© 2001 American Heart Association, Inc.
Vascular Biology |
ACE Inhibitor and AT1 Antagonist Blockade of Deformation-Induced Gene Expression in the Rabbit Jugular Vein Through B2 Receptor Activation
From the Department of Cardiovascular Physiology, University of Göttingen, Göttingen, Germany.
Correspondence to Dr Markus Hecker, Department of Cardiovascular Physiology, University of Göttingen, Humboldtallee 23, 37073 Göttingen, Germany. E-mail hecker{at}veg-physiol.med.uni-goettingen.de
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Abstract |
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Abstract—Deformation-induced endothelin-1 synthesis in endothelial cells may contribute to the intimal hyperplasia of venous bypass grafts. ACE inhibitors and angiotensin II type 1 (AT1) receptor antagonists are capable of reducing vein graft disease. Therefore, the effects of these drugs on endothelial preproendothelin-1 (ppET-1) and smooth muscle endothelin B receptor (ETB-R) expression were investigated in isolated perfused segments of the rabbit jugular vein. Pretreatment with ramiprilat (0.3 µmol/L) or irbesartan (0.01 to 1 µmol/L) had no effect on basal ppET-1 or ETB-R expression but markedly attenuated the deformation-induced expression of these gene products, and these effects were reversed by the B2 receptor antagonist icatibant (Hoe 140) and by the NO synthase inhibitor NG-nitro-L-arginine. Candesartan (1 µmol/L) mimicked the inhibitory effect of irbesartan. Moreover, reporter gene analysis with a rat ppET-1 promoter-luciferase construct transiently transfected into porcine aortic cultured endothelial cells revealed that the inhibitory effect of both ramiprilat and irbesartan on deformation-induced ppET-1 expression is species independent and mediated at the level of transcription. In addition, RT-PCR analysis detected only AT1 receptor expression in the endothelium-intact rabbit jugular vein, and neither irbesartan nor ramiprilat affected endothelial NO synthase expression. Thus, ACE inhibitors and AT1 receptor antagonists are capable of suppressing deformation-induced gene expression in the vessel wall in both an autocrine (ppET-1) and a paracrine (ETB-R) manner via a common mechanism of action that constitutes a B2 receptor–mediated increase in endothelial NO release.
Key Words: blood pressure • endothelin-1 • gene expression • graft failure • nitric oxide
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Introduction |
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Excessive mechanical strain after exposure to arterial levels of blood pressure could trigger the vasculopathy of venous bypass grafts and lead to graft failure.1 Moreover, pressure overload of the vessel wall seems to be involved in both hypertension-induced arterial remodeling2 and restenosis after PTCA.3 Among the various mediators implicated in these putatively deformation-induced changes in smooth muscle cell (SMC) phenotype, endothelin-1 (ET-1), a potent comitogen for vascular SMCs, may play a pivotal role.3 4 5
Thus, rhythmic deformation has been shown to enhance the synthesis of ET-1 in cultured endothelial cells (ECs), and this effect is presumed to occur at the level of transcription of the preproendothelin-1 (ppET-1) gene.6 7 To investigate whether a pressure-induced deformation of ECs also affects ppET-1 gene expression in the vessel wall in situ, we developed an experimental model in which isolated rabbit blood vessel segments are perfused at different levels of intraluminal pressure. With the aid of this model, we were recently able to demonstrate that ET-1 synthesis in the endothelium of both the carotid artery and the jugular vein of the rabbit is markedly upregulated on exposure to a supraphysiological increase in perfusion pressure and that this effect occurs at the level of ppET-1 gene expression.8 9 Moreover, this pressure-induced increase in ET-1 synthesis was accompanied by a marked increase in endothelin B receptor (ETB-R) expression in the vascular SMCs and subsequent changes in their phenotype ranging from apoptosis in the carotid artery9 to proliferation in the jugular vein (see also Porter et al10 regarding the human saphenous vein).
Both ACE inhibitors and angiotensin II type 1 (AT1) receptor antagonists not only are first-line antihypertensive drugs but also possess a substantial cardiac and vascular protective potential, as highlighted by several recent clinical and experimental studies.11 12 Moreover, ACE inhibitors, but not AT1 receptor antagonists, have been shown to attenuate the release of ET-1 from cultured ECs,13 presumably through a kinin-dependent mechanism.14 We have now investigated whether an ACE inhibitor and/or an AT1 receptor antagonist interferes with the pressure-induced rise in endothelial ET-1 synthesis and smooth muscle ETB-R abundance in the rabbit jugular vein and, if so, which signaling mechanism may be involved therein.
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Methods |
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In Situ Model
Segments of the external jugular vein of male New Zealand White rabbits were prepared and perfused with Tyrode’s solution as described previously.8 In experiments with drug treatment, these were added to the luminal perfusate during the equilibration phase at 0 mm Hg (usually 30 minutes) before the perfusion pressure was raised to 20 mm Hg for 6 hours. At the end of the perfusion period, the segments were snap frozen in liquid N2 and stored at -80°C.
Superfusion Bioassay
Four venous ring segments (3 to 4 mm long) were
tested simultaneously by mounting them between force
transducers and a rigid support for measurement of isometric force
(TSE). The rings were superfused at 1 mL/min with warmed (37°C),
oxygenated
(PO2
>300 mm Hg) Krebs-Henseleit solution, pH
7.4.8 Passive tension was
adjusted during a 30-minute equilibration period to 0.5 g.
Thereafter, increasing doses of bradykinin (Bachem) or sarafotoxin 6c
(Alexis) were applied as bolus injections in 30-minute intervals, and
the ensuing constrictor response was monitored with the aid of a
digital PC-operated analysis system (Biosys;
TSE).
Cell Culture
ECs were isolated from porcine aortae through
treatment with 1 U/mL dispase in HEPES-modified Tyrode’s solution for
7 minutes at 37°C and cultured on gelatin-coated 60-mm culture dishes
(2 mg/mL gelatin in 0.1 mol/L HCl for 30 minutes at ambient
temperature) in DMEM/Ham’s F-12 (1:1 v/v) containing 10 U/mL nystatin,
50 U/mL penicillin, 50 µg/mL streptomycin, 5 mmol/L HEPES,
5 mmol/L TES, and 20% FBS. They were passaged once with the use
of 0.5% trypsin/0.2% EDTA (wt/vol) and seeded onto BioFlex collagen
type I 6-well plates (Flexcell) that had also been coated with gelatin.
They were identified according to their typical cobblestone morphology,
positive immunostaining for von Willebrand’s
factor, and negative immunostaining for smooth muscle
-actin (all antibodies were from
Sigma-Aldrich).
RT-PCR Analysis
Isolation of total RNA, cDNA synthesis, and
semiquantitative PCR analysis with elongation factor-1 (EF-1)
as internal standard were performed as described
previously.8 PCR conditions
for the amplification of endothelial NO synthase (eNOS)
cDNA were 35 cycles of 30-second denaturation at 95°C, 30-second
annealing at 60°C, and 25-second primer extension at 72°C, with
product size of 311 bp. The forward primer was
5'-ATCTCTACCGCGACGAGG-3', and the reverse primer was
5'-GTCCTCGTGATAGCGTTGC-3' (corresponding to nucleotide
sequences 3227 to 3244 and 3537 to 3519 of the bovine eNOS gene,
GenBank accession No. M95674). PCR conditions for the amplification of
AT1 receptor cDNA were 40 cycles, annealing
temperature of 58°C, and product size of 547 bp. The forward
primer was 5'-TGTAAGATTGCTTCAGCCAGC-3', and the reverse primer was
5'-GCCCTGTCCACAATATCTGC-3' (corresponding to nucleotide
sequences 581 to 601 and 1127 to 1108 of the human
AT1 receptor gene, GenBank accession No.
M87290). PCR conditions for the amplification of
AT2 receptor cDNA were 40 cycles, annealing
temperature of 60°C, and product size of 527 bp. The forward
primer was 5'-TGAGTCCGCATTTAACTGC-3', and the reverse primer was
5'-ACCACTGAGCATATTTCTCGGG-3' (corresponding to nucleotide
sequences 226 to 247 and 771 to 749 of the human
AT2 receptor gene, GenBank accession No.
D16840).
Intravascular ET-1 Concentration
ET-1 was extracted from the weighted segments as
described, and the concentration was determined by using a commercially
available ELISA
kit.8
Reporter Gene Analysis
The pCMV TK luc+ expression vectors (GenBank
accession No. AF027129) containing a -1329-bp rat ppET-1 promoter
instead of the cytomegalovirus (CMV)
promoter15 and the control
vectors without either promoter or with the CMV promoter were kindly
provided by Prof Martin Paul (Institute of Clinical Pharmacology and
Toxicology, Free University of Berlin, Germany). Cotransfections for
normalization of transfection efficacy were performed with a pUC19
(GenBank accession No. M77789)–based SV40/ß-galactosidase expression
vector.
For transfection, 40% confluent porcine aortic cultured ECs were incubated with 1.5 µg plasmid DNA and 15 µL Effectene (Qiagen) for 6 hours; thereafter, the medium was replaced, and the cells were cultured until they attained 80% confluence (usually after 18 to 24 hours). They were then incubated statically or exposed to 20% cyclic strain at 0.5 Hz in a Flexercell FX-3000 computerized stretch device (Flexcell) for 6 hours. Luciferase and ß-galactosidase activities in the cell lysates were determined by using the corresponding chemiluminescence and photometric assay kits (Promega) and were normalized on the basis of their protein content.
Statistical Analysis
Unless indicated otherwise, all data in the figures
and text are expressed as mean±SEM of n experiments with segments or
cells from different animals. Statistical evaluation was performed by
Student’s t test for unpaired
data with a value of P<0.05
considered statistically
significant.
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Results |
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Pressure-Induced Activation of the Endothelin System
Pressurization of the venous segments to 20 mm Hg resulted in a maximum distention with an
3-fold increase in diameter
that did not affect the mRNA level of the housekeeping reference gene
EF-1. Moreover, there was no loss of ECs from the
endothelium-intact segments during the 6-hour perfusion
period (see Lauth et al8 and
Figure 4
).
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Raising the perfusion pressure from 0 to 20
mm Hg resulted in an average 5- to 6-fold increase in ppET-1 mRNA
abundance in the rabbit jugular vein
(Figures 1, 2, and 3B) that was confined to the
endothelium (see Lauth et
al8 ). In good agreement with
the mRNA level, the intravascular concentration of ET-1 in the
endothelium-intact venous segments was elevated by a
factor of 7 after a 6-hour perfusion at 20 mm Hg
(Figure 2B). Moreover, there was a 4- to 5-fold increase in
ETB-R mRNA abundance
(Figures 1 and 3) that, as demonstrated
previously,8 was independent
of the presence of an intact endothelium. In contrast,
neither ECE-1 nor ETA-R expression appeared to
be pressure sensitive
(Figure 1A). In contrast to the AT1
receptor (the expression of which was pressure sensitive), no mRNA
expression of the AT2 receptor could be detected
by RT-PCR analysis in the endothelium-intact
rabbit jugular vein, even after a 6-hour exposure to the elevated
perfusion pressure (not shown).
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P<0.05 vs control 20 mm Hg. 
P<0.05 vs 20 mm Hg plus ramiprilat or irbesartan. nd indicates not determined.
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Effects of Ramiprilat and
Irbesartan on Pressure-Induced Gene Expression
Ramiprilat was used at a concentration (0.3
µmol/L) that was previously determined to inhibit the ACE-dependent
constrictor response to angiotensin I in the rabbit jugular
vein by >80%.16
Pretreatment of the venous segments with ramiprilat
abolished both the pressure-induced increase in ppET-1 mRNA and
intravascular ET-1
(Figures 1B
and 2), whereas basal ppET-1 gene expression was
not significantly affected
(Figure 2A). This effect of ramiprilat was
completely prevented after the blockade of endogenous NO
synthesis with
NG-nitro-L-arginine
(NO2Arg; 100 µmol/L)
(Figure 1B) or B2 receptor antagonism
with icatibant (Hoe 140; 0.1 µmol/L)
(Figure 2). Ramiprilat attenuated the
pressure-induced increase in ETB-R mRNA
(Figure 3), too, and this effect was also reversed by Hoe 140
(Figure 3A) or NO2Arg
(Figure 1B). Ramiprilat exerted the same
inhibitory effect on pressure-induced
ETB-R expression in
endothelium-intact venous segments that had been
mechanically denuded (see Lauth et
al8 ) after the 6-hour
perfusion period but not in segments that had been denuded before the
perfusion pressure was raised to 20 mm Hg (not
shown).
Irbesartan at the maximum concentration used in the
present study (1 µmol/L) completely blocked the
AT1 receptor–mediated constrictor response to
angiotensin II (0.1 pmol to 1.0 nmol corresponding to
concentrations ranging from 0.1 nmol/L to 1.0 µmol/L) in isolated
ring segments of the rabbit jugular vein (not shown). Pretreatment of
the venous segments with irbesartan produced inhibitory
effects on deformation-induced but not basal gene expression similar to
those of ramiprilat
(Figures 2 and 3), which, however, tended to be less
effectively reversed with Hoe 140
(Figure 2).
The inhibitory effects of irbesartan on
pressure-dependent ppET-1 and ETB-R expression
were concentration dependent
(Figure 3B) with a maximum between 0.1 and 1.0 µmol/L.
Another AT1 receptor antagonist,
candesartan, mimicked the inhibitory effect of irbesartan
on both ppET-1 and ETB-R expression in response
to the rise in perfusion pressure but appeared to be less potent by
1 magnitude
(Figure 3B).
As a potential mechanism of action underlying their
effects on deformation-induced gene expression in the rabbit jugular
vein, ramiprilat or irbesartan may upregulate NO synthase
(NOS) expression in the endothelium of the isolated
blood vessels. However, this was not the case, as demonstrated by
monitoring mRNA expression of this enzyme, which was not significantly
different in control segments or segments perfused at 20 mm Hg
for 6 hours, in the absence or presence of either the ACE
inhibitor or the AT1 receptor
antagonist
(Figure 4).
Effects of Ramiprilat and
Irbesartan on ETB-R–Mediated
Venoconstriction
Apart from RT-PCR analysis, changes in
ETB-R expression in the rabbit jugular vein thus
far can only be determined by assaying the biological activity of the
receptor (see Lauth et al8 ).
Therefore, the constrictor response to sarafotoxin 6c (S6c), a
selective ETB-R
agonist,17 was compared in
venous segments perfused at 0 and 20 mm Hg for 3 hours with or
without irbesartan or ramiprilat pretreatment.
Pressurization of the segments significantly enhanced the constrictor
response to S6c, indicative of an increase in functional
ETB-R protein (from 0.19±0.03, 0.43±0.09, and
0.29±0.06 g to 0.51±0.08, 1.02±0.12, and 0.87±0.24 g at 1, 10, and
100 pmol S6c, respectively; n=6 to 12,
P<0.05). The putative
inhibitory effect of irbesartan or ramiprilat
on ETB-R protein expression, however, could not
be verified, because both drugs prevent the concomitant
pressure-dependent synthesis of ET-1 that results at least in part in a
desensitization of the ETB-R before any S6c has
been applied to the isolated segments (see Lauth et
al8 ). Indeed, pretreatment
with both drugs for 30 minutes somewhat augmented rather than inhibited
the constrictor response to S6c in both the pressurized and especially
the nonpressurized segments of the rabbit jugular vein (not
shown).
Effects of NOS and B2
Receptor Blockade on ppET-1 and ETB-R mRNA
Abundance
Brief exposure (30 minutes) of the venous segments to
NO2Arg alone had no effect on basal ppET-1
(117±26% of control, n=3) or ETB-R (98±6% of
control, n=3) mRNA expression; this was also true for segments that had
been perfused at 20 mm Hg for 6 hours (not shown). However,
continuous infusion of NO2Arg into the
perfusate during the 6-hour period clearly upregulated basal
ppET-1 mRNA abundance, albeit to a variable degree, in 3
independent experiments (cf
Figure 1A). Although in 1 experiment there also appeared to
be an upregulation of ETB-R mRNA under these
conditions
(Figure 1A), this effect of the NOS inhibitor
could not be reproduced in subsequent experiments.
B2 receptor antagonism alone,
on the other hand, had no significant effect on either basal (107±20%
and 95±6% of control, respectively, n=3) or deformation-induced
ppET-1 and ETB-R expression
(Figures 2A and 3A). Combined NOS and
B2 receptor blockade also did not affect the
pressure-induced increase in ETB-R mRNA (from
274±29% to 341±74% of control, ie, 0 mm Hg, n=4), whereas
ppET-1 mRNA expression was significantly enhanced (from 641±88% to
1080±154% of control, ie, 0 mm Hg, n=4,
P<0.05).
Effects of Ramiprilat and
Irbesartan on ppET-1 Gene Transcription
To verify that ramiprilat and irbesartan
interfere with pressure-induced gene expression at the level of
transcription, porcine aortic cultured ECs were transiently transfected
with a -1329-bp rat ppET-1 promoter-firefly luciferase gene
construct. These cells were chosen as a model because they respond to
rhythmic deformation with a pronounced increase in ppET-1
expression.18 Moreover, NO
synthesis in these cells has been shown to be enhanced by ACE
inhibitors.19
Cultured ECs transfected with the -1329-bp construct
revealed a >12-fold increase in luciferase activity when exposed to
cyclic strain for 6 hours
(Figure 5), which corresponded to 40% of the luciferase
activity in cells derived from the same batch but transfected with the
CMV-driven control construct (not shown). Pretreatment of the cells
with ramiprilat (0.3 µmol/L) for 30 minutes resulted in a
significant reduction in stretch-induced luciferase activity
(Figure 5). This effect of the ACE inhibitor was
much weaker in the presence of Hoe 140 (0.1 µmol/L) and fully
reversed by 100 µmol/L NO2Arg. Despite the
presence of L-arginine in
the medium (0.7 mmol/L), this concentration of
NO2Arg is sufficient to completely block NOS
activity in the porcine aortic cultured ECs, as
NO2Arg is taken up by an amino acid carrier
(neutral) other than
L-arginine (basic
y+
system)20 and within minutes
attains an intracellular concentration well beyond 1
mmol/L.21 Neither Hoe 140
nor NO2Arg alone
(Figure 5) significantly affected the deformation-induced
expression of the ppET-1 promoter construct in the cultured
ECs.
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Exposure of the cultured ECs to irbesartan (1
µmol/L) also significantly inhibited the deformation-induced increase
in luciferase activity, and this inhibitory effect was
almost fully reversed in the presence of Hoe 140
(Figure 5B). In a separate experiment, coincubation with
NO2Arg also reversed the inhibitory
effect of irbesartan (not shown).
Effects of Ramiprilat and
Irbesartan on the Constrictor Response to Bradykinin
The aforementioned findings clearly suggested
that both ramiprilat and irbesartan inhibit the pressure
(ie, deformation)-induced increase in ppET-1 and
ETB-R expression in the isolated perfused rabbit
jugular vein through stimulation of the endothelial
B2 receptor and secondary release of NO. ACE
inhibitors are known to potentiate the actions of
bradykinin on ECs by interfering with the internalization of the
B2 receptor and by protecting the kinin from
proteolytic degradation via
ACE.16 19
AT1 receptor antagonists are
supposed to be devoid of such effects. To verify this contention, we
compared the effects of ramiprilat and irbesartan on the
B2 receptor–mediated dose-dependent constrictor
response to bradykinin in the rabbit jugular vein. As shown in
Figure 6, ramiprilat indeed caused an 6-fold
leftward shift of the dose-response curve of bradykinin, whereas
irbesartan had no such effect (see also Hecker et
al16 ).
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), irbesartan (1 µmol/L, 
), and vehicle (•) on the dose-dependent constrictor response to bradykinin in non-perfused endothelium-intact segments of the rabbit jugular vein (n=5 to 7). *P<0.05 versus control. |
Discussion |
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The findings of the present study demonstrate that the deformation-induced increase in ET-1 synthesis in native ECs, as well as the deformation-induced increase in ETB-R abundance in native SMCs, is greatly attenuated, if not abolished, by an ACE inhibitor and 2 different AT1 receptor antagonists. These compounds seem to exert their effects via a common mechanism of action that involves the stimulation of endothelial B2 receptors and the secondary release of NO from these cells acting in both an autocrine (endothelial ppET-1 expression) and a paracrine (smooth muscle ETB-R expression) manner. Other than this increase in NOS activity, there does not seem to be an additional effect (eg, on NOS expression) involved therein.
Moreover, ppET-1, but not ETB-R, expression in the isolated perfused rabbit jugular vein was upregulated after continuously blocking the endogenous synthesis of NO in the endothelium of these blood vessels. These data thus confirm and extend previous observations in cultured ECs of a suppression of ET-1 synthesis by endogenous NO22 or ACE inhibitors.13 14 In addition, they support the notion that the vasculoprotective action of the ACE inhibitor class of compounds is to a significant extent due to enhancement of the B2 receptor–mediated stimulatory effect of endogenous kinins on EC autacoid production, namely that of NO.14 16 19
The inhibition by NO of endothelial ET-1 synthesis is thought to be mediated by an increase in intracellular cGMP acting on the transcription of the ppET-1 gene by an as-yet-unknown mechanism.22 Perhaps, a certain threshold concentration of NO is necessary for this effect to occur, as expression of the ppET-1 promoter-luciferase reporter gene construct was not affected by pretreatment with NO2Arg in the cultured ECs, whereas continuous NOS blockade clearly raised the basal level of ppET-1 mRNA in the native ECs. Indeed, NOS activity in freshly isolated ECs is significantly higher compared with ECs isolated from the same vascular bed and grown under static conditions for several days.23 Moreover, NO formation in the endothelium of the perfused segments was presumably higher due to the moderate shear stress to which the native ECs are exposed to in this model. It remains to be elucidated, however, which transcription factor or factors serve as a target for the inhibitory action of NO/cGMP on ppET-1 gene expression.
In this context, it is perhaps interesting to note that brief exposure of the endothelium-intact segments of the rabbit jugular vein to NO2Arg augmented the pressure-induced increase in ppET-1 mRNA abundance only when the B2 receptor had been additionally blocked with Hoe 140. It may be, therefore, that deformation of the native ECs not only leads to an increase in ET-1 synthesis but also triggers activation of the B2 receptor and thus the secondary formation of endothelial autacoids other than NO (eg, prostacyclin)16 19 that can also interfere with ppET-1 gene expression.
In contrast to ET-1 synthesis, an inhibition of ETB-R expression in native SMCs (no difference between endothelium-intact and denuded segments)8 by endothelial autacoids, including NO, has not yet been described. When compared with the synthesis of ET-1, however, both the endothelium-dependent inhibitory effect of ramiprilat on pressure-induced ETB-R expression and the efficacy of Hoe 140 in prevention of this effect were somewhat less pronounced. Moreover, unlike ppET-1 expression, combined NOS and B2 receptor blockade did not significantly augment the pressure-induced increase in ETB-R expression in the native SMCs. If ETB-R expression at the transcriptional level is regulated principally similar to that of ppET-1, these findings suggest either that endothelial autacoids, including NO, are less efficacious when acting in a paracrine manner or that there are additional mechanisms that govern the deformation-induced expression of the ETB-R in the native SMCs, such as the formation of angiotensin II in the endothelium.24
What was truly unprecedented, however, is that both AT1 receptor antagonists appeared to act in the same way as the ACE inhibitor ramiprilat. Thus far, the B2 receptor–mediated increase in endothelial autacoid formation is thought to be a salient feature of the ACE inhibitors with respect to their protective effects in the cardiovascular system.12 16 19 24 Nonetheless, there are reports that suggest the cardioprotective effect of AT1 receptor antagonists in the rat25 26 and in the pig27 may be at least in part due to AT2 receptor activation and subsequent (presumably kinin-mediated) release of endothelial autacoids.26 27 This, however, may be different in the isolated rabbit jugular vein for two reasons: (1) according to RT-PCR analysis, the AT1, but not the AT2, receptor is abundant in endothelium-intact segments of these blood vessels; and (2) irbesartan, in contrast to ramiprilat, does not augment the smooth muscle B2 receptor–mediated constrictor response to bradykinin in the rabbit jugular vein. It appears, therefore, that blockade of another endothelial angiotensin receptor or perhaps an interference with the ETB-R per se is responsible for the in large part NO-mediated inhibitory effect of the AT1 receptor antagonist on deformation-induced gene expression in the rabbit jugular vein.
The pressure-dependent increase in endothelial and, hence, intravascular ET-1 synthesis and the rise in ETB-R abundance in the SMCs appear to profoundly alter the phenotype of these cells depending on the type of blood vessel studied. Recent findings from this laboratory suggest that in the rabbit jugular vein, the deformation-induced change in gene expression enhances medial SMC proliferation (see also Porter et al10 regarding the human saphenous vein), whereas in the rabbit carotid artery, part of these cells undergo apoptosis9 , potentially leading to medial hypertrophy. The pressure-induced activation of the endothelin system in the vessel wall may thus contribute not only to the vasculopathy of venous bypass grafts but also to hypertension-induced arterial remodeling and possibly to restenosis after angioplasty.3 The inhibitory effects of both ACE inhibitors and AT1 receptor antagonists on the pressure-induced activation of the endothelin system in the vessel wall may therefore provide new opportunities for the accessory therapy of the aforementioned cardiovascular interventions28 or the prospective treatment of patients with borderline hypertension.
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Acknowledgments |
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This work was supported by the Deutsche Forschungsgemeinschaft (He 1587/7-1) and a grant from Sanofi Recherche. The authors are grateful to Aventis and Astra-Zeneca for the generous supply of icatibant and ramiprilat, and candesartan, respectively. They are also indebted to Renate Dohrmann for expert technical assistance.
Received June 12, 2000; accepted August 14, 2000.
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References |
|---|
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TopAbstractIntroductionMethodsResultsDiscussionReferences |
|---|
-
Motwani
JG, Topol EJ. Aortocoronary saphenous vein graft disease:
pathogenesis, predisposition, and prevention.
Circulation. 1998;97:916–931.
[Abstract/Free Full Text] - Langille BL. Arterial remodeling: relation to hemodynamics. Can J Physiol Pharmacol. 1996;874:834–841.
-
Kirchengast
M, Munter K. Endothelin and restenosis.
Cardiovasc Res. 1998;39:550–555.
[Free Full Text] - Haynes WG, Webb DJ. Endothelin as a regulator of cardiovascular function in health and disease. J Hypertens. 1998;16:1081–1091.[Medline] [Order article via Infotrieve]
- Schiffrin EL, Touyz RM. Vascular biology of endothelin. J Cardiovasc Pharmacol. 1998;32(suppl):S2–S13.
- 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]
- Wang DL, Wung BS, Peng YC, Wang JJ. Mechanical strain increases endothelin-1 gene expression via protein kinase C pathway in human endothelial cells. J Cell Physiol. 1995;163:400–406.[Medline] [Order article via Infotrieve]
-
Lauth M,
Berger MM, Cattaruzza M, Hecker M. Pressure-induced up-regulation of
preproendothelin-1 and endothelin B receptor expression in rabbit
jugular vein in situ:
implications for vein graft failure?
Arterioscler Thromb Vasc Biol. 2000;20:96–103.
[Abstract/Free Full Text] -
Lauth M,
Berger MM, Cattaruzza M, Hecker M. Elevated perfusion pressure
up-regulates endothelin-1 and endothelin B receptor expression in the
rabbit carotid artery.
Hypertension. 2000;35:648–654.
[Abstract/Free Full Text] - Porter KE, Olojugba DH, Masood I, Pemberton M, Bell PRF, London NJM. Endothelin-B receptors mediate intimal hyperplasia in an organ culture of human saphenous vein. J Vasc Surg. 1998;28:695–701.[Medline] [Order article via Infotrieve]
-
Brown NJ,
Vaughan DE. Angiotensin-converting enzyme
inhibitors.
Circulation. 1998;97:1411–1420.
[Abstract/Free Full Text] - Unger T, Culman J, Gohlke P. Angiotensin II receptor blockade and end-organ protection: pharmacological rationale and evidence. J Hypertens. 1998;16(suppl):S3–S9.
- Yoshida H, Nakamura M. Inhibition by angiotensin converting enzyme inhibitors of endothelin secretion from cultured human endothelial cells. Life Sci. 1992;50:195–200.[Medline] [Order article via Infotrieve]
-
Momose N,
Fukuo K, Morimoto S, Ogihara T. Captopril inhibits endothelin-1
secretion from endothelial cells through bradykinin.
Hypertension. 1993;21:921–924.
[Abstract/Free Full Text] -
Paul M,
Zintz M, Böcker W, Dyer M. Characterization and functional
analysis of the rat endothelin-1 promoter.
Hypertension. 1995;25:683–693.
[Abstract/Free Full Text] - Hecker M, Blaukat A, Bara AT, Müller-Esterl W, Busse R. ACE inhibitor potentiation of bradykinin-induced venoconstriction. Br J Pharmacol. 1997;121:1475–1481.[Medline] [Order article via Infotrieve]
- Douglas SA, Ohlstein EH. Signal transduction mechanisms mediating the vascular actions of endothelin. J Vasc Res. 1997;34:152–164.[Medline] [Order article via Infotrieve]
-
Cattaruzza
M, Dimigen C, Ehrenreich H, Hecker M. Stretch-induced endothelin B
receptor-mediated apoptosis in vascular smooth muscle cells.
FASEB J. 2000;14:991–998.
[Abstract/Free Full Text] -
Benzing T,
Fleming I, Blaukat A, Müller-Esterl W, Busse R.
Angiotensin-converting enzyme inhibitor
ramiprilat interferes with the sequestration of the
B2 kinin receptor within the plasma membrane of
native endothelial cells.
Circulation. 1999;99:2034–2040.
[Abstract/Free Full Text] - Bogle RG, Moncada S, Pearson JD, Mann GE. Identification of inhibitors of nitric oxide synthase that do not interact with the endothelial cell L-arginine transporter. Br J Pharmacol. 1992;105:768–770.[Medline] [Order article via Infotrieve]
- Hecker M, Mitchell JA, Harris HJ, Katsura M, Thiemermann C, Vane JR. Endothelial cells metabolize NG-monomethyl-L-arginine to L-citrulline and subsequently to L-arginine. Biochem Biophys Res Commun. 1990;167:1037–1043.[Medline] [Order article via Infotrieve]
- Kourembanas S, McQuillan LP, Leung GK, Faller DV. Nitric oxide regulates the expression of vasoconstrictors and growth factors by vascular endothelium under both normoxia and hypoxia. J Clin Invest. 1993;91:99–104.
- Hecker M, Mülsch A, Bassenge E, Förstermann U, Busse R. Subcellular localisation and characterization of nitric oxide synthase(s) in endothelial cells: physiologic implications. Biochem J. 1994;299:247–252.
- Kanno K, Hirata Y, Tsujino M, Imai T, Shichiri M, Ito H, Marumo F. Up-regulation of ETB receptor subtype mRNA by angiotensin II in rat cardiomyocytes. Biochem Biophys Res Commun. 1993;194:1282–1287.[Medline] [Order article via Infotrieve]
- Liu YH, Yang XP, Sharov VG, Nass O, Sabbah HN, Peterson E, Carretero OA. Effects of angiotensin-converting enzyme inhibitors and angiotensin II type 1 receptor antagonists in rats with heart failure: role of kinins and angiotensin II type 2 receptors. J Clin Invest. 1997;99:1926–1935.[Medline] [Order article via Infotrieve]
-
Gohlke P,
Pees C, Unger T. AT2 receptor stimulation
increases aortic cyclic GMP in SHRSP by a kinin-dependent mechanism.
Hypertension. 1998;31:349–355.
[Abstract/Free Full Text] - Jalowy A, Schulz R, Dorge H, Behrends M, Heusch G. Infarct size reduction by AT1-receptor blockade through a signal cascade of AT2-receptor activation, bradykinin and prostaglandin in pigs. J Am Coll Cardiol. 1998;33:1787–1796.
- O’Donohoe MK, Schwartz LB, Radic ZS, Mikat EM, McCann RL, Hagen PO. Chronic ACE inhibition reduces intimal hyperplasia in experimental vein grafts. Ann Surg. 1991;214:727–732.[Medline] [Order article via Infotrieve]
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