| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
(Hypertension. 1997;30:29-34.)
© 1997 American Heart Association, Inc.
Articles |
\E Role for Endothelin-1 in Angiotensin II– Mediated Hypertension
From the Department of Medicine, Division of Cardiology, Emory University School of Medicine (S.R., J.B.L., A.B., S.K., D.G.H.), Atlanta, Ga; the Atlanta (Ga) Veterans Administration Medical Center (D.G.H.); Department of Pathology, McGill University, Montreal, Canada (J.B.L., A.G.); Rigshospital, Copenhagen, Denmark (J.B.L.); and Parke-Davis Pharmaceutical Research, Ann Arbor, Mich (J.K., S.H.).
Correspondence to David G. Harrison, MD, Division of Cardiology, Emory University School of Medicine, 1639 Pierce Dr, WMB-319, Atlanta, GA 30322.
 |
Abstract |
|---|
 Top Abstract IntroductionMethodsResultsDiscussionReferences |
|---|
Abstract Experiments in cultured vascular smooth muscle cells have shown that angiotensin II (Ang II) stimulates expression of endothelin-1. We sought to examine role of endothelin-1 in the effects of Ang II in vivo. Ang II infusion in rats (0.7 mg/kg per day for 5 days) was associated with marked increases in vascular smooth muscle endothelin-1 levels, as assessed by immunostaining. Administration of the selective endothelin type A (ETA) receptor antagonist PD 155080 (50 mg/kg per day) abrogated the hypertensive response to a 5-day infusion of Ang II (0.7 mg/kg per day), as did losartan (25 mg/kg per day). ETA receptor blockade during Ang II–mediated hypertension was associated with marked elevations of plasma endothelin-1 levels. Ang II–mediated hypertension was associated with heightened vascular responsiveness to a variety of vasoconstrictor agents except endothelin-1. Blockade of ETA receptor invariably corrected this vasoconstrictor hyperresponsiveness. We conclude that some of the vascular effects of Ang II thought to be unique to this hormone are likely mediated by endothelin-1.
Key Words: angiotensin II • endothelin • receptors, endothelin
|
Introduction |
|---|
|
TopAbstractIntroductionMethodsResultsDiscussionReferences |
|---|
Traditionally, it has been assumed that the vasoconstriction and hypertension caused by Ang II is related to a direct action on the AT1 receptor and subsequent activation of second messenger pathways immediately linked to the receptor. These signaling events include increases in intracellular calcium, stimulation of protein kinase C, and activation of other phosphorylation pathways.1 During the past 5 years, it has been shown that Ang II can stimulate expression of preproendothelin mRNA and protein in both cultured vascular smooth muscle2 and endothelial3 4 cells. This has been shown to occur via activation of the AT1 receptor2 3 5 6 and presumably involves activation of transcription via activator protein-1/protein kinase C–mediated mechanisms. Furthermore, in rat cultured cardiomyocytes, endogenously produced ET-1 contributes to the hypertrophic response to Ang II.5
These observations in tissue culture raise the possibility that ET-1 might in part be responsible for alterations of vascular tone encountered in conditions in which Ang II is chronically elevated. This hypothesis is attractive because ET-1 is an extremely potent vasoconstrictor and may have other effects on BP regulation, such as stimulation of aldosterone synthesis7 and of conversion of Ang I to Ang II. Despite these considerations, the evidence that endothelin has any role in hypertension is inconclusive. Although plasma levels of ET-1 are elevated in patients with essential hypertension, there is a poor correlation between these levels and the degree of hypertension.8 Furthermore, mice deficient in the ET-1 gene have paradoxically elevated BP.9
Recently, selective antagonists of ET-1 receptors have become available that permit the study of the role of this peptide in various pathophysiological conditions. In the present study, we examined the hypothesis that locally generated ET-1 might contribute to alterations of vascular tone and hypertension caused by chronic elevations of angiotensin by examining the effects of a selective ETA receptor antagonist on Ang II–mediated hypertension.
|
Methods |
|---|
|
TopAbstractIntroductionMethodsResultsDiscussionReferences |
|---|
Animal Preparation
Male Sprague-Dawley rats (250 to 300 g) were housed under constant temperature and humidity with a 12-hour light/dark cycle. Before and during the experimental period, all rats had free access to a standard rat chow and water. The rats were anesthetized with intraperitoneal ketamine (80 mg/kg) and xylazine (10 mg/kg). With the use of sterile techniques, a catheter (medical-grade Tygon) was implanted through the left carotid artery and advanced so that its tip was in the ascending aorta. The catheter was then externalized between the scapulae and secured by a polyester felt disk placed subcutaneously. The catheter was filled with a solution of 50% glucose and 500 IU/mL heparin and plugged with a nylon pin. After catheter implantation, the rats were housed individually until they had regained their preoperative weights and appeared healthy (6 to 8 days after catheter implantation).
At the end of the recovery period, the rats were reanesthetized, a skin incision was made in the abdominal region, and osmotic minipumps (Alzet model 2001, Alza Corp) were implanted subcutaneously (day 0). The minipumps were loaded with either Ang II (0.7 mg/kg per day, n=13) or vehicle (saline, n=13). In six of the animals in each of these groups, the ETA receptor antagonist PD 155080 (50 mg/kg per day) was administered twice daily by gavage feeding. To establish that Ang II effects were mediated by the AT1 receptor, an additional group of animals was treated with losartan (25 mg/kg per day, n=6) added to the drinking water.
Arterial Pressure Measurements
The animals were handled daily and exposed to the environment
eventually used for BP measurement. On day 5 of osmotic minipump
implantation, mean arterial BP was measured in conscious
animals. After BP recording, the animals were given a lethal
injection of sodium pentobarbital. After injection but before death,
heparin (2500 U) was given via intracardiac injection. The aortas were
then removed and used in subsequent studies.
Isolated Vascular Ring Experiments
Five-millimeter ring segments of the thoracic aorta were
suspended in individual organ chambers for measurement of isometric
tension and were studied using methods previously
described.10 Responses of various vasoconstrictors,
including serotonin, phenylephrine, ET-1 (all 1
nmol/L to 100 µmol/L), and KCl (5 to 80 mmol/L) were
examined by cumulative addition of the various agents to the organ
chamber.
Measurements of ET-1 Plasma Concentrations
Blood samples were obtained at the time of death and transferred
to a chilled EDTA (2 mg/mL) tube. The chilled samples were
centrifuged at 3000g for 15 minutes at 4°C, and
plasma was stored at -20°C until assayed. ET-1 was extracted from 1
mL of plasma with 1.5 mL of extraction solvent composed of acetone/HCl
(1 mol/L)/water (40:1:5). The mixture was centrifuged for 20
minutes at 3000 rpm and 4°C. The supernatant was dried down with a
centrifugal evaporator, and the pellet was reconstituted in sample
diluent and assayed using a solid-phase enzyme-linked immunosorbent
assay kit (Parameter, R&D Systems). Optical density
readings of unknown samples were plotted against a standard curve of
synthetic ET-1–spiked rat plasma samples over a range of 1 to 113
pg/mL.
Immunostaining Analysis
Two polyclonal antisera against human ET-1 were used as
described recently11 12 —one against the C-terminal
of ET-1 and the other against the C-terminal fragment of big ET-1 (big
ET22-38). A commercial antiserum against human ET-1
(Peninsula Laboratories) was also used. In addition, antiserum to von
Willebrand factor (factor VIII–related antigen) (Dako) was
used as an endothelial cell marker. The
avidin-biotin-peroxidase complex method was used as previously
described. Negative controls were prepared with the specific antiserum
absorbed with the cross-reactive endothelins or with nonimmune serum
instead of primary antiserum, or by omitting steps in the
avidin-biotin-peroxidase procedure. For each antisera, three sections
were stained.
Data Analysis
Data are expressed as mean±SEM. Comparisons between groups of
animals or treatments were made with one-way ANOVA. When significance
was indicated, a Student-Newman-Keuls post hoc analysis was
used. To examine interactions between Ang II or sham treatment and
treatment with PD 155080, two-way ANOVA was used, in which treatment
with Ang II was assigned as one independent variable and treatment
with PD 155080 as the other independent variable. Significance was
considered at a value of P<.05.
|
Results |
|---|
|
TopAbstractIntroductionMethodsResultsDiscussionReferences |
|---|
BP Responses
In control animals, the mean arterial pressure was 98±5 mm Hg. In rats receiving only Ang II infusion for 5 days, the mean arterial pressure was 185±5 mm Hg. Administration of the ETA receptor antagonist PD 155080 markedly attenuated the pressor response to Ang II (128±5 mm Hg) and had a minimal effect on BP in rats not receiving Ang II (Fig 1
). As expected, losartan
also prevented the increase in BP caused by Ang II.
|
Plasma ET-1 Concentrations
Plasma ET-1 levels averaged 1.62±0.36 pg/mL in control rats. At
the end of 5 days of Ang II infusion, ET-1 levels were slightly but not
significantly increased to 1.89±0.17 pg/mL (Fig 2).
Treatment with PD 155080 increased circulating ET-1 levels in animals
receiving infusions of either vehicle or Ang II. The greatest increase
in circulating ET-1 concentration was, however, in animals receiving
both Ang II and PD 155080 (3.94±0.47 pg/mL). Losartan lowered
ET-1 levels in Ang II–treated animals to values below those observed
in control animals (Fig 2).
|
P<.05 vs control plus PD 155080.
Isometric Tension Studies
Vessels from rats treated with Ang II were more sensitive to KCl
than control vessels, as evidenced by an EC50 of 18±2
versus 26±1 mmol/L (P<.05). Treatment with the
ETA receptor antagonist normalized this
increased sensitivity in vessels from Ang II–treated animals, while
having no effect in controls (Fig 3 and Table 1). Likewise, treatment with losartan prevented
the increased sensitivity to KCl in vessels from rats treated with Ang
II (Table 1).
|
|
Sensitivity to both serotonin and
phenylephrine (reflected by EC50 values) was
markedly increased in vessels from Ang II–treated animals (Fig 3
and
Table 1). These values were normalized by treatment with the endothelin
receptor antagonist (Table 1 and Fig 4).
Peak responses to phenylephrine and serotonin
were also increased in vessels from animals receiving Ang II infusion
(Fig 3 and Table 2). Peak responses to
phenylephrine, but not to serotonin, were
normalized by treatment with the ETA antagonist
(Fig 4 and Table 2). Losartan likewise prevented the increase
in sensitivity and peak responses to serotonin and
phenylephrine (Tables 1 and 2).
|
|
In contrast to the generalized increase in responses to
vasoconstrictors such as phenylephrine,
serotonin, and KCl, constrictions in response to ET-1 of
vessels from rats treated with Ang II were suppressed compared with
controls (Fig 3 and Table 2). Losartan prevented this effect of
Ang II (Table 2).
Immunohistochemical Analysis of ET-1 Expression
In control rat aorta, only faint staining for either ET-1 or big
endothelin was visible (Fig 5A). In contrast, in Ang
II–treated animals, staining for ET-1 was readily apparent in the
media (Fig 5B). Staining for big endothelin appeared slightly increased
in the aortas of Ang II–treated rats (Fig 5C and 5D). No staining was
apparent when the primary antibody was omitted (Fig 5E).
|
|
Discussion |
|---|
|
TopAbstractIntroductionMethodsResultsDiscussionReferences |
|---|
Previous studies of cultured endothelial cells, vascular smooth muscle cells, and cardiomyocytes have shown that Ang II potently increases preproendothelin mRNA and ET-1 protein.2 3 4 5 These studies of cultured cells raise the possibility that some of the vascular effects of Ang II in vivo might be mediated by endogenously expressed endothelin. The present studies suggest that this hypothesis is correct. A substantial portion of the hypertension caused by Ang II, and the enhanced vasoconstrictor responsiveness in Ang II–mediated hypertension, was prevented by concomitant administration of the selective ETA receptor antagonist PD 155080. This enhanced vascular responsiveness was accompanied by an increase in synthesis of ET-1 in the vessel wall, as demonstrated by immunohistochemistry. It is conceivable that a higher dose of this agent would have been more effective in lowering BP. The dose used in this study has been found to completely prevent ET-1–induced constriction of the hindlimb in rabbits. Furthermore, after oral gavage, a dose approximately one third of this produces plasma levels substantially in excess of the IC50 values in Wistar-Kyoto rats.13
To our knowledge, this is the first report to show that endothelin might participate in the alteration of either vascular reactivity or BP in Ang II–induced hypertension. Reports on the involvement of endothelin in various experimental models of hypertension have conflicted.14 15 Our present findings suggest that in the setting of hypertension caused by elevations of Ang II, endothelin-receptor antagonists may be effective BP-lowering agents.
An interesting finding in the present study is the effect of the ETA receptor antagonist PD 155080 on plasma levels of ET-1. PD 155080 produced a modest increase in plasma ET-1 in control animals and a marked increase in plasma ET-1 in Ang II–treated animals. The mechanisms underlying this increase remain unclear. The ETA receptor (blocked by PD 155080) is not thought to be involved in the clearance of ET-1, and it is therefore unlikely that a change in clearance participated in this phenomenon.16 ET-1 is tightly bound by its receptors, and it is possible that the antagonist simply displaced the peptide from vascular receptors, resulting in spillover into the plasma. Notwithstanding the mechanisms responsible for this increase in plasma ET-1, the data are compatible with an increase in ET-1 synthesis caused by Ang II.
Related to the possible activation of endogenous endothelin production, it is of interest that constrictions in response to ET-1 of vessels from Ang II–treated rats were paradoxically reduced compared with those from control animals. Although other explanations are possible, this finding is compatible with the possibility that vascular endothelin receptors were occupied by endogenous endothelin, thus preventing the additional constrictor effect of exogenously added ET-1. This conclusion is in keeping with the observation that ET-1 immunostaining is increased in the aortas of Ang II–treated rats. A similar situation has been observed in the case of prolonged nitroglycerin treatment, in which an increase in vascular ET-1 immunoreactivity is associated with increased responses to several vasoconstrictor substances and paradoxically decreased constrictions to ET-1.
It is now well accepted that even low concentrations of ET-1, which alone produce either no or minimal vasoconstriction, can substantially enhance vasoconstrictions to numerous other vasoconstrictor agents.12 17 18 This process seems to involve activation of protein kinase C, in that it can be prevented by several chemically unrelated protein kinase C antagonists. Of note, the enhanced vasoconstrictor responses to phenylephrine, KCl, and serotonin found in vessels from animals treated with Ang II mirror responses that we have observed in vessels incubated with low concentrations of ET-1.12
In addition to direct vascular actions of ET-1, it is also likely that enhanced ET-1 production could contribute to hypertension via other mechanisms. It has been reported that endothelin can increase aldosterone synthesis, which could augment sodium and water retention and predispose to a volume-dependent form of hypertension.7 Furthermore, ET-1 has been shown to enhance conversion of Ang I to Ang II. This might result in a positive feedback–like situation in which Ang II could stimulate ET-1 production, which could in turn increase Ang II production. Finally, ET-1 is a mitogen for vascular smooth muscle,19 20 and it is conceivable that over the long term, increased levels of ET-1 might promote vascular hypertrophy and narrowing of the vascular lumen, resulting in elevated peripheral vascular resistance.
The mechanisms whereby ET-1 protein synthesis and preproendothelin mRNA are increased in response to Ang II remain poorly defined. It has been postulated that this is due to Ang II activation of protein kinase C and consequent activation of c-Fos and c-Jun binding to activator protein-1 sites in the endothelin promoter. In vivo, this process may be even more complex. It is known that nitric oxide can inhibit ET-1 expression. Recently, we showed that chronic elevations of Ang II increase vascular superoxide production via activation of NADH/NADPH-dependent oxidases.10 This increase in vascular superoxide results in a loss of the bioactivity of endothelium-derived nitric oxide, probably via a radical-radical reaction between superoxide and nitric oxide. It is therefore conceivable that loss of the effect of nitric oxide via Ang II–induced oxidase activation might contribute to an increase in ET-1 expression. It is also possible that changes in redox state caused by Ang II might stimulate transcription of the preproendothelin gene in a manner similar to that observed recently for other genes. Although controversial, there is evidence that c-Fos and c-Jun activation is stimulated by oxidant stress. In particular, reactive oxygen intermediates may be important in c-Fos and c-Jun heterodimer binding to activator protein-1 in response to Ang II in myoblasts.21
One potential explanation for these findings is that PD 155080 might nonspecifically inhibit Ang II binding to the AT1 receptor. We believe that this is unlikely. In additional experiments, we found that very high concentrations of PD 155080 (1 mmol/L) had no effect on the constriction of rat aortas in response to Ang II.
In summary, we have shown that Ang II–mediated hypertension is associated with enhanced production of ET-1 in vivo. The obligatory role of endothelin in mediating some of the effects of Ang II was further substantiated by the effects of selective ETA receptor blockade. Although several previous reports have shown that Ang II can stimulate ET-1 expression in tissue culture, this is, to our knowledge, the first demonstration that increased endogenous synthesis of ET-1 might contribute to Ang II–mediated hypertension in vivo. The interactions between these two hormones may be of importance in other conditions in which both have been shown to be elevated, such as myocardial infarction22 23 and congestive heart failure.24 25 Some of the beneficial effects of angiotensin-converting enzyme inhibition in congestive heart failure26 27 28 thus may stem from favorable modulation of endothelin levels.
|
Selected Abbreviations and Acronyms |
|---|
|
Received November 7, 1996; first decision November 26, 1996; accepted January 2, 1997.
|
References |
|---|
|
TopAbstractIntroductionMethodsResultsDiscussionReferences |
|---|
1. Griendling K, Alexander R. Cellular mechanisms of angiotensin II action. In: Swales J, ed. Textbook of Hypertension. 1st ed. Oxford, UK: Blackwell Scientific Publications; 1994:244-253.
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. Chua BH, Chua CC, Diglio CA, Siu BB. Regulation of endothelin-1 mRNA by angiotensin II in rat heart endothelial cells. Biochim Biophys Acta. 1993;1178:201-206.[Medline] [Order article via Infotrieve]
5. Ito H, Hirata Y, Adachi S, Tanaka M, Tsujino M, Koike A, Nogami A, Murumo F, 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.
6. Ishiye M, Umemura K, Uematsu T, Nakashima M. Angiotensin AT1 receptor-mediated attenuation of cardiac hypertrophy due to volume overload: involvement of endothelin. Eur J Pharmacol. 1995;280:11-17.[Medline] [Order article via Infotrieve]
7.
Cozza EN, Chiou S, Gomez-Sanchez CE.
Endothelin-1 potentiation of angiotensin II stimulation of
aldosterone production. Am J
Physiol. 1992;262:R85-R89.
8. Saito Y, Nakao K, Mukoyama M, Imura H. Increased plasma endothelin level in patients with essential hypertension. N Engl J Med. 1990;322:205. Letter.[Medline] [Order article via Infotrieve]
9. Kurihara Y, Kurihara H, Suzuki H, Kodama T, Maemura K, Nagai R, Oda H, Kuwaki T, Cao WH, Kamada N, Jishage K, Ouchi Y, Azuma S, Toyoda Y, Ishikawa T, Kumada M, Yazaki Y. Elevated blood pressure and craniofacial abnormalities in mice deficient in endothelin-1. Nature. 1994;368:703-710.[Medline] [Order article via Infotrieve]
10. Rajagopalan S, Kurz S, Münzel T, Tarpey M, Freeman B, Griendling K, Harrison D. Angiotensin II-mediated hypertension in the rat increases vascular superoxide production via membrane NADH/NADPH oxidase activation: contribution to alterations of vasomotor tone. J Clin Invest. 1996;97:1916-1923.[Medline] [Order article via Infotrieve]
11.
Giaid A, Yanagisawa M, Langleben D, Michel RP, Levy R,
Shennib H, Kimura S, Masaki T, Duguid WP, Stewart D. Expression
of endothelin-1 in the lungs of patients with pulmonary
hypertension. N Engl J Med. 1993;328:1732-1739.
12.
Münzel T, Giaid A, Kurz S, Stewart DJ, Harrison
DG. Evidence for a role of endothelin-1 and protein kinase C in
nitroglycerin tolerance. Proc Natl Acad
Sci U S A. 1995;92:5244-5248.
13. Doherty A, Patt W, Edmunds J, Berryman K, Ralsdorph B, Plummer M, Shahripour A, Lee C, Chang X-M, Walker D, Haleen S, Kaiser J, Flynn M, Welch K, Hallack H, Taylor D, Reynolds E. Discovery of a novel series of orally active non-peptide endothelin-A (ETA) receptor-sensitive antagonists. J Med Chem. 1995;38:1259-1263.[Medline] [Order article via Infotrieve]
14. Nishikibe M, Tsuchida S, Okada M, Fukuroda T, Shimamoto K, Yano M, Ishikawa K, Ikemoto F. Antihypertensive effect of a newly synthesized endothelin antagonist, BQ-123, in a genetic hypertensive model. Life Sci. 1993;52:717-724.[Medline] [Order article via Infotrieve]
15. Okada M, Fukuroda T, Shimamoto K, Takahashi R, Ikemoto F, Yano M, Nishikibe M. Antihypertensive effects of BQ-123, a selective endothelin ETA receptor antagonist, in spontaneously hypertensive rats treated with DOCA-salt. Eur J Pharmacol. 1994;259:339-342.[Medline] [Order article via Infotrieve]
16. Fukuroda T, Fujikawa T, Ozaki S, Ishikawa K, Yano M, Nishikibe M. Clearance of circulating endothelin-1 by ETB receptors in rats. Biochem Biophys Res Commun. 1994;199:1461-1465.[Medline] [Order article via Infotrieve]
17.
Yang ZH, Richard V, von Segesser L, Bauer E, Stulz P,
Turina M, Luscher TF. Threshold concentrations of endothelin-1
potentiate contractions to norepinephrine and
serotonin in human arteries: a new mechanism of
vasospasm? Circulation. 1990;82:188-195.
18.
Henrion D, Laher I. Potentiation of
norepinephrine-induced contractions by endothelin-1 in the
rabbit aorta. Hypertension. 1993;22:78-83.
19. Hirata Y, Takagi Y, Fukuda Y, Marumo F. Endothelin is a potent mitogen for rat vascular smooth muscle cells. Atherosclerosis. 1989;78:225-228.[Medline] [Order article via Infotrieve]
20. Komuro I, Kurihara H, Sugiyama T, Yoshizumi M, Takaku F, Yazaki Y. Endothelin stimulates c-fos and c-myc expression and proliferation of vascular smooth muscle cells. FEBS Lett. 1988;238:249-252.[Medline] [Order article via Infotrieve]
21.
Puri PL, Avantaggiati ML, Burgio VL, Chirillo P,
Collepardo D, Natoli G, Balsano C, Levrero M. Reactive oxygen
intermediates mediate angiotensin II-induced c-Jun c-Fos
heterodimer DNA binding activity and proliferative hypertrophic
responses in myogenic cells. J Biol Chem. 1995;270:22129-22134.
22. Watanabe T, Suzuki N, Shimamoto N, Fujino M, Imada A. Endothelin in myocardial infarction. Nature. 1990;344:114.[Medline] [Order article via Infotrieve]
23.
Latini R, Maggioni AP, Flather M, Sleight P, Tognoni
G. ACE inhibitor use in patients with myocardial
infarction: summary of evidence from clinical trials.
Circulation. 1995;92:3132-3137.
24.
Wei CM, Lerman A, Rodeheffer RJ, McGregor CG, Brandt
RR, Wright S, Heublein DM, Kao PC, Edwards WD, Burnett JC Jr.
Endothelin in human congestive heart failure. Circulation. 1994;89:1580-1586.
25.
Omland T, Lie RT, Aakvaag A, Aarsland T, Dickstein
K. Plasma endothelin determination as a prognostic indicator of
1-year mortality after acute myocardial infarction.
Circulation. 1994;89:1573-1579.
26. Acute Infarction Ramipril Efficacy Study Investigators. Effect of ramipril on mortality and morbidity of survivors of acute myocardial infarction with clinical evidence of heart failure. Lancet. 1993;342:821-828.[Medline] [Order article via Infotrieve]
27. The SOLVD Investigators. Effect of enalapril on mortality and the development of heart failure in asymptomatic patients with reduced left ventricular ejection fractions. N Engl J Med. 1992;327:685-691.[Abstract]
28. Pfeffer M, Braunwald E, Moyé L, Basta L, Brown EJ, Cuddy T, Davis B, Geltman E, Goldman S, Flaker GC, Klein M, Lamas G, Packer M, Rouleau J, Rouleau J, Rutherford J, Wertheimer J, Hawkins C, and the SAVE Investigators. Effect of captopril on mortality and morbidity in patients with left ventricular dysfunction after myocardial infarction: results of the survival and ventricular enlargement trial. N Engl J Med. 1992;327:669-677.[Abstract]
This article has been cited by other articles:
 |
|
 |
|
  N. W. Rajapakse, C. De Miguel, S. Das, and D. L. Mattson Exogenous L-Arginine Ameliorates Angiotensin II-Induced Hypertension and Renal Damage in Rats Hypertension, December 1, 2008; 52(6): 1084 - 1090. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. Heeneman, J. C. Sluimer, and M. J.A.P. Daemen Angiotensin-Converting Enzyme and Vascular Remodeling Circ. Res., August 31, 2007; 101(5): 441 - 454. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
U. C. Kopp, M. Z. Cicha, and L. A. Smith Activation of Endothelin-A Receptors Contributes to Angiotensin-Induced Suppression of Renal Sensory Nerve Activation Hypertension, January 1, 2007; 49(1): 141 - 147. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 U. C. Kopp, M. Z. Cicha, and L. A. Smith Differential effects of endothelin on activation of renal mechanosensory nerves: stimulatory in high-sodium diet and inhibitory in low-sodium diet Am J Physiol Regulatory Integrative Comp Physiol, November 1, 2006; 291(5): R1545 - R1556. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
C. Yzydorczyk, F. Gobeil Jr., G. Cambonie, I. Lahaie, N. L. O. Le, S. Samarani, A. Ahmad, J. C. Lavoie, L. L. Oligny, P. Pladys, et al. Exaggerated vasomotor response to ANG II in rats with fetal programming of hypertension associated with exposure to a low-protein diet during gestation Am J Physiol Regulatory Integrative Comp Physiol, October 1, 2006; 291(4): R1060 - R1068. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
U. Hink and T. Munzel COX-2, Another Important Player in the Nitric Oxide-Endothelin Cross-Talk: Good News for COX-2 Inhibitors? Circ. Res., June 9, 2006; 98(11): 1344 - 1346. [Full Text] [PDF]
|
|
|
|
|
|
H. E. Cingolani, M. C. Villa-Abrille, M. Cornelli, A. Nolly, I. L. Ennis, C. Garciarena, A. M. Suburo, V. Torbidoni, M. V. Correa, M. C. Camilionde Hurtado, et al. The Positive Inotropic Effect of Angiotensin II: Role of Endothelin-1 and Reactive Oxygen Species Hypertension, April 1, 2006; 47(4): 727 - 734. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. J. An, R. Boyd, Y. Wang, X. Qiu, and H. D. Wang Endothelin-1 expression in vascular adventitial fibroblasts Am J Physiol Heart Circ Physiol, February 1, 2006; 290(2): H700 - H708. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 D. M. Shah Role of the renin-angiotensin system in the pathogenesis of preeclampsia Am J Physiol Renal Physiol, April 1, 2005; 288(4): F614 - F625. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
D. M. Pollock, J. M. Jenkins, A. K. Cook, J. D. Imig, and E. W. Inscho L-type calcium channels in the renal microcirculatory response to endothelin Am J Physiol Renal Physiol, April 1, 2005; 288(4): F771 - F777. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
D. M. Pollock Endothelin, Angiotensin, and Oxidative Stress in Hypertension Hypertension, April 1, 2005; 45(4): 477 - 480. [Full Text] [PDF]
|
|
|
|
|
|
A. A. Elmarakby, E. D. Loomis, J. S. Pollock, and D. M. Pollock NADPH Oxidase Inhibition Attenuates Oxidative Stress but Not Hypertension Produced by Chronic ET-1 Hypertension, February 1, 2005; 45(2): 283 - 287. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
Z. Bagi, A. Koller, and G. Kaley PPAR{gamma} activation, by reducing oxidative stress, increases NO bioavailability in coronary arterioles of mice with Type 2 diabetes Am J Physiol Heart Circ Physiol, February 1, 2004; 286(2): H742 - H748. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 N. G Perez, M. C Villa-Abrille, E. A Aiello, R. A Dulce, H. E Cingolani, and M. C Camilion de Hurtado A low dose of angiotensin II increases inotropism through activation of reverse Na+/Ca2+ exchange by endothelin release Cardiovasc Res, December 1, 2003; 60(3): 589 - 597. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. Montanari, A. Biggi, N. Carra, M. Ziliotti, E. Fasoli, L. Musiari, P. Perinotto, and A. Novarini Endothelin-A Receptors Mediate Renal Hemodynamic Effects of Exogenous Angiotensin II in Humans Hypertension, October 1, 2003; 42(4): 825 - 830. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A. Zeidan, J. Broman, P. Hellstrand, and K. Sward Cholesterol Dependence of Vascular ERK1/2 Activation and Growth in Response to Stretch: Role of Endothelin-1 Arterioscler. Thromb. Vasc. Biol., September 1, 2003; 23(9): 1528 - 1534. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. P. Granger Endothelin Am J Physiol Regulatory Integrative Comp Physiol, August 1, 2003; 285(2): R298 - R301. [Full Text] [PDF]
|
|
|
|
|
|
H. E Cingolani, N. G Perez, B. Pieske, D. von Lewinski, and M. C Camilion de Hurtado Stretch-elicited Na+/H+ exchanger activation: the autocrine/paracrine loop and its mechanical counterpart Cardiovasc Res, March 15, 2003; 57(4): 953 - 960. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 D. L. Brutsaert Cardiac Endothelial-Myocardial Signaling: Its Role in Cardiac Growth, Contractile Performance, and Rhythmicity Physiol Rev, January 1, 2003; 83(1): 59 - 115. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
K. Moridaira, J. Morrissey, M. Fitzgerald, G. Guo, R. McCracken, T. Tolley, and S. Klahr ACE inhibition increases expression of the ETB receptor in kidneys of mice with unilateral obstruction Am J Physiol Renal Physiol, January 1, 2003; 284(1): F209 - F217. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. M. Sasser, J. S. Pollock, and D. M. Pollock Renal endothelin in chronic angiotensin II hypertension Am J Physiol Regulatory Integrative Comp Physiol, July 1, 2002; 283(1): R243 - R248. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
E. A. Aiello, M. C. Villa-Abrille, and H. E. Cingolani Autocrine Stimulation of Cardiac Na+-Ca2+ Exchanger Currents by Endogenous Endothelin Released by Angiotensin II Circ. Res., March 8, 2002; 90(4): 374 - 376. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S.-S. Ding, C. Qiu, P. Hess, J.-F. Xi, J.-P. Clozel, and M. Clozel Chronic endothelin receptor blockade prevents renal vasoconstriction and sodium retention in rats with chronic heart failure Cardiovasc Res, March 1, 2002; 53(4): 963 - 970. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 F. Brunner, G. Wolkart, and S. Haleen Defective Intracellular Calcium Handling in Monocrotaline-Induced Right Ventricular Hypertrophy: Protective Effect of Long-Term Endothelin-A Receptor Blockade with 2-Benzo[1,3]dioxol-5-yl-3-benzyl-4-(4-methoxy-phenyl-)- 4-oxobut-2-enoate-sodium (PD 155080) J. Pharmacol. Exp. Ther., February 1, 2002; 300(2): 442 - 449. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. Montanari, N. Carra, P. Perinotto, V. Iori, E. Fasoli, A. Biggi, and A. Novarini Renal Hemodynamic Control by Endothelin and Nitric Oxide Under Angiotensin II Blockade in Man Hypertension, February 1, 2002; 39(2): 715 - 720. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 N. Uhlenius, O. Vuolteenaho, and I. Tikkanen Renin-angiotensin blockade improves renal cGMP production via non-AT2-receptor mediated mechanisms in hypertension-induced by chronic NOS inhibition in rat Journal of Renin-Angiotensin-Aldosterone System, December 1, 2001; 2(4): 233 - 239. [Abstract] [PDF]
|
|
|
|
 |
|
 F. Fakhouri, S. Placier, R. Ardaillou, J.-C. Dussaule, and C. Chatziantoniou Angiotensin II Activates Collagen Type I Gene in the Renal Cortex and Aorta of Transgenic Mice through Interaction with Endothelin and TGF-{beta} J. Am. Soc. Nephrol., December 1, 2001; 12(12): 2701 - 2710. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
I. LEHRKE, R. WALDHERR, E. RITZ, and J. WAGNER Renal Endothelin-1 and Endothelin Receptor Type B Expression in Glomerular Diseases with Proteinuria J. Am. Soc. Nephrol., November 1, 2001; 12(11): 2321 - 2329. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. R. Ballew and G. D. Fink Role of endothelin ETB receptor activation in angiotensin II-induced hypertension: effects of salt intake Am J Physiol Heart Circ Physiol, November 1, 2001; 281(5): H2218 - H2225. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 Y. Suzuki, O. Lopez-Franco, D. Gomez-Garre, N. Tejera, C. Gomez-Guerrero, T. Sugaya, R. Bernal, J. Blanco, L. Ortega, and J. Egido Renal Tubulointerstitial Damage Caused by Persistent Proteinuria Is Attenuated in AT1-Deficient Mice : Role of Endothelin-1 Am. J. Pathol., November 1, 2001; 159(5): 1895 - 1904. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. C. Ortiz, M. C. Manriquez, J. C. Romero, and L. A. Juncos Antioxidants Block Angiotensin II-Induced Increases in Blood Pressure and Endothelin Hypertension, September 1, 2001; 38(3): 655 - 659. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. R. Ballew and G. D. Fink Role of ETA receptors in experimental ANG II-induced hypertension in rats Am J Physiol Regulatory Integrative Comp Physiol, July 1, 2001; 281(1): R150 - R154. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. Riggleman, J. Harvey, and C. Baylis Endothelin Mediates Some of the Renal Actions of Acutely Administered Angiotensin II Hypertension, July 1, 2001; 38(1): 105 - 109. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
W. Boemke, B. Hocher, N. Schleyer, M. O. Krebs, and G. Kaczmarczyk Hemodynamic, renal, and endocrine responses to acute ETA blockade at different ANG II plasma levels Am J Physiol Regulatory Integrative Comp Physiol, May 1, 2001; 280(5): R1322 - R1331. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
B. T. Alexander, K. L. Cockrell, A. N. Rinewalt, J. N. Herrington, and J. P. Granger Enhanced renal expression of preproendothelin mRNA during chronic angiotensin II hypertension Am J Physiol Regulatory Integrative Comp Physiol, May 1, 2001; 280(5): R1388 - R1392. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. R. Ballew, S. W. Watts, and G. D. Fink Effects of Salt Intake and Angiotensin II on Vascular Reactivity to Endothelin-1 J. Pharmacol. Exp. Ther., April 13, 2001; 296(2): 345 - 350. [Abstract] [Full Text]
|
|
|
|
|
|
Tong Chuang Feng, Wang Yui Ying, Ren Jang Hua, Y. Y Ji, and M. de Gasparo Effect of valsartan and captopril in rabbit carotid injury. Possible involvement of bradykinin in the antiproliferative action of the renin-angiotensin blockade Journal of Renin-Angiotensin-Aldosterone System, March 1, 2001; 2(1): 19 - 24. [Abstract] [PDF]
|
|
|
|
|
|
N.-E. Rhaleb, H. Peng, P. Harding, M. Tayeh, M. C. LaPointe, and O. A. Carretero Effect of N-Acetyl-Seryl-Aspartyl-Lysyl-Proline on DNA and Collagen Synthesis in Rat Cardiac Fibroblasts Hypertension, March 1, 2001; 37(3): 827 - 832. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. C. Ortiz, E. Sanabria, M. C. Manriquez, J. C. Romero, and L. A. Juncos Role of Endothelin and Isoprostanes in Slow Pressor Responses to Angiotensin II Hypertension, February 1, 2001; 37(2): 505 - 510. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
G. P. Rossi, A. Sacchetto, D. Rizzoni, S. Bova, E. Porteri, G. Mazzocchi, A. S. Belloni, M. Bahcelioglu, G. G. Nussdorfer, and A. C. Pessina Blockade of Angiotensin II Type 1 Receptor and Not of Endothelin Receptor Prevents Hypertension and Cardiovascular Disease in Transgenic (mREN2)27 Rats via Adrenocortical Steroid-Independent Mechanisms Arterioscler. Thromb. Vasc. Biol., April 1, 2000; 20(4): 949 - 956. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. C. C. de Hurtado, B. V. Alvarez, I. L. Ennis, and H. E. Cingolani Stimulation of Myocardial Na+-Independent Cl--HCO3- Exchanger by Angiotensin II Is Mediated by Endogenous Endothelin Circ. Res., March 31, 2000; 86(6): 622 - 627. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J.-J. Boffa, P.-L. Tharaux, S. Placier, R. Ardaillou, J.-C. Dussaule, and C. Chatziantoniou Angiotensin II Activates Collagen Type I Gene in the Renal Vasculature of Transgenic Mice During Inhibition of Nitric Oxide Synthesis : Evidence for an Endothelin-Mediated Mechanism Circulation, November 2, 1999; 100(18): 1901 - 1908. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. Winegrad, D. Henrion, L. Rappaport, and J. L. Samuel Self-Protection by Cardiac Myocytes Against Hypoxia and Hyperoxia Circ. Res., October 15, 1999; 85(8): 690 - 698. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
E. L. Schiffrin Role of Endothelin-1 in Hypertension Hypertension, October 1, 1999; 34(4): 876 - 881. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
G. P. Rossi, A. Sacchetto, M. Cesari, and A. C Pessina Interactions between endothelin-1 and the renin-angiotensin-aldosterone system Cardiovasc Res, August 1, 1999; 43(2): 300 - 307. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
H. Berthold, K. Munter, A. Just, H. R. Kirchheim, and H. Ehmke Contribution of endothelin to renal vascular tone and autoregulation in the conscious dog Am J Physiol Renal Physiol, March 1, 1999; 276(3): F417 - F424. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
H. E. Cingolani, B. V. Alvarez, I. L. Ennis, and M. C. Camilion de Hurtado Stretch-Induced Alkalinization of Feline Papillary Muscle : An Autocrine-Paracrine System Circ. Res., October 19, 1998; 83(8): 775 - 780. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
T. J Rabelink, E. S.G Stroes, K.P. Bouter, and P. Morrison Endothelin blockers and renal protection: a new strategy to prevent end-organ damage in cardiovascular disease? Cardiovasc Res, September 1, 1998; 39(3): 543 - 549. [Full Text] [PDF]
|
|
|
|
|
|
L. V. d'Uscio, S. Shaw, M. Barton, and T. F. Luscher Losartan but Not Verapamil Inhibits Angiotensin II–Induced Tissue Endothelin-1 Increase : Role of Blood Pressure and Endothelial Function Hypertension, June 1, 1998; 31(6): 1305 - 1310. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. S. Li, R. M. Touyz, and E. L. Schiffrin Effects of AT1 and AT2 Angiotensin Receptor Antagonists in Angiotensin II-Infused Rats Hypertension, January 1, 1998; 31(1): 487 - 492. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
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]
|
|
|
|
|
|
E. A. Aiello, M. C. Villa-Abrille, and H. E. Cingolani Autocrine Stimulation of Cardiac Na+-Ca2+ Exchanger Currents by Endogenous Endothelin Released by Angiotensin II Circ. Res., March 8, 2002; 90(4): 374 - 376. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. P.J. Halcox, K. R.A. Nour, G. Zalos, and A. A. Quyyumi Coronary Vasodilation and Improvement in Endothelial Dysfunction With Endothelin ETA Receptor Blockade Circ. Res., November 23, 2001; 89(11): 969 - 976. [Abstract] [Full Text] [PDF]
|
|
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||