(Circulation. 1996;93:1214-1222.)
© 1996 American Heart Association, Inc.
Articles |
Endogenous Endothelin-1 Participates in the Maintenance of Cardiac Function in Rats With Congestive Heart Failure
Marked Increase in Endothelin-1 Production in the Failing Heart
Presented in part at the 58th Annual Meeting of the Japanese Circulation Society, Tokyo, Japan, March 28, 1994, and published in abstract form in Jpn Circ J (1994;58:523) and presented in part at the 68th Scientific Sessions of the American Heart Association, Anaheim, Calif, November 14, 1995, and published in abstract form in Circulation (1995;92:I-182).
From the Department of Internal Medicine (S.S., T.M., I.Y., Y.S.), Institute of Clinical Medicine, and the Department of Pharmacology (T.S., Y.K., K.G.), Institute of Basic Medical Sciences, University of Tsukuba (Japan); and Tsukuba Research Institute (M.I.), Banyu Pharmaceutical Co, Tsukuba, Japan.
Correspondence to Takashi Miyauchi, MD, PhD, Department of Internal Medicine, Institute of Clinical Medicine, University of Tsukuba, Tsukuba, Ibaraki 305, Japan.
 |
Abstract |
|---|
 Top Abstract IntroductionMethods Results Discussion References |
|---|
Background Although it was demonstrated that circulating endothelin-1 (ET-1) levels are elevated in congestive heart failure (CHF), the production and roles of ET-1 in the failing heart are not known. We investigated the production of ET-1 in the heart and the density of myocardial ET receptors in rats with CHF. We also investigated the effects of intravenously infused BQ-123, an endothelinA (ETA) receptor antagonist, on both heart rate and myocardial contractility in rats with CHF.
Methods and Results We used the left coronary artery–ligated rat model of CHF (CHF rats). Three weeks after surgery, the rats developed CHF. Plasma ET-1 concentration was significantly higher in the CHF rats than in the sham-operated rats (P<.01). In the left ventricle, the expression of prepro–ET-1 mRNA was markedly higher in the CHF rats than in the sham-operated rats. The peptide level of ET-1 in the left ventricle was also significantly higher in the CHF rats than in the sham-operated rats (500±41 versus 102±10 pg/g tissue, P<.01). Myocardial ET receptors were significantly higher in the CHF rats than in the sham-operated rats (243±20 versus 155±17 fmol/mg protein, P<.05). In the CHF rats, intravenous BQ-123 infusion (0.1 mg·kg-1·min-1 for 120 minutes) significantly decreased both heart rate (P<.01) and LV+dP/dtmax (P<.05) but not mean blood pressure. BQ-123 infusion did not affect these hemodynamic parameters in the sham-operated rats.
Conclusions In the present study, we demonstrated that the production of ET-1 in the heart is markedly increased and that the density of myocardial ET receptors is significantly elevated in the CHF rats. Intravenous BQ-123 infusion significantly reduced both heart rate and LV+dP/dtmax in the CHF rats but not in the sham-operated rats. Therefore, the ET receptor–mediated signal transduction system in the heart appears to be markedly stimulated in the CHF rats, and endogenous ET-1 may be involved in the maintenance of the cardiac function in these rats.
Key Words: endothelin • heart failure • heart rate • genes • contractility
|
Introduction |
|---|
|
TopAbstractIntroductionMethods Results Discussion References |
|---|
Cardiac myocytes1 as well as vascular endothelial cells2 produce ET-1. In addition to its potent vasocontractile effects,2 ET-1 has potent positive inotropic and chronotropic effects on isolated heart muscles in vitro3 4 and induces myocardial cell hypertrophy.5 Although it has been reported that plasma ET-1 concentrations are elevated in CHF in both humans6 7 8 and experimental animal models,9 10 the production of ET-1 in the failing heart is not known. Furthermore, it is not known whether myocardial ET-1 participates in the modulation of cardiac function in CHF.
It has been reported that the production of ET-1 in vascular endothelial cells is increased by some humoral factors (eg, angiotensin II,11 vasopressin,11 and norepinephrine2 ) and mechanical factors (eg, shear stress12 and endothelial stretching13 ). In cultured ventricular myocytes, it has also been shown that the expression of prepro–ET-1 mRNA is increased by angiotensin II.14 Therefore, it is thought that the production of ET-1 in the heart may be also regulated by several stimuli in vitro. Using an in vivo model of rats with cardiac hypertrophy, we previously reported that the production of ET-1 was markedly increased in the hypertrophied heart because of hemodynamic pressure overload due to either aortic banding15 or pulmonary hypertension.16 These results suggested that the production of ET-1 in the heart is altered in some pathological conditions in vivo. However, because these rats did not have CHF, it could not be determined whether the production of ET-1 is altered in the failing heart.
In the present study, we investigated the production of ET-1 in the heart and the density of myocardial ET receptors in rats with CHF. Furthermore, to study the pathophysiological roles of myocardial ET-1 in CHF, we investigated the effects of intravenously infused BQ-123, an ETA receptor antagonist,17 on both heart rate and myocardial contractility in rats with CHF and in sham-operated rats. In the present study, we used rats with coronary artery ligation as a model of experimental CHF because this is a well-established model representing pathophysiological alterations similar to those seen in the most common contemporary cause of heart failure in humans, ischemic heart disease.18 19
|
Methods |
|---|
|
TopAbstractIntroductionMethods Results Discussion References |
|---|
Experimental Heart Failure
We used the left coronary artery–ligated rat model of CHF, which is well established.18 Left ventricular free wall myocardial infarction was induced in male Sprague-Dawley rats weighing 170 to 200 g by the method of Pfeffer et al.18 In brief, each rat was anesthetized with ether. A thoracotomy was performed, the heart was rapidly exteriorized, and the proximal portion of the left coronary artery was ligated with a 5-0 silk suture. The heart was then returned to its normal position, and the thorax was closed. Except for coronary arterial ligation, sham-operated rats were produced by an identical procedure. Mortality in the animals with myocardial infarction was
67% within
the first 24 hours. The surviving rats (CHF rats) were maintained on
standard rat chow and water ad libitum for 3 weeks.
Study Protocols
In the present study, two series of
experiments were
performed. The purpose of the first series of experiments was to
investigate the production of ET-1 in the heart and the density
of myocardial ET receptors in the CHF rats. The purpose of the second
series of experiments was to investigate the effects of an ET receptor
antagonist on the hemodynamics of the CHF
rats in vivo.
First Series of Experiments
Hemodynamic Measurement and
Tissue
Sampling
On the day of the experiment, the rats were anesthetized
with sodium pentobarbital (50 mg/kg IP). A microtip pressure transducer
catheter (model SPC-320, Millar Instruments) was inserted into the
right carotid artery. After arterial blood pressure was
monitored, the catheter was advanced into the left ventricle for
evaluation of left ventricular pressure. These
hemodynamic measurements were recorded with the use
of a polygraph system (AP-601G amplifier and WT-687G thermal pen
recorder). In addition, LV+dP/dtmax and
LV[+dP/dt/Pi]max were derived by active analogue
differentiation of the pressure signal differentiation amplifier (model
EQ-601G, Nihon Koden). Subsequently, a polyethylene catheter was
inserted into the right jugular vein to measure CVP and right
ventricular pressure. Sham-operated rats were randomly
selected as control animals. Only rats that underwent ligation with
LVEDP 
15 mm Hg were considered to have CHF. After
hemodynamic measurement, a blood sample was collected
from the right carotid artery. The heart was subsequently excised and
divided into the right ventricle and left ventricle, including septum,
in cold Krebs-Ringer solution. Each ventricle was weighed before and
after removal of the scarred area and was frozen in liquid nitrogen.
Some of the left ventricles were immersion-fixed in 10% buffered
formalin. The plasma and tissue samples were stored at -80°C
for mature ET-1 peptide assay by an EIA, for determination of
prepro–ET-1 mRNA expression by Northern blot analysis, and for
binding assay of ET receptors. The lungs and kidneys were also weighed
and frozen in liquid nitrogen.
To measure the infarct size, the following experiments were performed. After being weighed, the left ventricle was immersion-fixed in 10% buffered formalin. At a later time, the ventricle was cut into four transverse sections from apex to base. These sections were processed in standard fashion and embedded in paraffin. A Masson-trichrome–stained thin section from each level was projected, and the perimeters of the infarcted and noninfarcted epicardial and endocardial surfaces were traced and digitized. The infarcted portion (proportion of the infarcted left ventricle) was calculated from these measurements.18
EIA for
Determination of Plasma and Heart ET-1 Levels
Each blood sample was
placed into a chilled tube containing
aprotinin (300 kallikrein inhibiting units/mL) and EDTA (2 mg/mL) and
centrifuged at 3000g for 15 minutes at 4°C. The
plasma was stored at -80°C until use. Plasma ET-1 concentration
was measured by an EIA as previously
described.16 20 21 In
brief, plasma (1 mL) was acidified with 3 mL of 4% acetic acid, and
immunoreactive ET-1 was extracted with a Sep-Pak C-18 cartridge (Waters
Associates). The elutes were reconstituted with 0.25 mL of assay buffer
and subjected to EIA for ET-1. EIA for ET-1 was carried out as
previously described with immobilized mouse monoclonal
antibody AwETN40, which recognizes the amino-terminal portion of
ET-1, and peroxidase-labeled rabbit anti–ET-1
carboxyl-terminal peptide(15-21)
Fab'.15 20 21 The
assay for ET-1 did not cross-react with ET-3 or big ET-1
(cross-reactivity, <0.1%). The detection limit of this EIA was
0.4 pg/mL.20 21
The left ventricular ET-1 level was determined as previously described.15 Briefly, the left ventricle without scar tissue, which was frozen in liquid nitrogen and stored at -80°C, was homogenized with a Polytron homogenizer for 60 seconds in 10 vol of 1 mol/L acetic acid containing 10 µg/mL pepstatin (Peptide Institute) and immediately boiled for 10 minutes. After being chilled, the homogenate was centrifuged at 20 000g for 30 minutes at 4°C and the supernatant was stored at -80°C until use. The supernatant was subjected to an EIA for ET-1.
The samples of the plasma and heart were stored at -80°C, and the measurements of ET-1 levels were performed within 1 month. Under these conditions, we have confirmed that ET-1 levels of fresh samples of the plasma (1.1±0.1 pg/mL, n=6) and heart (107±7 pg/g tissue, n=4) are not different than those of stored frozen samples (plasma, 1.0±0.1 pg/mL, n=6; heart, 112±9 pg/g tissue, n=4). We reported that general anesthesia (isoflurane, nitrous oxide/oxygen, pentobarbital) does not affect plasma ET-1 levels in humans.22 In the present study, the plasma of the rats was collected with the animals under pentobarbital anesthesia. We have also confirmed that pentobarbital anesthesia does not affect plasma ET-1 levels in rats.16
Northern Blot Analysis for
Prepro–ET-1 mRNA in Heart
and Kidney
Total RNA was prepared from tissues by selective
precipitation
in 3 mol/L LiCl and 6 mol/L urea.16 23 Total RNA (15
µg
per lane) from the left and right ventricles, excluding scar tissue or
kidney, was separated with the use of formamide/1.1% agarose gel
electrophoresis and transferred onto nylon membranes (Hybond N,
Amersham). The membranes were prehybridized at 42°C for 3 hours in a
solution containing 5x standard saline citrate, 50% formamide, 1%
sodium dodecyl sulfate, and 150 µg/mL fragmented salmon sperm
DNA and were then hybridized with a 32P-labeled cDNA probe
in the same solution at 42°C for 24 hours. After hybridization, the
filter was finally washed in 0.1x standard saline citrate/0.1% sodium
dodecyl sulfate at 50°C and autoradiographed with
intensifying screens at -80°C for 5 days. The prepro–ET-1 cDNA
used as a probe in the present study was a previously described
full-length insert of 
rET1-223 that was labeled by
random priming with [
-32P]dCTP (3000 Ci/mmol,
Amersham). To normalize the prepro–ET-1 signals for the loaded amounts
and transfer efficiencies, the same membranes were rehybridized with a
GAPDH cDNA or ethidium bromide staining of 18S ribosomal RNA
as the internal control.
Cardiac Membrane Preparation and
Binding Experiments for ET
Receptors
The left ventricles of both sham-operated rats and CHF rats,
which were stored at -80°C until use, were placed in
3-(N-morpholino)propanesulfonic acid buffer containing 20%
(wt/vol) sucrose at 4°C, cut into small pieces, and
homogenized for 60 seconds with a Polytron
homogenizer. The homogenates were
centrifuged at 1000g for 15 minutes at 4°C. The
supernatants were centrifuged at 10 000g for 15
minutes at 4°C. Finally, the resulting supernatants were
centrifuged at 105 000g for 40 minutes at 4°C.
Then, the pellets were suspended in 5 mmol/L HEPES-Tris buffer (pH 7.4)
and stored at -80°C until use. Protein concentration was
determined with the use of bicinchoninic protein
assay.24
Experiments regarding the binding of
[125I]ET-1 to the
membranes of the left ventricle of CHF rats and sham-operated rats
were performed according to a previously described
method.25 The membranes were incubated with 10 pmol/L
[125I]ET-1 and unlabeled ET-1 at concentrations ranging
from 900 fmol/L to 200 µmol/L in triplicate at 25°C in 50 mmol/L
Tris-HCl, pH 7.4, containing 0.1 mmol/L phenylmethylsulfonyl
fluoride, 2 µmol/L leupeptin, 1 mmol/L 1,10,-phenanthroline,
1 mmol/L EDTA, and 0.1% BSA. After 4 hours of incubation, buffer A
(cold 5 mmol/L HEPES-Tris, pH 7.4, containing 0.3% BSA) was added to
the mixture. Free and bound [125I]ET-1 were separated
with the use of a cell harvester (model M-24, Brandel) by rapid
filtration through glass fiber filters (GF/C, Whatman) that had been
presoaked in buffer A. After the filters were washed with buffer A,
radioactivity was measured with a 
counter (ARC-1000M, Aloka).
Specific [125I]ET-1 binding was defined as the difference
between total binding and nonspecific binding in the presence of 200
nmol/L ET-1. The Bmax and
Kd values were determined by regression
analysis of displacement curves with the use of the LIGAND
program.26 Furthermore, to study the ratio of
ETA and ETB receptor subtypes in the normal rat
heart, we conducted competitive displacement experiments of
[125I]ET-1 binding to rat cardiac membranes with BQ-123
(an ETA receptor antagonist) in the
sham-operated rats.
Determination of Plasma Renin Activity
Plasma renin activity was assessed by a standard
technique27 with a commercial radioimmunoassay kit
(Travenol Corp) to quantify the amount of angiotensin I
generated from angiotensinogen.
Second Series of Experiments
Effects of Intravenously
Infused BQ-123, an
ETA Receptor Antagonist, on
Hemodynamics in Rats
Rats were anesthetized with urethane (750 mg/kg
IP, Wako
Pure Chemical) and -chloralose (80 mg/kg IP, Wako). BQ-123,
which was a gift from Dr Masaru Nishikibe (Tsukuba Research Institute,
Banyu Pharmaceutical Co, Tsukuba, Japan), was dissolved in saline (2
mg/mL) and infused into the rats by syringe pump (CFV-2100, Nihon
Koden) through the right femoral vein for 120 minutes. The rats were
divided into the following three groups: (1) sham-operated rats
infused with BQ-123 (0.1
mg·kg-1·min-1)
(n=7), (2) CHF rats infused with saline (0.05
mL·kg-1·min-1)
(n=7), and (3) CHF rats infused with BQ-123 (0.1
mg·kg-1·min-1)
(n=8).
The total volume of infused saline alone or saline containing BQ-123 was 6 mL/kg for 120 minutes. Heart rate and arterial blood pressure were measured continuously before and during BQ-123 infusion. LVSP, LV+dP/dtmax, LV[+dP/dt/Pi]max, and LVEDP were measured at two time points: before and at the end of the 120-minute infusion of BQ-123.
In the sham-operated rats infused with saline (3 mL·kg-1·h-1), a bolus injection of ET-1 (1 nmol/kg) produced a marked increase in blood pressure (56.1±4.7 mm Hg [n=7]). However, in the sham-operated rats infused with BQ-123 (0.1 mg·kg-1·min-1), a potent pressor effect of ET-1 (1 nmol/kg) was greatly attenuated (increase in blood pressure by ET-1, 3.8±1.4 mm Hg [n=6]). Therefore, the present data indicated that the dosage of BQ-123 (0.1 mg·kg-1·min-1) used in the present study was sufficiently high to almost completely block the potent pressor effect of exogenously applied ET-1.
Statistical Analysis
Data are expressed as mean±SEM.
All statistical comparisons
were performed with a commercially available statistical package for
the Macintosh personal computer (STAT VIEW, version 4.0,
Abacus Concepts). Differences in data between the CHF rats and the
sham-operated rats were assessed by unpaired t test.
ANOVA for repeated measures followed by Bonferroni's
multiple-comparison tests was used for statistical comparison of
changes in heart rate and arterial blood pressure during
BQ-123 infusion. Paired two-tailed t test comparisons
were used to analyze the changes in LVSP, LVEDP,
LV+dP/dtmax, and
LV[+dP/dt/Pi]max induced by BQ-123 infusion.
Differences
were considered significant at the level of P<.05.
|
Results |
|---|
|
TopAbstractIntroductionMethods Results Discussion References |
|---|
First Series of Experiments
Hemodynamic Parameters and Tissue Weights
MAP and LVSP were significantly lower in the CHF rats than in the sham-operated rats (Table 1
).
LV+dP/dtmax was also significantly lower in the CHF
rats than in the sham-operated rats (Table 1). LVEDP was
markedly
elevated in the CHF rats (Table 1). RVSP and CVP were
significantly
higher in the CHF rats than in the sham-operated rats (Table
1).
These data indicated that the CHF rats had developed CHF.
|
The CHF rats
weighed less than the sham-operated rats (Table 2). The lung
weight/mass index for body weight was
markedly higher in the CHF rats than in the sham-operated rats,
suggesting the presence of pulmonary congestion in the CHF rats
(Table 2). The right ventricular mass index for body weight
was significantly higher in the CHF rats in accordance with the
elevation of RVSP. The left ventricular wet weight was
significantly lower in the CHF rats than in the sham-operated rats
(Table 2), although the left ventricular mass index for
body weight did not differ between the two groups (Table 2).
These
results indicated that there was substantial left
ventricular thinning in the CHF rats. The infarcted area of
the left ventricular free wall was replaced by a thin
fibrous tissue. The mean myocardial infarct size was 48±4%.
|
ET-1 Levels in Plasma and Tissues (Peptide, mRNA) and
Levels of
ET Receptors
The plasma ET-1 concentration of the CHF rats was
3.3-fold
higher than that of the sham-operated rats (Fig 1).
Plasma ET-1 level was significantly correlated with LVEDP
(r=.71, P<.01) and
LV+dP/dtmax (r=-.69,
P<.01) in the CHF rats. However, in the sham-operated
rats, plasma ET-1 level was significantly correlated with neither LVEDP
(r=.49, P=NS) nor LV+dP/dtmax
(r=-.33, P=NS). Plasma ET-1 level was
significantly correlated with the level of the percent infarct size
(r=.65, P<.05).
|
The expression of
prepro–ET-1 mRNA in the left ventricle of both CHF
rats and sham-operated rats was determined with Northern blot
analysis. Typical examples of the left ventricle 3 weeks after
surgery are shown in Fig 2A. Fig 2B depicts
densitometric analysis of these blots corrected for the levels
of GAPDH mRNA, which was used as normalization for a constitutively
expressed message in the left ventricle. The expression of prepro–ET-1
mRNA in the left ventricle was markedly higher in the CHF rats than in
the sham-operated rats (Fig 2A and 2B). The
expression of
prepro–ET-1 mRNA in the hypertrophied right ventricle in the CHF rats
was markedly enhanced (Fig 2A). The densitometric analysis of
these blots also showed that the ratio of the levels of prepro–ET-1
mRNA to GAPDH mRNA in the right ventricle was significantly higher in
the CHF rats than in the sham-operated rats (1.5±0.3 versus
0.2±0.1, both n=5, P<.05). However, in the kidney,
the
expression of prepro–ET-1 mRNA did not differ between the CHF rats and
the sham-operated rats (data not shown).
|
The peptide level of ET-1 in
the left ventricle was approximately
fivefold higher in the CHF rats than in the sham-operated rats (Fig
3).
|
In the left ventricle,
[125I]ET-1 binding density
(Bmax) was 57% higher in the CHF rats
than in the sham-operated rats (Fig 4). However, the
dissociation constant (Kd) in the CHF rats did
not differ from that in the sham-operated rats (28.7±7.0 versus
29.8±1.9 pmol/L, both n=4). The displacement experiments with
BQ-123
showed that the cardiac membranes of the sham-operated rats
contained ETA and ETB receptors in a ratio of
91:9 (n=4).
|
Plasma Renin Activity
The plasma
renin activity was significantly higher in the CHF rats
than in the sham-operated rats (33.8±1.2 versus 25.6±2.1
ng·mL-1·h-1,
both n=7, P<.01). There was no significant correlation
between the plasma renin activity and plasma ET-1 level in the CHF rats
(r=.52, P=NS).
Second Series of Experiments
Effects of Intravenous
BQ-123 Infusion on
Hemodynamics
Intravenous infusion by syringe pump of BQ-123, an
ETA receptor antagonist, significantly reduced
heart rate in the CHF rats by 20% (Fig 5, right) but
not MAP (Fig 6, right) or LVSP (Table 3).
Intravenous BQ-123 infusion also decreased
LV+dP/dtmax, a parameter of
cardiac contractility, by 26% in the CHF rats (Fig 7,
right). Intravenous BQ-123 infusion
increased LVEDP in the CHF rats (Table 3). In the sham-operated
rats, BQ-123 infusion did not alter these hemodynamic
parameters (Figs 5 through 7,
left; and Table 3). In the
CHF rats, saline infusion did not affect the studied
hemodynamic parameters (ie, heart rate,
MAP, LV+dP/dtmax,
LV[+dP/dt/Pi]max, LVSP, and LVEDP; Figs
5 and 6,
right; Fig 7, middle; and Table 3).
|
, n=8) was significantly
decreased during BQ-123 infusion, whereas that of CHF rats did not
change during saline infusion (
, n=7). Heart rate of
sham-operated rats did not change during BQ-123 infusion (
,
n=7).
|
, n=7) did
not change from baseline value (time=0 minutes) during infusion of
saline.
|
|
Because LV+dP/dtmax is reported to be heart rate dependent and because BQ-123 infusion significantly reduced heart rate in the CHF rats, we added the following experiments. The rat hearts were paced at their prior rates of BQ-123 application, and this pacing was continued for 2 hours during BQ-123 infusion. Ventricular pacing of the rat in vivo was performed according to the method of Bittl et al.28 In brief, the CHF rats were artificially ventilated, and the chest was opened. Bipolar pacing electrodes were attached to the posterior wall of the left ventricle and ventricular pacing was performed with square-wave pulses of 5-millisecond duration. The pacing was continued during BQ-123 infusion (2 hours) at prior rates of BQ-123 application (323±8 beats per minutes, n=7). Under this condition, intravenous BQ-123 infusion for 2 hours also significantly decreased LV+dP/dtmax (by 16%; from 5601±357 to 4676±193 mm Hg/s, n=7, P<.05) in the CHF rats.
Because our preliminary study revealed that a decrease in heart rate by
continuous BQ-123 infusion reached a plateau level at 2 hours in the
CHF rats, we infused BQ-123 for 120 minutes in the present
study.
|
Discussion |
|---|
|
TopAbstractIntroductionMethods Results Discussion References |
|---|
Cardiac myocytes1 as well as vascular endothelial cells2 produce ET-1. The present study revealed for the first time that the production of ET-1 in the heart is markedly increased in CHF rats as demonstrated by both mRNA and peptide levels and that the density of myocardial ET receptors is also significantly increased in CHF rats, suggesting that the ET receptor–mediated signal transduction system in the heart may be markedly stimulated in these rats. We also demonstrated that intravenous infusion of BQ-123, an ETA receptor antagonist,17 significantly decreased both heart rate and LV+dP/dtmax without altering MAP in CHF rats, whereas intravenous BQ-123 infusion did not affect these hemodynamic parameters in sham-operated rats. Furthermore, the present study showed that under constant heart rate condition by ventricular pacing, intravenous BQ-123 infusion also significantly decreased LV+dP/dtmax in CHF rats. These data suggest that endogenous ET-1 is involved in the maintenance of both heart rate and myocardial contractility in CHF rats.
There are three isopeptides of ET (ET-1, ET-2, and
ET-329 30 ) and two subtypes of ET receptors
(ETA receptor31 ) and ETB
receptor32 ). The affinity rank order of ETs for the
ETA receptor is ET-1ET-2 >> ET-3, and that for
the ETB receptor is ET-1=ET-2=ET-3.33
Both
subtypes of ET receptor have been shown to exist on
myocytes.34 In the rat heart, binding experiments showed
that the cardiac membranes of normal rats contained ETA and
ETB receptors in a ratio of 91:9. Therefore, it appears
that ETA receptors are dominant in the rat heart. It has
also been reported that ETA receptors are dominant in the
human heart.35 Our previous study indicated that ET-1 has
potent positive inotropic and chronotropic effects on isolated heart
muscle.3 4 Kasai et al36 showed that the
positive inotropic effect of ET-1 on isolated rabbit heart was
partially antagonized by BQ-123, indicating the presence of positive
inotropic responses elicited by the stimulation of ETA
receptors. Therefore, the inhibitory effect of
intravenous BQ-123 infusion on cardiac
contractility in CHF rats in the present study may
have been due to the blocking of myocardial ETA receptors.
The amount of intravenously infused BQ-123 (0.1
mg·kg-1·min-1)
used in the present study was sufficiently high to almost
completely block the potent pressor effect of exogenously applied ET-1
(1 nmol/kg). Because intravenous BQ-123 infusion did not
affect the cardiac function of the sham-operated rats, it is
conceivable that the potency of the stimulation of myocardial
ETA receptors by endogenous ET-1 may not be
sufficient to elicit inotropic effects in normal rats.
To our knowledge, there are no reports indicating which subtype of ET receptor is involved in the positive chronotropic effect of ET-1 in the normal heart in vitro. Because ET-1 has a potent positive chronotropic action, the reduction in heart rate induced by intravenous BQ-123 infusion in CHF rats may be due to the blocking effect of BQ-123 on ETA receptors in the pacemaker cells of CHF rats. Therefore, it appears that the ETA receptor–mediated signal transduction system was at least partially involved in mediating the positive chronotropic effects of ET-1 in CHF rats.
We recently demonstrated that prepro–ET-1 mRNA was increased in the heart under some pathological conditions in vivo: pressure overload to the left ventricle due to aortic banding15 or pressure overload to the right ventricle due to pulmonary hypertension.16 However, the studied rats did not have CHF, and the production of ET-1 in the failing heart was not known. The present study revealed for the first time that the production of ET-1 in the heart is markedly increased in CHF rats. The question arises of how the production of ET-1 is increased in the heart of CHF rats. The expression of c-jun proto-oncogene has been shown to be induced in the failing heart of rats with myocardial infarction.37 It has been demonstrated that the 5' flanking region of the prepro–ET-1 gene has three octanucleotide sequences that conform with a consensus of AP-1/Jun-binding elements and that phorbol ester, an activator of protein kinase C, which is a necessary upstream prerequisite for the regulation of the AP-1/Jun-binding elements, actually activates prepro–ET-1 mRNA expression in cultured endothelial cells.38 39 Therefore, it is likely that failing of the heart may induce prepro–ET-1 mRNA expression via the expression of trans-acting transcription factors such as activator protein-1 in CHF rats. Because the expression of prepro–ET-1 mRNA in the kidney did not differ between the two groups, tissue-specific enhancement of the expression of prepro-ET-1 mRNA may occur in the heart of CHF rats. The present study revealed that the heart was one of the origins of elevated plasma ET-1 in CHF rats. In the present study, plasma ET-1 level was positively correlated with LVEDP and negatively correlated with LV+dP/dtmax. Furthermore, the present study showed that plasma ET-1 level was significantly correlated with the level of the percent infarct size. In patients with chronic heart failure, plasma ET-1 concentration is well correlated with the clinical class of heart failure, New York Heart Association functional class.6 Taken together, it is considered that plasma ET-1 concentration may reflect the severity of cardiac damage in CHF.
It has been reported that the production of ET-1 in vascular endothelial cells is increased by some humoral factors such as angiotensin II,11 arginine vasopressin,11 and norepinephrine.2 Plasma concentrations of angiotensin II, arginine vasopressin, and norepinephrine have been demonstrated to be increased in CHF.40 41 Therefore, some researchers6 42 have speculated that the increased plasma level of ET-1 in CHF may be due to increased production of ET-1 in systemic endothelial cells that were stimulated by increased circulating angiotensin II, arginine vasopressin, and norepinephrine.42 However, in the present study, the expression of prepro–ET-1 mRNA in the kidney, an endothelial cell–rich tissue, was almost the same in CHF rats as in sham-operated rats. Therefore, it was thought that circulating humoral factors did not cause the observed increase in the production of ET-1 in the endothelial cells of the vessels in the systemic circulation of the CHF rats. However, further study is needed to determine whether the production of ET-1 in the endothelial cells of the systemic vessels is higher in the more severe stages of CHF than in the present stage. On the other hand, it has been reported that angiotensin II induces prepro–ET-1 mRNA in cultured myocardium14 and that the activity of the intracardiac renin-angiotensin system is increased in CHF.43 44 Therefore, it seems possible that the activation of the intracardiac renin-angiotensin system contributed to the enhanced production of ET-1 in the hearts of the CHF rats in an autocrine/paracrine fashion. This consideration is in accord with the present results that the renin-angiotensin system was stimulated in the CHF rats. Alternatively, because it has been demonstrated that mechanical factors such as shear stress12 and endothelial stretching13 increase the production of ET-1, hemodynamic overload to the cardiac myocytes appears to be capable of directly increasing the production of ET-1 in the heart of CHF. Our previous report indicated that pressure overload to the left ventricle caused an increase in the production of ET-1 in the left, but not in the right, ventricle of rats.15
It has been reported that ET-1 binding sites on cultured cardiocytes are downregulated by pretreatment with ET-1.45 Furthermore, we have demonstrated that the level of ETB receptor mRNA is downregulated by ET-1 via a decrease in the intracellular stability of mRNA molecules in rat osteosarcoma cells.46 Therefore, it can be anticipated that agonist-induced receptor downregulation exists in the ET system. Although ET-1 levels in plasma and in the heart were markedly increased in CHF rats, unexpectedly, ET-1 binding sites were also significantly increased in the hearts of CHF rats. The precise mechanism of the increase of ET receptors in the hearts of CHF rats is unclear at present; however, the results of this study strongly suggest that the ET receptor–mediated signal transduction system in the heart is markedly stimulated in CHF rats.
It has been reported that the acute administration of bosentan, an ETA/B combined receptor antagonist,47 lowers blood pressure in rats with CHF due to myocardial infarction.48 However, in the present study, BQ-123 at a dosage (0.1 mg·kg-1·min-1) that was sufficiently high to block the potent pressor effect of exogenously applied ET-1 (1 nmol/kg) almost completely unaltered MAP in CHF rats. Furthermore, Love et al49 reported that intra-arterial BQ-123 infusion did not affect mean blood pressure in patients with heart failure. One possible explanation for the discrepancy in effects between bosentan and BQ-123 is that the blockade of both ETA and ETB receptors by bosentan may contribute to its blood pressure–lowering effect in CHF rats, because both ETA- and ETB-mediated mechanisms for vascular contraction exist in various blood vessels.42 50 This argument is in good agreement with the fact that the blood pressure of spontaneously hypertensive rats is lowered by the acute administration of Ro 47-0203 (bosentan)51 and by SB 209670 (an ETA/B combined receptor antagonist52 ) but not by BQ-123.53 ) The acute administration of bosentan did not reduce heart rate in rats with CHF.48 Because bosentan lowered blood pressure in rats with CHF,48 we considered the activation of the sympathetic nervous system by the reflex to hypotension to have occurred in these rats and that this activation may compensate for the decrease in heart rate due to the blockade of cardiac ET receptors, thereby maintaining the heart rate in these rats. This may be a reason for the discrepancy in the effects of BQ-123 (the present study) and bosentan48 on the heart rate of rats with CHF.
In conclusion, the results of the present study indicate that the production of ET-1 in the heart is markedly increased and that the density of myocardial ET receptors is significantly elevated in CHF rats. These findings suggest that the ET receptor–mediated signal transduction system in the heart is markedly stimulated in CHF rats. Because intravenous BQ-123 infusion significantly reduced both heart rate and myocardial contractility in CHF rats but not in sham-operated rats, endogenous ET-1 may be involved in the maintenance of cardiac function in CHF rats.
Study Limitations
In general, heart rate increased in
patients with CHF. However, in
the present study, the heart rate of the CHF rats under
anesthesia did not differ from that of the
sham-operated rats in both the first and the second series. We
consider the reason for this discrepancy to be the following. We used
pentobarbital in both groups at the same dose (50 mg/kg IP) in the
first series. In the second series, we used urethane in both groups at
the same dose (750 mg/kg IP). Both anesthetic agents have a
cardiodepressant effect. In the CHF rats, the metabolic
rate of anesthetic agents might be decreased. Therefore, it was thought
that a cardiodepressant action was augmented in the CHF rats, thereby
resulting in no difference in heart rate between in these rats. Other
researchers have also reported that there was no difference in heart
rate between rats with CHF and control rats under pentobarbital
anesthesia.54 Because we have previously
confirmed that plasma ET-1 levels were not affected by pentobarbital
anesthesia in rats,16 we used this drug for
anesthesia in the first series (measurement of ET levels).
Because pentobarbital is short acting and the second series of
experiments (effects of BQ-123 infusion [120 minutes] on the
hemodynamics) required a long-lasting
anesthesia, we switched anesthetic agent from pentobarbital
to urethane. We considered urethane to be a more suitable anesthetic
agent for the second series. However, it is not known whether urethane
anesthesia affects plasma ET-1 levels.
The plasma renin activity in the sham-operated rats (25.6±2.1 ng·mL-1·h-1) appears to be higher than the level in the other report.55 Because anesthesia with pentobarbital causes an increase in the plasma renin activity and we used this agent for anesthesia in the first series of experiments, this may be a major reason for a relatively high level in the plasma renin activity in the sham-operated rats.
LV+dP/dtmax is reported to be heart rate dependent. In the present study, BQ-123 infusion significantly reduced heart rate in CHF rats. The present study showed that the degree of the percent decrease in LV+dP/dtmax due to BQ-123 infusion in CHF rats with ventricular pacing is less than that in CHF rats without ventricular pacing (16% versus 26%). Therefore, it is possible that a decrease in LV+dP/dtmax due to BQ-123 infusion in CHF rats without ventricular pacing may be in part attributed to the decrease in heart rate due to BQ-123, in addition to the direct blocking effect of BQ-123 for the positive inotropic action induced by endogenous ET-1.
In the present study, the rats that had myocardial infarction 3 weeks earlier were used as CHF model animals. The right ventricle of the CHF rats was markedly hypertrophied by pressure overload, whereas there was substantial left ventricular thinning in the CHF rats. We consider this decline in left ventricular weight to possibly be due to a lack of opportunity for full compensation in the CHF rats. Therefore, it remains to be elucidated whether the production of ET-1 is altered in the left ventricle of rats with CHF that are fully compensated.
|
Selected Abbreviations and Acronyms |
|---|
|
|
Acknowledgments |
|---|
This study was supported by a grant from the Special Research Project on the Circulation Biosystem from University of Tsukuba, by the Uehara Memorial Foundation, by the Ciba-Geigy Foundation (Japan) for the Promotion of Science, by the Japan Research Foundation for Clinical Pharmacology, by the Kato Memorial Bioscience Foundation, by the Study Group of Molecular Cardiology, and by grants-in-aid for scientific research from the Ministry of Education, Science and Culture of Japan (7407019, 7557053, 7670751, and 7770493). We thank Dr Masaru Nishikibe and Dr Mitsuo Yano (Tsukuba Research Institute, Banyu Pharmaceutical Co, Tsukuba, Japan) for useful discussions concerning our study and for their generous gift of BQ-123.
Received September 27, 1995; accepted October 31, 1995.
|
References |
|---|
|
TopAbstractIntroductionMethods Results Discussion References |
|---|
1. Suzuki T, Kumazaki T, Mitsui Y. Endothelin-1 is produced and secreted by neonatal rat cardiac myocytes in vitro. Biochem Biophys Res Commun.. 1993;193:823-830.
2. Yanagisawa M, Kurihara H, Kimura S, Tomobe Y, Kobayashi M, Mitsui Y, Yazaki Y, Goto K, Masaki T. A novel potent vasoconstrictor peptide produced by vascular endothelial cells. Nature.. 1988;332:411-415. [Medline] [Order article via Infotrieve]
3. Ishikawa T, Yanagisawa M, Kimura S, Goto K, Masaki T. Positive inotropic action of novel vasoconstrictor peptide endothelin on guinea pig atria. Am J Physiol. 1988;255(Heart Circ Physiol 24):H970-H973.
4. Ishikawa T, Yanagisawa M, Kimura S, Goto K, Masaki T. Positive chronotropic effects of endothelin, a novel endothelium-derived vasoconstrictor peptide. Pflugers Arch.. 1988;413:108-110. [Medline] [Order article via Infotrieve]
5.
Shubeita HE, McDonough PM, Harris AN, Knowlton KU,
Glembotski CC, Brown JH, Chien KR. Endothelin induction of
inositol phospholipid hydrolysis, sarcomere assembly, and cardiac gene
expression in ventricular myocytes. J
Biol Chem.. 1990;265:20555-20562.
6. Hiroe M, Hirata Y, Fujita N, Umezawa S, Ito H, Tsujino M, Koike A, Nogami A, Takamoto T, Marumo F. Plasma endothelin-1 levels in idiopathic dilated cardiomyopathy. Am J Cardiol.. 1991;68:1114-1115. [Medline] [Order article via Infotrieve]
7.
McMurray JJ, Ray SG, Abdullah IA, Dargie HJ, Morton
JJ. Plasma endothelin in chronic heart failure.
Circulation. 1992;85:1374-1379.
8.
Stewart DJ, Cernacek P, Costello KB, Rouleau
JL. Elevated endothelin-1 in heart failure and loss of normal
response to postural change. Circulation. 1992;85:510-517.
9.
Margulies KB, Hildebrand FL Jr, Lerman A, Perrella MA,
Burnett JC Jr. Increased endothelin-1 in experimental heart failure.
Circulation. 1990;82:2226-2230.
10. Underwood RD, Aarhus LL, Heublein DM, Burnett JC Jr. Endothelin in thoracic inferior vena caval constriction model of heart failure. Am J Physiol. 1992;263(Heart Circ Physiol 32):H951-H955.
11. Emori T, Hirata Y, Ohta K, Shichiri M, Marumo F. Secretory mechanism of immunoreactive endothelin in cultured bovine endothelial cells. Biochem Biophys Res Commun.. 1989;160:93-100. [Medline] [Order article via Infotrieve]
12. Yoshizumi M, Kurihara H, Sugiyama T, Takaku F, Yanagisawa M, Masaki T, Yazaki Y. Hemodynamic shear stress stimulates endothelin production by cultured endothelial cells. Biochem Biophys Res Commun.. 1989;161:859-864. [Medline] [Order article via Infotrieve]
13. Sumpio BE, Widmann MD. Enhanced production of endothelium-derived contracting factor by endothelial cells subjected to pulsatile stretch. Surgery.. 1990;108:277-281. [Medline] [Order article via Infotrieve]
14. Ito H, Hirata Y, Adachi S, Tanaka M, Tsujino M, Koike A, Nogami A, Marumo F, Hiroe M. Endothelin-1 is an autocrine/paracrine factor in the mechanism of angiotensin II-induced hypertrophy in cultured rat cardiomyocytes. J Clin Invest.. 1993;92:398-403.
15. Yorikane R, Sakai S, Miyauchi T, Sakurai T, Sugishita Y, Goto K. Increased production of endothelin-1 in the hypertrophied rat heart due to pressure overload. FEBS Lett.. 1993;332:31-34. [Medline] [Order article via Infotrieve]
16.
Miyauchi T, Yorikane R, Sakai S, Sakurai T, Okada M,
Nishikibe M, Yano M, Yamaguchi I, Sugishita Y, Goto K.
Contribution of endogenous endothelin-1 to the progression
of cardiopulmonary alterations in rats with
monocrotaline-induced pulmonary hypertension.
Circ Res.. 1993;73:887-897.
17. Ihara M, Noguchi K, Saeki T, Fukuroda T, Tsuchida S, Kimura S, Fukami T, Ishikawa K, Nishikibe M, Yano M. Biological profiles of highly potent novel endothelin antagonists selective for the ETa receptor. Life Sci.. 1992;50:247-255. [Medline] [Order article via Infotrieve]
18.
Pfeffer MA, Pfeffer JM, Fishbein MC, Fletcher PJ,
Spadaro J, Kloner RA, Braunwald E. Myocardial infarct size and
ventricular function in rats. Circ Res.. 1979;44:503-512.
19. Teerlink JR, Goldhaber SZ, Pfeffer MA. An overview of contemporary etiologies of congestive heart failure. Am Heart J.. 1991;121:1852-1853.[Medline] [Order article via Infotrieve]
20. Suzuki N, Matsumoto H, Kitada C, Masaki T, Fujino M. A sensitive sandwich-enzyme immunoassay for human endothelin. J Immunol Methods.. 1989;118:245-250. [Medline] [Order article via Infotrieve]
21. Miyauchi T, Yanagisawa M, Tomizawa T, Sugishita Y, Suzuki N, Fujino M, Aisaka R, Goto K, Masaki T. Increased plasma concentrations of endothelin-1 and big endothelin-1 in acute myocardial infarction. Lancet.. 1989;1:53-54. [Medline] [Order article via Infotrieve]
22. Onizuka M, Miyauchi T, Mitsui K, Suzuki N, Masaki T, Goto K, Hori M. Endothelin-1 mediates regional blood flow during and after pulmonary operations. J Thorac Cardiovasc Surg.. 1992;104:1696-1701. [Abstract]
23. Sakurai T, Yanagisawa M, Inoue A, Ryan U, Kimura S, Mitsui Y, Goto K, Masaki T. cDNA cloning, sequence analysis and tissue distribution of rat preproendothelin-1 mRNA. Biochem Biophys Res Commun.. 1991;175:44-47. [Medline] [Order article via Infotrieve]
24. Wiechelman K, Braun R, Fitzpatrick J. Investigation of the bicinchoninic acid protein assay: identification of the groups responsible for color formation. Anal Biochem.. 1988;175:231-237. [Medline] [Order article via Infotrieve]
25. Ihara M, Fukuroda T, Saeki T, Nishikibe M, Kojiri K, Suda H, Yano M. An endothelin receptor (ETa) antagonist isolated from Streptomyces misakiensis. Biochem Biophys Res Commun.. 1991;178:132-137. [Medline] [Order article via Infotrieve]
26. Munson PJ, Rodbard D. LIGAND: a versatile computerized approach for characterization of ligand-binding systems. Anal Biochem.. 1980;107:220-239.[Medline] [Order article via Infotrieve]
27.
Haber E, Koerner T, Page LB, Kliman B, Purnode
A. Application of a radio-immunoassay for
angiotensin I to the physiologic measurements of plasma
renin activity in normal human subjects. J Clin
Endocrinol Metab.. 1969;29:1349-1355.
28. Bittl JA, Balschi JA, Ingwall JS. Effect of norepinephrine infusion on myocardial high-energy phosphate content and turnover in the living rat. J Clin Invest.. 1987;79:1852-1859.
29.
Inoue A, Yanagisawa M, Kimura S, Kasuya Y, Miyauchi T,
Goto K, Masaki T. The human endothelin family: three
structurally and pharmacologically distinct isopeptides predicted by
three separate genes. Proc Natl Acad Sci U S A.. 1989;86:2863-2867.
30.
Masaki T, Kimura S, Yanagisawa M, Goto K.
Molecular and cellular mechanism of endothelin regulation: implication
for vascular function. Circulation. 1991;84:1457-1468.
31. Arai H, Hori S, Aramori I, Ohkubo H, Nakanishi S. Cloning and expression of a cDNA encoding an endothelin receptor. Nature.. 1990;348:730-732. [Medline] [Order article via Infotrieve]
32. Sakurai T, Yanagisawa M, Takuwa Y, Miyazaki H, Kimura S, Goto K, Masaki T. Cloning of a non-selective subtype of the endothelin receptor. Nature.. 1990;348:732-735. [Medline] [Order article via Infotrieve]
33. Sakurai T, Yanagisawa M, Masaki T. Molecular characterization of endothelin receptors. Trends Pharmacol Sci.. 1992;13:103-108. [Medline] [Order article via Infotrieve]
34.
Hori S, Komatsu Y, Shigemoto R, Mizuno M, Nakanishi
S. Distinct tissue distribution and cellular localization of two
messenger ribonucleic acids encoding different subtypes of rat
endothelin receptors. Endocrinology.. 1992;130:1885-1895.
35.
Molenaar P, O'Reilly G, Sharkey A, Kuc RE, Harding DP,
Plumpton C, Gresham GA, Davenport AP. Characterization and
localization of endothelin receptor subtypes in the human
atrioventricular conducting system and
myocardium. Circ Res.. 1993;72:526-538.
36. Kasai H, Takanashi M, Takasaki C, Endoh M. Pharmacological properties of endothelin receptor subtypes mediating positive inotropic effects in rabbit heart. Am J Physiol. 1994;266(Heart Circ Physiol 35):H2220-H2228.
37. Reiss K, Capasso JM, Huang H, Meggs LG, Li P, Anversa P. ANG II receptors, c-myc, and c-jun in myocytes after myocardial infarction and ventricular failure. Am J Physiol. 1993;264(Heart Circ Physiol 33):H760-H769.
38.
Inoue A, Yanagisawa M, Takuwa Y, Mitsui Y, Kobayashi M,
Masaki T. The human preproendothelin-1 gene.
J Biol Chem.. 1989;264:14954-14959.
39. Yanagisawa M, Inoue A, Takuwa Y, Mitsui Y, Kobayashi M, Masaki T. The human preproendothelin-1 gene: possible regulation by endothelial phosphoinositide turnover signaling. J Cardiovasc Pharmacol. 1989;13(suppl 5):S13-S17.
40. Francis GS, Goldsmith SR, Levine TB, Olivari MT, Cohn JN. The neurohumoral axis in congestive heart failure. Ann Intern Med.. 1984;101:370-377.
41. Creager MA, Faxon DP, Cutler SS, Kohlmamm O, Ryan TJ, Garvas H. Contribution of vasopressin to vasoconstriction in patients with congestive heart failure: comparison with the renin-angiotensin system. J Am Coll Cardiol.. 1986;7:758-765. [Abstract]
42. Rubanyi GM, Polokoff MA. Endothelins: molecular biology, biochemistry, pharmacology, physiology, and pathophysiology. Pharmacol Rev.. 1994;45:325-415.
43. Baker KM, Booz GW, Dostal DE. Cardiac actions of angiotensin II: role of an intracardiac renin-angiotensin system. Annu Rev Physiol.. 1992;54:227-241. [Medline] [Order article via Infotrieve]
44. Dostal DE, Baker KM. Evidence for a role of an intracardiac renin-angiotensin system in normal and failing hearts. Trends Cardiovasc Med.. 1993;3:67-74.
45. Hirata Y, Fukuda Y, Yoshimi H, Emori T, Shichiri M, Marumo F. Specific receptor for endothelin in cultured rat cardiocytes. Biochem Biophys Res Commun.. 1989;160:1438-1444. [Medline] [Order article via Infotrieve]
46. Sakurai T, Morimoto H, Kasuya Y, Takuwa Y, Nakauchi H, Masaki T, Goto K. Level of ETb mRNA is down-regulated by endothelins through decreasing the intracellular stability of mRNA molecules. Biochem Biophys Res Commun.. 1992;186:342-347. [Medline] [Order article via Infotrieve]
47.
Clozel M, Breu V, Gray GA, Kalina B, Loffler BM, Burri
K, Cassal JM, Hirth G, Muller M, Neidhart W, Ramuz H.
Pharmacological characterization of bosentan, a new potent orally
active nonpeptide endothelin receptor antagonist.
J Pharmacol Exp Ther.. 1994;270:228-235.
48.
Teerlink JR, Loffler BM, Hess P, Maire JP, Clozel M,
Clozel JP. Role of endothelin in the maintenance of
blood pressure in conscious rats with chronic heart failure: acute
effects of the endothelin receptor antagonist Ro 47-0203
(bosentan). Circulation. 1994;90:2510-2518.
49. Love MP, Hynes WG, Webb DJ, McMurray JJV. Anti-endothelin therapy is of potential benefit in heart failure. Circulation. 1994;90(suppl I):I-547. Abstract.
50. Davenport AP, Maguire JJ. Is endothelin-induced vasoconstriction mediated only by ETa receptors in humans? Trends Pharmacol Sci.. 1994;15:9-11. [Medline] [Order article via Infotrieve]
51. Clozel M, Clozel JP, Hess P. Endothelin antagonism: a new therapeutic approach in experimental hypertension. Circulation. 1994;88(suppl I):I-316. Abstract.
52.
Ohlstein EH, Nambi P, Douglas SA, Edwards RM, Gellai M,
Lago A, Leber JD, Cousins RD, Gao A, Frazee JS, Peishoff CE, Bean JW,
Eggleston DS, Elshourbagy NA, Kumar C, Lee JA, Yue T, Louden C, Brooks
DP, Weinstock J, Feuerstein G, Poste G, Ruffolo RR, Gleason JG, Elliott
JD. SB 209670, a rationally designed potent nonpeptide
endothelin receptor antagonist. Proc Natl
Acad Sci U S A.. 1994;91:8052-8056.
53. Nishikibe M, Tsuchida S, Okada M, Fukuroda T, Shimamoto K, Yano M, Ishikawa K, Ikemoto F. Antihypertensive effect of a newly synthesized endothelin antagonist, BQ-123, in a genetic hypertensive model. Life Sci.. 1993;52:717-724. [Medline] [Order article via Infotrieve]
54. Afzal N, Dhalla NS. Differential changes in left and right ventricular SR calcium transport in congestive heart failure. Am J Physiol. 1992;262(Heart Circ Physiol 31):H868-H874.
55. Teerlink JR, Clozel M, Fischli W, Clozel JP. Temporal evolution of endothelial dysfunction in a rat model of chronic heart failure. J Am Coll Cardiol.. 1993;22:615-620.[Abstract]
This article has been cited by other articles:
 |
|
 |
|
  G. D. Lewis, R. Shah, K. Shahzad, J. M. Camuso, P. P. Pappagianopoulos, J. Hung, A. Tawakol, R. E. Gerszten, D. M. Systrom, K. D. Bloch, et al. Sildenafil Improves Exercise Capacity and Quality of Life in Patients With Systolic Heart Failure and Secondary Pulmonary Hypertension Circulation, October 2, 2007; 116(14): 1555 - 1562. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 N. Shimojo, S. Jesmin, S. Zaedi, T. Otsuki, S. Maeda, N. Yamaguchi, K. Aonuma, Y. Hattori, and T. Miyauchi Contributory role of VEGF overexpression in endothelin-1-induced cardiomyocyte hypertrophy Am J Physiol Heart Circ Physiol, July 1, 2007; 293(1): H474 - H481. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. Fielitz, S. Philipp, L. R. Herda, E. Schuch, B. Pilz, C. Schubert, V. Gunzler, R. Willenbrock, and V. Regitz-Zagrosek Inhibition of prolyl 4-hydroxylase prevents left ventricular remodelling in rats with thoracic aortic banding Eur J Heart Fail, April 1, 2007; 9(4): 336 - 342. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
T.-M. Lee, M.-S. Lin, T.-F. Chou, and N.-C. Chang Additive effects of combined blockade of AT1 receptor and HMG-CoA reductase on left ventricular remodeling in infarcted rats Am J Physiol Heart Circ Physiol, September 1, 2006; 291(3): H1281 - H1289. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 N. F. Kelland and D. J. Webb Clinical Trials of Endothelin Antagonists in Heart Failure: A Question of Dose? Experimental Biology and Medicine, June 1, 2006; 231(6): 696 - 699. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. Iemitsu, S. Maeda, T. Otsuki, K. Goto, and T. Miyauchi Time course alterations of myocardial endothelin-1 production during the formation of exercise training-induced cardiac hypertrophy. Experimental Biology and Medicine, June 1, 2006; 231(6): 871 - 875. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
N. Shimojo, S. Jesmin, S. Zaedi, M. Soma, T. Kobayashi, S. Maeda, I. Yamaguchi, K. Goto, and T. Miyauchi Effect of eicosapentaenoic Acid on the different endothelin system components in endothelin-1-induced hypertrophied cardiomyocytes. Experimental Biology and Medicine, June 1, 2006; 231(6): 888 - 892. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 H.-K. Yip, C.-J. Wu, H.-W. Chang, C.-H. Yang, T.-H. Yu, Y.-H. Chen, and C.-L. Hang Prognostic Value of Circulating Levels of Endothelin-1 in Patients After Acute Myocardial Infarction Undergoing Primary Coronary Angioplasty Chest, May 1, 2005; 127(5): 1491 - 1497. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
D. Merkus, B. Houweling, A. H. van den Meiracker, F. Boomsma, and D. J. Duncker Contribution of endothelin to coronary vasomotor tone is abolished after myocardial infarction Am J Physiol Heart Circ Physiol, February 1, 2005; 288(2): H871 - H880. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 C. Di Filippo, F. Rossi, E. Ongini, P. Del Soldato, M. Perretti, and M. D'Amico The Distinct Alterations Produced in Cardiovascular Functions by Prednisolone and Nitro-prednisolone (NCX-1015) in the Rat Highlight a Causal Role for Endothelin-1 J. Pharmacol. Exp. Ther., September 1, 2004; 310(3): 1133 - 1141. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 T. Ogata, T. Miyauchi, S. Sakai, M. Takanashi, Y. Irukayama-Tomobe, and I. Yamaguchi Myocardial fibrosis and diastolic dysfunction in deoxycorticosterone acetate-salt hypertensive rats is ameliorated by the peroxisome proliferator-activated receptor-alpha activator fenofibrate, partly by suppressing inflammatory responses associated with the nuclear factor-kappa-b pathway J. Am. Coll. Cardiol., April 21, 2004; 43(8): 1481 - 1488. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
O. Zolk, F. Munzel, and T. Eschenhagen Effects of chronic endothelin-1 stimulation on cardiac myocyte contractile function Am J Physiol Heart Circ Physiol, April 1, 2004; 286(4): H1248 - H1257. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. D. Parker and J. J. Thiessen Increased endothelin-1 production in patients with chronic heart failure Am J Physiol Heart Circ Physiol, March 1, 2004; 286(3): H1141 - H1145. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
L. L. Yang, R. Gros, M. G. Kabir, A. Sadi, A. I. Gotlieb, M. Husain, and D. J. Stewart Conditional Cardiac Overexpression of Endothelin-1 Induces Inflammation and Dilated Cardiomyopathy in Mice Circulation, January 20, 2004; 109(2): 255 - 261. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. Motte, R. van Beneden, J. Mottet, B. Rondelet, M. Mathieu, X. Havaux, P. Lause, C. Clercx, J.-M. Ketelslegers, R. Naeije, et al. Early activation of cardiac and renal endothelin systems in experimental heart failure Am J Physiol Heart Circ Physiol, December 1, 2003; 285(6): H2482 - H2491. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 R. M. Kedzierski, P. A. Grayburn, Y. Y. Kisanuki, C. S. Williams, R. E. Hammer, J. A. Richardson, M. D. Schneider, and M. Yanagisawa Cardiomyocyte-Specific Endothelin A Receptor Knockout Mice Have Normal Cardiac Function and an Unaltered Hypertrophic Response to Angiotensin II and Isoproterenol Mol. Cell. Biol., November 15, 2003; 23(22): 8226 - 8232. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
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]
|
|
|
|
|
|
J. Piuhola, M. Makinen, I. Szokodi, and H. Ruskoaho Dual role of endothelin-1 via ETA and ETB receptors in regulation of cardiac contractile function in mice Am J Physiol Heart Circ Physiol, June 5, 2003; 285(1): H112 - H118. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 L. Chu, R. Takahashi, I. Norota, T. Miyamoto, Y. Takeishi, K. Ishii, I. Kubota, and M. Endoh Signal Transduction and Ca2+ Signaling in Contractile Regulation Induced by Crosstalk Between Endothelin-1 and Norepinephrine in Dog Ventricular Myocardium Circ. Res., May 16, 2003; 92(9): 1024 - 1032. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
T. Maki, Y. Nasa, K. Tanonaka, M. Takahashi, and S. Takeo Beneficial Effects of Sampatrilat, a Novel Vasopeptidase Inhibitor, on Cardiac Remodeling and Function of Rats with Chronic Heart Failure following Left Coronary Artery Ligation J. Pharmacol. Exp. Ther., April 1, 2003; 305(1): 97 - 105. [Abstract] [Full Text]
|
|
|
|
|
|
A. F. Leite-Moreira, C. Bras-Silva, C. A. Pedrosa, and A. A. Rocha-Sousa ET-1 increases distensibility of acutely loaded myocardium: a novel ETA and Na+/H+ exchanger-mediated effect Am J Physiol Heart Circ Physiol, April 1, 2003; 284(4): H1332 - H1339. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 L. Li, J. J. Galligan, G. D. Fink, and A. F. Chen Vasopressin Induces Vascular Superoxide Via Endothelin-1 in Mineralocorticoid Hypertension Hypertension, March 1, 2003; 41(3): 663 - 668. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 T. Tsutamoto, A. Wada, M. Hayashi, T. Tsutsui, K. Maeda, M. Ohnishi, M. Fujii, T. Matsumoto, T. Yamamoto, T. Takayama, et al. Relationship between transcardiac gradient of endothelin-1 and left ventricular remodelling in patients with first anterior myocardial infarction Eur. Heart J., February 2, 2003; 24(4): 346 - 355. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. Piuhola, I. Szokodi, P. Kinnunen, M. Ilves, R. deChatel, O. Vuolteenaho, and H. Ruskoaho Endothelin-1 Contributes to the Frank-Starling Response in Hypertrophic Rat Hearts Hypertension, January 1, 2003; 41(1): 93 - 98. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. Iemitsu, T. Miyauchi, S. Maeda, T. Tanabe, M. Takanashi, Y. Irukayama-Tomobe, S. Sakai, H. Ohmori, M. Matsuda, and I. Yamaguchi Aging-induced decrease in the PPAR-alpha level in hearts is improved by exercise training Am J Physiol Heart Circ Physiol, November 1, 2002; 283(5): H1750 - H1760. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 K. Ogino, K. Ogura, Y. Kinugasa, Y. Furuse, K. Uchida, M. Shimoyama, T. Kinugawa, S. Osaki, M. Kato, Y. Tomikura, et al. Parathyroid Hormone-Related Protein Is Produced in the Myocardium and Increased in Patients with Congestive Heart Failure J. Clin. Endocrinol. Metab., October 1, 2002; 87(10): 4722 - 4727. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
W. Johnson, A. Nohria, L. Garrett, J. C. Fang, J. Igo, M. Katai, P. Ganz, and M. A. Creager Contribution of endothelin to pulmonary vascular tone under normoxic and hypoxic conditions Am J Physiol Heart Circ Physiol, August 1, 2002; 283(2): H568 - H575. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 O. Zolk, J. Quattek, U. Seeland, A. El-Armouche, T. Eschenhagen, and M. Bohm Activation of the cardiac endothelin system in left ventricular hypertrophy before onset of heart failure in TG(mREN2)27 rats Cardiovasc Res, February 1, 2002; 53(2): 363 - 371. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. Clozel, C. Qiu, C.-S. Qiu, P. Hess, and J.-P. Clozel Short-term endothelin receptor blockade with tezosentan has both immediate and long-term beneficial effects in rats with myocardial infarction J. Am. Coll. Cardiol., January 2, 2002; 39(1): 142 - 147. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. Iemitsu, T. Miyauchi, S. Maeda, S. Sakai, T. Kobayashi, N. Fujii, H. Miyazaki, M. Matsuda, and I. Yamaguchi Physiological and pathological cardiac hypertrophy induce different molecular phenotypes in the rat Am J Physiol Regulatory Integrative Comp Physiol, December 1, 2001; 281(6): R2029 - R2036. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
K. Tadano, J. Suzuki, K. Hanada, M. Nakao, R. Nakao, S. Uehara, H. Ohta, T. Miyauchi, and M. Nishikibe Pathophysiological Roles of Endogenous Endothelin-1 in Dogs with Chronic Heart Failure Produced by Rapid Right Ventricular Pacing J. Pharmacol. Exp. Ther., August 1, 2001; 298(2): 729 - 736. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. Aleksic, Z. Szabo, U. Scheffel, H. T. Ravert, W. B. Mathews, L. Kerenyi, P. A. Rauseo, R. E. Gibson, H. D. Burns, and R. F. Dannals In Vivo Labeling of Endothelin Receptors with [11C]L-753,037: Studies in Mice and a Dog J. Nucl. Med., August 1, 2001; 42(8): 1274 - 1280. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
C. Boixel, S. Dinanian, L. Lang-Lazdunski, J.-J. Mercadier, and S. N. Hatem Characterization of effects of endothelin-1 on the L-type Ca2+ current in human atrial myocytes Am J Physiol Heart Circ Physiol, August 1, 2001; 281(2): H764 - H773. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. P. Loennechen, A. Stoylen, V. Beisvag, U. Wisloff, and O. Ellingsen Regional expression of endothelin-1, ANP, IGF-1, and LV wall stress in the infarcted rat heart Am J Physiol Heart Circ Physiol, June 1, 2001; 280(6): H2902 - H2910. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
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]
|
|
|
|
|
|
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]
|
|
|
|
|
|
T. Suzuki and T. Miyauchi A novel pharmacological action of ET-1 to prevent the cytotoxicity of doxorubicin in cardiomyocytes Am J Physiol Regulatory Integrative Comp Physiol, May 1, 2001; 280(5): R1399 - R1406. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
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]
|
|
|
|
|
|
S. Morin, P. Paradis, A. Aries, and M. Nemer Serum Response Factor-GATA Ternary Complex Required for Nuclear Signaling by a G-Protein-Coupled Receptor Mol. Cell. Biol., February 15, 2001; 21(4): 1036 - 1044. [Abstract] [Full Text]
|
|
|
|
|
|
D. Lepailleur-Enouf, G. Egidy, M. Philippe, L. Louedec, J.-P. Henry, P. Mulder, and J.-B. Michel Pulmonary endothelinergic system in experimental congestive heart failure Cardiovasc Res, February 1, 2001; 49(2): 330 - 339. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
T. F. Luscher and M. Barton Endothelins and Endothelin Receptor Antagonists : Therapeutic Considerations for a Novel Class of Cardiovascular Drugs Circulation, November 7, 2000; 102(19): 2434 - 2440. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
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]
|
|
|
|
|
|
P. A. Modesti, S. Vanni, I. Bertolozzi, I. Cecioni, G. Polidori, R. Paniccia, B. Bandinelli, A. Perna, P. Liguori, M. Boddi, et al. Early sequence of cardiac adaptations and growth factor formation in pressure- and volume-overload hypertrophy Am J Physiol Heart Circ Physiol, September 1, 2000; 279(3): H976 - H985. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
P. Kinnunen, I. Szokodi, M. G. Nicholls, and H. Ruskoaho Impact of NO on ET-1- and AM-induced inotropic responses: potentiation by combined administration Am J Physiol Regulatory Integrative Comp Physiol, August 1, 2000; 279(2): R569 - R575. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
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]
|
|
|
|
|
|
M. P Love, C. J Ferro, W. G Haynes, C. Plumpton, A. P Davenport, D. J Webb, and J. J.V McMurray Endothelin receptor antagonism in patients with chronic heart failure Cardiovasc Res, July 1, 2000; 47(1): 166 - 172. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. Sakai, T. Miyauchi, and I. Yamaguchi Long-Term Endothelin Receptor Antagonist Administration Improves Alterations in Expression of Various Cardiac Genes in Failing Myocardium of Rats With Heart Failure Circulation, June 20, 2000; 101(24): 2849 - 2853. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
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]
|
|
|
|
|
|
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]
|
|
|
|
|
|
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]
|
|
|
|
|
|
C. Wei and J. C. Burnett Jr. Inhibition by calcium antagonism of circulating and renal endothelin in experimental congestive heart failure Am J Physiol Heart Circ Physiol, January 1, 2000; 278(1): H263 - H268. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
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]
|
|
|
|
|
|
M. Ueno, T. Miyauchi, S. Sakai, T. Kobayashi, K. Goto, and I. Yamaguchi Effects of physiological or pathological pressure load in vivo on myocardial expression of ET-1 and receptors Am J Physiol Regulatory Integrative Comp Physiol, November 1, 1999; 277(5): R1321 - R1330. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
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]
|
|
|
|
|
|
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]
|
|
|
|
|
|
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]
|
|
|
|
|
|
B. Pieske, B. Beyermann, V. Breu, B. M. Loffler, K. Schlotthauer, L. S. Maier, S. Schmidt-Schweda, H. Just, and G. Hasenfuss Functional Effects of Endothelin and Regulation of Endothelin Receptors in Isolated Human Nonfailing and Failing Myocardium Circulation, April 13, 1999; 99(14): 1802 - 1809. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
T. Kobayashi, T. Miyauchi, S. Sakai, M. Kobayashi, I. Yamaguchi, K. Goto, and Y. Sugishita Expression of endothelin-1, ETA and ETB receptors, and ECE and distribution of endothelin-1 in failing rat heart Am J Physiol Heart Circ Physiol, April 1, 1999; 276(4): H1197 - H1206. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
H. Ehmke, J. Faulhaber, K. Munter, M. Kirchengast, and R. J. Wiesner Chronic ETA Receptor Blockade Attenuates Cardiac Hypertrophy Independently of Blood Pressure Effects in Renovascular Hypertensive Rats Hypertension, April 1, 1999; 33(4): 954 - 960. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
K. Onishi, M. Ohno, W. C. Little, and C.-P. Cheng Endogenous Endothelin-1 Depresses Left Ventricular Systolic and Diastolic Performance in Congestive Heart Failure J. Pharmacol. Exp. Ther., March 1, 1999; 288(3): 1214 - 1222. [Abstract] [Full Text]
|
|
|
|
 |
|
 M Mundhenke, B Schwartzkopff, M Köstering, U Deska, R M Klein, and B E Strauer Endogenous plasma endothelin concentrations and coronary circulation in patients with mild dilated cardiomyopathy Heart, March 1, 1999; 81(3): 278 - 284. [Abstract] [Full Text]
|
|
|
|
|
|
S. Maeda, T. Miyauchi, S. Sakai, T. Kobayashi, M. Iemitsu, K. Goto, Y. Sugishita, and M. Matsuda Prolonged exercise causes an increase in endothelin-1 production in the heart in rats Am J Physiol Heart Circ Physiol, December 1, 1998; 275(6): H2105 - H2112. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
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]
|
|
|
|
|
|
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]
|
|
|
|
|
|
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]
|
|
|
|
|
|
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]
|
|
|
|
|
|
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]
|
|
|
|
|
|
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]
|
|
|
|
|
|
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]
|
|
|
|
|
|
T. Tonnessen, P. Kristian Lunde, A. Giaid, O. M Sejersted, and G. Christensen Pulmonary and cardiac expression of preproendothelin-1 mRNA are increased in heart failure after myocardial infarction in rats. Localization of preproendothelin-1 mRNA and endothelin peptide Cardiovasc Res, September 1, 1998; 39(3): 633 - 643. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
I. Szokodi, F. Horkay, B. Merkely, F. Solti, L. Geller, P. Kiss, L. Selmeci, V. Kekesi, O. Vuolteenaho, H. Ruskoaho, et al. Intrapericardial infusion of endothelin-1 induces ventricular arrhythmias in dogs Cardiovasc Res, May 1, 1998; 38(2): 356 - 364. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
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]
|
|
|
|
 |
|
 C. Haug, W. Koenig, M. Hoeher, M. Kochs, V. Hombach, A. Gruenert, and H. Osterhues Direct enzyme immunometric measurement of plasma big endothelin-1 concentrations and correlation with indicators of left ventricular function Clin. Chem., February 1, 1998; 44(2): 239 - 243. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. Gheorghiade and R. O. Bonow Chronic Heart Failure in the United States : A Manifestation of Coronary Artery Disease Circulation, January 27, 1998; 97(3): 282 - 289. [Full Text] [PDF]
|
|
|
|
|
|
D. Fraccarollo, K. Hu, P. Galuppo, P. Gaudron, and G. Ertl 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 Circulation, December 2, 1997; 96(11): 3963 - 3973. [Abstract] [Full Text]
|
|
|
|
|
|
K. Graf, Y. S. Do, N. Ashizawa, W. P. Meehan, C. M. Giachelli, C. C. Marboe, E. Fleck, and W. A. Hsueh Myocardial Osteopontin Expression Is Associated With Left Ventricular Hypertrophy Circulation, November 4, 1997; 96(9): 3063 - 3071. [Abstract] [Full Text]
|
|
|
|
|
|
F. G. Spinale, M. de Gasparo, S. Whitebread, L. Hebbar, M. J. Clair, D. M. Melton, R. S. Krombach, R. Mukherjee, J. P. Iannini, and S.-J. O Modulation of the Renin-Angiotensin Pathway Through Enzyme Inhibition and Specific Receptor Blockade in Pacing-Induced Heart Failure : I. Effects on Left Ventricular Performance and Neurohormonal Systems Circulation, October 7, 1997; 96(7): 2385 - 2396. [Abstract] [Full Text]
|
|
|
|
|
|
E. Oie, L. E. Vinge, T. Tonnessen, H. K. Grogaard, H. Kjekshus, G. Christensen, O. A. Smiseth, and H. Attramadal Transient, isopeptide-specific induction of myocardial endothelin-1 mRNA in congestive heart failure in rats Am J Physiol Heart Circ Physiol, October 1, 1997; 273(4): H1727 - H1736. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
P. Mulder, V. Richard, G. Derumeaux, M. Hogie, J. P. Henry, F. Lallemand, P. Compagnon, B. Mace, E. Comoy, B. Letac, et al. Role of Endogenous Endothelin in Chronic Heart Failure : Effect of Long-term Treatment With an Endothelin Antagonist on Survival, Hemodynamics, and Cardiac Remodeling Circulation, September 16, 1997; 96(6): 1976 - 1982. [Abstract] [Full Text]
|
|
|
|
|
|
F. G. Spinale, J. D. Walker, R. Mukherjee, J. P. Iannini, A. T. Keever, and K. P. Gallagher 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 Circulation, April 1, 1997; 95(7): 1918 - 1929. [Abstract] [Full Text]
|
|
|
|
|
|
T. Tonnessen, G. Christensen, E. Oie, E. Holt, H. Kjekshus, O. A. Smiseth, O. M. Sejersted, and H. Attramadal Increased cardiac expression of endothelin-1 mRNA in ischemic heart failure in rats Cardiovasc Res, March 1, 1997; 33(3): 601 - 610. [Abstract] [PDF]
|
|
|
|
|
|
W. S. Colucci Myocardial Endothelin : Does It Play a Role in Myocardial Failure? Circulation, March 15, 1996; 93(6): 1069 - 1072. [Full Text]
|
|
|
|
 |
|
 K. Yamashita, D. J. Discher, J. Hu, N. H. Bishopric, and K. A. Webster Molecular Regulation of the Endothelin-1 Gene by Hypoxia. CONTRIBUTIONS OF HYPOXIA-INDUCIBLE FACTOR-1, ACTIVATOR PROTEIN-1, GATA-2, AND p300/CBP J. Biol. Chem., April 13, 2001; 276(16): 12645 - 12653. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
L. Moser, J. Faulhaber, R. J. Wiesner, and H. Ehmke Predominant activation of endothelin-dependent cardiac hypertrophy by norepinephrine in rat left ventricle Am J Physiol Regulatory Integrative Comp Physiol, May 1, 2002; 282(5): R1389 - R1394. [Abstract] [Full Text] [PDF]
|
|
| |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||