(Circulation. 1997;95:1918-1929.)
© 1997 American Heart Association, Inc.
Articles |
Concomitant Endothelin Receptor Subtype-A Blockade During the Progression of Pacing-Induced Congestive Heart Failure in Rabbits
Beneficial Effects on Left Ventricular and Myocyte Function
From the Division of Cardiothoracic Surgery, Medical University of South Carolina, Charleston, and Parke-Davis Pharmaceutical Research, Ann Arbor, Mich (K.P.G.).
Correspondence to Francis G. Spinale, MD, PhD, Division of Cardiothoracic Surgery, RM 418 CSB, 171 Ashley Ave, Medical University of South Carolina, Charleston, SC 29425.
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Abstract |
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Background Plasma levels of endothelin-1 (ET-1) are increased in patients and animals with severe congestive heart failure (CHF). It remains unknown, however, whether ET-1 plays a direct and contributory role in the progression of CHF. Accordingly, the present project tested the hypothesis that chronic blockade of the ETA receptor would have direct and beneficial effects on left ventricular (LV) and myocyte function in a model of CHF.
Methods and Results Global LV and isolated myocyte function were examined in rabbits in the following groups (12 per group): chronic rapid ventricular pacing (RVP; 400 bpm, 3 weeks), RVP and concomitant administration of the selective ETA receptor antagonist (PD 156707 24 mg/d), and sham controls. LV fractional shortening decreased after RVP (17±5 versus 42±3%) and end-diastolic dimension increased (2.36±0.44 versus 1.24±0.18 cm) compared with controls (P<.05). With RVP plus ETA blockade, LV fractional shortening was increased (33±6%) and end-diastolic dimension decreased (2.02±0.30 cm) compared with RVP-only values (P<.05). Plasma norepinephrine and endothelin increased twofold in the RVP group. In the RVP plus ETA blockade group, plasma endothelin increased threefold compared with RVP values. Isolated myocyte shortening velocity declined after RVP (42±13 versus 72±10 µm/s, P<.05) compared with controls but was normalized with RVP plus ETA blockade (77±16 µm/s). Myocyte inotropic response to extracellular Ca2+, ß-receptor stimulation, and ET-1 was reduced in the RVP group and returned to control levels with RVP and concomitant ETA receptor blockade.
Conclusions The results from this study suggest that chronically elevated ET-1 levels and subsequent activation of the ETA receptor play a direct and contributory role in the progression of the CHF process. Thus, specific ETA receptor blockade may provide a new and useful therapeutic modality in the setting of CHF.
Key Words: heart failure • endothelin • ventricles • contractility • receptor
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Introduction |
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TopAbstractIntroductionMethodsResultsDiscussionReferences |
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Endothelin-1 is a potent bioactive peptide that has a number of diverse physiological effects. For example, ET-1 modulates systemic, pulmonary, and coronary vascular tone and influences neurohormonal system activity.1 2 3 4 The diverse physiological actions of ET-1 appear to be mediated through two receptor subtypes, the ETA and ETB receptors.5 6 Production of ET-1 was first described in endothelial cells,7 but the synthesis of ET-1 has now been identified to occur in a number of cell types.8 9 10 A commonly used index of ET-1 production is the degree of spillover into the plasma, which can then be detected by radioimmunoassay.11
Increased plasma ET-1 levels have been identified in a number of disease states, including CHF. For example,clinical and experimental studies have reported that severe CHF is accompanied by a twofold to threefold increase in plasma endothelin concentrations.4 10 11 12 13 14 In light of the significant vasoconstrictive effects of ET-1 on arteriolar smooth muscle, increased plasma ET-1 levels have been postulated to play a contributory role in exacerbating LV dysfunction and symptoms associated with CHF.10 11 12 15 In addition to the systemic effects of ET-1, it has been demonstrated that activation of the ETA receptor has direct effects on myocyte contractile function, protein expression, and electrophysiology.10 16 17 18 19 20 21 22 23 24 25 26 27 28 29 These past observations suggest that ET-1 production and subsequent ETA receptor activation may directly influence both LV and myocyte function in the setting of CHF.
Recently, a number of potent ETA receptor antagonists have been described.30 31 32 33 Through the use of a specific receptor antagonist in an animal model of CHF, it may be possible to define more precisely the contributory role of ETA receptor activation in the development of CHF. Chronic rapid pacing in animals causes progressive and predictable time-dependent changes in LV geometry and function.34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 Specifically, chronic rapid pacing causes LV dilation and dysfunction and neurohormonal activation. These changes in LV function and neurohormonal systems are similar to the clinical spectrum of CHF.49 50 Most importantly, this model of CHF is associated with a significant elevation in plasma endothelin levels.4 10 14 37 Accordingly, the present project used a model of RVP-induced CHF in rabbits43 44 to test the central hypothesis that chronic ETA receptor blockade will have beneficial effects on LV and myocyte function.
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Methods |
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TopAbstractIntroductionMethodsResultsDiscussionReferences |
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Animal Preparation
Adult age- and weight-matched rabbits (New Zealand White; weight, 3.8 to 4.2 kg; age, 5 months) were used in this study. All rabbits were treated and cared for in accordance with the NIH Guidelines for the Care and Use of Laboratory Animals (1985). In the rabbits to undergo chronic rapid pacing, a ventricular pacing lead and modified pacemaker were implanted. The rabbits were anesthetized with isoflurane (2.0% at 1.5 L/min) and nitrous oxide (0.5 L/min), and a shielded stimulation electrode was sutured onto the right ventricular outflow tract and connected to a programmable pacemaker modified for programming heart rates up to 400 bpm (Spectrax, Medtronic Inc) to induce RVP. The pacemaker was then buried in a subcutaneous pocket. Seven to 10 days after the surgery, the rabbits were assigned to a specific protocol as outlined in the following section. The control rabbits were treated and cared for in a similar manner except for pacemaker implantation.
Experimental Design
To define the potential role of chronic ETA receptor
activation in the progression of CHF, a highly specific ETA
receptor antagonist was chronically administered.32 33 The
dosage protocol adopted for the ETA antagonist used in this
study was based on previously performed in vitro
studies32 33 and preliminary in vivo studies performed by
this laboratory. The ETA antagonist PD 156707 (Parke-Davis)
has been demonstrated previously to have a 1000-fold higher affinity
for the ETA receptor than the ETB receptor in
rabbit renal artery vascular smooth muscle cells.32 In
addition, this ETA antagonist has been demonstrated to
eliminate the ET-1–induced tension response in rabbit femoral artery
vessels at nanomolar concentrations.32 33 When
administered orally, the ETA antagonist has been
demonstrated in rats to have high bioavailability and to significantly
block the ET-1–mediated pressor response at 1 mg/kg.32
Before the initiation of the protocol described in the following
paragraph, 3 rabbits (4.5±0.2 kg) were implanted with subcutaneous
pellets (Innovative Research) to deliver 24 mg/d of the ETA
antagonist. Three days after pellet implantation, blood was drawn for
the determination of plasma levels of the ETA antagonist.
The plasma levels for these three rabbits were 50±7 ng/mL PD156707 and
significantly exceeded the computed IC50 for this potent
and selective ETA antagonist.32 33
Accordingly, this dosage of the ETA antagonist was used for
the studies described below.
After pacemaker implantation or sham procedures, the rabbits were assigned to the following treatment groups. Group 1 received RVP plus ETA blockade. Subcutaneous pellets were implanted to deliver 24 mg/d of the selective ETA antagonist (PD156707, Parke-Davis; n=12). After pellet implantation, the pacemaker was activated to 400 bpm, and RVP continued at this rate for 3 weeks. Group 2 received RVP only. Subcutaneous pellets containing vehicle only were implanted, and the pacemaker was activated to 400 bpm for 3 weeks (n=12). Group 3 was the control plus ETA blockade group. Subcutaneous pellets were implanted to deliver an identical dose of the ETA antagonist as in group 1. These rabbits were studied 3 weeks after pellet implantation (n=10). Group 4 was sham controls. In this group, the rabbits underwent sham procedures and implantation of subcutaneous vehicle pellets (n=12). These rabbits were studied 3 weeks after pellet implantation. In the RVP groups, the rabbits were auscultated daily, and an ECG was performed weekly throughout the pacing protocol to ensure proper operation of the pacemaker. Three weeks after initiation of the protocols described above, the rabbits were brought to the laboratory for terminal study, which included measurements of LV function, blood collection, and myocyte isolation.
LV Function and Terminal Studies
LV pump function was assessed in all rabbits in the
conscious state. The rabbits were sedated (10 mg diazepam), the
pacemaker was deactivated (RVP groups only), and an ECG was
established. The rabbits were allowed to rest in a dimly lit laboratory
for 30 minutes before LV function measurements. LV function was
assessed by two-dimensional and M-mode echocardiographic recordings
(7.5-MHz transducer, Interspec) from a parasternal approach. The LV
end-diastolic and end-systolic dimensions, LV end-systolic and
end-diastolic wall thickness, and fractional shortening were computed
from the two-dimensional targeted M-mode recordings. LV fractional
shortening was computed as end-diastolic dimension minus end-systolic
dimension divided by end-diastolic dimension and was expressed as a
percent. In six rabbits from each treatment group, echocardiographic
measurements were performed weekly.
At the completion of the specific treatment protocols and echocardiographic measurements, the rabbits were anesthetized with 1% isoflurane and 100% oxygen. The right carotid artery was exposed, and a fluid-filled 5F catheter was inserted. Arterial pressures were recorded from the catheter connected to a previously balanced and calibrated pressure transducer (Statham P23ID). Arterial pressure measurements were performed in all groups under identical anesthetic conditions. From the arterial pressure recordings and echocardiographic measurements, LV peak systolic wall stress was computed as described previously.34 35 After the arterial pressure measurements, 30 cm3 blood was drawn into chilled tubes containing EDTA (1.5 mg/mL) and centrifuged (2000g, 10 minutes, 4°C). The plasma was placed in separate tubes, frozen in liquid nitrogen, and stored at -80°C until the time of neurohormonal assay.
After the collection of blood samples for neurohormonal assays, the rabbits were deeply anesthetized with 4% isoflurane, 500 U heparin was delivered, and a sternotomy was performed. The heart was then rapidly removed and placed in chilled Krebs' solution, and the ascending aorta was cannulated. In seven rabbits from each group, the LV was prepared for myocyte isolation as described later. In the remaining rabbits, the LV was perfusion fixed with 100 cm3 of 3.7% buffered formaldehyde, maintaining a perfusion pressure of 50 mm Hg. Then, a full-thickness section of the midregion of the LV was prepared and stained with hematoxylin and eosin. From these stained LV sections, myocyte cross-sectional area was measured with computer-assisted techniques as described previously.34 35 44
Neurohormonal Assays
The plasma samples were assayed for renin activity, endothelin
concentration, and norepinephrine levels. Plasma renin activity was
determined by computing angiotensin I production with a
radioimmunoassay (NEA-026, New England Nuclear). For the endothelin
assays, the plasma was first eluted over a cation exchange column (C-18
Sep-Pak, Waters Associates) and then dried by vacuum-centrifugation.
The samples were reconstituted in 0.02 mol/L borate buffer, and a
high-sensitivity radioimmunoassay was performed (RPA545, Amersham).
Recovery from the extraction procedure was 65±5% on the basis of
plasma spiked standards (4 to 20 fmol/mL). The interassay and
intra-assay variations were 10% and 9%, respectively, for the
endothelin radioimmunoassay procedure. Plasma norepinephrine was
measured by use of high-performance liquid chromatography and
normalized to picograms per milliliter of plasma. All assays were
performed in duplicate.
Myocyte Isolation and Contractile Function
LV myocytes were isolated through coronary perfusion of a
low-calcium collagenase solution described
previously.10 34 38 40 41 45 46 The liberated myocytes
were resuspended in cell culture media (Media M199, 2 mmol/L
Ca2+, GIBCO Laboratories). With these methods, a high yield
(75±5%) of viable myocytes was obtained with no difference in the
percent yield in any of the treatment groups. Viable myocytes were
defined as those that were quiescent in culture, maintained a
rod-shaped morphology with increased extracellular Ca2+,
and excluded trypan blue. Isolated myocyte function was examined as
previously reported by this laboratory.38 40 41 45 46
Briefly, a thermostatically controlled chamber (37°C) containing a
volume of 2.5 mL and two stimulating platinum electrodes was used to
image the isolated myocytes on an inverted microscope (Axiovert IM35,
Zeiss Inc). Myocyte contractions were elicited by field stimulating the
tissue chamber at 1 Hz (S11, Grass Instruments) with current pulses of
5-ms duration and voltages 10% above the contraction threshold. The
distance between the left and right myocyte edges was converted into a
voltage signal, digitized, and entered into a computer (80386; ZBV2526,
Zenith Data Systems) for analysis. After the determination of baseline
contractile function, myocyte contractile function was examined in the
presence of 8 mmol/L extracellular Ca2+, 25 nmol/L
isoproterenol (Sigma Chemical Co), or 100 pmol/L ET-1 (E7764, Sigma).
The concentration of isoproterenol used in this study has been
demonstrated previously to provide nearly maximal contractile response
for this myocyte preparation.41 The concentration of ET-1
used for this series of experiments was determined from preliminary
dose-response studies in which 100 pmol/L ET-1 produced a maximal
contractile response in control rabbit myocytes.
Data Analysis
Indexes of LV and myocyte function were compared among the
treatment groups with ANOVA. For the myocyte cross-sectional area and
contractile function studies, an ANOVA using a randomized block
split-plot design was used. The treatment effects were pacing and
ETA receptor antagonist therapy. Each rabbit was considered
a complete block. Thus, the number of myocytes studied from each rabbit
was considered repeated observations within each block. If the ANOVA
revealed significant differences, pairwise tests of individual group
means were compared by use of Bonferroni probabilities. For comparisons
of neurohormonal profiles, the Mann-Whitney rank sum test was used. All
statistical procedures were performed with the BMDP statistical
software package (BMDP Statistical Software Inc). Results are presented
as mean±SD. Values of P<.05 were considered statistically
significant.
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Results |
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Chronic RVP for 3 weeks in rabbits resulted in clinical symptoms of CHF that included tachypnea, lethargy, and reduced appetite. In the RVP group, one rabbit died during the third week of pacing. In the RVP plus ETA blockade group, there were no mortalities, and activity levels and food intake were unchanged from baseline. In the rabbits undergoing chronic ETA receptor blockade, plasma levels of the ETA receptor antagonist (PD156707) obtained at terminal study were 42±9 ng/mL. In one drug control and one RVP rabbit, plasma levels of the drug were below quantification (<10 ng/mL). A likely explanation for this finding is that the pellet expired before terminal study with a resultant reduction in plasma drug levels. These rabbits were not excluded from the study and are included in the results. Table 1
gives
the final sample size for each treatment group.
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LV Function and Hemodynamics With RVP: Effects of
ETA Blockade
Table 1
summarizes the heart rate, arterial pressure, and LV
pump function measured for the four groups of rabbits. Basal resting
heart rate was increased in the RVP-only group compared with the sham
control group and returned to within normal values in the RVP plus
ETA blockade group. LV function and heart rate were
unchanged in the control plus chronic ETA blockade group
compared with untreated sham controls. In the RVP group, LV fractional
shortening was significantly lower and end-diastolic dimension was
significantly higher than sham control values. In the RVP plus
ETA blockade group, LV fractional shortening was >80%
higher compared with RVP-only values. However, LV pump function
remained significantly lower in the RVP plus ETA blockade
group compared with sham controls. LV end-diastolic dimension was lower
in the RVP plus ETA blockade group compared with RVP-only
values but remained significantly higher than sham control values. Fig 1 shows the weekly changes in LV end-diastolic dimension
and fractional shortening for the RVP group and the RVP plus
ETA blockade group. In the RVP group, LV end-diastolic
dimension increased and fractional shortening decreased
time-dependently. In the RVP plus ETA blockade group, LV
end-diastolic dimension increased in a similar fashion to that in the
RVP-only group, but the degree of LV dilation was reduced after 3 weeks
of pacing. In the RVP plus ETA blockade group, LV
fractional shortening declined from baseline (week 0) values after 1
week of pacing and appeared to plateau with longer durations of rapid
pacing. Mean arterial pressure and pulse pressure were similar between
the sham control and the control and ETA blockade groups
(Table 1). Mean arterial pressure and pulse pressure were reduced in
the RVP-only group. In the RVP plus ETA blockade group,
mean arterial pressure and pulse pressure were similar to control
values. LV peak systolic wall stress was unchanged in the control and
ETA blockade group compared with sham controls. LV peak
wall stress was increased more than twofold in the RVP group. In the
RVP plus ETA blockade group, LV peak wall stress was
reduced from RVP-only values but remained significantly higher compared
with control values.
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LV mass obtained at autopsy for the four groups of rabbits is
summarized in Table 1. LV mass normalized to body weight was unchanged
in the RVP groups, regardless of treatment. LV myocyte cross-sectional
area was determined from perfusion-fixed sections for each group; this
analysis resulted in an approximate gaussian distribution for this
parameter (Fig 2). In the control plus ETA
blockade group, myocyte cross-sectional area was unchanged from sham
control values (176±87 versus 165±74 µm2,
respectively; P=.14). In the RVP-only group, myocyte
cross-sectional area was significantly decreased from control values
(145±46 µm2, P<.05) and was similarly
reduced in the RVP plus ETA blockade group (135±40
µm2, P<.05).
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Neurohormonal Activation With Chronic RVP: Effects of
ETA Blockade
Table 2 summarizes changes in plasma
norepinephrine, renin activity, and endothelin levels with RVP and
after ETA receptor blockade. RVP resulted in a fourfold
increase in plasma norepinephrine and more than a twofold increase in
endothelin levels and plasma renin activity compared with sham control
values. In the RVP plus ETA blockade group, plasma
norepinephrine levels and renin activity were unchanged from RVP-only
values. With RVP plus ETA receptor blockade, plasma
endothelin levels were sixfold higher than sham control values and more
than twofold higher than RVP-only values. In the control plus
ETA receptor blockade group, plasma norepinephrine was
unchanged from sham control values. However, in the normal rabbits with
ETA receptor blockade, plasma renin activity and endothelin
levels were increased from sham control values.
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Isolated Myocyte Contractile Function With Chronic RVP: Effects of
ETA Blockade
Baseline LV myocyte function was examined in >500 isolated
myocytes taken from each of the four treatment groups, with a minimum
of 55 myocytes studied from each rabbit. Table 3
summarizes the indexes of myocyte contractile function. In the RVP
group, isolated myocyte length was longer than sham control values.
Myocyte percent and velocity of shortening were reduced by >40% in
the RVP group compared with the sham control group. In addition,
relengthening velocity, an index of myocyte active relaxation, was
reduced by over 50% from sham control values. In the RVP plus
ETA blockade group, myocyte length was reduced compared
with the RVP-only group but remained longer than sham control values.
In the RVP plus ETA blockade group, indexes of myocyte
contractile function were similar to sham control values. In the
control plus ETA blockade group, basal myocyte contractile
function was unchanged from sham control values. Thus, consistent with
past reports,38 40 41 45 46 chronic RVP caused LV myocyte
lengthening and contractile dysfunction. Chronic RVP and concomitant
ETA receptor blockade normalized indexes of myocyte
contractile function. Chronic ETA receptor blockade in
normal rabbits had no effect on indexes of basal myocyte contractile
performance.
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To more carefully examine the capacity of the myocyte to respond to an
inotropic stimulus, contractile function was examined in the presence
of increased isoproterenol and ET-1. Table 3 summarizes the results
from this series of experiments. Myocyte contractile function
significantly increased in all groups after ß-receptor stimulation
with isoproterenol. However, myocyte contractile function was
significantly lower in the RVP-only group after ß-adrenergic receptor
stimulation. In the RVP plus ETA blockade group, myocyte
ß-adrenergic responsiveness was normalized. Myocyte contractile
responses to Ca2+ and isoproterenol were similar between
the control plus ETA receptor blockade group and sham
controls. In the presence of 100 pmol/L ET-1, myocyte contractile
function significantly increased in the sham control group. However,
myocyte contractile response to ET-1 was significantly blunted in the
RVP group. In both the RVP plus ETA blockade and the
control plus ETA blockade groups, myocyte contractile
responses to ET-1 were similar to sham control values. In light of the
differences in baseline myocyte function in the different treatment
groups, the magnitude of the response to inotropic stimulation was
examined as the absolute increase in velocity of shortening. This
analysis was performed by use of paired values for shortening velocity
in those myocytes exposed to extracellular Ca2+,
isoproterenol, or ET-1. Fig 3 summarizes the results of
this analysis. In the control plus ETA blockade group,
myocyte response to Ca2+ and isoproterenol was increased
from sham control values. In the RVP-only group, myocyte response was
diminished in the presence of both isoproterenol and ET-1. With RVP
plus ETA receptor blockade, myocyte contractile response to
Ca2+, isoproterenol, and ET-1 was normalized.
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Discussion |
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It has been postulated that increased plasma levels of the potent vasoactive peptide ET-1 may contribute to the progression of CHF through activation of the ETA subtype receptor. Chronic RVP in animals invariably causes LV dilation, pump dysfunction, and neurohormonal activation.34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 In the present study, chronic RVP was induced in rabbits to order to test the central hypothesis that chronic activation of the endothelin ETA receptor plays a contributory role in the progression of LV dysfunction. There were three significant findings of this study. First, chronic RVP plus concomitant ETA receptor blockade improved LV pump function and reduced LV peak wall stress without a significant compromise in systemic blood pressure. Second, chronic RVP plus concomitant ETA receptor blockade was associated with a significant increase in plasma endothelin levels and plasma renin activity. Third, chronic RVP plus concomitant ETA receptor blockade significantly improved isolated myocyte contractile function and normalized inotropic responsiveness. These results demonstrate that ETA receptor blockade in a model of CHF provides beneficial effects on both LV and myocyte function and provide evidence that chronic ETA receptor activation plays a contributory role in the progression of LV dysfunction in the setting of experimental CHF.
LV Function and Chronic ETA Receptor Blockade
To the best of our knowledge, this is the first study to examine
the direct effects of chronic ETA receptor blockade on LV
function and geometry in a model of progressive CHF. Consistent with
past reports, the present study demonstrated that chronic RVP resulted
in LV dilation and pump dysfunction.34 35 36 40 41
Specifically, chronic RVP in rabbits resulted in reduced LV fractional
shortening and was accompanied by increased LV peak wall stress and
decreased isolated myocyte contractile performance. Concomitant
ETA receptor blockade with chronic RVP significantly
improved LV pump function and was associated with reduced LV peak wall
stress and improved indexes of myocyte contractile function. Thus,
contributory mechanisms for the increased LV ejection performance with
ETA receptor blockade in this model of CHF include reduced
LV afterload and improved contractility. Although previous experimental
and clinical studies have examined the effects of acute administration
of nonspecific endothelin receptor antagonists in the setting of
CHF,27 30 51 these past studies did not examine the
effects of chronic and specific endothelin receptor blockade on LV and
myocyte function. In the present study, chronic administration of a
specific ETA receptor antagonist in a rapid pacing model of
progressive CHF provided beneficial effects on both LV loading
conditions and intrinsic myocyte contractile function. The significance
of these findings is twofold. First, the improved LV function with
chronic ETA receptor blockade suggests that ETA
receptor activation plays a contributory role in the progression of LV
dysfunction in this model of CHF. Second, the improved LV pump function
observed with chronic ETA receptor blockade in this
model of CHF was not due to alterations in LV loading conditions alone
but also to an intrinsic protective effect on LV contractile
performance.
In addition to the effects on systemic vascular resistance, ET-1 modulates resistance in the coronary and pulmonary vascular systems. For example, ET-1 infusion has been demonstrated to cause coronary vasoconstriction and ischemia in the intact rabbit heart.2 The changes in coronary vascular resistance caused by elevations in circulating ET-1 levels may be of particular importance with CHF and may contribute to myocardial oxygen demand/delivery mismatch. Although active ischemia and/or infarction appear to be absent in the RVP model of CHF, coronary vascular resistance and endothelial control of myocardial blood flow are significantly affected.4 35 36 In a recent clinical report, it has been demonstrated that in patients with nonischemic cardiomyopathy, abnormalities in myocardial oxygen delivery/demand exist.52 Thus, a potential contributory mechanism for the improved LV function with chronic RVP and ETA receptor blockade observed in the present study may have been due to improved myocardial blood flow. In a model of CHF caused by chronic caval occlusion, Cannan and colleagues4 demonstrated that the coronary vasoconstrictor effects of ET-1 were mediated by the ETB subtype receptor. Thus, the potential role of selective ETA and/or ETB receptor blockade in the setting of CHF with respect to reducing coronary vascular resistance and improving myocardial oxygen delivery warrants further investigation. In patients with CHF, a relationship between circulating levels of ET-1 and the degree of pulmonary vascular resistance has been reported.12 13 15 Kiowski et al51 reported that acute administration of the nonselective endothelin receptor antagonist bosentan significantly reduced pulmonary vascular resistance in patients with CHF. Thus, in the present study, potential contributory factors for the beneficial effects of chronic ETA receptor blockade in the rabbit model of pacing-induced CHF include a reduction in pulmonary vascular resistance, which in turn would improve right ventricular function and oxygenation capacity.
In the present study, chronic administration of an ETA receptor antagonist during chronic RVP reduced ambient heart rates compared with untreated CHF rabbits. This heart rate effect with chronic ETA blockade and RVP occurred despite significantly increased catecholamine levels. In a rat model of chronic ischemia, Sakai and colleagues27 demonstrated that acute infusion of an endothelin receptor antagonist decreased heart rate. Abundant ETA and ETB receptors have been localized to the myocardial conduction system and AV node.28 Furthermore, ET-1 has been demonstrated to influence a number of voltage-gated ion channels.19 20 21 24 In the present study, reduced arterial pulse pressure occurred with the development of RVP-induced CHF whereas, concomitant ETA receptor blockade normalized pulse pressure. Thus, likely contributory factors for the reduced heart rate with ETA blockade and RVP observed in the present study include direct negative chronotropic effects on the myocardium and reduced baroreceptor activity. In the control and ETA receptor blockade groups, heart rate was not affected. These observations suggest that the potential chronotropic effects of ETA receptor activity involve a number of neuroendocrine interactions that could not be completely addressed in the present study.
ET-1 modulates systemic vascular resistance through activation of two primary receptor systems, ETA and ETB, that when stimulated appear to have opposite effects. Activation of the ETA receptor, which has a high affinity for ET-1, causes increased contraction of vascular smooth muscle cells.1 3 5 18 ETB receptor stimulation causes synthesis and release of endothelium-derived relaxing factors.1 5 6 In the present study, arterial pressure was reduced and endothelin levels were increased in normal rabbits with chronic ETA receptor blockade. This reduction in systemic blood pressure was probably the result of both diminished ETA receptor–mediated vascular tone and the unopposed vasodilatory effects of ETB receptor activation. Consistent with diminished LV pump function and hemodynamic compromise, chronic RVP in rabbits was associated with a reduction in mean arterial pressure. Interestingly, RVP with concomitant ETA receptor blockade did not result in a further decline in mean arterial pressure, despite significantly elevated endothelin levels. Thus, the significantly increased plasma endothelin levels that occurred both with ETA receptor blockade and with RVP-induced CHF did not appear to be associated with ETB-mediated hypotension. In experimental models of CHF, endothelin receptor desensitization has been reported.42 In addition, Seo and colleagues53 demonstrated that ETB receptor activation can mediate blood vessel contraction. Although the contributory mechanisms responsible for systemic blood pressure control with chronic ETA receptor blockade remain unclear, the present study demonstrated that concomitant ETA receptor blockade in this model of pacing-induced CHF did not result in a significant compromise in systemic perfusion pressure.
In the present study and as is consistent with past reports,34 38 40 44 chronic RVP caused LV dilation with concomitantly increased myocyte length and reduced cross-sectional area. Whereas ETA receptor blockade with chronic RVP reduced the degree of LV dilation and myocyte lengthening, these effects were modest. Moreover, ETA receptor blockade with chronic RVP was associated with a persistent reduction in myocyte cross-sectional area. ET-1 has been reported to influence cellular growth and gene expression.9 16 18 29 For example, Ito and colleagues29 demonstrated that mRNA expression and synthesis of contractile proteins were increased in neonatal myocytes exposed to increasing concentrations of ET-1. Thus, in the present study, chronic ETA receptor blockade may have removed a trophic factor that influences myocyte growth. Nevertheless, results from the present study suggest that inhibition of ETA receptor activation in this model of CHF did not significantly prevent LV and myocyte remodeling. The fibroblast is the predominant cell type within the LV myocardium and has been identified as a participant in the LV remodeling process that occurs in a number of cardiac disease states.54 55 Past reports have demonstrated functionally active ETA and ETB receptors in fibroblasts.56 Thus, increased fibroblast ETB receptor activation may play an important role in the LV remodeling that occurs during the progression RVP-induced CHF. In light of the findings from the present study, further studies that more carefully examine the potential contributory role of ETA and ETB receptor activation with respect to the LV remodeling process and the progression of CHF are warranted.
Although concomitant ETA receptor blockade with chronic RVP improved LV pump function, persistent defects in LV ejection performance were observed. Thus, it is unlikely that chronic ETA receptor activation is the sole determinant responsible for the progression of LV dysfunction in this model of CHF. In the present study, weekly echocardiographic studies during the progression to RVP-induced CHF revealed that the degree of LV dilation and pump dysfunction changed in a very similar fashion during the first 2 weeks of RVP regardless of ETA receptor blockade. After 2 weeks of RVP, LV ejection performance stabilized and the degree of LV dilation was ameliorated with chronic ETA receptor blockade. With chronic RVP in dogs, it was reported that plasma endothelin levels were increased only after several weeks of pacing.37 These findings suggest that ETA receptor activation may not be an initial event in the development of RVP-induced CHF but rather may contribute to the progression of the CHF process. A recent study from this laboratory has demonstrated that concomitant ACE inhibition with chronic pacing tachycardia improved LV and myocyte function.40 Taken together, the results from these past reports and the present study suggest that activation of specific neurohormonal systems plays a direct and contributory role in the progression of LV dysfunction. It has been demonstrated that combined ACE inhibition and endothelin receptor blockade caused a synergistic reduction in blood pressure.30 In light of the findings from the present study and the fact that ACE inhibition is now a fundamental treatment modality in patients with CHF, a future study designed to examine the combined effects of ACE inhibition and ETA receptor blockade on LV and myocyte function using this model of CHF is necessary.
Neurohormonal System Activation and Chronic ETA
Receptor Blockade
Increased circulating levels of catecholamines, endothelin,
and elevated plasma renin activity commonly occur with the development
of severe CHF in patients.11 12 13 15 49 50 In the present
study and as is consistent with past reports,10 14 37 40
pacing-induced CHF was accompanied by a similar profile of
neurohormonal activation. RVP plus concomitant ETA receptor
blockade had no effect on plasma catecholamine values. Interestingly,
in rabbits with chronic ETA receptor blockade, a
significant increase in plasma renin activity was observed. The
increased plasma renin activity observed with chronic ETA
receptor blockade may have been secondary to a relative reduction in
renal perfusion. In addition, an interaction has been reported to occur
in vitro between endothelin receptor density and angiotensin II
production.57 The specific interactive effects of the
renin-angiotensin system and ETA receptor activity in both
the normal and CHF states were beyond the scope of the present study
and warrant further investigation. Chronic ETA receptor
blockade significantly increased circulating levels of immunoreactive
plasma endothelin in both normal and RVP rabbits. These findings
suggest that the ETA receptor is an integral component in
the control of synthesis and degradation of endothelin. The mature
21–amino-acid peptide ET-1 is synthesized from a 38–amino-acid
precursor, also known as "big endothelin."1 5 In
patients with CHF, increased plasma levels of big endothelin have been
reported.11 In the present study, a high-sensitivity
radioimmunoassay procedure was used to quantify plasma levels of
endothelin but was unable to distinguish between big endothelin and
mature ET-1.58 Through in vitro assay systems, it has been
demonstrated that big endothelin is rapidly cleaved to ET-1 by an
endothelin-converting enzyme.5 Teerlink and
colleagues30 reported that in a rat model of CHF, the
ratio of circulating levels of ET-1 to big endothelin increased. Thus,
the increased levels of immunoreactive endothelin observed in the
present study with RVP plus chronic ETA blockade most
likely reflect enhanced production of plasma ET-1. In light of the fact
that chronic ETA blockade in both normal and RVP rabbits
increased circulating levels of immunoreactive endothelin, future
studies that more carefully examine the mechanisms of endothelin
synthesis and degradation with chronic endothelin receptor blockade are
appropriate.
Myocyte Contractile Processes and Chronic ETA
Receptor Blockade
Whereas a number of studies have demonstrated that ET-1 has
acute effects on myocyte contractile
processes,10 16 17 21 22 25 26 the present study is the
first to directly examine the effects of chronic ETA
blockade on myocyte contractility in the normal state and in a model of
CHF. In normal rabbits that underwent chronic ETA receptor
blockade, there was no change in steady-state myocyte function compared
with sham controls. These results suggest that chronic administration
of the ETA receptor antagonist used in the present study
did not significantly influence myocyte contractile function.
RVP-induced CHF caused a significant reduction in LV myocyte
steady-state contractile performance. These changes in LV myocyte
contractile function with pacing-induced CHF are consistent with
previous reports from this laboratory.10 38 40 41 44 In
the present study, chronic RVP plus concomitant ETA
receptor blockade normalized several indexes of myocyte contractile
function. Thus, in the absence of external loading conditions and
extracellular influences, basal myocyte contractile function was
normalized with RVP plus concomitant ETA receptor blockade.
However, persistent abnormalities in LV function and geometry and
myocyte geometry were observed with RVP plus ETA blockade.
These results suggest that under ambient loading conditions in the
intact LV myocardium, persistent abnormalities exist in the
transduction of myocyte shortening to overall LV ejection with
RVP-induced CHF plus concomitant ETA receptor blockade.
Past reports have provided evidence that ETA receptor activation causes the release and/or mobilization of intracellular Ca2+ by two mechanisms. First, ETA receptor activation results in the production of inositol triphosphate with subsequent release of Ca2+ from the sarcoplasmic reticulum.16 17 18 Second, ETA receptor activation has been demonstrated to influence L-type calcium current.19 20 21 22 For example, Lauer et al20 demonstrated that ET-1 increased the L-type calcium current in rabbit ventricular myocytes. Past reports by this laboratory and others have demonstrated that pacing-induced CHF is associated with alterations in Ca2+ homeostasis, sarcoplasmic reticulum calcium ATPase activity, and L-type calcium current.45 46 47 48 Moreover, this laboratory has demonstrated previously that significant elevations in myocyte intracellular Ca2+ occurred after the development of pacing-induced CHF.45 Thus, although ETA receptor activation may increase intracellular Ca2+ availability and contractile performance acutely, prolonged ETA receptor activation during the progression of pacing induced CHF may exacerbate preexisting defects in Ca2+ homeostatic processes. Therefore, a potential contributory mechanism for the normalization of myocyte inotropic response to extracellular Ca2+ with chronic ETA receptor blockade in this model of CHF is improved intracellular Ca2+ homeostasis.
The development of pacing-induced CHF is accompanied by a reduction in ß-adrenergic receptor density, alterations in the expression and function of the stimulatory and inhibitory subunits of the guanine nucleotide binding regulatory protein (G-protein) complex, and diminished cAMP production.39 40 41 A proposed mechanism for the changes in ß-adrenergic receptor systems with chronic LV dysfunction is that the elevated circulating catecholamine levels result in long-term ß receptor activation with subsequent receptor downregulation.49 In the present study, ETA receptor blockade during chronic RVP significantly improved isolated myocyte ß-adrenergic responsiveness but was associated with persistent elevations in plasma catecholamines. Thus, in this rabbit model of RVP and ETA blockade, it is unlikely that the improved myocyte ß-adrenergic response with ETA blockade was due solely to increased myocyte ß-adrenergic receptor density. It was demonstrated previously that ET-1 can induce ADP-ribosylation of the inhibitory subunit of the G-protein complex.21 22 23 In addition to influencing the function of several classes of G-proteins,23 ETA receptor activation may influence adenylate cyclase activity and subsequent cAMP formation.19 24 In guinea pig ventricular myocyte preparations, it has been demonstrated that ETA receptor activation caused diminished cAMP production.19 24 Thus, in the present study, ETA receptor blockade may have attenuated the alterations in G-protein function and cAMP production that occur with pacing-induced CHF, which would in turn result in improved myocyte ß-adrenergic receptor response.
In the present study and as is consistent with past reports, ET-1 increased isolated myocyte contractile function.10 16 17 22 25 26 With RVP-induced CHF, a significant reduction in myocyte inotropic response to ET-1 occurred that was prevented by concomitant ETA receptor blockade. As outlined earlier, potential contributory mechanisms for improved myocyte inotropic response with ETA blockade and RVP include a normalization of Ca2+ homeostatic processes and intracellular transduction pathways. In addition to changes in intracellular Ca2+ levels, a number of other intracellular events may occur after sarcolemmal ETA receptor occupancy. For example, Kramer and colleagues25 demonstrated that after ET-1 stimulation of rat ventricular myocytes, intracellular alkalosis occurred that appeared to be mediated by a protein kinase C–dependent Na+/H+ exchanger. Prolonged ETA receptor activation may result in sustained changes in intracellular pH and subsequent defects in myofilament sensitivity to intracellular Ca2+. In addition, ET-1 has been demonstrated to alter actomyosin kinetics in rat myocardial preparations.26 In the present study, ETA receptor blockade with RVP may have prevented alterations in myofilament Ca2+ sensitivity and cross-bridge kinetics, which in turn resulted in improved myocyte ET-1 response. In a recent study,10 this laboratory demonstrated that the increased plasma endothelin levels that occur with the development of pacing-induced CHF were not associated with changes in myocyte sarcolemmal ETA receptor density or affinity. Nevertheless, the possibility remains that the improved myocyte contractile response to ET-1 observed with RVP and ETA receptor blockade may have been due to increased sarcolemmal ETA receptor expression.
Study Limitations
In light of the fact that chronic pacing tachycardia reliably
causes LV dysfunction and attendant neurohormonal activation, this is a
useful model in which to examine fundamental effects of pharmacological
interventions with CHF. In the present study, a rabbit model of
pacing-induced CHF was chosen because of the small animal size and
because previous ETA antagonist pharmacokinetic profiles
were generated in this species.32 33 However, unlike in
humans, it has been reported that alterations in myosin isoforms can
occur in rabbits.59 Furthermore, because of the intrinsic
differences in ambient heart rate, neuroendocrine systems, and size,
this rabbit model prevents detailed and integrative cardiovascular
physiological studies and therefore prevents direct extrapolation of
the findings in this small animal model to larger animals or
humans.60 In the present study, the ETA
antagonist was administered through time-release subcutaneous implants
and thereby provided constant plasma levels of compound. However,
clinical application of ETA receptor blockade in the
setting of CHF will require oral administration. To examine potential
drug effects of chronic ETA receptor blockade in normal
myocardium, LV and myocyte function were examined in a comparable drug
control group. Whereas chronic ETA receptor blockade did
not appear to have significant effects on LV and myocyte contractile
function in normal rabbits, plasma endothelin levels and renin activity
were increased. These issues with respect to chronic ETA
receptor blockade warrant further investigation. Finally, the present
study used a specific ETA receptor antagonist. Because
ETB receptors can mediate vasodilation and
vasoconstriction,4 53 particularly in the venous
system,61 ETB receptor activity may be of
significance during the progression of CHF. The chronic administration
of selective ETB and nonselective
ETA/ETB receptor antagonists in this model of
CHF will be necessary to clarify these issues.
Summary
Plasma endothelin levels are significantly increased in patients
with CHF and appear to be related to the degree of hemodynamic
compromise,11 13 15 but whether increased circulating
levels of endothelin play a contributory role in the progression of the
CHF process remains unclear. The endothelin ETA receptor
has been the most carefully characterized and has been demonstrated to
mediate systemic vasoconstriction and modulate myocyte contractile
processes.1 5 10 16 17 18 19 20 21 22 23 24 25 26 27 28 31 53 56 61 The present study
demonstrated that chronic ETA receptor blockade in a model
of pacing-induced CHF had direct and beneficial effects on LV pump
function, myocyte geometry, and contractile function. The unique
results from this study suggest that chronically elevated endothelin
levels and subsequent activation of the ETA receptor play
direct and contributory roles in the progression of the CHF process.
Thus, specific endothelin receptor blockade may provide a new and
useful therapeutic modality in the setting of CHF.
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Selected Abbreviations and Acronyms |
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Acknowledgments |
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This work was supported by NIH grant HL-45024 (Dr Spinale), a Basic Research Grant from Parke-Davis Laboratories (Dr Spinale), Thoracic Surgery Foundation for Research and Education (Dr Walker), MUSC Post-Doctoral Research Award (Dr Walker), and an American Heart Association Grant-in-Aid (Dr Spinale). Dr Walker participated in this study as a Nina S. Braunwald Research Fellow. Dr Spinale is an Established Investigator of the American Heart Association. We wish to express our deep appreciation to Charles Basler, Stephen Krombach, Mark Clair, and Jennifer Hendrick for their expert technical assistance throughout the execution of this project.
Received September 23, 1996; revision received December 10, 1996; accepted January 2, 1997.
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R. Schulz, S. Aker, S. Belosjorow, I. Konietzka, U. Rauen, and G. Heusch Stress kinase phosphorylation is increased in pacing-induced heart failure in rabbits Am J Physiol Heart Circ Physiol, November 1, 2003; 285(5): H2084 - H2090. [Abstract] [Full Text] [PDF]
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T. Noguchi, Z. Chen, S. P. Bell, L. Nyland, and M. M. LeWinter Endothelin receptor blockade has an oxygen-saving effect in Dahl salt-sensitive rats with heart failure Am J Physiol Heart Circ Physiol, October 1, 2003; 285(4): H1428 - H1434. [Abstract] [Full Text] [PDF]
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Y. Matsumoto, H. Aihara, R. Yamauchi-Kohno, Y. Reien, T. Ogura, H. Yabana, Y. Masuda, T. Sato, I. Komuro, and H. Nakaya Long-Term Endothelin A Receptor Blockade Inhibits Electrical Remodeling in Cardiomyopathic Hamsters Circulation, July 30, 2002; 106(5): 613 - 619. [Abstract] [Full Text] [PDF]
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F. G. Spinale The bioactive peptide endothelin causes multiple biologic responses relevant to myocardial and vascular performance after cardiac surgery J. Thorac. Cardiovasc. Surg., June 1, 2002; 123(6): 1031 - 1034. [Full Text] [PDF]
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F. Qin, N. K. Rounds, W. Mao, K. Kawai, and C.-s. Liang Antioxidant vitamins prevent cardiomyocyte apoptosis produced by norepinephrine infusion in ferrets Cardiovasc Res, September 1, 2001; 51(4): 736 - 748. [Abstract] [Full Text] [PDF]
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A. Luchner, F. Muders, O. Dietl, E. Friedrich, F. Blumberg, A.A. Protter, G.A.J. Riegger, and D. Elsner Differential expression of cardiac ANP and BNP in a rabbit model of progressive left ventricular dysfunction Cardiovasc Res, August 15, 2001; 51(3): 601 - 607. [Abstract] [Full Text] [PDF]
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B. R. Bond, B. H. Dorman, M. J. Clair, C. A. Walker, M. L. Pinosky, S. T. Reeves, S. Walton, J. M. Kratz, J. L. Zellner, A. J. Crumbley III, et al. Endothelin-1 during and after cardiopulmonary bypass: Association to graft sensitivity and postoperative recovery J. Thorac. Cardiovasc. Surg., August 1, 2001; 122(2): 358 - 364. [Abstract] [Full Text] [PDF]
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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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Y. Kakinuma, T. Miyauchi, K. Yuki, N. Murakoshi, K. Goto, and I. Yamaguchi Novel Molecular Mechanism of Increased Myocardial Endothelin-1 Expression in the Failing Heart Involving the Transcriptional Factor Hypoxia-Inducible Factor-1{{alpha}} Induced for Impaired Myocardial Energy Metabolism Circulation, May 15, 2001; 103(19): 2387 - 2394. [Abstract] [Full Text] [PDF]
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L. E. Spieker, G. Noll, F. T. Ruschitzka, and T. F. Luscher Endothelin receptor antagonists in congestive heart failure: a new therapeutic principle for the future? J. Am. Coll. Cardiol., May 1, 2001; 37(6): 1493 - 1505. [Abstract] [Full Text] [PDF]
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C.-P. Cheng, T. Ukai, K. Onishi, N. Ohte, M. Suzuki, Z.-S. Zhang, H.-J. Cheng, H. Tachibana, A. Igawa, and W. C. Little The role of ANG II and endothelin-1 in exercise-induced diastolic dysfunction in heart failure Am J Physiol Heart Circ Physiol, April 1, 2001; 280(4): H1853 - H1860. [Abstract] [Full Text] [PDF]
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Y.-T. Shen, P. S Buie, J. J Lynch, S. M Krause, and X.-L. Ma Chronic therapy with an ETA/B receptor antagonist in conscious dogs during progression of congestive heart failure: Intracellular Ca2+ regulation and nitric oxide mediated coronary relaxation Cardiovasc Res, November 1, 2000; 48(2): 332 - 345. [Abstract] [Full Text] [PDF]
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R. B. New, A. C. Sampson, M. K. King, J. W. Hendrick, M. J. Clair, J. H. McElmurray III, J. Mandel, R. Mukherjee, Marc de Gasparo, and F. G. Spinale Effects of Combined Angiotensin II and Endothelin Receptor Blockade With Developing Heart Failure : Effects on Left Ventricular Performance Circulation, September 19, 2000; 102(12): 1447 - 1453. [Abstract] [Full Text] [PDF]
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A. Luchner, M. Jougasaki, E. Friedrich, D. D. Borgeson, T. L. Stevens, M. M. Redfield, G. A. J. Riegger, and J. C. Burnett Jr. Activation of cardiorenal and pulmonary tissue endothelin-1 in experimental heart failure Am J Physiol Regulatory Integrative Comp Physiol, September 1, 2000; 279(3): R974 - R979. [Abstract] [Full Text] [PDF]
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E. Thorin, M. Lucas, P. Cernacek, and J. Dupuis Role of ETA receptors in the regulation of vascular reactivity in rats with congestive heart failure Am J Physiol Heart Circ Physiol, August 1, 2000; 279(2): H844 - H851. [Abstract] [Full Text] [PDF]
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P. Mulder, H. Boujedaini, V. Richard, G. Derumeaux, J. P. Henry, S. Renet, J. Wessale, T. Opgenorth, and C. Thuillez Selective Endothelin-A Versus Combined Endothelin-A/Endothelin-B Receptor Blockade in Rat Chronic Heart Failure Circulation, August 1, 2000; 102(5): 491 - 493. [Abstract] [Full Text] [PDF]
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A. Ergul, C. A. Walker, A. Goldberg, S. C. Baicu, J. W. Hendrick, M. K. King, and F. G. Spinale ET-1 in the myocardial interstitium: relation to myocyte ECE activity and expression Am J Physiol Heart Circ Physiol, June 1, 2000; 278(6): H2050 - H2056. [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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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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G. W Moe and P. Armstrong Pacing-induced heart failure: a model to study the mechanism of disease progression and novel therapy in heart failure Cardiovasc Res, June 1, 1999; 42(3): 591 - 599. [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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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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D. Saad, R. Mukherjee, P. B. Thomas, J. P. Iannini, C. G. Basler, L. Hebbar, S.-J. O, S. Moreland, M. L. Webb, J. R. Powell, et al. The effects of endothelin-A receptor blockade during the progression of pacing-induced congestive heart failure J. Am. Coll. Cardiol., November 15, 1998; 32(6): 1779 - 1786. [Abstract] [Full Text] [PDF]
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G. W Moe, A. Albernaz, G. O Naik, M. Kirchengast, and D. J Stewart Beneficial effects of long-term selective endothelin type A receptor blockade in canine experimental heart failure Cardiovasc Res, September 1, 1998; 39(3): 571 - 579. [Abstract] [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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M. Suzuki, N. Ohte, Z.-M. Wang, D. L. Williams Jr., W. C. Little, and C.-P. Cheng Altered inotropic response of endothelin-1 in cardiomyocytes from rats with isoproterenol-induced cardiomyopathy Cardiovasc Res, September 1, 1998; 39(3): 589 - 599. [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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Y. Zhang, J. R. Oliver, and J. D. Horowitz Endothelin B receptor-mediated vasoconstriction induced by endothelin A receptor antagonist Cardiovasc Res, September 1, 1998; 39(3): 665 - 673. [Abstract] [Full Text] [PDF]
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D. D. Borgeson, J. A. Grantham, E. E. Williamson, A. Luchner, M. M. Redfield, T. J. Opgenorth, and J. C. Burnett Jr Chronic Oral Endothelin Type A Receptor Antagonism in Experimental Heart Failure Hypertension, March 1, 1998; 31(3): 766 - 770. [Abstract] [Full Text] [PDF]
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Y. Yazaki and T. Yamazaki Reversing Congestive Heart Failure With Endothelin Receptor Antagonists Circulation, April 1, 1997; 95(7): 1752 - 1754. [Full Text]
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