(Hypertension. 1999;33:816-822.)
© 1999 American Heart Association, Inc.
Scientific Contributions |
Endothelin System–Dependent Cardiac Remodeling in Renovascular Hypertension
From the Department of Nephrology, Universitätsklinikum Charité der Humboldt Universität zu Berlin (B.H., J.R., A.S., H.-H.N.), and the Institute of Molecular Biology and Biochemistry, Free University of Berlin (B.H., I.G., J.R., A.B., A.S., C.B.), Berlin, Germany.
Correspondence to PD Dr Berthold Hocher, Universitätsklinikum Charité der Humboldt Universität zu Berlin, Abteilung für Nephrologie, Schumannstrasse 20-21, 10098 Berlin, Germany. E-mail berthold.hocher{at}rz.hu-berlin.de
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Abstract |
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Abstract—The aim of the present study was to analyze whether the cardiac endothelin system contributes to cardiac remodeling in rats with 2-kidney, 1 clip (2K1C) renovascular hypertension. The endothelin system seems to be a promising candidate for cardiac remodeling because endothelin (ET)-1 promotes growth of cardiomyocytes in vitro and induces cardiac collagen synthesis. The activity of the cardiac endothelin system was analyzed by measuring cardiac tissue big ET-1 and ET-1 concentrations as well as by estimating the cardiac expression of the ETA and ETB receptors 10 days, 4 weeks, and 12 weeks after the renal artery was clipped. The effects of long-term treatment with ETA, ETB, and combined ETA/ETB receptor antagonists on cardiac hypertrophy, media/lumen ratio of intracardiac arteries, and left ventricular fibrosis were also analyzed. This study demonstrated that the overall left ventricular cardiac endothelin system has a similar activity in the early, middle, and late stages of 2K1C renovascular hypertension compared with sham-operated controls. Fibrosis of the left ventricle and hypertrophy of intracardiac arteries, however, were markedly altered after long-term treatment with endothelin receptor antagonists in a blood pressure–independent manner. These 2 effects are mediated by different subtypes of endothelin receptors. ETA receptor blockade completely normalized the hypertrophy of intracardiac arteries (P<0.01 compared with 2K1C without treatment) in renovascular hypertension, whereas the ETB antagonist reduced cardiac fibrosis of the left ventricle (P<0.001 compared with 2K1C without treatment) to baseline values. This study demonstrates that the cardiac endothelin system plays an important role in the development of cardiac fibrosis as well as in hypertrophy of intracardiac arteries in 2K1C renovascular hypertensive rats.
Key Words: hypertension, renovascular • endothelins • remodeling
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Introduction |
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Renovascular hypertension leads to cardiac remodeling owing to an increased afterload imposed on the left ventricle by the progressively increased blood pressure and by neurohormonal stimulation, particularly by activation of the renin-angiotensin system. The process of cardiac remodeling in renovascular hypertension is characterized by both an increased left ventricular mass as well as an altered composition of cardiac proteins, especially matrix proteins. Increased fibronectin and collagen contents have been described and have been shown to be responsible for increased wall stiffness.1 2
There is growing evidence that an activated renin-angiotensin system as is observed in renovascular hypertension results in secondary activation of the paracrine endothelin system in vivo and that chronic effects of angiotensin (Ang) II, for example, on vascular remodeling are mediated at least partially by the paracrine endothelin system.3 4 Thus, the aim of the present study was to analyze whether the cardiac endothelin system contributes to cardiac hypertrophy and/or cardiac fibrosis in rats with renovascular hypertension. The endothelin system seems to be a promising candidate for cardiac remodeling in renovascular hypertension because endothelin (ET)-1 promotes growth of cardiomyocytes in vitro5 6 7 8 and induces cardiac collagen synthesis.9 10 Renovascular hypertension was induced by clipping the left renal artery (2-kidney, 1 clip [2K1C] model). The activity of the cardiac endothelin system was analyzed by measuring cardiac tissue big ET-1 and ET-1 concentrations as well as by estimating the cardiac expression of the ETA and ETB receptors 10 days, 4 weeks, and 12 weeks after the renal artery was clipped. The effects of long-term treatment with ETA, ETB, and combined ETA/ETB receptor antagonists on cardiac hypertrophy and fibrosis were also analyzed.
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Methods |
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Materials
125I–ET-1 (2000 Ci/mmol) was obtained from Du Pont. Unlabeled ET-1 was from Peninsula Laboratories, Inc. The selective endothelin receptor ligands (BQ 123, BQ 3020, and IRL 1038) were from California Peptides Inc. The mixed (A/B) endothelin receptor antagonist bosentan was a generous gift from Dr Martine Clozel, Pharma Division, F. Hoffmann–La Roche Ltd (Basel, Switzerland). Unless otherwise stated, all reagents were of analytical grade and were purchased from Merck, Boehringer Mannheim, or Sigma.
Animal Experiments
Male Wistar-Kyoto rats were obtained from Møllegard,
Denmark; fed a commercial diet (Altromin, Altromin GmbH); and given
water ad libitum. All animal experiments were conducted in accordance
with local institutional guidelines for the care and use of laboratory
animals. Renovascular hypertension was induced by the Goldblatt 2K1C
method adapted to the rat.11 A silver clip (0.2-mm
internal diameter) was placed on the left renal artery of 9-week-old
male Wistar-Kyoto rats. Anesthesia was performed with an
intraperitoneal injection of ketamine (80
mg/kg) and Rompun (12 mg/kg). Body weight, heart rate, and blood
pressure were measured once a week. To analyze the paracrine
cardiac endothelin system, we studied rats with renovascular
hypertension 10 days, 4 weeks, and 12 weeks after the artery was
clipped and compared them with corresponding sham-operated controls.
After decapitation, the left ventricle was prepared and separated into
2 equal parts by longitudinal sectioning and frozen in
LN2. One part was used for measurement of tissue
ET-1 and big ET-1 and the other was used for binding studies.
Five additional groups of rats were established for analyzing the effects of treatment with ETA, ETB, and combined ETA/ETB receptor antagonists: (1) a sham-operated group treated for 44 days with intraperitoneal placebo (solvent for BQ 123 and IRL 1038); (2) a group with renovascular (2K1C) hypertension treated for 44 days with intraperitoneal placebo (solvent for BQ 123 and IRL 1038); (3) a group with renovascular (2K1C) hypertension treated for 44 days with the ETA antagonist BQ 123 (30 mg · kg-1 · d-1 IP); (4) a group with renovascular (2K1C) hypertension treated for 44 days with the ETB antagonist IRL 1038 (22 mg · kg-1 · d-1 IP); and (5) a group with renovascular (2K1C) hypertension treated for 44 days with the combined ETA/ETB antagonist bosentan (100 mg · kg-1 · d-1 PO) and intraperitoneal placebo (see above). Bosentan was given by gavage.
Treatment was started 24 hours after clipping. The drugs were given at 8 AM. Blood pressure measurement was performed once a week at noon. The antagonists were given without any interruption. The ETA antagonist BQ 123 and the ETB antagonist IRL 1038 were given by intraperitoneal injection. The solvent for both drugs consisted of 140 mmol/L NaCl and 20 mmol/L Tris, pH 8.4. No signs of peritonitis or any other infectious disease were seen. The animals tolerated the treatment very well.
Blood Pressure Measurement
Measurement of arterial blood pressure was performed
as recently described by Hocher et al.12 13 The rats were
placed in a retaining box and warmed for 15 minutes until a pulse was
detected in the tail. Systolic pressure was measured using a
tail cuff and pressure transducer in conjunction with an automatic
pressure delivery system and chart recorder (Harvard indirect
rat-tail blood pressure system, Harvard Apparatus Ltd).
Blood pressure was measured weekly exactly 3 hours after administration
of the drugs.
Big ET-1 and ET-1 Measurement: Tissue Preparation
The probes (200 mg) were stored in LN2
until further analysis. The frozen tissue was powdered in the
presence of LN2. The powdered samples were
suspended and subsequently homogenized with a motor-driven
pestle homogenizer in 2 mL buffer solution at 4°C
(0.14 mol/L NaCl; 2.6 mmol/L KCl; 8 mmol/L
Na2HPO4; 1.4 mmol/L
KH2PO4; and 1% Triton
X-100, pH 7.4). The homogenates were centrifuged at
4°C for 60 minutes at 100 000g. The supernatants were
retained for big ET-1 and ET-1 ELISAs. The recovery rate for big ET-1
and ET-1 after tissue preparation as described above was always between
98% and 99%.
Enzyme-Linked Immunosorbent Assays
The commercially available enzyme immunoassays for big ET-1 and
ET-1 suitable for direct measurement of big ET-1 as well as ET-1 in
plasma and after tissue preparation were obtained from BioMedica GmbH
and were performed according to the instructions given by the
manufacturer. This assay needs no extraction step for ET-1 from plasma.
For the purpose of this study, we measured plasma ET-1 concentrations
and big ET-1 as well as ET-1 tissue concentrations.
Both ELISAs have the same assay principle. In brief, the big ET-1 and ET-1 ELISAs incorporate an immunoaffinity-purified polyclonal capture antibody and a monoclonal detection antibody, both highly specific for big ET-1 and ET-1, respectively. In the first step, the sample and the monoclonal detection antibody are added simultaneously to the wells. Big ET-1 or ET-1 binds to the precoated capture antibody and forms a "sandwich" with the detection antibody. After a washing step, a peroxidase-conjugated antibody detects the presence of bound detection antibodies. After removal of unbound conjugate by washing, tetramethylbenzidine is added to the wells as substrate. Big ET-1 and ET-1 are quantified by an enzyme-catalyzed color change detectable on a standard ELISA reader. The amount of color developed is directly proportional to the amount of big ET-1 or ET-1, respectively. Cross-reactivity for the ET-1 ELISA is as follows: ET-1(1–21), 100%; ET-2(1–21), 100%; ET-3(1–21), <5%; big ET-1(1–38), <1%; and big ET-1(22–38), <1%. Cross-reactivity for the big ET-1 ELISA is as follows: big ET-1(1–38), 100%; big ET-1(22–38), <1%; ET-1(1–21), <1%; ET-2(1–21), <1%; and ET-3(1–21), <1%. Tissue protein concentrations were determined according to Lowry et al.14
Binding Assays for ETA and ETB Receptors
To analyze the expression of endothelin receptor
subtypes (ETA/ETB) in the heart, binding assays were performed in the
presence or absence of the subtype-specific endothelin receptor ligands
BQ 123 (3 µmol/L) and/or BQ 3020 (3 µmol/L). The assay
buffer for binding studies contained 1 mg/mL bacitracin, 100
mmol/L Tris-HCl, 5 mmol/L MgCl2, and 1 g/L
BSA, pH 7.4, in a total volume of 150 µL. The
125I–ET-1 tracer concentration was kept constant
at 40 000 counts per minute per tube while the concentration of
unlabeled ET-1 was increased from 0 to 25 nmol/L (competition studies
with "cold saturation"). Samples from crude plasma membranes were
used at a concentration of 0.53 mg protein ·
mL-1 according to Hocher et al.15
Binding studies were performed at room temperature for 120 minutes.
Nonspecific binding was assessed in the presence of excess ET-1 (5
µmol/L). After adding 1 mL of cold binding buffer, free and
receptor-bound radioactivity was separated by
centrifugation at 30 000g (4°C) for 15
minutes, and the pellets thus obtained were washed 2 additional times
with 1 mL of cold binding buffer. 125I was
counted in a Packard gamma counter (78% counting efficiency for
125I). Protein concentrations were determined
according to Lowry et al.14
Bmax and Kd values
were calculated by linear regression analysis of Scatchard
plots.
Histological Evaluation
For pathohistological evaluation, all samples
were embedded in paraffin, cut into 3-µm sections, subjected to
hematoxylin-eosin and Sirius red staining, and analyzed as
recently described.16 17 18 The samples were always obtained
from the middle part of the left ventricle to exclude possible
differences in matrix protein content in different regions of the left
ventricle. Media/lumen ratio of the intracardiac arteries was
analyzed by using a videomicroscope connected to a personal
computer. The severity of cardiac fibrosis was evaluated after Sirius
red staining with the use of an image analysis system
(Quantimed 500). We measured the relationship of red-stained area
(connective tissue) to total area of the whole heart section. The data
thus obtained were analyzed with the Image 1.61 program. The
degree of perivascular fibrosis was evaluated after hematoxylin-eosin
and Sirius red staining. The perivascular fibrosis of intracardiac
arteries was assessed in 30 randomly selected arteries per sample
observed at x400 magnification on the following scale: 0=no
perivascular fibrosis; 1=minor perivascular fibrosis; 2=moderate
perivascular fibrosis; 3=strong perivascular fibrosis; and 4=very
strong perivascular fibrosis. All tissue samples for scoring
(analysis of perivascular fibrosis) were evaluated
independently by 2 investigators without prior knowledge of the group
to which the rats belonged.
Analysis of Data
The unpaired Student's t test determination of
statistical differences of group means was used for plasma and tissue
ET-1 concentrations, receptor binding assays, cardiac weights,
computer-added analysis of media/lumen ratio, and cardiac
fibrosis. ANOVA followed by the t test was used when
appropriate. The Mann-Whitney U test was used for
analysis of statistical differences after scoring perivascular
fibrosis. Results were considered significantly different at a value of
P<0.05.
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Results |
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Characteristics of 2K1C Hypertensive Rats
The characteristics of renovascular hypertensive rats (2K1C model) and their corresponding controls at 10 days, 4 weeks, and 12 weeks after clipping the left renal artery or sham operation are given in Table 1. There were no significant differences in body weight and heart rate between sham-operated and 2K1C hypertensive rats. The 2K1C animals showed significantly increased blood pressure, heart weight, and plasma ET-1 concentrations compared with sham-operated controls (Table 1).
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Big ET-1 and ET-1 Tissue Concentrations and ETA and ETB Receptor
Expression in the Left Ventricle of Rats With Renovascular
Hypertension
Tissue ET-1 as well as tissue big ET-1 concentrations 10 days, 4
weeks, and 12 weeks after clipping the left renal artery were similar
in the left ventricles of rats with 2K1C renovascular hypertension and
sham-operated control rats (Figure 1). Also, the big ET-1/ET-1
ratio, a parameter describing the activity of the cardiac
endothelin-converting enzyme, was not different in rats with
renovascular hypertension and corresponding controls (Figure 1).
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In addition, the density (Bmax) as well as the binding affinity (Kd) of both endothelin receptor subtypes (ETA and ETB) in the left ventricle were similar in 2K1C renovascular hypertensive rats and corresponding controls 10 days, 4 weeks, and 12 weeks after clipping the left renal artery (Table 2). Thus, our data indicate that the paracrine cardiac endothelin system is not activated in the early, middle, and late stages of 2K1C renovascular hypertension.
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Effects of Endothelin Receptor Antagonists on Blood
Pressure, Plasma ET-1 Concentrations, Heart Rate, and Body and
Heart Weights
Blood pressure and heart rate were measured weekly 3 hours after
administration of the drugs and were not different during the whole
treatment period in the 2K1C, 2K1C plus ETA antagonist (BQ
123), 2K1C plus ETB antagonist (IRL 1038), and 2K1C plus
combined ETA/ETB antagonist (bosentan) groups (data not
shown). There was no significant effect of endothelin receptor
antagonists on blood pressure, heart rate, or body and
heart weight. Long-term treatment with bosentan and IRL 1038 increased
plasma ET-1 concentrations.
Effects of Endothelin Receptor Antagonists on Cardiac
Fibrosis and Vascular Remodeling of Intracardiac Blood Vessels
Perivascular fibrosis of intramyocardial arteries was not enhanced
in rats with renovascular hypertension compared with sham-operated
controls. Endothelin receptor antagonists also had no
influence on perivascular fibrosis (Table 3).
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The media/lumen ratio of intramyocardial arteries, on the other hand, was markedly increased in 2K1C renovascular hypertensive rats. Treatment with the ETA antagonist BQ 123 completely normalized the media/lumen ratio in renovascular hypertension. BQ 123–treated 2K1C rats had a media/lumen ratio of intramyocardial arteries similar to that of sham-operated controls (Figure 2).
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Myocardial fibrosis was enhanced in the left ventricles of rats with 2K1C renovascular hypertension. Treatment with the ETA antagonist BQ 123 did not reduce this fibrotic remodeling of the left ventricle, whereas treatment of renovascular hypertensive rats with the ETB antagonist IRL 1038 resulted in a completely normal content of fibrotic tissue in the left ventricle compared with sham-operated controls (Figures 3 and 4).
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Discussion |
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This study demonstrates that the overall left ventricular cardiac endothelin system, as characterized by measuring tissue big ET-1 and ET-1 concentrations as well as by analyzing the cardiac expression of endothelin receptors, is not activated in the early, middle, and late stages of 2K1C renovascular hypertension. Treatment with endothelin receptor antagonists, on the other hand, had important, blood pressure–independent effects on cardiac remodeling in rats with 2K1C renovascular hypertension. The ETA antagonist normalized the media/lumen ratio of intramyocardial arteries, whereas the ETB antagonist reduced cardiac fibrosis of the left ventricle to baseline values.
Activity of the Cardiac Endothelin System in Rats With
Renovascular Hypertension
Ang II stimulates in vitro5 as well as in
vivo3 4 the synthesis of ET-1 in many cell types. This was
also shown in cardiomyocytes.19 Thus, we
expected that the cardiac tissue concentrations of ET-1 in rats with
renovascular hypertension might be elevated compared with sham-operated
controls owing to the elevated circulating or locally produced Ang II.
However, our study failed to demonstrate increased cardiac big-ET-1 or
ET-1 tissue concentrations in the early, middle, and late stages of
renovascular hypertension. To explain this finding, we have to consider
the following points:
The finding of no activation of the cardiac ET system was not due to technical reasons, because the sizes of the groups were large enough and the methods to analyze tissue big ET-1 and ET-1 as well as ETA and ETB receptor expression are well established.12 13 15 16 These data are in agreement with a recent study analyzing cardiac ET-1 gene expression in rats with renovascular hypertension.20 They demonstrated by in situ hybridization techniques that myocardial ET-1 gene expression is not enhanced in 2K1C hypertensive rats, whereas the ET-1 gene is upregulated within the coronary arteries in these hypertensive rats.20 21
Second, the renin-angiotensin system returns to baseline activity in the middle and late stages of renovascular hypertension.22 23 This may explain the normal cardiac tissue ET-1 concentrations 4 weeks and 12 weeks after clipping.
The third point is that the cardiac endothelin system is also not activated in the early stage of renovascular hypertension (characterized by high plasma Ang II levels), indicating that there are additional local factors, like increased afterload, altered activity of the sympathic nerve system, etc, probably modulating the paracrine cardiac endothelin system, and the net effect of these stimuli results in a normal tissue ET-1 concentration. There are several reports showing increased left ventricular ET-1 concentrations in rat models of left ventricular hypertrophy due to volume but not to pressure overload.24 25 26 These studies suggest that volume overload of the left ventricle itself might be an important stimuli of the cardiac endothelin system in vivo. Volume overload of the left ventricle is not a characteristic finding in the hearts of rats with renovascular hypertension.
Fourth, the cells probably mediating the effects of endothelin antagonists on cardiac remodeling in renovascular hypertension (cardiac fibroblasts and cells of intracardiac arteries, as discussed below) represent only a small fraction of all cardiac cells. Therefore, an altered activation of these cells in rats with renovascular hypertension might be undetectable when analyzing the overall left ventricular cardiac endothelin system.
Effects of Endothelin Antagonists on Blood
Pressure
Treatment with the combined endothelin receptor
antagonist bosentan had no effect on blood pressure in rats
with 2K1C renovascular hypertension. This finding is in agreement with
a recent report21 also showing no effect of a combined
ETA/ETB receptor antagonist on blood pressure in rats with
renovascular hypertension. The present study additionally
demonstrated that the long-term selective blockade of the ETA receptor
with BQ 1235 and of the ETB receptor with the selective
ETB antagonist IRL 103827 28 did not lower
blood pressure in 2K1C rats, indicating that the endothelin system does
not contribute to the maintenance of high blood pressure in
renovascular hypertension.
Effects of ET Receptor Antagonists on Left
Ventricular Remodeling
The most important finding of our study was a blood
pressure–independent effect of endothelin receptor
antagonists on the growth of intracardiac arteries and
cardiac fibrosis in the left ventricles of rats with renovascular
hypertension. These 2 effects seems to be mediated by different
subtypes of endothelin receptor.
ETA receptor blockade completely normalized the hypertrophy of intracardiac arteries in renovascular hypertension. ETA receptors are located on smooth muscle cells of blood vessels, and it is well known that ET-1 promotes smooth muscle cell growth by way of the ETA receptor in vitro (for a review, see Reference 55 ) and in vivo.3 4 Thus, our data suggest a direct inhibition of cardiac smooth muscle cell growth in 2K1C hypertension.
In contrast to the growth-inhibiting effect of the ETA antagonist on cardiac blood vessels (Figure 2), the effect of the endothelin system on interstitial cardiac fibrosis is mediated by the ETB receptor (Figures 3 and 4). Cardiac fibroblasts express ETB receptors,29 30 whereas cardiac myocytes express mainly ETA receptors.31 In addition, it is also well known that ET-1 is a very potent stimulus of matrix protein synthesis in cardiac fibroblasts.32 Thus, the antifibrotic effect of long-term blockade of the cardiac ETB receptor in rats with renovascular hypertension is most probably mediated by blockade of the ETB receptors on cardiac fibroblasts. The ETB-mediated effect on cardiac fibrosis, as well as the ETA-mediated effect on the hypertrophy of intracardiac arteries in 2K1C hypertension, is blood pressure independent, because the endothelin receptor antagonists do not reduce blood pressure in renovascular hypertension.
Our study indicates that the different components of the cardiac remodeling process in renovascular hypertension (ie, cardiac hypertrophy, cardiac fibrosis, hypertrophy of intracardiac arteries, and perivascular fibrosis) are controlled independently by the cardiac endothelin system. Cardiac hypertrophy seems not to be influenced by endothelin receptor blockers in 2K1C rats; in contrast, cardiac fibrosis is obviously dependent on cardiac ETB receptors, and ETA receptor blockade completely normalized the hypertrophy of intracardiac arteries in this model. A beneficial effect of endothelin receptor antagonists on cardiac remodeling has been demonstrated, for example, in a rat chronic heart failure model due to coronary artery ligation33 and also in deoxycorticosterone acetate salt hypertensive rats.34 The combined ETA/ETB antagonist bosentan was used in these studies33 34 (also see Reference 3535 ). It was therefore not possible in these important studies to distinguish between ETA- and ETB-mediated effects on cardiac remodeling.
In 2K1C rats the combined ETA/ETB receptor antagonist bosentan attenuated both the increased media/lumen ratio of intracardiac arteries and myocardial fibrosis. Although these findings were not significant (P=0.051 for media/lumen ratio and P=0.08 for myocard fibrosis), they rather support than contradict the concept of an ETA-mediated effect on growth of intracardiac arteries and an ETB-mediated effect on myocardial fibrosis. There are several points to consider to explain the less-pronounced effects of bosentan.
First, bosentan was given orally, whereas BQ 123 and IRL 1038 were given by intraperitoneal injections. Oral application of bosentan might be less effective. Second, activation of the endothelial ETB receptors results, by a G protein–coupled release of intracellular calcium, in activation of endothelial nitric oxide synthase.5 Nitric oxide has antiproliferative effects on the growth of smooth muscle cells.36 37 38 Bosentan thus might inhibit the ETB-mediated synthesis of nitric oxide. Blocking the ETB receptor might promote vascular hypertrophy and attenuate the antiproliferative effects of ETA antagonism on vascular smooth muscle cell growth. These obviously oppositional effects of ETA and ETB antagonism on the media/lumen ratio of intracardiac arteries may explain the results after long-term bosentan treatment. Third, the simultaneous blockade of ETA and ETB receptors (with bosentan) on cardiac fibroblasts may attenuate the antifibrotic effect of selective ETB blockers. However, this hypothesis needs to be confirmed by in vitro studies with cultured cardiac fibroblasts.
These remarkable effects of selective ETA or ETB endothelin receptor antagonists on cardiac remodeling in renovascular hypertension could not be explained by activation of the overall cardiac endothelin system. The finding of an antifibrotic effect of ETB antagonists on the left ventricle in renovascular hypertension, despite no measurable increased activity of the local endothelin system, resembles those studies demonstrating a beneficial effect of angiotensin-converting enzyme inhibitors on cardiac remodeling and cardiac hypertrophy, for example, in patients with essential hypertension39 40 characterized by low or normal activity of the renin-angiotensin system.
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Acknowledgments |
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This study was supported by grants from the Deutsche Forschungsgemeinschaft (Ho 1665/2-1). The technical assistance of Christine Lehmann and Ines Müller is greatly appreciated.
Received July 31, 1998; first decision August 24, 1998; accepted November 10, 1998.
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