(Circulation. 2000;102:2765.)
© 2000 American Heart Association, Inc.
Basic Science Reports |
Exaggerated Vascular and Renal Pathology in Endothelin-B Receptor–Deficient Rats With Deoxycorticosterone Acetate–Salt Hypertension
From the Department of Pharmacology (Y.M., T.K., Y.K., F.K., M.T.), Osaka University of Pharmaceutical Sciences, Nasahara, Takatsuki, Osaka, Japan; the Diabetes and Vascular Research Division (J.L.W., T.J.O.), Abbott Laboratories, Abbott Park, Ill; and the Howard Hughes Medical Institute (C.E.G., M.Y), Department of Molecular Genetics, University of Texas Southwestern Medical Center, Dallas.
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Abstract |
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Background—Endothelin (ET)-1 plays an important role in the pathogenesis of deoxycorticosterone acetate (DOCA)-salt–induced hypertension. We evaluated the pathological role of ETB receptors in DOCA-salt–induced hypertension, cardiovascular hypertrophy, and renal damage by using the spotting-lethal (sl) rat, which carries a naturally occurring deletion in the ETB receptor gene.
Methods and Results—Homozygous (sl/sl) rats exhibit abnormal development of neural crest–derived epidermal melanocytes and the enteric nervous system, and they do not live beyond 1 month because of intestinal aganglionosis and intestinal obstruction. The dopamine ß-hydroxylase (DßH) promoter was used to direct ETB transgene expression in sl/sl rats to support normal enteric nervous system development. DßH-ETB sl/sl rats live into adulthood and are healthy, expressing ETB receptors in adrenal glands and other adrenergic neurons. When homozygous (sl/sl) and wild-type (+/+) rats, all of which were transgenic, were treated with DOCA-salt, homozygous rats exhibited earlier and higher increases in systolic blood pressure than did wild-type rats. Chronic treatment with ABT-627, an ETA receptor antagonist, completely suppressed DOCA-salt–induced hypertension in both groups. Renal dysfunction and histological damage were more severe in homozygous than in wild-type rats. Marked vascular hypertrophy was observed in homozygous rats than in wild-type rats. Renal and vascular injuries were significantly improved by ABT-627. In DOCA-salt–treated homozygous rats, there were notable increases in renal, urinary, and aortic ET-1, all of which were normalized by ABT-627.
Conclusions—ETB-mediated actions are protective in the pathogenesis of DOCA-salt–induced hypertension. Enhanced ET-1 production and ETA-mediated actions are responsible for the increased susceptibility to DOCA-salt hypertension and tissue injuries in ETB receptor–deficient rats.
Key Words: endothelin • receptors • hypertension
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Introduction |
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Endothelin (ET)-1 is considered to participate in cardiovascular diseases, such as hypertension, vasospasm, atherosclerosis, and ischemia.1 ET-1 is implicated in the development and maintenance of hypertension because of its potent vasoconstrictor action.1 Other studies2 3 4 and our previous studies5 6 have found that ET-1 plays an important role in the pathogenesis of deoxycorticosterone acetate (DOCA)-salt–induced hypertension, on the basis of evidence showing that acute administration of ETA-selective receptor antagonists or nonselective ETA/ETB receptor antagonists to DOCA-salt rats produces a hypotensive effect and that long-term treatment with these agents suppresses the development of hypertension. We have found that chronic treatment with ETA-selective receptor antagonists improves tissue injuries in DOCA-salt rats.6 7 However, the pathological role of ETB receptor–mediated action in the DOCA-salt model of hypertension remains controversial.8 A recent study indicates that nonselective ETA/ETB receptor antagonists cause decreases in blood pressure to a degree similar to that found with ETA receptor–selective antagonists.9 We have found that chronic treatment with an ETB receptor–selective antagonist to DOCA-salt rats leads to a deterioration in DOCA-salt–induced cardiovascular and renal injuries,7 thereby suggesting that blockade of this receptor could be harmful in such pathological conditions. To confirm this view, we used the spotting-lethal (sl) rat, which carries a naturally occurring deletion in the ETB receptor gene,10 and we examined responses to DOCA-salt treatment.
The sl rat carries a naturally occurring 301-bp deletion in the 3' end of the first exon of the ETB gene. The deletion encompasses the first 2 transmembrane-spanning domains of the receptor and results in the activation of a cryptic splice donor site 15 bp upstream from the deletion. The shortened transcript does not encode a functional ETB receptor.10 Homozygous (sl/sl) rats exhibit abnormal development of neural crest–derived epidermal melanocytes and of the enteric nervous system that is similar to that described in ETB receptor–deficient mice and men; these rats do not live beyond 1 month because of intestinal aganglionosis and resulting intestinal obstruction. Studies using a dopamine ß-hydroxylase (DßH)/lacZ transgene have indicated that enteric neuroblasts are transiently adrenergic during gut colonization and that this colonization process is defective in ETB receptor–deficient mice.11 Therefore, the DßH promoter was used to direct ETB transgene expression in sl/sl rats to support normal enteric nervous system development.12 DßH-ETB sl/sl rats live into adulthood and are healthy, expressing ETB receptors in adrenal glands and other adrenergic neurons. They are ETB deficient in other tissues, but most important is the deficiency in the kidney, vascular endothelium, and vascular smooth muscle.13 Thus, the "rescued" ETB receptor–deficient rats are a useful tool in determining the pathophysiological roles of ETB receptors.
We report in the present study that ETB receptor–deficient rats exhibit an exaggerated blood pressure sensitivity and enhanced tissue injuries to DOCA-salt treatment, suggesting that ETB receptor–mediated actions are protective in the pathogenesis of DOCA-salt–induced hypertensive diseases. Furthermore, we examined the effect of chronic treatment with an ETA-selective receptor antagonist.
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Methods |
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Animals
The creation of DßH-ETB transgenic rats has been described previously.12 Homozygous sl/sl rats have dark eyes and pigmented coats only in small spots on their heads. Wild-type and heterozygous rats have pigmented heads, backs, and tails. To definitively differentiate these rats, polymerase chain reaction was performed on DNA isolated from tail biopsy specimens, as described.12
Experimental Protocol
Homozygous (sl/sl) and wild-type (+/+)
rats (weighing 160 to 180 g, aged 6 weeks), all of which were
DßH-ETB transgenic, were unilaterally
nephrectomized. After a 1-week postsurgical recovery period, the rats
were treated twice weekly with DOCA suspended in corn oil, administered
subcutaneously (15 mg/kg), and 1% NaCl was added to their drinking
water. These rats were randomly divided into 2 groups and given ABT-627
(10 mg/kg per day, twice daily by gavage; Abbott Laboratories), which
is a selective ETA receptor
antagonist, or vehicle. The dose of ABT-627 was shown to
abolish the ET-1–induced pressor effect.14 Control
rats were uninephrectomized (UN) but not given DOCA and salt.
Systolic blood pressure (SBP) was monitored once a week by the
tail-cuff method 
6 hours after drug administration. After 4 weeks of
treatment, urine was collected overnight by housing the rats in
individual metabolic cages. After urine collection, the
rats were exsanguinated, and arterial blood samples were
obtained. The heart, left kidney, and aorta were excised and weighed.
The thoracic aorta and left kidney were used for morphometric
analysis. A portion of left kidney and aortic tissues was
frozen separately for determination of tissue ET-1.
ET-1 Measurement
ET-1 was extracted from the kidney and aorta, according to our
method.15 Radioimmunoassay for tissue ET-1 was performed
with the use of ET-1 antiserum (a generous gift from Dr Marvin R.
Brown, University of California, San Diego), which does not cross-react
with big ET-1. ET-1 concentrations in plasma and urine were determined
by direct ELISA method without the extraction step (BIOMEDICA
Gesellschaft mbH).
Analytical Procedures
Blood urea nitrogen (BUN), protein, and creatinine
levels in plasma or urine were determined by use of the BUN-Test-Wako,
Total Protein-Test-Wako, and Creatinine-Test-Wako (Wako
Pure Chemical Industries), respectively. Urinary
ß-N-acetylglucosaminidase (NAG) activity, as an index of
proximal tubule damage, was measured by using the synthesized substrate
sodio-m-cresolsulfonphthaleinyl
ß-N-acetyl-D-glucosaminide. Urine
and plasma sodium concentrations were determined by use of a flame
photometer.
Histological Studies
The thoracic aorta and the left kidney of each rat were
preserved in phosphate-buffered 10% formalin, after which the tissues
were chopped into small pieces, embedded in paraffin, cut at 4
µm, and stained with hematoxylin-eosin. Three different cross
sections of each vessel placed under a microscope were photographed,
and the vessel wall area, thickness, and wall-to-lumen ratio were
determined by using an image analyzer (AE-6905C, ATTO). For
each kidney, one paraffin section, including 150 glomeruli and 85
small arteries, was evaluated by a blinded observer. For the evaluation
of tubular dilatation and atrophy, proteinaceous casts in tubuli,
fibrinoid-like necrosis in glomeruli, interstitial cell
infiltration, and thickening of small arteries, each cross section of
tissues was graded semiquantitatively. For all parameters,
each score mainly reflects changes in extent rather than intensity: -
indicates intact; ±, minimal; +, mild; ++, moderate; and +++,
severe.
Drugs
ABT-627 was dissolved in a mixture of 10% ethanol, 40%
propylene glycol, and 50% distilled water. Other chemicals were
obtained from Nacalai Tesque and Wako Pure Chemical Industries.
ABT-62716 is the active enantiomer of the racemate
A-127722,14 an orally active and highly potent
ETA-selective receptor antagonist.
Statistical Analysis
Values were expressed as mean±SEM. For statistical
analysis, we used the unpaired Student t test for
2-group comparison (homozygous versus wild-type rats). Multicomparisons
within groups were performed by 1-way ANOVA followed by a Bonferroni
multiple comparison test. Histological data for the
kidney were analyzed by the Kruskal-Wallis
nonparametric test combined with a Steel-type
multiple comparison test. For all comparisons, differences were
considered significant at P<0.05.
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Results |
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Changes in SBP
Basal SBPs (before the DOCA-salt treatment) of homozygous (sl/sl) and wild-type (+/+) rats were 131.3±1.3 mm Hg (n=31, P<0.001 versus wild-type) and 122.9±1.3 mm Hg (n=25), respectively. As shown in Figure 1
, SBP of both groups was progressively
elevated by treatment with DOCA and salt, but hypertensive effects were
much more pronounced in homozygous than in wild-type rats
(respec-tive values were 156.7±3.4 versus 133.0± 3.7 mm Hg at
1 week, P<0.01; 188.5±5.2 versus 144.3±3.7 mm Hg at 2
weeks, P<0.01; 208.1±5.5 versus 151.6±3.7 mm Hg at 3
weeks, P<0.01; and 206.0±4.5 versus 164.3±4.8 mm Hg at 4
weeks, P<0.01). Three of the 12 homozygous rats died at 3
weeks, although we could not determine the cause of death. UN control
rats from both groups showed no significant changes from each basal SBP
value. In both homozygous and wild-type rats, daily oral administration
of ABT-627 suppressed almost completely the development of hypertension
induced by DOCA-salt, although a significant increase in SBP was
observed only at 4 weeks in homozygous rats compared with UN control
rats.
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P<0.01 vs wild-type DOCA-salt rats.
Body, Heart, Kidney, and Aorta Weights
In homozygous rats, the body weight gain in vehicle-treated
DOCA-salt rats was much less than that in UN control rats (Table 1). ABT-627 treatment led to recovery of
losses. When heart and left kidney weights were corrected by body
weight, there were significant increases in each organ weight–to–body
weight ratio in vehicle-treated DOCA-salt rats. Aortic weight showed a
significant increase by the DOCA-salt treatment. These increments were
significantly suppressed by ABT-627 administration. Qualitatively
similar findings were obtained in wild-type rats, although changes
induced by DOCA-salt and ABT-627 treatments were less.
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Renal Function
Figures 2 and 3 illustrate changes of renal function
parameters at the end of the experimental period. Plasma
creatinine in homozygous rats revealed high levels compared
with levels in wild-type rats. In homozygous rats, DOCA-salt treatment
slightly increased plasma creatinine and BUN, whereas the
level of creatinine clearance decreased markedly, showing
diminished glomerular function. These changes were overcome
by ABT-627 administration. In wild-type rats, no significant
alterations in renal parameters were observed. DOCA-salt
treatment produced significant increases in the urinary excretion of
protein in both groups, although increases in the homozygous group were
greater. ABT-627 treatment markedly suppressed this increase in the
urinary excretion of protein in both groups (Figure 2). As shown
in Figure 3, NAG, the fractional excretion of sodium, and the
urinary excretion of sodium were markedly elevated by DOCA-salt
treatment in both homozygous and wild-type rats, and the level of each
parameter was significantly higher in homozygous rats
compared with wild-type rats. ABT-627 administration suppressed the
DOCA-salt–induced changes.
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P<0.05 and
Histological Findings in Kidney
Wild-type DOCA-salt rats revealed relatively mild damage
characterized by tubular dilatation and atrophy, proteinaceous casts in
tubuli, fibrinoid-like necrosis in glomeruli, interstitial
cell infiltration, and thickening of small arteries. These lesions were
significantly reduced by ABT-627 treatment. More severe histopathologic
changes were observed in homozygous DOCA-salt rats. ABT-627 treatment
markedly and significantly improved these changes (Table 2). Typical photographs of
different experimental groups are shown in Figure 4.
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Morphological Analysis of Aorta
Figures 5 and 6 show typical examples of
representative cross sections of the aorta obtained
from one each of UN control and DOCA-salt (with or without ABT-627)
rats in both the homozygous (Figure 5) and wild-type (Figure 6) groups. Increase in vascular medial thickness (wall
thickness), a characteristic finding for hypertensive
arterial hypertrophy, was evident in
vehicle-treated DOCA-salt rats from both homozygous and wild-type
groups. Treatment with ABT-627 suppressed this vascular change induced
by DOCA-salt. There were significant increases in wall thickness, wall
area, and the wall-to-lumen ratio in vehicle-treated DOCA-salt rats
compared with UN control rats, and the effects were more marked in
homozygous than in wild-type rats. Wall thickness and the wall-to-lumen
ratio were significantly greater in DOCA-salt–treated homozygous rats
than in wild-type rats. In both groups, ABT-627 markedly decreased
these parameters, and the observed values did not
significantly differ from those for UN control rats (Table 3).
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Renal, Urinary, Aortic, and Plasma ET-1 Contents
When ET-1 contents in renal tissues of UN control rats were
determined, there were significant increases in homozygous compared
with wild-type rats (0.402±0.033 versus 0.263±0.030 ng/g tissue,
respectively; P<0.01). DOCA-salt treatment markedly
increased the renal ET-1 content in homozygous rats, and this increase
was abolished by ABT-627 administration. No significant changes
occurred in the renal ET-1 content in wild-type rats. In contrast,
DOCA-salt treatment significantly increased aortic ET-1 content in both
homozygous and wild-type rats, although the extent in wild-type rats
was small (from 1.090±0.501 to 6.270±1.310 ng/g tissue in homozygous
rats, P<0.01; from 0.484±0.108 to 1.070±0.098 ng/g tissue
in wild-type rats, P<0.01). These increases were abolished
by ABT-627 administration. There were no differences in plasma ET-1
levels in homozygous and wild-type UN control rats. In homozygous rats,
DOCA-salt treatment did not affect plasma ET-1 levels, but there were
notable increases with ABT-627 administration. In the wild-type rats,
slight but significant increases in plasma ET-1 level were observed.
Urinary ET-1 content was significantly increased by treatment with
DOCA-salt in both homozygous and wild-type rats, although observed
values were higher in homozygous rats. ABT-627 efficiently suppressed
these increases in both groups (Figure 7).
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Discussion |
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We investigated the pathological role of the ETB receptor in DOCA-salt–induced hypertension and related tissue injuries with the use of rescued ETB-deficient rats.12 These rats express ETB receptors in the adrenal glands and other adrenergic neurons, but they are ETB deficient in other tissues, but most important is the deficiency in the kidney, vascular endothelium, and vascular smooth muscle.13 In addition, we preliminarily confirmed that ETB receptor–mediated responses, endothelium-dependent vasorelaxation, endothelium-independent vasoconstriction, and diuretic action were not observed in these rats. Thus, rescued ETB-deficient rats are a useful tool in evaluating the pathophysiological roles of ETB receptors, particularly in renal and/or cardiovascular diseases. In the present study, these rats clearly exhibited an exaggerated blood pressure sensitivity to DOCA-salt treatment compared with the sensitivity in wild-type rats, as noticed in our preliminary report,17 in which homozygous rats treated with DOCA-salt exhibited an earlier onset of hypertension than did heterozygous and wild-type rats. In addition, the ETB-deficient rats had enhanced cardiovascular hypertrophy and worsening of renal dysfunction and tissue damage after the DOCA-salt treatment. These findings lead us to propose that ETB receptor–mediated actions are protective in the pathogenesis of DOCA-salt–induced hypertension.
Long-term treatment with selective ETA receptor antagonists or nonselective ETA/ETB receptor antagonists prevents DOCA-salt–induced hypertension and related tissue injuries, such as vascular hypertrophy, in a qualitatively similar fashion.4 6 7 9 18 Chronic treatment with selective ETA receptor antagonists attenuates the development of hypertension and renal injury in Dahl salt-sensitive rats19 and in salt-loaded stroke-prone spontaneously hypertensive rats.20 Thus, although it is unknown which type of antagonist is favorable for the treatment of these hypertensive models, there is general agreement that ETA receptor–mediated action plays an important role in the development of salt-dependent hypertension and associated tissue injury.8 We have recently found that chronic treatment of DOCA-salt rats with A-192621, an orally active and highly potent ETB-selective receptor antagonist,16 leads to an exaggerated deterioration of cardiovascular and renal injuries,7 thereby suggesting that the blockade of this receptor subtype is harmful in such pathological conditions. In addition, the hypertensive effect induced by an intravenous bolus injection of Ro 46-8443, a selective ETB receptor antagonist, in DOCA-salt rats was greater than that in UN control rats.21 Renal vasoconstrictor effects induced by BQ-788 were also enhanced in DOCA-salt hypertensive rats.22 These findings suggest that the lack of ETB-mediated systemic and renal vasodilative activities is at least partly responsible for the deterioration of DOCA-salt–induced hypertensive diseases observed in ETB-deficient rats.
Exaggerated blood pressure sensitivity and enhanced cardiovascular and renal injuries observed in ETB-deficient homozygous rats were markedly suppressed by the daily administration of ABT-627, a potent ETA-selective receptor antagonist.16 Previous studies, including ours, have demonstrated that ET-1 content and ET-1 mRNA expression were elevated in vascular tissues of DOCA-salt hypertensive rats5 23 24 and Dahl salt-sensitive rats.25 In the present study, ET-1 contents in aortic and renal tissues were markedly increased in DOCA-salt–treated homozygous rats, and increments were abolished by blockade of ETA receptors, accompanied by marked elevation in plasma ET-1. Taken together, it seems likely that the enhancement of ET-1 production and ETA-mediated action mainly contributes to the augmentation of DOCA-salt–induced hypertensive injuries observed in ETB-deficient homozygous rats and that the greater part of aortic and renal ET-1 derives from ETA receptor binding. In addition, our preliminary investigation (authors’ unpublished data, 2000) indicated that ETB-deficient rats exhibit increased sensitivity to ETA-mediated hypertensive and vasoconstrictor actions induced by exogenous ET-1, both in vivo and in vitro. These results suggest that the antagonism of the ETA receptor is essential for the protection from DOCA-salt–induced hypertensive injuries, irrespective of the presence of the ETB receptor. This view might explain the findings that selective ETA receptor antagonists and nonselective ETA/ETB receptor antagonists similarly improve DOCA-salt–induced hypertension and related tissue injuries.4 6 7 9 18 Further studies on tissue distribution, localization, density, and affinity of ETA receptors in the ETB-deficient rats are required to clarify the mechanisms of increased susceptibility to ETA-mediated ET-1 action in these animals.
In contrast to renal ET-1 content in homozygous rats, renal ET-1 content in wild-type rats was not increased by DOCA-salt treatment. We previously noted that ET-1 mRNA expression but not ET-1 content increased in the kidney of DOCA-salt hypertensive rats.5 26 One possible explanation for the discrepancy between gene and peptide expression is that the renal tissues are abundant in ET-1–degrading enzymes, such as neutral endopeptidase.27 28 On the basis of the finding that the urinary ET-1 level, which is known to reflect the renal ET-1 expression,29 was significantly increased by the DOCA-salt treatment, it seems likely that ET-1 production in the kidney is upregulated in DOCA-salt–treated wild-type rats. In homozygous rats, the augmentation of renal ET-1 production may overcome the capacity for enzymatic degradation, leading to higher tissue content. This view may be applicable to aortic ET-1 content.
DOCA-salt–induced cardiovascular hypertrophy and renal injury were markedly augmented in ETB-deficient homozygous rats compared with wild-type rats. It is unclear whether the augmentation results from exaggerated blood pressure sensitivity to DOCA-salt treatment. In our recent study,7 daily administration of A-192621 caused greater deterioration of the DOCA-salt–induced cardiovascular and renal injuries, with no changes in SBP. Thus, the above augmentation seems to be independent of blood pressure. Elevated blood pressure itself has been known to play a major role in cardiovascular hypertrophy and remodeling. However, there is growing evidence that the cardiovascular hypertrophy and remodeling are not simply a response to elevated blood pressure and that various vasoactive substances, such as angiotensin II, are implicated in the development of these structural changes.30 ET-1 has potent mitogenic and hypertrophic properties, mainly via the stimulation of ETA receptors.31 On the other hand, ETB receptor–mediated action may protect against cardiovascular hypertrophy via endothelial NO generation, which inhibits mitogenesis and the proliferation of vascular smooth muscle cells.32 It is reasonable to consider that the augmentation of cardiovascular hypertrophy in ETB-deficient homozygous rats is attributable to both an increase in ETA-mediated hypertrophic activity and a lack of ETB-mediated antihypertrophic activity.
We recently noted that chronic treatment with A-192621 to DOCA-salt rats failed to further increase the blood pressure.7 This is in conflict with the present finding but may be explained by an increased ETA-mediated ET-1 action in ETB-deficient homozygous rats. In addition, the exaggerated blood pressure sensitivity in homozygous rats was observed at an early phase of DOCA-salt treatment (1 to 2 weeks). In our previous study,7 A-192621 was administered 2 weeks after the start of DOCA-salt treatment. Thus, ETB-mediated protection from DOCA-salt–induced hypertension may be most important at an early phase.
Blood pressure assessment of homozygous rats before DOCA-salt treatment revealed a higher level than that seen in wild-type rats. The lack of ETB-mediated ET-1 activity (eg, vasodilatory mechanisms) and/or an increase in ETA-mediated action may be involved in this phenomenon. Another possible explanation is that elevated blood pressure may be related to the enhanced salt sensitivity of these animals.13 Several studies indicate that ETB receptor stimulation inhibits sodium reabsorption at the tubular level,22 33 suggesting a role of ETB receptors in natriuretic mechanisms. It is possible that an ETB-deficient condition leads to the enhancement of tubular sodium reabsorption, which is known to be a causal factor of salt-sensitive hypertension.34
We conclude that ETB receptor–mediated actions are protective in the pathogenesis of DOCA-salt–induced hypertension. Enhancements of ET-1 production and ETA-mediated actions are responsible for the increased susceptibility to DOCA-salt–induced hypertension and tissue injuries in ETB receptor–deficient rats.
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Acknowledgments |
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This study was supported in part by a Grant-in-Aid for Scientific Research from the Ministry of Education, Science, Sports, and Culture of Japan, the Science Research Promotion Fund of Japan Private School Promotion Foundation, and the Naito Foundation. Dr Yanagisawa is an investigator and Dr Gariepy is an associate of the Howard Hughes Medical Institute. The authors are grateful to Dr Eugene I. Novosad (Abbott Laboratories) for supporting this work.
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Footnotes |
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Reprint requests to Yasuo Matsumura, PhD, Department of Pharmacology, Osaka University of Pharmaceutical Sciences, 4-20-1 Nasahara, Takatsuki, Osaka 569-1094, Japan.
Received April 26, 2000; revision received June 21, 2000; accepted June 21, 2000.
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