minutes. The homogenate was then centrifuged for 20 minutes at 15 000g at 4°C. The supernatant was collected and the extraction performed as described for plasma samples. The eluates reconstituted in assay buffer were subjected to ET-1 ELISA (Amersham International PLC). The assay did not cross-react with ET-3 or big ET-1, and the detection limit was 4 pg per tube.
Cardiac Membrane Preparation and ET-1 Receptor Binding
Assay
Cardiac membranes were prepared according to the method of
Ishikawa et al33 with some modifications. Tissue
homogenates were diluted 1:20 with ice-cold buffer (50
mmol/L Tris/HCl, 0.1 mmol/L PMSF, and 0.25
mol/L sucrose, pH 7.4) and centrifuged at
600g for 10 minutes at 4°C. The supernatants were
centrifuged at 8400g for 10 minutes at 4°C,
decanted, and centrifuged at 105 000g for 60
minutes at 4°C. The resultant pellets were suspended in ice-cold
50 mmol/L Tris buffer containing 10 mmol/L
MgCl2, 0.1 mmol/L PMSF, and 0.25
mol/L sucrose (pH 7.4). Protein concentration was determined
according to Lowry34 with BSA as standard. A
binding assay was performed in binding buffer (50 mmol/L
Tris/HCl, 10 mmol/L MgCl2, 0.1
mmol/L PMSF, 0.25 mol/L sucrose, and 0.1% BSA, pH 7.4)
with 50 µg membrane proteins per tube in a final volume of 250 µL.
Incubation was done at 25°C for 2 hours with increasing
concentrations of 125I-ET-1 (8 pmol/L to
0.3 nmol/L) for saturation experiments. After dilution with 4 mL
ice-cold binding buffer, bound and free 125I-ET-1
were separated by rapid vacuum filtration through Whatman GF/C filters,
followed by three additional washes with 3 mL of binding buffer. The
radioactivity of the filters was counted in a gamma counter.
Nonspecific binding was defined in the presence of 0.2
µmol/L unlabeled ET-1.
PRA and NT-proANP
PRA was measured by radioimmunoassay of angiotensin
I generated after 90 minutes of incubation of the plasma sample at
37°C and pH 6.0 (Sorin Biomedica Diagnostic). NT-proANP
was measured by radioimmunoassay (Immunodiagnostic GmbH).
The test kit uses a specific antiserum against NT-proANP without
extraction and a second antibody for the separation of the antibody
bound and free fractions.
Left Ventricular Tissue Catecholamines
Left ventricular tissue homogenates,
placed in 0.2 mol/L perchloric acid, were immediately
rehomogenized and centrifuged for 15 minutes at
10 000g at 4°C. The supernatant was extracted on aluminum
oxide (pH 8.6), and the catecholamines were eluted with 0.1
mol/L perchloric acid (100 µL) and assayed by
high-performance liquid chromatography with
electrochemical detection. The limit of detection was 2 pg.
Determination of Infarct Size
The left ventricles of hearts included in the
hemodynamic study, after pressure-volume curves were
made, were infused with a volume of 10% buffered formalin
corresponding to pressure of 5 mm{ths}Hg, and the heart (with
catheter and closed three-way stopcock) was further fixed in formalin
for 24 hours. The right and left ventricles were separated and weighed,
and infarct size was quantified histologically by
planimetry as previously reported.32 Briefly, the
left ventricle was embedded in paraffin, and ten 10-µm thin sections
were cut serially from apex to base at 1-mm intervals. Sections were
stained with picrosirius red. The boundary lengths of the infarcted and
noninfarcted endocardial and epicardial surfaces were traced with a
planimeter digital image analyzer (Sony). Infarct size
(fraction of the infarcted left ventricle) was calculated as the
average of all slices and expressed as a percentage of length.
Because left ventricular myocardium of hearts included in biochemical studies was used for ET-1, catecholamine, and receptor binding assays, infarct size could not be measured histologically. Four longitudinal incisions were made in the left ventricular septum and inferoposterior wall so that endocardial and epicardial surfaces could be pressed flat on glass plates, as previously described by Yamagishi et al.12 A clear macroscopic boundary of scar could be seen, which made the identification of infarcted area reliable. The boundary lengths of the infarcted and noninfarcted epicardial and endocardial surfaces were traced and digitized as described previously for histological slices. This method systematically underestimated infarct size compared with standard histological technique. Because animals were randomly assigned to hemodynamic or biochemical study, "true" infarct size should be similar within various infarct groups.
Statistical Analysis
For hemodynamic and ventricular
volume studies, animals with infarcts were classified as small to
moderate (5% to 40%) and large (
40%) infarct groups, and for
biochemical studies as small to moderate (5% to 25%) and large
(25%) infarct groups. For within-treatment comparisons, one-way
ANOVA followed by Newman-Keuls test was performed to compare each
infarct group with its respective noninfarcted group. Unpaired
t test assessed differences between placebo- and
bosentan-treated rats within groups with comparable infarct sizes.
Correlations were determined by linear regression analysis.
These statistical comparisons were performed with the statistical
program NCSS, Unisoft. The pressure-volume curves were also examined by
a multifactor factorial ANOVA for repeated measures, with group (sham,
small to moderate MI, large MI) and treatment (placebo, bosentan) as
between factors and pressure at various levels as within factors. This
statistical analysis was performed with the statistical program
SuperANOVA, version 1.11, Abacus Concepts, Inc. Differences were
considered significant at a level of P<.05, and values were
expressed as mean±SEM.
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Results |
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Hemodynamic Measurements and Ventricular Volume Studies
Differences in mortality between placebo and bosentan treatment were not found during 7-day and 8-week protocols.
Seven-Day Protocol
Myocardial infarct size distribution was similar in placebo- and
bosentan-treated rats (Table 1
). Body
weight and ratio of right ventricular weight/body weight
were unchanged by infarction or treatment. The ratio of left
ventricular weight to body weight declined in the acute
myocardial infarct phase in the rats with large infarcts treated with
bosentan.
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Left ventricular end-diastolic pressure
increased and systolic pressure declined with increasing
infarct size. Cardiac and stroke volume indexes decreased with
increasing infarct size at rest and during acute volume loading,
whereas peripheral resistance increased compared with
sham-operated rats. There were no differences between placebo- and
bosentan-treated rats (Table 2).
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MI resulted in a rightward shift of the passive pressure-volume curve,
indicating an increase of left ventricular volume. No
difference was found between placebo and bosentan (Fig 1A).
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P<.05 bosentan large MI vs bosentan sham,
§P<.05 placebo small to moderate MI vs placebo sham,
%P<.05 bosentan small to moderate MI vs bosentan sham,
P<.05 bosentan large MI vs placebo large MI.
Eight-Week Protocol
The infarct size distribution was similar in placebo- and
bosentan-treated groups. Body weight and left ventricular
weight/body weight ratio were unchanged by infarction or treatment.
Right ventricular weight corrected for body weight
increased with increasing infarct size and was not significantly
different between placebo- and bosentan-treated animals (Table 3).
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The effects of bosentan on hemodynamics 8 weeks after
MI are shown in Table 4. Left
ventricular systolic and mean arterial
pressures and heart rate were significantly decreased by bosentan
treatment in rats with large infarcts. Left ventricular
end-diastolic pressure was increased in rats with large
infarcts compared with sham-operated rats, and there were no
differences between bosentan-treated and untreated rats. In untreated
rats with large infarcts, resting and peak cardiac indexes were
significantly lower than in sham-operated rats, and total
peripheral resistance index tended to increase. Bosentan
prevented the reduction of cardiac index and increase in
peripheral resistance in rats with large infarcts. In the
animals with large infarcts, stroke volume index was also significantly
increased by bosentan versus placebo with rats both at rest and during
volume loading.
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A further rightward shift of the left ventricular
pressure-volume curve occurred in all infarct-size groups 8 weeks
versus 7 days after MI. Bosentan partially prevented the rightward
shift of left ventricular volume in rats with large
infarcts (Fig 1B
). The multifactor factorial ANOVA for
repeated-measures analysis showed a significant difference
between placebo and bosentan in the large MI group
(P=.019).
Biochemical Studies
Infarct size, body weights, and heart weights of rats included in
the biochemical study are summarized in Table 5. The rat subdivision produced groups
with similar infarct sizes, scar weights indexed for body weight, and
right ventricular weight corrected for body weight,
essential for a correct comparison between placebo and bosentan
treatment. In placebo and bosentan rats, there was a similar
correlation between infarct sizes and scar weight/body weight ratio
(placebo, r=.92, P=.0001; bosentan,
r=.95, P<.0001). Body weight and left
ventricular weight/body weight ratio were unchanged by
infarction or treatment. The right ventricular weight
corrected for body weight was significantly elevated (compared with
noninfarcted rats) in placebo and bosentan rats with large
infarcts.
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Endothelin-1
Plasma ET-1 levels as shown in Fig 2
increased in rats with large infarcts compared with noninfarcted rats
and rats with small to moderate infarcts. Bosentan increased plasma
ET-1 levels in sham-operated and small to moderate infarct rats but not
in rats with large infarcts.
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ET-1 levels increased in left ventricular
myocardium of rats with infarcts compared with
sham-operated rats. Left ventricular ET-1 levels were
significantly lower in bosentan-treated rats with large infarcts than
in untreated rats. In right ventricular
myocardium, ET-1 concentration increased with increasing
infarct size. There were no differences between left and right
ventricular ET-1 (Fig 3).
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Left ventricular ET-1 levels (Fig 4) significantly correlated with scar
weight/body weight ratio. In untreated rats, a correlation was observed
between right ventricular ET-1 levels and scar weight/body
weight ratio (r=.59, P<.01).
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Endothelin-1 Receptors
The results of ET-1 receptor binding assays are shown in Table 6. In placebo-treated rats, left
ventricular 125I-ET-1 binding density
(Bmax) was increased in rats with large infarcts
compared with sham-operated rats, whereas the dissociation constant
(Kd) was almost the same. In fact,
Scatchard analyses of saturation binding data showed linear
plots of similar slope
(Kd-1) and different
x intercepts (Bmax) from sham and
large infarct groups (Fig 5). Bosentan
treatment for 8 weeks significantly decreased the maximum number of
ET-1 receptors in rats with large infarcts compared with
placebo-treated rats with comparable infarct size. In the right
ventricle, the density of ET-1 receptors was increased in both
untreated and bosentan-treated rats with large infarcts compared with
sham-operated rats, and the dissociation constant of the various groups
of both treated and untreated rats was not altered. The receptor
density and the dissociation constant were similar between the left and
right ventricles within the various groups of placebo- and
bosentan-treated rats (P=NS, paired t test). As
with ET-1 cardiac levels, a correlation has been observed between both
left and right ventricular receptor density levels and scar
weight/body weight ratio (r=.63, P<.001;
r=.72, P<.001, respectively).
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PRA and NT-proANP
The PRA tended to increase with MI and was unaffected by bosentan
therapy. NT-proANP concentration was elevated (compared with
noninfarcted rats) in placebo rats with small to moderate and large
infarcts and in bosentan-treated rats with large infarcts. There were
no differences between untreated and treated rats (Table 7).
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DHPG and NE Ratios
NE levels in left ventricular myocardium
were lower in rats with large infarcts than in sham-operated rats in
both treatment groups (placebo, 224±18 versus 360±36 ng/g
tissue, P<.05; bosentan, 198±20 versus 373±32 ng/g
tissue, P<.05). The epinephrine and dopamine levels
also decreased, but not significantly, in rats with large infarcts
(data not shown). The ratio of the NE metabolite DHPG to NE was
elevated in rats with large infarcts compared with sham-operated rats,
and chronic bosentan therapy did not alter this ratio (Fig 6).
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Discussion |
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This study demonstrates for the first time that chronic treatment for 8 weeks with the mixed ETA and ETB receptor antagonist bosentan prevents progressive left ventricular dilatation and improves cardiac function in rats with large MI. We found that in large infarcts, chronic endothelin receptor blockade reduced left ventricular systolic and arterial pressure and prevented the increase in systemic vascular resistance and a reduction of stroke volume and cardiac index at rest and during volume load. Furthermore, chronic bosentan treatment decreased circulating ET-1 levels and the ET-1 levels and receptor density in left ventricular myocardium. These findings suggest that chronic endothelin receptor blockade improved left ventricular performance via a combined effect on peripheral circulation and on the myocardial endothelin system. Furthermore, this study revealed that blockade of the endothelin system has no effects on development of structural dilatation in the "acute" postinfarction phase, defined in this study as 7 days after MI.
Acute Endothelin Receptor Blockade
Progressive thinning and enlargement of the infarct segment
(infarct expansion) associated with cavity enlargement is an event of
the first days after MI; dilatation of surviving myocardium
follows later.28-29 A variety of interventions
have been shown to promote acute cardiac dilatation, such as
administration of anti-inflammatory agents and ventricular
load, whereas other interventions, such as reperfusion and
vasodilatation, reduced shape alterations in the early postinfarction
period.5
It has been hypothesized that endothelin receptor blockade can favorably alter the loading conditions on the left ventricle and attenuate ventricular dilatation already in the early stages after infarction. However, in this model, no beneficial effects of bosentan treatment on hemodynamic parameters and early left ventricular dilatation were found. We attribute the failure of bosentan to alter any variable measured in this study to the absence of control of these variables by ET-1 or a lack of activation of the endothelin system during this phase after MI.
Chronic Endothelin Receptor Blockade
We suppose that the favorable effects of bosentan 8 weeks after MI
were achieved in part by a reduction of afterload. However, other drugs
that reduce afterload but not preload have failed to prevent
remodeling.9 The effects of chronic bosentan
treatment are similar in part to those of chronic treatment with
captopril.9,10 Like the ACE
inhibitor, it favorably alters systolic loading
conditions on the left ventricle and may thus reduce progressive left
ventricular dilation and dysfunction after MI. However,
chronic captopril treatment produced a significant decrease in left
ventricular end-diastolic
pressure,10 with a downward displacement of
volume on the pressure-volume relation (less ventricular
distension). Similar reduction of end-diastolic pressure
was observed by Sakai et al27 for the use of the
specific ETA receptor antagonist
BQ-123. In contrast, bosentan had no effect on left
ventricular filling pressure, and the effect on progressive
ventricular enlargement was only the result of an
attenuation of the rightward shift of the pressure-volume curve,
without a downward displacement of volume in that relation. This shift
of the pressure-volume curve occurred at low pressures and therefore
suggests a reduction of volume rather than an increase in myocardial
stiffness.35 Thus, although ACE
inhibitors reduced left ventricular volume in
part by a reduction of distending pressure, the effect of bosentan was
completely structural, because left ventricular volume was
significantly smaller at identical filling pressures. The reason for
the different effects of bosentan and BQ-123 remains unclear. It may be
due to their different actions on only ETA or on
both ETA and ETB receptors,
respectively. It may also be due to different protocols in this and the
previous study by Sakai et al,27 in which rats
were studied for 4 weeks longer and the treatment started 10 days after
MI. Sakai et al36 also reported that BQ-123
treatment over a 2-week period did not affect left
ventricular end-diastolic pressure.
Bosentan treatment may have reduced heart rate by preventing the positive chronotropic effect of ET-1.22 This may have favorable effects on myocardial energetics and function similar to ß-blocker therapy. However, ß-blockers have rather increased left ventricular dimensions in this or similar models after MI.37 Thus, hemodynamic unloading effects of bosentan do not conclusively explain its substantial reduction of left ventricular volume. However, pressure-volume curves obtained in arrested hearts do not reflect pressure-volume relations of beating hearts. Conclusions on interrelations between in vivo hemodynamics and structure on the basis of this analysis should therefore be drawn with some caution.
The cardiac DHPG/NE ratio provides an index of increased NE turnover and sympathetic activity in rats with chronic left ventricular dysfunction.38 Bosentan treatment did not increase left ventricular DHPG/NE ratio of rats with large infarcts. Therefore, we suppose that its effects were not achieved by an influence on cardiac sympathetic activity.
Recent studies report that the production of ET-1 and its binding sites were increased in the left ventricles of rats 3 weeks after MI.26 In the present study, we show that this increase in ET-1 levels and density of ET-1 receptors in left ventricle is sustained for 8 weeks after MI in a later stage of progressive left ventricular dysfunction. In addition, we find that both are related to infarct size, the degree of left ventricular dysfunction, and activation of other humoral systems represented in this study by PRA and NT-proANP. An increase in ET-1 levels and density of ET-1 receptors was found only in animals with large infarcts, not in animals with small to moderate infarcts. In fact, correlations were found between scar weight and the tissue level of ET-1 and its binding sites, respectively, in both left and right ventricular myocardium. Effects of bosentan were also observed only in rats with large infarcts. These data suggest strongly that an activation of the ET-1 system is a prerequisite for the bosentan effects.
In agreement with previous investigations,20,26
we also observed an increase of plasma ET-1 levels in rats with large
infarcts. The increased plasma concentrations in rats with large
infarcts may reflect the severity of cardiac
dysfunction.26 In addition, impaired
pulmonary and renal clearance of ET-1, which might be expected
in rats with large MI, may lead to elevated circulating ET-1
levels.20 Sham-operated rats and rats with small
to moderate infarcts treated with bosentan had higher ET-1 levels than
untreated rats, whereas we did not observe such a difference in rats
with large infarcts. Other investigators39
demonstrated that endothelin receptor antagonists increased
circulating ET-1 and suggested that this increase was related to
displacement of endothelin from the ETB receptor,
which is involved in endothelin clearance and an increase of ET-1 gene
expression in some vessels. Therefore, it was thought that bosentan
enhanced ET-1 production in some vascular tissue of
sham-operated rats and rats with small to moderate infarcts but not of
rats with severe left ventricular dysfunction. The
observation that ET-1 plasma levels in bosentan-treated rats with large
infarcts were not different from those of untreated rats was
surprising. There is no simple explanation, but indirect mechanisms,
such as improvement of left ventricular function and
systemic hemodynamics, could have contributed.
Recently, Li et al40 demonstrated that plasma
ET-1 levels were normalized by cilazapril in spontaneously hypertensive
rats treated with
N
-nitro-L-arginine methyl
ester, and they suggest that the blood pressure–lowering effect of ACE
inhibition may reduce ET-1 spillover into the bloodstream.
The finding that vascular endothelin secretion is mainly polar, being directed toward the interstitial region rather than the vascular lumen,41 supports the hypothesis that endothelin acts in a paracrine fashion rather than as a circulating hormone. The marked concentration difference between plasma and tissue levels of endothelin, as our study underlines, provides further evidence for a local role of endothelin. The upregulation of the cardiac endothelin system in rats with large infarcts may represent a neurohumoral compensatory response related to compromised left ventricular function. The vasoconstrictor actions of endothelin in the coronary circulation and a chronic positive inotropic and chronotropic effect21-24 may result in a worsening of cardiac dysfunction. We speculate that bosentan blocked the effects of this neurohormonal system and therefore favorably altered the natural progression of left ventricular dysfunction and dilatation.
ACE inhibitors reduce left ventricular weight in rats with or without MI and independent of infarct size.10 In contrast, bosentan had no effect on left ventricular weight in the present study. In fact, it reduced left ventricular volume in rats with large infarcts while weight remained similar. Although left ventricular hypertrophy was not analyzed on a cellular basis, these data strongly suggest that bosentan did not prevent concentric hypertrophy of surviving myocardium, which was previously shown on the basis of quantitative histomorphology by Olivetti et al.42 Infarct expansion, elongation (eccentric hypertrophy) of muscle fibers, and fiber slippage contribute to left ventricular dilatation after MI. Our data do not suggest that bosentan prevented infarct expansion, because this effect would have shown up at 1 week after infarction. It remains unclear from this study whether bosentan prevented fiber slippage, eccentric hypertrophy, or both.
Several studies9,13-15 indicate that ACE inhibitors and angiotensin type 1 receptor antagonists also prevent right ventricular hypertrophy. These effects were attributed to a reduction of afterload of the right ventricle and inhibition of a hypertrophic effect of myocardial angiotensin II. Chronic endothelin receptor blockade did not prevent the increase of right ventricular weight after MI in our study, in accordance with a lack of bosentan to reduce left ventricular filling pressure. In addition, a direct contribution of endogenous endothelin on right ventricular hypertrophy in this model is unlikely. ET-1 induces hypertrophy of cultured rat cardiomyocytes,43 whereas in vivo, it is involved in monocrotaline-induced pulmonary hypertension44 and in the mechanism of left ventricular hypertrophy during the early phase of pressure overload45 but not in eccentric cardiac hypertrophy induced by volume overload.46 Moreover, the production of ET-1 and its binding sites is upregulated in pressure overload cardiac hypertrophy.25 In this study, we found that in right ventricular myocardium, ET-1 level and the number of ET-1 binding sites were increased in association with the increase of infarct size. The inability of bosentan to maintain inhibitory effects argues against ET-1 being directly causative for right ventricular hypertrophy in this postinfarction phase.
The present study was performed in female rats. Pfeffer et al10 also used female rats to determine the influence of captopril on left ventricular remodeling. Other studies on the effect of ACE inhibitors on ventricular hypertrophy were performed in male rats.13-15 Our results are confined to females, because sex differences have been reported in ventricular hypertrophy.47,48
In conclusion, the present study demonstrates that bosentan treatment had beneficial effects on hemodynamics and left ventricular volume in rats with chronic left ventricular dysfunction after large infarcts. These findings suggest that the effects of ET-1 receptor blockade are related to the extent of left ventricular dysfunction and are apparent only in rats with chronic upregulation of the circulating and cardiac endothelin systems. These observations support the hypothesis that ET-1, in concert with activation of other neurohumoral systems, may contribute after MI in the acute phase to maintain systemic perfusion but may be detrimental in chronic stages of cardiac dysfunction. Conversely, ET-1 antagonists may prove to be useful agents for prevention of progressive left ventricular dysfunction after MI. A combination with an ACE inhibitor could be of specific interest, because bosentan did not reduce left ventricular filling pressure, an effect that is considered important for the action of ACE inhibitors on remodeling.9
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Selected Abbreviations and Acronyms |
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Acknowledgments |
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This study was supported by SFB355, Pathophysiologie der Herzinsuffizienz, Universität Würzburg and the Forschungsfond of the Fakultät für klinische Medizin Mannheim der Universität Heidelberg, Germany. Bosentan was kindly provided by Dr Martine Clozel, Hoffmann-La Roche, Basel, Switzerland. We wish to gratefully acknowledge the technical assistance of Andreas Mangol, Anskar Platte, Oliver Lutz, and Hans-Peter Schepky.
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Footnotes |
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Guest editor for this article was Douglas L. Mann, MD, VA Medical Center, Houston, Tex.
Received April 15, 1997; revision received August 13, 1997; accepted August 21, 1997.
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References |
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 S.-M. Herrmann, K. Schmidt-Petersen, J. Pfeifer, A. Perrot, N. Bit-Avragim, C. Eichhorn, R. Dietz, R. Kreutz, M. Paul, and K.J. Osterziel A polymorphism in the endothelin-A receptor gene predicts survival in patients with idiopathic dilated cardiomyopathy Eur. Heart J., October 2, 2001; 22(20): 1948 - 1953. [Abstract] [PDF]
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P.J. Cowburn and J.G.F. Cleland Endothelin antagonists for chronic heart failure: do they have a role? Eur. Heart J., October 1, 2001; 22(19): 1772 - 1784. [PDF]
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J. Bauersachs, P. Galuppo, D. Fraccarollo, M. Christ, and G. Ertl Improvement of Left Ventricular Remodeling and Function by Hydroxymethylglutaryl Coenzyme A Reductase Inhibition With Cerivastatin in Rats With Heart Failure After Myocardial Infarction Circulation, August 28, 2001; 104(9): 982 - 985. [Abstract] [Full Text] [PDF]
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J. Bauersachs, I. Fleming, D. Fraccarollo, R. Busse, and G. Ertl Prevention of endothelial dysfunction in heart failure by vitamin E: Attenuation of vascular superoxide anion formation and increase in soluble guanylyl cyclase expression Cardiovasc Res, August 1, 2001; 51(2): 344 - 350. [Abstract] [Full Text] [PDF]
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M. Hayashi, T. Tsutamoto, A. Wada, K. Maeda, N. Mabuchi, T. Tsutsui, H. Horie, M. Ohnishi, and M. Kinoshita Intravenous atrial natriuretic peptide prevents left ventricular remodeling in patients with first anterior acute myocardial infarction J. Am. Coll. Cardiol., June 1, 2001; 37(7): 1820 - 1826. [Abstract] [Full Text] [PDF]
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B. K. Podesser, D. A. Siwik, F. R. Eberli, F. Sam, S. Ngoy, J. Lambert, K. Ngo, C. S. Apstein, and W. S. Colucci ETA-receptor blockade prevents matrix metalloproteinase activation late postmyocardial infarction in the rat Am J Physiol Heart Circ Physiol, March 1, 2001; 280(3): H984 - H991. [Abstract] [Full Text] [PDF]
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J. Bauersachs, D. Fraccarollo, G. Ertl, N. Gretz, M. Wehling, and M. Christ Striking Increase of Natriuresis by Low-Dose Spironolactone in Congestive Heart Failure Only in Combination With ACE Inhibition : Mechanistic Evidence to Support RALES Circulation, November 7, 2000; 102(19): 2325 - 2328. [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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K. Yamamoto, T. Masuyama, Y. Sakata, R. Doi, K. Ono, T. Mano, H. Kondo, T. Kuzuya, T. Miwa, and M. Hori Local neurohumoral regulation in the transition to isolated diastolic heart failure in hypertensive heart disease: absence of AT1 receptor downregulation and 'overdrive' of the endothelin system Cardiovasc Res, June 1, 2000; 46(3): 421 - 432. [Abstract] [Full Text] [PDF]
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A. Igawa, T. Nozawa, N. Yoshida, N. Fujii, M. Inoue, S. Tazawa, H. Asanoi, and H. Inoue Heterogeneous cardiac sympathetic innervation in heart failure after myocardial infarction of rats Am J Physiol Heart Circ Physiol, April 1, 2000; 278(4): H1134 - H1141. [Abstract] [Full Text] [PDF]
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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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G. G. N. Serneri, I. Cecioni, S. Vanni, R. Paniccia, B. Bandinelli, A. Vetere, X. Janming, I. Bertolozzi, M. Boddi, G. F. Lisi, et al. Selective Upregulation of Cardiac Endothelin System in Patients With Ischemic but Not Idiopathic Dilated Cardiomyopathy : Endothelin-1 System in the Human Failing Heart Circ. Res., March 3, 2000; 86(4): 377 - 385. [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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P.A. van Zwieten The influence of antihypertensive drug treatment on the prevention and regression of left ventricular hypertrophy Cardiovasc Res, January 1, 2000; 45(1): 82 - 91. [Abstract] [Full Text] [PDF]
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P. Charron, F Tesson, O Poirier, V Nicaud, M Peuchmaurd, L Tiret, F Cambien, P Amouyel, O Dubourg, J.-B Bouhour, et al. Identification of a genetic risk factor for idiopathic dilated cardiomyopathy. Involvement of a polymorphism in the endothelin receptor type A gene Eur. Heart J., November 1, 1999; 20(21): 1587 - 1591. [Abstract] [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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J. Bauersachs, A. Bouloumie, D. Fraccarollo, K. Hu, R. Busse, and G. Ertl Endothelial Dysfunction in Chronic Myocardial Infarction Despite Increased Vascular Endothelial Nitric Oxide Synthase and Soluble Guanylate Cyclase Expression : Role of Enhanced Vascular Superoxide Production Circulation, July 20, 1999; 100(3): 292 - 298. [Abstract] [Full Text] [PDF]
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O. Zolk, J. Quattek, G. Sitzler, T. Schrader, G. Nickenig, P. Schnabel, K. Shimada, M. Takahashi, and M. Bohm Expression of Endothelin-1, Endothelin-Converting Enzyme, and Endothelin Receptors in Chronic Heart Failure Circulation, April 27, 1999; 99(16): 2118 - 2123. [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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G. Horstick, O. Berg, A. Heimann, H. Darius, H. A. Lehr, S. Bhakdi, O. Kempski, and J. Meyer Surgical procedure affects physiological parameters in rat myocardial ischemia: need for mechanical ventilation Am J Physiol Heart Circ Physiol, February 1, 1999; 276(2): H472 - H479. [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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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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P. Moreau Endothelin in hypertension: A role for receptor antagonists? Cardiovasc Res, September 1, 1998; 39(3): 534 - 542. [Abstract] [Full Text] [PDF]
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