(Hypertension. 2000;35:992.)
© 2000 American Heart Association, Inc.
Scientific Contributions |
Synergistic Effects of AT1 and ETA Receptor Blockade in a Transgenic, Angiotensin II–Dependent, Rat Model
From the Franz Volhard Clinic and Max Delbrück Center for Molecular Medicine (J.B., S.G., J.K., M.G., R.D.), Medical Faculty of the Charité, Humboldt University of Berlin, Germany; and Knoll AG (M.K.), Ludwigshafen, Germany.
Correspondence to Dr Jürgen Bohlender, Max-Delbrück-Center, Robert-Rössle-Str 10, D-13092 Berlin, Germany.
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Abstract |
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Abstract—Angiotensin II and endothelin may participate in increasing blood pressure and inducing end-organ damage, but the evidence is conflicting. We tested the hypothesis that endothelinA receptor blockade would ameliorate blood pressure and end-organ damage in a rat model of human renin-dependent hypertension. We studied rats that were transgenic for both the human renin and angiotensinogen genes. Experimental groups (n=12 each) of untreated transgenic rats, transgenic rats receiving subdepressor doses of losartan (10 mg/kg), transgenic rats receiving LU 135252 (30 mg/kg), transgenic rats receiving both drugs, and nontransgenic rats were studied between 6 to 10 weeks of age. Blood pressure was measured with tail-cuff sphygmomanometry. Gene expression for atrial natriuretic peptide, collagen III, and ACE was measured. The mortality rate in untreated transgenic rats was 42%, which is consistent with previous observations in this line. Single losartan or LU 135252 treatment reduced mortality incidence to 1 rat per group (8%), without significantly lowering blood pressure. In the combination group, blood pressure was normalized and all rats survived. The drug combination also decreased elevated water intake in transgenic rats to normal levels and significantly reduced cardiac hypertrophy. Furthermore, the combination of drugs decreased cardiac atrial natriuretic peptide, ACE gene, and renal collagen III gene expression. We suggest that endothelin participates in this model of angiotensin II–induced hypertension and end-organ damage. Our findings may have clinical implications and provide a rationale for combining angiotensin II type 1 receptor and endothelinA receptor blockade to obtain a synergistic effect.
Key Words: endothelin • angiotensin • rats, transgenic • hypertrophy, cardiac • thirst • hypertension, arterial
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Introduction |
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Numerous cellular events are triggered by angiotensin (Ang) II via its Ang II type 1 (AT1) receptor, which can directly stimulate cellular hypertrophy and hyperplasia. Ang II is capable of inducing severe end-organ damage, independent of its blood pressure (BP)–raising effects.1 ACE inhibitors, AT1 receptor blockers, and possibly the combination of these agents have proved to be effective treatment for much of Ang II–induced cardiovascular injury. However, complete amelioration is not generally achieved. One possible explanation includes the participation of other pathogenic factors in end-organ damage that are elicited by Ang II or facilitate Ang II–dependent effects. A strong candidate for such secondary effects is the endothelin (ET) system. Ang II was shown to be a powerful stimulator of ET synthesis and release in vascular smooth muscle and endothelial cells.2 3 Furthermore, Ang II promotes the ability of ET to produce vascular hypertrophy. The importance of ET in these interactions and for cardiovascular damage was recently reviewed.4 5 The availability of specific antagonists to the two ET receptors (ETA and ETB) permits the direct testing of such an interaction. We studied the possible pathophysiological role of ET in a unique, high human renin form of hypertension in the transgenic rat (TGR). Rats were made transgenic for the human renin (hREN) gene and crossed with rats transgenic for the human angiotensinogen (hAGT) gene.6 The rat and human renin-angiotensin systems are species specific. The animals develop hypertension and have a 50% mortality rate by 12 weeks of age. Because the expression of the two transgenes is distributed in various tissues, TGRs also produce Ang II locally at a tissue level. We used this unique model to test the hypothesis that Ang II and ET participate in the development of end-organ damage. We blocked AT1 receptors with low-dose losartan, which was not sufficient to reduce BP, and inhibited the ET system with LU 135252, a selective ETA receptor antagonist. This approach allowed us to observe pharmacological effects on the tissues, independent of BP-lowering effects.
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Methods |
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Animals
We used male double TGRs heterozygous for the hREN and hAGT gene lines 10Jx1623 and male nontransgenic Sprague-Dawley (SD) rats. The characteristics of these TGRs have been given in detail elsewhere.6 The rats we used were similar to, but not identical to, double TGRs derived from the same monogenic strains raised in Basel.7 Briefly, the rats have an highly elevated plasma renin activity (PRA) 20 to 30 times above that of control rats generated by transgenic hREN cleaving hAGT, whereas rat plasma renin is suppressed. Transgenic hREN does not interfere with rat hGT, and vice versa. As a consequence, the TGRs develop early malignant hypertension with significant end-organ damage and cardiac hypertrophy before the age of 3 months, when they die. Rats were held at the local animal facility under standard conditions with a conventional rodent diet (SNIFF; Soest) containing 0.25% NaCl and had free access to tap water. Experiments were performed in accordance with published American Physiological Society guidelines for animal care and with permission from local authorities.
Experimental Protocol
TGR aged 6 weeks were divided into 4 groups (n=12 per group). An
untreated TGR group served as the controls. A second TGR group received
losartan, a specific AT1 receptor
antagonist (10 mg/kg body wt, MSD; Haar). A third TGR group
received LU 135252,8 a specific ETA
receptor antagonist (30 mg/kg body wt; Knoll AG;). A fourth
TGR group received the combination of both compounds at these doses in
their drinking water during a period of 4 weeks. A nontransgenic
age-matched SD group without treatment was investigated in parallel.
One day before the treatment protocol was started, BP was measured with
tail-cuff sphygmomanometry under short ether anesthesia and
a blood sample was obtained by jugular vein puncture.
Na2-EDTA at 6.3x10-6 mol/L final
concentration was used for anticoagulation. Plasma was immediately
separated by centrifugation at 4°C and shock-frozen
before the determination of PRA and rat plasma renin concentration
(rPRC) with enzyme-kinetic assay as described previously.9
Further BP determinations were made at weekly intervals. Body weight,
drinking volume (daily), and survival rates were observed
longitudinally. At sacrifice, blood samples were collected, and PRA,
rPRC, and plasma ET-1 concentrations were measured with a commercial
kit (BI-20052; Biomedica GmbH). The hearts, kidneys, and aortas were
rapidly removed and rinsed in iced 0.9% NaCl solution before samples
were snap-frozen in liquid nitrogen for mRNA studies.
mRNA Studies
Total RNA was extracted from cardiac and aortic tissue according
to the LiCl/urea precipitation technique,10 and mRNA
expression levels for rat ACE, atrial natriuretic peptide
(ANP) and preprocollagen-III (col-3) were determined with RNase
protection assay9 with an Ambion RPA II kit (ITC
Biotechnology). A probe specific for GAPDH mRNA was used as internal
control. The probes for ANP, GAPDH, and col-3 were generated by reverse
transcription/polymerase chain reaction–based cloning techniques from
rat mRNA samples according to published sequences with a T-vector
(Promega) cloning kit. Linearized plasmids were transcribed by
T7-polymerase and labeled radioactively with 32P.
The ACE-specific probe11 spanned 132 protected
nucleotides (nt), and probes for ANP, col-3, and GAPDH
spanned 250, 205, and 80 nt, respectively. Probe specificity was tested
independently (data not shown). One microgram of cardiac RNA and 10
µg of aortic RNA was tested with a molar excess of specific probes,
respectively. Semiquantitative analysis of
autoradiograms was accomplished with a FUJIX-BASII
PhosphorImager system (Fuji Corp).
Statistical Analysis
Mean and SD values were calculated. Treatment effects on
survival were tested for statistical significance with a Latin-square
design and Woolf’s G test, a modified 
2 test
suitable for small numbers.12 Differences were otherwise
tested with ANOVA (either standard or including repeated measures) or
with Student’s t test as appropriate with StatView software
on a Macintosh personal computer. A value of P<0.05 was
accepted as significant.
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Results |
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Untreated TGRs had an overall mortality rate of 42% (5 of 12) during the 4 weeks of observation. In contrast, within the groups treated with either losartan or LU 135252 alone, only 1 animal per group died (8%), whereas there were no losses in the combined treatment TGR group (P=0.01) and none in the SD control group (P=0.01). The effect of single LU 135252 or losartan treatment on mortality rates was statistically significant (P=0.05). A further analysis of data was made with the actual number of animals remaining in each experimental group. Body weight, absolute, and relative heart weight are shown in the Table. Body weight in the experimental groups were similar at the end of the experiment. Terminal absolute and relative heart weights were significantly higher (32% and 41%, respectively) in untreated TGRs compared with nontransgenic control rats. Treatment with either LU 135252 or losartan did not change this relationship. However, the combined treatment group had heart weights that were not statistically different from normal SD values.
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The systolic BP of each experimental group before and during
the protocol is shown in Figure 1A. Mean
systolic BP values in the TGR groups before the experiment were 
160
to 180 mm Hg, significantly higher (P<0.05) than SD
controls (98 mm Hg), whereas BPs in the TGR groups were not
significantly different. BP during the 4-week period of monotherapy in
the TGR groups did not differ significantly from that of untreated
TGRs. However, the combined treatment with losartan and LU
135252 rapidly reduced BP to normal levels, as present in the SD
control rats (P<0.05). Figure 1B gives data on the
drinking behavior. In untreated TGRs, the daily drinking volume was
about twice that of SD controls during the entire experiment
(P<0.05). In LU 135252–treated TGRs, drinking behavior was
as it was in untreated TGRs. In TGRs treated with losartan,
drinking volume remained elevated initially without any apparent
changes, whereas in the combined treatment group, there was a
significant reduction in drinking volume to normal levels in parallel
with the BP reduction.
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PRA in the TGRs was 20 times higher than PRA in the SD control rats
(73±31 versus 3.8±1.9 ng Ang I ·
ml-1 · h-1). The
values did not change significantly in the TGR groups until the end of
the experiment (data not shown). rPRC in the TGRs was below the
detection level of the assay and did not increase to measurable levels,
regardless of the presence or absence of treatment. Losartan at
an efficient BP-lowering dose would have significantly increased rPRC.
In the SD control rats, rPRC was 10.5±3.5 ng Ang I ·
ml-1 · h-1 at
baseline and remained unchanged at those values at the end of the
experiment (P=NS). We measured ET-1 plasma levels at the end
of the experiments, as shown in Figure 2.
The levels were highly variable. The LU 135252 group had higher
ET-1 concentrations than the control TGRs but did not significantly
differ from any other group.
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Similar results were obtained with our mRNA expression studies (Figure 3). Ventricular ACE and ANP mRNA expressions were increased 3- to 8-fold (P<0.01) in TGR hearts compared with SD hearts. Treatment with losartan tended to decrease the high ACE mRNA levels in TGR by 20% to 25% (P=NS), whereas LU 135252 showed no drug effects. Overall, ANP mRNA levels remained unaffected except for the LU 135252/losartan–treated TGR group, which nearly normalized their ANP gene expression (P<0.05). The col-3 mRNA expression in TGR hearts was not significantly different from that of SD control rats, with no effect of LU 135252 treatment. In contrast, col-3 expression levels were elevated in TGR kidneys. The combined treatment reduced col-3 expression to normal values. Monotherapy with either drug alone had no effect. In the aorta, ACE mRNA levels were elevated 2- to 3-fold in TGR groups compared with the SD control rats. Drug treatment had no effect on these values.
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Discussion |
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The important findings in this study were that both ETA receptor blocker (LU 135252) treatment and AT1 receptor blocker treatment (losartan) reduced mortality rates in a double-TGR model of high human renin hypertension independent of BP-lowering effects. Furthermore, the drug combination lowered BP to levels observed in nontransgenic SD rats, reduced cardiac hypertrophy, and eliminated death. Single-drug therapy with either LU 135252 or losartan did not produce a similar BP fall, indicating synergistic effects of their combination. Finally, the polydypsia that typically occurs in these TGRs was also ameliorated with the drug combination. These interpretations are based on a conservative estimate, because the functional, humoral, and gene expression studies were performed only in the rats that survived the experiment. The TGRs in the untreated group that died very likely exhibited more severe end-organ damage than the rats that survived the study period. These data shed new light on the pathophysiological role of Ang II and its interaction with the ET system. The data may have clinical implications as well.
Ang II has important actions on cellular hypertrophy and replication.13 In activation of the AT1 receptor, Ang II can initiate a series of events that result in severe end-organ damage.14 In previous studies of this model, we showed that pharmacological inhibition of the transgenic human renin completely prevented BP increases and end-organ damage.6 7 The results indicate that an excess of Ang II generated via transgenic human renin was responsible for both the systemic hypertension and the end-organ damage. Massive cardiac hypertrophy, progressive renovascular damage, and nephrosclerosis were observed in TGRs.6 7 In the current experiment, we selected a relatively low dose of losartan to show a possible interaction between Ang II and the ET system. Our findings suggest that ET has no role in elevation of BP in this transgenic model; however, ET may play a supportive role. This interpretation is supported by the lack of any BP-lowering effect of losartan at the applied dose, whereas combination drug treatment was effective in reducing BP. Despite these observations, ET apparently played an important role in end-organ damage, because ETA receptor blockade significantly reduced overall mortality rates. The level of significance was not very robust, but we believe that the use of a higher number of TGRs per group or a longer observation period would have increased the level. Such beneficial effects of ET receptor–blocking treatment have also been observed in rats with experimental cardiac insufficiency15 and in humans with advanced heart failure.16
Both Ang II and mechanical stress can induce the expression of prepro-ET-1 mRNA in cardiomyocytes in vitro. Similarly, ET-1 can induce the growth of cultured cardiomyocytes directly and indirectly17 18 and therefore could have potentiated Ang II–related growth effects in the heart. In an aortic banding model, the concentration of ET-1 in the heart increased and ET binding sites were upregulated. Block of the ET system limited the progression of cardiac hypertrophy in this model. However, the inhibition was time dependent and efficient only during the early phase of cardiac growth, whereas long-term blockade had no effect.19 20 Cardiac growth in our TGR model with long-term chronic BP elevation did not directly depend on the ET system.
The interactions of Ang II with ET have been studied in a variety of similar, Ang II–dependent models of hypertension.4 5 However, these earlier experiments have provided conflicting evidence. Herizi et al21 showed that bosentan, a combined ETA and ETB receptor blocker, ameliorated end-organ damage in rats made hypertensive with chronic Ang II infusion. Others22 have shown that Ang II induces local ET-1 overproduction in the vessel wall in parallel with vascular hypertrophy, whereas both effects were prevented with ETA receptor blockade alone. Ehmke et al23 investigated cardiac hypertrophy in rats with 2-kidney 1-clip renovascular hypertension. They found a reduction in cardiac hypertrophy after ETA receptor blockade in the early phase of hypertension, independent of BP effects. The attenuation of cardiac hypertrophy was associated with reduced left ventricular ß-myosin heavy chain and ANP gene mRNA expression. In a similar experiment, others reported that the coronary artery hypertrophy was completely prevented with ETA receptor–blocking treatment.24 Nevertheless, Li et al25 found no long-term persistent effects of bosentan over 2 to 3 months after renal artery clipping. ETA receptor–blocking treatment in their experiment was begun late, when hypertension was already established, which may explain these discrepancies. Their results are consistent with our findings, because we also observed decreased ANP mRNA levels in TGR hearts and decreased col-3 mRNA levels in the kidney when a combined treatment of losartan with LU 135252 was administered. Interestingly, ACE mRNA was similarly reduced in the heart, whereas in the aorta, no such decrease of the ACE mRNA expression level was seen, independent of treatment. Col-3 mRNA expression was not activated in TGR hearts, possibly because the rats were still relatively young. In the kidneys, the increased col-3 gene expression was indicative of fibrotic interstitial remodeling. Upregulation of the ACE gene mRNA expression for example has also been seen in 2-kidney 1-clip renal hypertension.26
Our data and previous observations22 23 24 suggest that ET activation might be a general feature of Ang II–dependent hypertension. In contrast, the BP-lowering potential of ET receptor blockers possibly represents a conditional effect depending on the level of activation of the renin-angiotensin system and other cofactors. The reported beneficial effect of ET receptor blockade on BP, vascular structure, and function in the study by Herizi et al21 disappeared when higher Ang II concentrations were infused. Furthermore, BP-lowering effects of ET receptor blockers were reported in humans with mild essential hypertension and in animal models without a massive activation of the renin-angiotensin system.27 28 Finally, the combined ETA and AT1 receptor blocker treatment in TGRs may also have lowered BP via the activation of pharmacologically unopposed ETB and AT2 receptors, which possess a significant vasodilatory and growth-inhibitory potential.29 30 The combined treatment markedly reduced both BP and cardiac hypertrophy in our rats.
We were interested in finding a possible ET-mediated effect on drinking
in TGRs. The drinking volume in TGRs was twice that of nontransgenic
control rats. Ang II is known to elicit a strong drinking response when
injected into the cerebral ventricles and involves
AT1 receptor binding.31 In rats with
hypertension induced by long-term intravenous infusion of
Ang II, combined ETA/B receptor blockade with
bosentan did not influence the increased drinking
behavior.21 TGR treated with losartan had a
tendency to a lower water intake. The addition of LU 135252 to this
treatment completely normalized water intake to levels observed in
nontransgenic rats. This observation is the first evidence to our
knowledge that the ETA receptor may be involved
in pathological thirst in the context of renin-induced hypertension. We
did not perform urinary electrolyte studies. In normotensive rats, the
acute administration of 10 mg/kg LU 135252 IP reduced urinary volume by
36% for 
8 hours.32 In TGRs, such renal effects of LU
135252 could have contributed independently to the normalization of
drinking volume.
LU 135252 is a selective ETA blocker with a high affinity for this receptor. However, at a higher concentration, some occupancy of the ETB receptor may occur. The ETB receptor may be involved in ET clearance.27 33 The LU 135252 group had significantly higher ET plasma levels than the control TGR group; however, the variability of the measurements was such that no firm conclusions could be drawn. The LU 135252 group did not differ from the other treatment groups or from nontransgenic control rats; therefore, we cannot exclude some degree of ETB receptor occupancy in our study. In view of the ET plasma concentrations, we believe that the principal effects were mediated by ETA receptor blockade.
In summary, our data show that ETA receptor blockade significantly contributed to increased survival rates in TGRs when LU 135252 was given in combination with low-dose losartan. The combination also produced a synergistic BP-lowering effect, decreased water intake, prevented the development of cardiac hypertrophy, and reduced mortality rates to zero. Our results provide strong evidence for a direct participation of ET in Ang II–induced vascular damage. Furthermore, although the ET system may not play a direct role in BP elevation in this model, there may be an indirect role, because BP was normalized in TGRs when ETA receptor blockade was added to subdepressor doses of losartan. Our findings are clinically relevant because they provide a rationale for the combination of ETA receptor and AT1 receptor blockade to ameliorate Ang II–related cardiovascular injury.
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Acknowledgments |
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This work was supported by a grant-in-aid from Knoll AG (Ludwigshafen, Germany) and from MSD (Haar, Germany). The technical assistance of Ch. Lipka, A. Müller, G. Born, and I. Strauss is gratefully acknowledged. The authors wish to thank Drs Detlev and Ursula Ganten for critical comments and Drs J. Ambühl, J. Basten (MSD), and K. Münter (Knoll AG) for supporting this study.
Received October 18, 1999; first decision November 4, 1999; accepted December 3, 1999.
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References |
|---|
|
TopAbstractIntroductionMethodsResultsDiscussionReferences |
|---|
1. Robertson IAS, Nicholls GA, eds. The Renin-Angiotensin System. London: Mosby; 1993.
2.
Sung CP, Arleth AJ, Storer BL, Ohlstein EH.
Angiotensin type 1 receptors mediate smooth muscle
proliferation and endothelin biosynthesis in rat vascular smooth
muscle. J Pharmacol Exp Ther. 1994;271:429–437.
3.
Imai T, Hirata Y, Emori T, Yanagisawa M, Masaki T,
Marumo F. Induction of endothelin-1 gene by angiotensin and
vasopressin in endothelial cells.
Hypertension. 1992;19:753–757.
4. Schiffrin EL. Endothelin and endothelin antagonists in hypertension. J Hypertens. 1998;16:1891–1895.[Medline] [Order article via Infotrieve]
5. Kirchengast M, Münter K. Endothelin-1 and endothelin receptor antagonists in cardiovascular remodeling. Proc Soc Exp Biol Med. 1999;221:312–325.[Medline] [Order article via Infotrieve]
6.
Bohlender J, Fukamizu A, Lippoldt A, Nomura T, Dietz
R, Menard J, Murakami K, Luft FC, Ganten D. High human renin
hypertension in transgenic rats. Hypertension. 1997;29:428–434.
7.
Luft FC, Mervaala EMA, Muller DN, Gross V, Park J-K,
Schmitz C, Lippoldt A, Breu V, Dragun D, Dechend R, Schneider W, Ganten
D, Haller H. Hypertension-induced end-organ damage: a new transgenic
approach to an old problem. Hypertension. 1999;33:212–218.
8. Rohmeis P, Birck R, Braun C, Münter K, Van der Woude FJ, Kirchengast M. Pharmacology of the endothelin A receptor antagonist: LU 135252. Cardiovasc Drug Rev. 1998;16:391–412.
9.
Bohlender J, Menard J, Wagner J, Luft FC, Ganten D.
Human renin-dependent hypertension in rats transgenic for human
angiotensinogen. Hypertension. 1996;27:535–540.
10. Auffray C, Rougeon F. Purification of mouse immunoglobulin heavy-chain messenger RNAs from total myeloma tumor RNA. Eur J Biochem. 1980;107:303–314.[Medline] [Order article via Infotrieve]
11.
Costerousse O, Allegrini J, Huang H, Bouhnik J,
Alhenc-Gelas F. Regulation of ACE gene expression and plasma levels
during rat postnatal development. Am J Physiol. 1994;267:E745–E753.
12. Woolf B. The log likelihood ratio test (the G-Test). Methods and tables for tests of heterogeneity in contingency tables. Ann Hum Genet. 1957;397–409.
13. Rosendorff C. The renin-angiotensin system and vascular hypertrophy. J Am Coll Cardiol. 1996;28:803–812.[Abstract]
14.
Tan L-B, Jalil EJ, Pick R, Janicki JS, Weber KT.
Cardiac myocyte necrosis induced by angiotensin II.
Circ Res. 1991;69:1185–1195.
15. Sakai S, Miyauchi T, Kobayashi M, Yamaguchi I, Goto K, Sugishita Y. Inhibition of myocardial endothelin pathway improves long term survival in heart failure. Nature. 1996;384:353–355.[Medline] [Order article via Infotrieve]
16.
Sütsch G, Kiowski W, Yan X-W, Hunzicker P,
Christen S, Strobel W, Kim J-H, Richenbacher P, Bertel O. Short term
oral endothelin-receptor antagonist therapy in
conventionally treated patients with symptomatic severe
chronic heart failure. Circulation. 1998;98:2262–2268.
17.
Yamazaki T, Komuro I, Kudoh S, ZouY, Shiojima I, Hiroi
Y, Mizuno T, Maemura K, Kurihara H, Aikawa R, Takano H, Yazaki Y.
Endothelin-1 is involved in mechanical stress-induced
cardiomyocyte hypertrophy. J Biol
Chem. 1996;271:3221–3228.
18. Ito H, Hirata Y, Adachi S, Tanaka M, Tsujino M, Koike A, Nogami A, Marumo FM, Hiroe M. Endothelin-1 is an autocrine/paracrine factor in the mechanism of angiotensin II-induced hypertrophy in cultured rat cardiomyocytes. J Clin Invest. 1993;92:398–403.
19.
Arai M, Yoguchi A, Iso T, Imai S, Morata K, Suzuki T.
Endothelin-1 and its binding sites are upregulated in pressure overload
cardiac hypertrophy. Am J Physiol. 1995;268:H2084–H2091.
20.
Ito H, Hiroe M, Hirata Y, Fujisaki H, Adachi S, Akimoto
H, Ohta Y, Marumo F. Endothelin ETA receptor antagonist
blocks cardiac hypertrophy provoked by
hemodynamic overload. Circulation. 1994;89:2198–2203.
21.
Herizi A, Jover B, Bouriquet N, Mimran A. Prevention of
the cardiovascular and renal effects of
angiotensin II by endothelin blockade.
Hypertension. 1998;31:10–14.
22.
Moreau P, d’Uscio LV, Shaw S, Takase H, Barton M,
Lüscher TF. Angiotensin II increases tissue
endothelin and induces vascular hypertrophy: reversal by
ETA receptor antagonist.
Circulation. 1997;96:1593–1597.
23.
Ehmke H, Faulhaber J, Münter K, Kirchengast M,
Wiesner RJ. Chronic ETA receptor blockade
attenuates cardiac hypertrophy independently of blood
pressure effects in renovascular hypertensive rats.
Hypertension. 1999;33:954–960.
24.
Hocher B, George I, Rebstock J, Bauch A, Schwarz A,
Neumayer H-H, Bauer C. Endothelin system-dependent cardiac remodeling
in renovascular hypertension. Hypertension. 1999;33:816–822.
25. Li SJ, Knafo L, Turgeon A, Garcia R, Schiffrin EL. Effect of endothelin antagonism on blood pressure and vascular structure in renovascular hypertensive rats. Am J Physiol. 1996;40:H88–H93.
26.
Arnal JF, Battle T, Rasetti C, Challah M, Costerousse
O, Vicaut E, Michel JB, Alhenc-Gelas F. ACE in three tunicae of rat
aorta: expression in smooth muscle and effect of renovascular
hypertension. Am J Physiol. 1994;267:H1777–H1784.
27. Münter K, Ehmke H, Kirchengast M. Maintenance of blood pressure in normotensive dogs by endothelin. Am J Physiol. 1999;276:H1022–H1027.
28.
Krum H, Viskoper RJ, Lacourciere Y, Budde M, Charlon V.
Bosentan Hypertension Investigators: the effect of an
endothelin-receptor antagonist, bosentan, on blood pressure
in patients with mild hypertension. N Engl J Med. 1998;338:784–790.
29.
Strachnan FE, Spratt JC, Wilkinson IB, Johnston
NR, Gray GA, Webb DJ. Systemic blockade of endothelin-B receptor
increases peripheral vascular resistance in healthy men.
Hypertension. 1999;33:581–585.
30.
Matsuraba H. Pathophysiological
role of angiotensin II type 2 receptor in
cardiovascular and renal diseases. Circ Res. 1998;83:1182–1191.
31. Polidori C, Ciccocioppo R, Nisato D, Cazaubon C, Massi M. Evaluation of the ability of irbesartan to cross the blood-brain barrier following acute intragastric treatment. Eur J Pharmacol. 1998;352:15–21.[Medline] [Order article via Infotrieve]
32. Cernacek P, Strmen J, Levy M. Acute renal effects of ETA receptor blockade: interspecies differences. J Cardiovasc Pharmacol. 1997;31:S269–S272.
33. Löffler B-M, Breu V, Clozel M. Effect of different endothelin receptor antagonists and of the novel non-peptide antagonist Ro 46–2005 on endothelin levels in rat plasma. FEBS Lett. 1993;333:108–110.[Medline] [Order article via Infotrieve]
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 L. Ko, A. Maitland, P. W.M. Fedak, A. S. Dumont, M. Badiwala, F. Lovren, C. R. Triggle, T. J. Anderson, V. Rao, and S. Verma Endothelin blockade potentiates endothelial protective effects of ace inhibitors in saphenous veins Ann. Thorac. Surg., April 1, 2002; 73(4): 1185 - 1188. [Abstract] [Full Text] [PDF]
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 D. Fraccarollo, J. Bauersachs, M. Kellner, P. Galuppo, and G. Ertl Cardioprotection by long-term ETA receptor blockade and ACE inhibition in rats with congestive heart failure: mono- versus combination therapy Cardiovasc Res, April 1, 2002; 54(1): 85 - 94. [Abstract] [Full Text] [PDF]
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D. E. Dostal Regulation of Cardiac Collagen : Angiotensin and Cross-Talk With Local Growth Factors Hypertension, March 1, 2001; 37(3): 841 - 844. [Full Text] [PDF]
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 L. Moser, J. Faulhaber, R. J. Wiesner, and H. Ehmke Predominant activation of endothelin-dependent cardiac hypertrophy by norepinephrine in rat left ventricle Am J Physiol Regulatory Integrative Comp Physiol, May 1, 2002; 282(5): R1389 - R1394. [Abstract] [Full Text] [PDF]
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