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(Hypertension. 1999;33:759-765.)
© 1999 American Heart Association, Inc.
Scientific Contributions |
Different Contributions of Endothelin-A and Endothelin-B Receptors in the Pathogenesis of Deoxycorticosterone Acetate–Salt–Induced Hypertension in Rats
From the Department of Pharmacology, Osaka University of Pharmaceutical Sciences, Nasahara, Takatsuki, Osaka, Japan, and the Diabetes and Vascular Research Division (T.J.O.), Abbott Laboratories, Abbott Park, Ill.
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Abstract |
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Abstract—We investigated the involvement of actions mediated by endothelin-A (ETA) and endothelin-B (ETB) receptors in the pathogenesis of deoxycorticosterone acetate (DOCA)–salt–induced hypertension in rats. Two weeks after the start of DOCA-salt treatment, rats were given ABT-627 (10 [mg/kg]/d), a selective ETA receptor antagonist; A-192621 (30 [mg/kg]/d), a selective ETB receptor antagonist; or their vehicle for 2 weeks. Uninephrectomized rats without DOCA-salt treatment served as controls. Treatment with DOCA and salt for 2 weeks led to a mild but significant hypertension; in vehicle-treated DOCA-salt rats, systolic blood pressure increased markedly after 3 to 4 weeks. Daily administration of ABT-627 for 2 weeks almost abolished any further increases in blood pressure, whereas A-192621 did not affect the development of DOCA-salt–induced hypertension. When the degree of vascular hypertrophy of the aorta was histochemically evaluated at 4 weeks, there were significant increases in wall thickness, wall area, and wall-to-lumen ratio in vehicle-treated DOCA-salt rats compared with uninephrectomized control rats. The development of vascular hypertrophy was markedly suppressed by ABT-627. In contrast, treatment with A-192621 significantly exaggerated these vascular changes. In vehicle-treated DOCA-salt rats, renal blood flow and creatinine clearance decreased, and urinary excretion of protein, blood urea nitrogen, fractional excretion of sodium, and urinary N-acetyl-ß-glucosaminidase activity increased. Such damage was overcome by treatment with ABT-627 but not with A-192621; indeed, the latter agent led to worsening of the renal dysfunction. Histopathologic examination of the kidney in vehicle-treated DOCA-salt rats revealed tubular dilatation and atrophy as well as thickening of small arteries. Such damage was reduced in animals given ABT-627, whereas more severe histopathologic changes were observed in A-192621–treated animals. These results strongly support the view that ETA receptor–mediated action plays an important role in the pathogenesis of DOCA-salt–induced hypertension. On the other hand, it seems likely that the ETB receptor–mediated action protects against vascular and renal injuries in this model of hypertension. A selective ETA receptor antagonist is likely to be useful for treatment of subjects with mineralocorticoid-dependent hypertension, whereas ETB-selective antagonism alone is detrimental to such cases.
Key Words: receptors, endothelin • hypertension, DOCA-salt • renal function • vascular hypertrophy
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Introduction |
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There is accumulating evidence indicating that endothelin-1 (ET-1) plays an important role in the development and/or maintenance of hypertension in animal models such as the deoxycorticosterone acetate (DOCA)–salt–induced hypertensive rat1 2 3 4 5 6 and Dahl salt-sensitive rat.7 8 This view is based on findings indicating that acute administration of an endothelin-A (ETA)–selective receptor antagonist or nonselective ETA/ETB receptor antagonist to DOCA-salt rats produces a potent hypotensive effect and that long-term treatment with these agents efficiently suppresses the development of hypertension.2 3 4 7 8 Furthermore, it has been demonstrated that ET-1 content and ET-1 mRNA expression were elevated in vascular tissues of DOCA-salt hypertensive rats.4 5 6 Several studies have noted that hypertension-related renal damage in Dahl salt-sensitive rats and in rats with reduced renal mass was largely overcome by treatment with ETA-selective receptor antagonists.8 9 We noted the ameliorating effect of FR 139317, an ETA-selective receptor antagonist, on decreased renal function of DOCA-salt hypertensive rats.10 On the other hand, both ETA-selective and nonselective ETA/ETB receptor antagonists have been reported to prevent various cardiovascular diseases, such as acute ischemic renal failure11 12 13 and chronic heart failure,14 15 in animal models. Thus, it remains obscure as to whether blockade of the ETB receptor is beneficial for the treatment of subjects with cardiovascular diseases.
ABT-627 is the active enantiomer of the racemate A-127722, an orally active and highly potent ETA-selective receptor antagonist.16 The development of hypertension in DOCA-salt rats was significantly suppressed by long-term treatment with A-127722 (10 [mg/kg]/d).17 18 In addition, A-127722 has been reported to prevent hypoxia-induced pulmonary hypertension in rats19 and to reduce neointimal hyperplasia after balloon-induced vascular injury in pigs.20 A-192621 is an ETB-selective receptor antagonist developed from the structure-activity relationships of 1,2,4-trisubstituted pyrrolidine-3-carboxylic acid, which is also homologous to ABT-627.21 A-192621 displays high potency (Ki=8.8 nmol/L) in inhibiting 125I–ET-1 binding to human ETB receptors but is approximately 700-fold less potent (Ki=5.6 µmol/L) for human ETA receptors.22 A-192621 effectively inhibits sarafotoxin S6c–induced contractions in isolated endothelium-denuded rabbit pulmonary artery (ETB, pA2=8.4) but not ET-1–induced contractions in rat aorta (ETA, pA2=5.2).22 The oral administration of A-192621 in a dose of 30 mg/kg has been reported to inhibit almost completely ETB receptor–mediated depressor and pressor responses.22 In the present work, to differentiate the roles of ETA and ETB receptors in the pathogenesis of cardiovascular diseases, we investigated the effects of chronic treatment with A-192621 on the development of hypertension, cardiovascular hypertrophy, and renal injury in DOCA-salt hypertensive rats and compared them with the effects seen with ABT-627.
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Methods |
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Animals and Experimental Design
Male Sprague-Dawley rats (SLC, Inc, Hamamatsu, Japan) weighing 160 to 180 g were anesthetized with sodium pentobarbital (40 mg/kg IP), and the right kidney was removed via a right flank incision. After a 1-week recovery period, these rats were treated twice weekly with DOCA suspended in corn oil and administered subcutaneously (15 mg/kg), and 1% NaCl was added to their tap water for drinking. Control rats (n=10) were uninephrectomized but not given DOCA and salt. Two weeks after the start of DOCA-salt treatment, these rats were randomly divided into three groups and were given ABT-627 (n=8), A-192621 (n=6), or vehicle (n=10) for 2 weeks. Body weight and blood pressure (BP) did not differ significantly among the three groups before the initiation of drug treatment. ABT-627 (10 [mg/kg]/d), A-192621 (30 [mg/kg]/d), or vehicle was given twice daily by gavage. These doses of ABT-627 and A-192621 have previously been shown to almost abolish the exogenous ET-1–induced pressor effect and sarafotoxin S6c–induced depressor and pressor effects, respectively.16 22 Systolic BP was monitored once a week by the tail-cuff method and about 6 hours after drug administration. Two weeks after the start of drug administration, urine was collected overnight by housing the animals in individual metabolic cages (after the final drug treatment). After urine collection, all rats were anesthetized with sodium thiobutabarbital (Inactin, 100 mg/kg IP), and basal renal blood flow was measured with an electromagnetic flow probe (1.0 mm in diameter, Nihon Kohden) positioned on the left renal artery and connected to a square-wave flowmeter (MFV-2100, Nihon Kohden). The animals were then exsanguinated, and arterial blood samples were obtained. The heart, left kidney, and aorta were also excised. In some rats from each group, the thoracic aorta and left kidney were used for morphometric analysis.
In separate experiments, ABT-627 (n=4) or A-192621 (n=4) was given to uninephrectomized control animals in the same manner as described above, and these treatments did not affect body weight gain and renal functional parameters. These treatments also did not affect systolic BP, although A-192621 tended to increase it gradually (from 119±3 mm Hg at 2 weeks to 122±3 and 126±3 mm Hg at 3 and 4 weeks, respectively).
Analytical Procedures
Blood urea nitrogen (BUN) and protein and
creatinine levels in plasma or urine were determined with
the BUN-test-Wako, Total protein-test-Wako. and
Creatinine-test-Wako (Wako Pure Chemical Industries),
respectively. Urinary N-acetyl-ß-glucosaminidase (NAG)
activity was measured as an index of damage to the proximal tubules
using the synthesized substrate sodio-m-cresolsulfonphthaleinyl
N-acetyl-ß-D-glucosaminide. Urine
and plasma sodium concentrations were determined with a flame
photometer (Hitachi, 205D). Fractional excretion of sodium
(FENa) (%) was calculated from the formula
FENa=UNaV/(PNaxcreatinine
clearance)x100, where UNaV is urinary excretion
of sodium and PNa is plasma sodium
concentration.
Histological Studies
The thoracic aorta and left kidney of each rat was 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 and eosin. Three different cross sections of
each vessel placed under a microscope were photographed, and vessel
wall area, wall thickness, and wall-to-lumen ratio were determined with
an image analyzer (AE-6905C, ATTO).
Drugs
ABT-627 and A-192621 were provided by Abbott Laboratories.
ABT-627 was dissolved in a mixture of 10% ethanol, 40% propylene
glycol, and 50% distilled water. A-192621 was dissolved in 0.02N NaOH.
Other chemicals were obtained from Nacalai Tesque and Wako Pure
Chemical Industries.
Statistical Analysis
Values are expressed as mean±SEM. For statistical
analysis, we used one-way ANOVA followed by Bonferroni's
multiple comparison test. For all comparisons, differences were
considered significant at a value of P<0.05.
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Results |
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Effects of Treatment with ABT-627 or A-192621 on BP of DOCA-Salt Hypertensive Rats
As shown in Figure 1, systolic BP was progressively elevated by treatment with DOCA and salt. After 2 weeks of treatment, systolic BP increased significantly compared with systolic BP in the uninephrectomized control group. Four weeks after the start of DOCA-salt treatment, the systolic BP of vehicle-treated DOCA-salt rats was 185±6 mm Hg, whereas that of the uninephrectomized control group was 118±3 mm Hg. Daily oral administration of ABT-627 for 2 weeks markedly suppressed the development of hypertension induced by DOCA and salt. The observed increment during ABT-627 treatment for 2 weeks was only 4 mm Hg (from 136±3 mm Hg at 2 weeks to 140±3 mm Hg at 4 weeks). In contrast, A-192621 treatment did not affect the development of hypertension induced by DOCA and salt.
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P<0.01 vs vehicle-treated DOCA-salt
rats.
Effects of Treatment with ABT-627 or A-192621 on Body, Heart, and
Kidney Weights of DOCA-Salt Hypertensive Rats
At 2 weeks of the experimental period, body weights of
uninephrectomized control, vehicle-treated DOCA-salt, ABT-627–treated
DOCA-salt, and A-192621–treated DOCA-salt rats were 285±6, 280±3,
284±4, and 288±4 g, respectively. At the end of the experimental
period (at 4 weeks), the gain in body weight in vehicle-treated
DOCA-salt rats was less than that in uninephrectomized control rats. As
shown in Table 1, treatment with
ABT-627 led to the recovery of losses. On the other hand, treatment
with A-192621 accelerated body weight losses induced by DOCA and salt.
Unexpectedly, 1 of the 6 rats treated with A-192621 died at 4 weeks
(before urine collection). No brain hemorrhage was
observed.
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When heart, left ventricular, and left kidney weights were corrected for body weight, each organ weight–to–body weight ratio increased significantly in vehicle-treated DOCA-salt hypertensive rats. These increments were significantly suppressed by treatment with ABT-627 but not with A-192621 (Table 1).
Effects of Treatment With ABT-627 or A-192621 on Blood and Urinary
Parameters of DOCA-Salt Hypertensive Rats
Table 2 summarizes renal functional
parameters at the end of the experimental period. The
levels of urinary excretion of protein, FENa, and
urinary NAG activity in vehicle-treated DOCA-salt hypertensive rats
were markedly elevated compared with findings in uninephrectomized
control rats, although BUN in DOCA-salt rats did not increase
significantly. On the other hand, significant decreases in
creatinine clearance and renal blood flow were observed in
vehicle-treated DOCA-salt hypertensive rats. These functional changes
were markedly overcome by treatment with ABT-627. In contrast, A-192621
led to greater deterioration in functional parameters
(except for FENa) than was seen in
vehicle-treated DOCA-salt rats, achieving statistical significance in
the levels of urinary excretion of protein and BUN.
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Effects of Treatment With ABT-627 or A-192621 on
Histological Renal Damage in DOCA-Salt
Hypertensive Rats
Figure 2 shows typical examples in
renal tissues of uninephrectomized control and DOCA-salt rats.
Histological examination of the kidney in
vehicle-treated DOCA-salt rats revealed relatively mild damage
characterized by tubular dilatation and atrophy as well as thickening
of small arteries (Figure 2b). Treatment with ABT-627 reduced
such damage (Figure 2c), whereas more severe histopathologic
changes—such as fibrinoid-like necrosis in glomeruli, thickening of
small arteries, tubular dilatation and atrophy, proteinaceous casts in
tubuli, and interstitial cell infiltration—were observed
in A-192621–treated animals (Figure 2d).
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Effects of Treatment With ABT-627 or A-192621 on the Vascular
Hypertrophy of DOCA-Salt Hypertensive Rats
Figure 3 shows examples of
representative cross sections of the aorta obtained
from 1 animal of each group. An increase in vascular medial thickness
(wall thickness), a characteristic finding for hypertensive
arterial hypertrophy, was clearly evident in
vehicle-treated DOCA-salt rats. Treatment with ABT-627 but not with
A-192621 markedly suppressed this vascular change induced by DOCA and
salt. As summarized in Table 3, wall
thickness, wall area, and wall-to-lumen ratio showed significant
increases in vehicle-treated DOCA-salt rats compared with
uninephrectomized control rats. ABT-627 decreased these
parameters of vascular hypertrophy, and the
observed values did not significantly differ from those for
uninephrectomized control rats. In contrast, treatment with A-192621
significantly enhanced DOCA-salt–induced vascular changes.
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Discussion |
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Physiological and pathophysiological responses to ET-1 in various tissues are mediated by interactions with ETA and ETB receptor subtypes. Both subtypes on smooth muscle cells mediate vasoconstriction, whereas the ETB receptor subtype on endothelial cells mediates vasodilation, possibly through the release of endothelium-derived relaxing factor.23 ET-1 may contribute to the maintenance or regulation of BP through potent vasoconstrictive effects.24 However, the pathophysiological role of this peptide in the development and/or maintenance of hypertension has not been fully elucidated.
We have found that chronic treatment with FR 139317, an
ETA-selective tripeptide antagonist,
suppressed the development of hypertension and
cardiovascular hypertrophy in DOCA-salt
hypertensive rats.3 Similar observations were obtained
using the nonselective
ETA/ETB receptor
antagonist bosentan.2 In the present
study, we used a newly developed ETB-selective
receptor antagonist, A-192621,22 and a highly
potent ETA-selective receptor
antagonist, ABT-627,16 both of which are
active when ingested orally. Our findings clearly indicated that daily
administration of ABT-627 2 weeks after the start of DOCA-salt
treatment markedly suppressed further increments in BP, accompanied by
a significant decrease in cardiac and vascular wall hypertrophies.
These results were qualitatively similar to those seen with FR 139317,
although the antihypertensive effect of ABT-627 was indeed efficacious.
In contrast, ETB receptor blockade with A-192621
produced no significant effects on the development of hypertension
induced by DOCA and salt. To our knowledge, this is the first report
examining the long-term effect of an
ETB-selective receptor antagonist on
the pathogenesis of an animal model of hypertension. Although heart
weight and left ventricular weight corrected by body weight
were not significantly changed, the ETB-selective
receptor antagonist enhanced DOCA-salt–induced
arteriosclerotic changes. The latter finding
suggests that ETB receptor–mediated action
protects against vascular hypertrophy in this type of
hypertension. This ETB receptor–mediated action
may be attributed to endogenous endothelial
nitric oxide generation, which inhibits mitogenesis and proliferation
of vascular smooth muscle cells.25 We recently noted that
the aorta weight of DOCA-salt hypertensive rats was further increased
by long-term treatment with the nitric oxide synthase
inhibitor
NG-nitro-L-arginine
(Y.M. et al, unpublished data, 1998). Li et al26 also
noted the increased severity of conduit artery hypertrophy
by treatment with
N
-nitro-L-arginine
methyl ester in DOCA-salt hypertensive rats, although the agent reduced
small artery hypertrophy through undetermined mechanisms.
Regardless of mechanisms underlying ETB
receptor–mediated actions, our findings mean that
ETB receptor blockade is deleterious in this
model of hypertension.
Effects of ABT-627 and A-192621 on renal function are of particular interest. Nephroprotective effects of chronic treatment with ETA-selective receptor antagonists have been noted using LU 135252 in stroke-prone spontaneously hypertensive rats27 and using A-127722 in Dahl salt-sensitive rats.8 In the present study, we also noted that treatment with ABT-627 markedly improved both glomerular and tubular functions in DOCA-salt hypertensive rats. On the other hand, Allcock et al18 have recently observed that ETA receptor antagonism with A-127722 does not improve the decreased renal function in DOCA-salt hypertensive rats, although the agent attenuated the development and maintenance of hypertension in these rats. The reason for this discrepancy is unknown, but differences in experimental protocol (eg, drug administration in drinking water in Allcock's study versus by gavage twice daily in our study) may influence the efficacy of the drug. In contrast, functional damage of the kidney induced by DOCA and salt was accelerated by treatment with A-192621, as indicated by increases in urinary excretion of protein and BUN. In addition, these functional changes were accompanied by histopathologic changes in the kidney. Thus, ETA and ETB receptor antagonists revealed highly contrasting results against renal damage induced by DOCA and salt. Although further studies are required to clarify the mechanisms underlying the detrimental effect of ETB receptor blockade, endogenous ET-1/ETB receptor systems seem to function as a nephroprotective factor in DOCA-salt–induced hypertension.
Long-term treatment with A-192621 to uninephrectomized control animals produced no changes in renal functional parameters. ABT-627 also had no significant effect in uninephrectomized animals. We noted that renal vasoconstrictive effects induced by an intravenous bolus injection of BQ-788, a selective ETB receptor antagonist,28 were markedly enhanced in DOCA-salt hypertensive rats.29 On the other hand, we found that acute administration of FR 139317 to DOCA-salt hypertensive rats had a potent hypotensive effect and natriuretic effect (when renal perfusion pressure was protected from FR 139317–induced hypotension with an aortic clamp), although the agent had no significant effects on hemodynamic and excretory responses in normotensive animals.10 Taken together, it seems likely that endogenous endothelin does not play an important role in the regulation of renal function under normal conditions, in contrast to the case of DOCA-salt–induced hypertension, in which vascular and renal endothelin production is enhanced.4 5 6 30
In the present study, systolic BP was monitored once a week and about 6 hours after drug administration (drugs were given twice daily every 12 hours). Thus, we did not observe BP changes that might occur immediately after drug administration. We recently noted that the hypertensive effects induced by an intravenous bolus injection of BQ-788 in DOCA-salt hypertensive rats were greater than those in uninephrectomized control normotensive animals (increase of 10 to 20 mm Hg in DOCA-salt rats versus one of 5 to 10 mm Hg in sham rats), although the increased level recovered at about 30 minutes after BQ-788 administration.29 Similar findings were observed using Ro 46–8443, the nonpeptide selective ETB receptor antagonist.31 In separate experiments, intravenous administration of A-192621 (3 mg/kg) to DOCA-salt hypertensive rats produced increases of 10 to 15 mm Hg in BP and decreases of about 60% in renal blood flow, changes that were greater than those observed in uninephrectomized control normotensive animals (increases of 5 to 10 mm Hg in BP and decreases of about 40% in renal blood flow) (Y.M. et al, unpublished data, 1998). Taken together, the possibility cannot be ruled out that transient changes in BP and renal hemodynamics induced by A-192621 administration are related to its deleterious effect on vascular hypertrophy and renal damage.
It is unclear whether the ameliorating effects of ABT-627 on the above vascular and renal changes result from its antihypertensive action. Recent studies indicated that the ET-1/ETA receptor system may be an important mediator in the pathogenesis of postischemic acute renal failure, based on findings that ET-1 mRNA expression is markedly enhanced in the postischemic kidney32 and that a selective ETA receptor antagonist prevents postischemic renal damage, such as decreases in renal blood flow and glomerular filtration rate, and tubular dysfunction.11 12 Further investigations are required to clarify whether the ABT-627–induced improvement in vascular hypertrophy and renal damage in DOCA-salt hypertension is independent of its antihypertensive activity.
In conclusion, selective ETA receptor blockade efficiently overcame the development of hypertension, vascular hypertrophy, and renal injury in DOCA-salt hypertensive rats, whereas selective ETB receptor blockade led to a deterioration in DOCA-salt–induced pathologies. Our working hypothesis is that ETA receptor–mediated actions are causal factors and ETB receptor–mediated actions are protective factors in the pathogenesis of DOCA-salt–induced hypertension. A selective ETA receptor antagonist should prove effective for treating subjects with mineralocorticoid-dependent hypertension.
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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. The authors are grateful to Mariko Ohara for critical comments and Drs Eugene I. Novosad and Jerry L. Wessale (Abbott Laboratories, Abbott Park, Ill) for supporting this work. We also thank Dr Mamoru Koyama (Yoshitomi Pharmaceutical Industries, Ltd, Osaka, Japan) for assistance with morphometric studies.
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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 August 17, 1998; first decision September 23, 1998; accepted November 11, 1998.
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