(Hypertension. 1999;34:969-975.)
© 1999 American Heart Association, Inc.
Scientific Contributions |
AT1 Receptor Antagonism Reduces Endothelial Dysfunction and Intimal Thickening in Atherosclerotic Rabbits
From Novartis Pharma (M.D., J.M.), Basle, Switzerland; Unidad de Hipertensión, Hospital 12 de Octubre (L.M.R.), Madrid, Spain; Departamento de Fisiología, Facultad de Medicina, Universidad Complutense (N.d.l.H., R.M., S.V.-P., J.N.-C., V.C., V.L.), Madrid, Spain; and Servicio de Anatomía Patológica, Unidad II, Hospital Universitario de San Carlos (P.A.), Madrid, Spain.
Correspondence to V. Lahera, Departamento de Fisiología, Facultad de Medicina, Universidad Complutense, Madrid 28040, Spain. E-mail htnren{at}eucmax.sim.ucm.es
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Abstract |
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Abstract—The effects of angiotensin (AT)1 receptor antagonists on functional and morphological alterations associated with atherosclerosis are not well known. The current study was performed to examine the long-term effects of valsartan (3 or 10 mg/kg per day for 10 weeks) on endothelial function and structural changes in aorta from rabbits fed with either a control diet or a cholesterol-enriched diet. Rabbits fed with the cholesterol-rich diet showed higher (P<0.05) plasma levels of cholesterol than did controls. Treatment with valsartan (3 or 10 mg/kg per day) did not alter plasma cholesterol levels or systolic arterial pressure in any group. Contractions induced by angiotensin II were comparable in both control and hypercholesterolemic rabbits and were markedly reduced by treatment with valsartan. Relaxations induced by acetylcholine were lower in hypercholesterolemic rabbits than in controls. Treatment with valsartan (3 or 10 mg/kg per day) enhanced (P<0.05) this response in hypercholesterolemic rabbits but not in controls. Lumen and media cross-sectional areas were comparable in control and hypercholesterolemic rabbits. Vessel area was higher (P<0.05) in hypercholesterolemic rabbits than in controls. Intimal lesion was 29.5±6% in cholesterol-fed rabbits and nonexistent in control rabbits. Treatments with 3 and 10 mg/kg per day valsartan reduced (P<0.05) intimal lesion to 2.4±0.7% and 2.7±0.9%, respectively, and increased lumen area in hypercholesterolemic rabbits. No changes in either vessel or media cross-sectional areas were observed in these animals. In summary, angiotensin II, through AT1 receptors, appears to play a key role in the development of the vascular functional and structural changes associated with hypercholesterolemia. AT1 receptor antagonists, besides their antihypertensive effects, could be an important therapeutic tool to reduce the development of atherosclerosis.
Key Words: angiotensin II • receptors, angiotensin II • atherosclerosis • hypercholesterolemia • endothelium
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Introduction |
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Vascular endothelium regulates vascular function and structure through the release of numerous factors such as nitric oxide (NO), endothelin-1 (ET-1), arachidonic acid derivatives, reactive oxygen species, monocyte adhesion molecules, growth factors, coagulation and fibrinolytic agents, and so on.1 2 In the presence of hypertension, diabetes, or hypercholesterolemia, dysfunctional endothelial cells lack their homeostatic role and mediate the functional and structural alterations associated with these cardiovascular risk factors.3 4 5 Endothelial dysfunction produced by hypercholesterolemia has been characterized by reduced endothelium-dependent relaxations in both humans and experimental animals, suggesting a reduced availability of NO.6 7 8 The major determinant of this phenomenon appears to be related to elevated concentrations of oxidized LDL (ox-LDL).9 This has been shown to decrease the expression of NO synthase in endothelial cells and to stimulate the production of superoxide anions, which inactivates NO, leading to the formation of peroxynitrate.10 11 Oxidized LDL are likewise able to increase ET-1 and thromboxane (TX) A2, which could also account for functional alterations.12 13 All these factors could also be involved in the morphological modifications of the vessel wall associated with the development of atherosclerosis.
In addition to endothelium-derived vasoactive agents, angiotensin II (Ang II) can be considered as a proatherogenic agent because it is able to stimulate most of the processes involved in the development of atherosclerosis. 14 Furthermore, hypercholesterolemia, and especially ox-LDL, has been reported to augment Ang II production through the enhancement of angiotensin-converting enzyme (ACE) activity.14 All these facts justify the beneficial effects of ACE inhibitors in atherosclerotic patients and animals.15 16 In addition, an upregulation of AT1 receptor gene expression by LDL in vascular smooth muscle cells has been shown recently.17 However, the effects of AT1 receptor antagonists on functional and morphological changes associated with atherosclerosis are not well known. Consequently, the current study was performed to examine the long-term effects of the AT1 receptor antagonist valsartan on vascular reactivity and structural changes in aorta from rabbits fed with a cholesterol-enriched diet.
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Methods |
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General Procedure
Forty-eight male New Zealand rabbits (Granja Cunicular San Bernardo, Navarra, Spain) initially weighing 1957±40 g were used for the study. The animals were maintained under controlled light and temperature conditions and fed with either a normal rabbit chow or a diet containing 1% cholesterol (UAR) for 10 weeks with free access to tap water. Rabbits of each diet group were treated with valsartan (3 or 10 mg/kg per day) given in the food for the same period. All experimental procedures were approved by the Animal Care and Use Committee of Universidad Complutense, according to the guidelines for ethical care of experimental animals of the European Community.
Arterial Pressure Measurement
On the first day of the experiment, arterial
pressure was directly measured in the medial ear artery in awake
rabbits through a catheter connected to a pressure transducer (model
P23XL; Spectromed) and recorded on a polygraph (7E; Grass
Instruments).
Biochemical Measurements
After arterial pressure measurement, blood samples
were collected in prechilled glass tubes containing EDTA at a final
concentration of 10-7 mol/L through the catheter
inserted in the ear artery of the rabbits. Plasma
cholesterol levels were measured by use of a
colorimetric reaction with a commercial kit
(Boehringer-Mannheim).
Vascular Reactivity
After blood samples were taken, the animals were
anesthetized with sodium pentobarbital (25 mg/kg IV); the
descending thoracic aorta was exposed through a midline incision and
excised. Aortic rings were prepared as previously
described.18 Contractile responses to KCl (80 mmol/L)
were used as references to express contractions to other
vasoconstrictor agents. Contractile responses induced by Ang II
(10-7 mol/L), phenylephrine (PE,
10-9 to 10-5 mol/L), ET-1
(10-10 to 10-7 mol/L),
and the TXA2 receptor agonist U46619
(10-10 to 10-7 mol/L)
were also evaluated. The vasorelaxing response to the
endothelium-dependent vasodilator acetylcholine (ACh,
10-9 to 10-5 mol/L) and
the endothelium-independent vasodilator sodium
nitroprusside (SNP, 10-10 to
10-6 mol/L) were studied in aortic rings from
normocholesterolemic and
hypercholesterolemic rabbits precontracted with a
submaximal dose of PE (10-6 mol/L).
To evaluate the possible mechanisms underlying the effects of hypercholesterolemia and/or valsartan treatment on relaxing responses to ACh, aortic rings were incubated with (1) NG-nitro-L-arginine methyl ester (L-NAME) (10-5 mol/L) to evaluate the role of NO; (2) either superoxide dismutase (SOD) (10-4 mol/L), catalase (10-4 mol/L), or deferoxamine (10-4 mol/L) to study the possible involvement of superoxide anions, H2O2, and hydroxyl radicals; (3) either the TXA2 receptor antagonist ifetroban (10-4 mol/L) or the ETA/ETB receptor antagonist PD 154 (10-5 mol/L) to study the involvement of TXA2 and ET-1.
Histology and Morphometric Analysis
Aortic segments were fixed in 35% sodium phosphate-buffered
formaldehyde, processed, impregnated, and embedded in paraffin and cut
into 3- to 4-µm sections by microtome. The sections were stained with
hematoxylin and eosin, Mason's trichrome, and orcein. Morphometric
(quantitative) determination of the area of the intima, media, and the
vessel was performed with a MICROM image analyzer (Hardware
IMCO 10, Kontron Bildanalyse, Software Microm IP) as previously
described.19 Briefly, all microscopic images of the
sections were recorded on videotape with a videocamera, and the
histological sections were digitalized,
segmented-colored, and traced for calculation of the areas. To
determine the luminal area, the cross-sectional area enclosed by the
internal elastic lamina was corrected to a circle by applying the form
factor l2/4
to the
measurement of the internal elastic lamina, where l is the length of
the lamina. Vessel area was determined by the cross-sectional area
enclosed by the external elastic lamina corrected to a circle, applying
the same form factor
(l2/4) to the
measurement of the external elastic lamina. This method avoids
miscalculations of areas caused by eventual collapse of aortic
segments.20 It should be mentioned that both functional
and morphological studies were performed by 2 different blinded
operators who were not aware of the group to which the animals
belonged.
Drugs
Valsartan was kindly supplied by Novartis Pharma. All other
drugs used for vascular reactivity experiments were purchased from
Sigma Chemical Co. Stock solutions of these drugs were prepared in
distilled water and diluted to desired concentrations with Krebs
solution immediately before the experiment. Concentrations are
expressed as final molar concentration in the organ chamber. Drugs and
chemicals for morphological studies were purchased from Merck
AG.
Calculations and Statistical Analysis
For vascular reactivity studies, the contractile response was
expressed as percentage of the reference constrictor response to
80 mmol/L KCl. For agents that elicit relaxation of
PE-preconstricted aortic rings, response is expressed as percent
reduction of tension in the preconstricted state. Results are expressed
as mean±SEM of rings from 8 rabbits unless otherwise specified.
Vascular reactivity dose-response curves were compared by
multivariate ANOVA for repeated measures with the use
of the Complete Statistical System (CSS) program (Statoft Inc). All
other data were analyzed by use of 1-way ANOVA followed by a
Newman-Keuls test if differences were noted. The null hypothesis was
rejected when the probability value was <0.05.
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Results |
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Blood Pressure and Cholesterol Levels
Rabbits fed with the cholesterol-enriched diet for 10 weeks showed higher (P<0.05) plasma levels of cholesterol than did animals fed with a control diet (Table 1). The concomitant treatment with valsartan, either 3 or 10 mg/kg per day for 10 weeks, did not alter plasma cholesterol levels in any group (Table 1). Systolic arterial pressures were similar in both diet groups and were not affected by the treatment with any dose of valsartan used (Table 1).
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Vascular Reactivity
Maximal contractions induced by Ang II were comparable in both
control and experimental rabbits and were markedly reduced by
treatments with both doses of valsartan to a similar extent (Figure 1). Dose-related contractions induced by
PE, ET-1, or U46619 were comparable in both control and
hypercholesterolemic rabbits and were not affected by
treatment with valsartan (data not shown). Dose-related relaxations
induced by ACh were lower in hypercholesterolemic
rabbits than in controls (Figure 2).
Treatment with valsartan, either 3 or 10 mg/kg per day, did not modify
this response in control rabbits. However, both doses of valsartan
enhanced the response to ACh in hypercholesterolemic
rabbits to a similar extent (Figure 2). Dose-related relaxations
induced by SNP were comparable in both control and
hypercholesterolemic rabbits (maximal response
87.6±2.7 vs 92.1±2.8, % of PE contraction; control and
hypercholesterolemic rabbits, respectively) and were
not affected by valsartan treatment.
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Incubation of aortic rings with L-NAME (10-5 mol/L) blocked relaxations to ACh in all groups (data not shown), indicating that NO is the main factor accounting for endothelium-dependent relaxations in aortic rings from control and hypercholesterolemic rabbits. Incubation of aortic rings with SOD, catalase, or deferoxamine did not show any effect on ACh-induced relaxations (data not shown), either in control or hypercholesterolemic rabbits, untreated or treated with valsartan. This rules out the involvement of these reactive oxygen species in any of the observed effects of hypercholesterolemia or valsartan treatments. Incubation of aortic rings with ifetroban did not modify dose-related relaxations to ACh in control rabbits but increased this response in hypercholesterolemic rabbits, indicating an enhancement of TXA2 in this latter group (Figure 3). Incubation of aortic rings with ifetroban did not further enhance ACh relaxations in any group of rabbits treated with valsartan, either 3 or 10 mg/kg per day (Figure 3). In contrast, incubation of aortic rings with PD154 did not affect ACh-induced relaxations (data not shown), either in control or hypercholesterolemic rabbits, untreated or treated with valsartan, ruling out the involvement of ET-1 (data not shown).
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Histological Studies
Lumen and media cross-sectional areas were comparable in control
and atherosclerotic rabbits (Table 2).
However, vessel area was higher (P<0.05) in atherosclerotic
rabbits than in control rabbits (Table 2). Intimal lesion was
calculated as the area encompassed by the internal elastic lamina minus
lumen area. In cholesterol-fed rabbits, the lesion occupied
29.5±6% of the intimal surface and was nonexistent in control
rabbits. Treatments with 3 and 10 mg/kg per day valsartan reduced
(P<0.05) the intimal lesion (2.4±0.7% and 2.7±0.9%,
respectively) and increased lumen area in
hypercholesterolemic rabbits (Table 2). No
changes in either vessel or media cross-sectional areas were observed
in these animals. Representative photographs of cross
sections of aortic segments are included in Figure 4.
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Discussion |
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The current study shows that in the absence of changes in both arterial pressure and plasma cholesterol levels, the AT1 receptor antagonist valsartan was able to enhance the diminished relaxing response to ACh induced by hypercholesterolemia in rabbit aorta. Moreover, the intimal thickening observed in hypercholesterolemic animals was also prevented by valsartan treatment. These results suggest an important role of Ang II, through AT1 receptors, in the functional and morphological alterations produced by hypercholesterolemia.
In the current study, aortic rings from hypercholesterolemic rabbits presented a reduced response to ACh but not to an endothelium-independent agent such as SNP. In contrast, endothelium-dependent or endothelium-independent contractile responses to Ang II, PE, ET-1, and the TXA2 agonist U46619 were not affected by hypercholesterolemia. Comparable results have been previously reported in experimental animals and humans, indicating that during hypercholesterolemia and during the early stages of atherosclerosis, the most common vascular functional alteration is a reduction of endothelium-dependent relaxation.6 7 8 This effect could rely on a diminished availability of NO as the result of an enhanced production of ox-LDL, which has been demonstrated to reduce the expression of NO synthase by endothelial cells.10 In contrast, reactive oxygen species do not appear to be involved in the diminished response to ACh observed in hypercholesterolemic rabbits because incubation of aortic rings with either SOD, catalase, or deferoxamine did not affect this relaxing response in any group. However, endogenous TXA2 could have contributed to the reduced ACh relaxations because incubation of aortic rings with ifetroban enhanced this response in hypercholesterolemic rabbits. This is supported by a previous report showing that ox-LDL were able to stimulate TXA2 by endothelial cells.12 In contrast, ET-1 does not appear to be involved in the diminished response to ACh because incubation of aortic rings with the ETA/ETB receptor antagonist PD 154 did not affect this response.
Another alteration that could contribute to the observed reduced relaxing response to ACh in hypercholesterolemic rabbits is the intimal thickening, which constitutes a physical barrier, preventing NO from reaching smooth muscle cells.21 22 Proliferation of cellular components, especially foam cells and smooth muscle cells migrating from media to subintimal space, could have contributed to intimal thickening.21 22 In agreement with previous reports,23 24 the study shows that despite the intimal thickening, a reduction in aortic lumen was not observed. This probably was due to an outward displacement of the vessel wall, which preserved the lumen from narrowing and was demonstrated by the increase in the vessel cross-sectional area, together with the maintenance of lumen area.20 25 26
The results also show that the diminished relaxing response to ACh observed in hypercholesterolemic rabbits was enhanced by valsartan treatments. As expected, this effect was accompanied by a marked reduction of Ang II–induced contractions and suggests an important role of Ang II through AT1 receptors in the endothelial dysfunction produced by hypercholesterolemia. In addition, it should be mentioned that either dose of valsartan produced a similar effect on ACh-induced relaxation, probably because the dose of 3 mg/kg per day produced the maximal effect possible on this parameter. Inhibition of several mechanisms activated by Ang II through AT1 receptors, such as direct vasoconstriction or facilitation of sympathetic activity, could account for the observed amelioration of ACh relaxation in hypercholesterolemic rabbits. Inhibition of TXA2 also could have contributed to the observed enhancement of ACh relaxations in hypercholesterolemic rabbits treated with valsartan. This notion is supported by the previous report showing that Ang II stimulates TXA2 through the activation of AT1 receptors.12 In the current study, the enhancement of ACh relaxation produced by the incubation with ifetroban in aortic rings from hypercholesterolemic rabbits was not observed in the animals treated with valsartan. This might indicate that AT1 antagonism with valsartan could have reduced TXA2 availability, and consequently incubation of aortic rings with ifetroban did not show any further effect. In contrast, neither inhibition of ET-1 or reactive oxygen species appear to be involved in the amelioration of ACh relaxations produced by valsartan in hypercholesterolemic rabbits. Increased NO availability also could have contributed to the observed amelioration of ACh relaxations in hypercholesterolemic rabbits treated with valsartan, although we do not have direct evidence of this notion. In previous studies in spontaneously hypertensive rats, we found that prolonged treatment with different AT1 receptor antagonists enhanced ACh-induced relaxations in aortic, mesenteric, and renal vasculature from adult and senescent spontaneously hypertensive rats.27 28 29 30 This improvement was mainly attributed to an enhancement of NO availability, and it was postulated that this could also involve the participation of AT2 receptors.31 32 33
The reduction of the intimal lesion could have accounted for the
observed improvement of endothelium-dependent
relaxation in the hypercholesterolemic rabbits treated
with valsartan. As was mentioned above for ACh relaxation, both doses
of valsartan reduced intimal thickening to a similar extent, suggesting
that the low dose of valsartan was enough to prevent the structural
changes produced by a cholesterol-rich diet. Ang II can be
considered as an important proatherogenic agent.34 35
Although we do not have direct evidence from the current study,
inhibition of several mechanisms activated by Ang II through
AT1 receptors could theoretically account for the
observed reduction of the atherosclerotic lesion. Ang II through
AT1 receptors stimulates modification of
LDL.10 36 Ang II activates the transcription
nuclear factor-
B, which promotes the expression of monocyte adhesion
and chemoattractant molecules (vascular cell adhesion molecule-1,
monocyte chemotactic protein-1, and monocyte colony stimulating
factor), enhancing monocyte adhesiveness to
endothelium and their penetration to the subintimal
space.37 Once monocytes are activated to
macrophages, Ang II stimulates the expression of scavenger
receptors in the cell membrane, facilitating the formation of foam
cells. Furthermore, Ang II stimulates smooth muscle cell
pro-liferation and migration from the media layer to the
subintima.38 39 Consequently, the antagonism of these
AT1-mediated effects of Ang II could have
contributed to the observed reduction of atherosclerotic lesion in
hypercholesterolemic rabbits. Finally, all these
results further support the usefulness of drugs blocking the
renin-angiotensin system (ACE inhibitors and
AT1 receptor antagonists) to
ameliorate the functional and structural vascular alterations
associated not only with hypertension but with
atherosclerosis.15 16 40
In summary, the current study suggests that Ang II, through AT1 receptors, plays a critical role in the development of the vascular functional and structural alterations associated with hypercholesterolemia. Furthermore, AT1 receptor antagonists, besides their antihypertensive effects, could be important therapeutic tools to reduce the development of the atherosclerotic process.
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Acknowledgments |
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This work was supported by a grant from Novartis Pharma and by a grant from Comisión Interministerial de Ciencia y Tecnología, Spain (SAF 98-0077). Sandra Vázquez-Pérez received the support of a grant from Fundación Mapfre Medicina. We thank Blanca Martínez and Antonio Carmona for technical assistance.
Received May 10, 1999; first decision June 15, 1999; accepted July 15, 1999.
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References |
|---|
|
TopAbstractIntroductionMethodsResultsDiscussionReferences |
|---|
1. Jaffe EA. Physiologic functions of normal endothelial cells. In: Loscalzo J, Creager MA, Dzau V, eds. Vascular Medicine. A Textbook of Vascular Biology and Diseases. Boston, Mass: Little, Brown & Co; 1996:3–46.
2. Rubanyi GM. The role of endothelium on cardiovascular homeostasis and diseases. J Cardiovasc Pharmacol. 1993;2(suppl 4):S1–S14.
3.
Panza JA, Casino PR, Kilcoyne RN, Quyyumi AA. Role of
endothelium-derived nitric oxide in the abnormal
endothelium-dependent vascular relaxation of patients
with essential hypertension. Circulation. 1993;87:1468–1474.
4.
Berliner JA, Navab M, Fogelman AM, Frank JS, Demer LL,
Edwards PA, Watson AD, Lusis AJ. Atherosclerosis: basic
mechanisms: oxidation, inflammation and genetics.
Circulation. 1995;91:2488–2496.
5. Lorenzini M, Cagliero E. Pathobiology of endothelial and other vascular cells in diabetes mellitus: call for data. Diabetes. 1991;40:653–659.[Abstract]
6.
Zeiher AM, Drexler H, Wollschläger H, Just H.
Modulation of coronary vasomotor tone in humans: progressive
endothelial dysfunction with different early stages of
coronary atherosclerosis.
Circulation.. 1991;83:391–401.
7. Chowienezyk PJ, Watts GF, Cockcroft JR, Ritter JM. Impaired endothelium-dependent vasodilation of forearm resistance vessels in hypercholesterolemia. Lancet. 1992;340:1430–1432.[Medline] [Order article via Infotrieve]
8.
Jayakody L, Senaratne M, Thompson A, Kappagoda T.
Endothelium-dependent relaxation in experimental
atherosclerosis in the rabbit. Circ Res. 1987;60:251–264.
9. Chin JH, Azhar S, Hoffman BB. Inactivation of endothelial-derived relaxing factor by oxidized lipoproteins. J Clin Invest. 1992;89:10–18.
10. Hernández-Perera O, Pérez-Sala D, Navarro-Antolín J, Sánchez-Pascuala R, Hernández G, Díaz C, Lamas S. Effects of the 3-hydroxy-3-methylglutaryl-CoA reductase inhibitors, atorvastatin and simvastatin, on the expression of endothelin-1 and endothelial nitric oxide synthase in vascular endothelial cells. J Clin Invest. 1998;101:2711–2719.[Medline] [Order article via Infotrieve]
11. Ohara Y, Peterson TE, Harrison DG. Hypercholesterolemia increases endothelial superoxide anion production. J Clin Invest. 1993;91:2546–2551.
12. Bank N, Aynedjian HS. Role of thromboxane in impaired renal vasodilatation response to acetylcholine in hypercholesterolemic rats. J Clin Invest. 1992;89:1636–1642.
13.
Boulanger CM, Tanner FC, Bea ML, Hahn AW, Wermer A,
Luscher TF. Oxidized low density lipoproteins induce mRNA expression
and release of endothelin from human and porcine
endothelium. Circ Res. 1992;70:1191–1197.
14. Gibbons GH. Endothelial function as a determinant of vascular function and structure: a new therapeutic target. Am J Cardiol. 1997;79(5A):3–8.
15.
Chobanian AV, Haudenschild CC, Nickerson C, Drago R.
Antiatherogenic effect of captopril in the Watanabe heritable
hyperlipidemic rabbit. Hypertension.. 1990;15:327–331.
16.
Mancini GB, Henry GC, Macaya C, O'Neill BJ, Pucillo
AL, Carere RG, Wargovich TJ, Mudra H, Lüscher TF, Klibaner MI,
Haber HE, Uprichard ACG, Pepine CJ, Pitt B.
Angiotensin-converting enzyme inhibition with quinapril
improves endothelial vasomotor dysfunction in patients
with coronary artery disease: The TREND (Trial on Reversing
Endothelial Dysfunction) Study. Circulation. 1996;94:258–265.
17.
Nickenig G, Sachinidis A, Michaelsen F, Böhm M,
Seewald S, Vetter H. Upregulation of vascular angiotensin
II receptor gene expression by low-density lipoprotein in vascular
smooth muscle cells. Circulation. 1997;95:473–478.
18. Maeso R, Rodrigo E, Muñoz-García R, Navarro-Cid J, Ruilope LM, Lahera V, Cachofeiro V. Losartan reduces constrictor responses to endothelin-1 and the thromboxane A2 analogue in aortic rings from spontaneously hypertensive rats: role of nitric oxide. J Hypertens. 1997;15:1677–1684.[Medline] [Order article via Infotrieve]
19.
Tan D, Cernadas MR, Aragoncillo P, Castilla MA,
Alvarez-Arroyo MV, Lopez-Farré AJ, Casado S, Caramelo P. Role of
nitric oxide-related mechanisms in renal function in ageing rats.
Nephrol Dial Transplant. 1998;13:594–601.
20.
Bonthu S, Heistad DD, Chappell, Lamping KG, Faraci FM.
Atherosclerosis, vascular remodeling, and impairment of
endothelium-dependent relaxation in genetically altered
hyperlipidemic mice. Arterioscler Thromb Vasc
Biol. 1997;17:2333–2340.
21. Ross R. The pathogenesis of atherosclerosis: a perspective for the 1990s. Nature. 1993;362:801–809.[Medline] [Order article via Infotrieve]
22. Segrest JP, Anantharamaiah GM. Pathogenesis of atherosclerosis. Curr Opin Cardiol.. 1994;9:404–410.[Medline] [Order article via Infotrieve]
23. Amstrong ML, Heistad DD, Marcus ML, Megan MB, Piergos DJ. Structural and hemodynamic responses of peripheral arteries of macaque monkeys to atherogenic diet. Atherosclerosis. 1985;5:336–346.
24. Brizzolara AL, Tomlinson A, Abedeen J, Gourdie RG, Burnstock G. Sex and age as factors influencing the vascular reactivity in Watanabe heritable hyperlipidaemic (WHHL) rabbits: a pharmacological and morphological study of the hepatic artery. J Cardiovasc Pharmacol. 1992;19:86–95.[Medline] [Order article via Infotrieve]
25. Glagov S, Weisenberg E, Zarins CK, Stankunavicius R, Kolettis GJ. Compensatory enlargement of human atherosclerotic coronary arteries. N Engl J Med. 1987;316:1371–1375.[Abstract]
26.
Pasterkamp G, Schoneveld AH, van Wolferen W, Hillen B,
Clarijs RJG, Haudenschild CC, Borst C. The impact of atherosclerotic
arterial remodeling on percentage of luminal
stenosis varies widely within the arterial system:
a postmortem study. Arterioscler Thromb Vasc Biol. 1997;17:3057–3063.
27. Rodrigo E, Maeso R, Muñoz-García R, Navarro-Cid J, Ruilope LM, Cachofeiro V, Lahera V. Endothelial dysfunction in spontaneously hypertensive rats: consequences of chronic treatment with losartan or captopril. J Hypertens. 1997;15:613–618.[Medline] [Order article via Infotrieve]
28. Maeso R, Rodrigo E, Muñoz-García R, Navarro-Cid J, Ruilope LM, Cachofeiro V, Lahera V. Chronic treatment with losartan ameliorates vascular dysfunction induced by aging in spontaneously hypertensive rats. J Hypertens. 1998;16:665–672.[Medline] [Order article via Infotrieve]
29. Muñoz-García R, Maeso R, Rodrigo E, Navarro J, Ruilope LM, Cruz Casal M, Cachofeiro V, Lahera V. Chronic treatment with losartan ameliorates vascular dysfunction induced by aging in spontaneously hypertensive rats. J Hypertens. 1995;13:1779–1784.[Medline] [Order article via Infotrieve]
30.
Tschudi MR, Criscione L, Novosel D, Pfeiffer K,
Lüscher TF. Antihypertensive therapy augments
endothelium-dependent relaxations in coronary
arteries of spontaneously hypertensive rats. Circulation. 1994;89:2212–2218.
31.
Maeso R, Navarro-Cid J,
Muñoz-García R, Rodrigo E, Ruilope LM, Lahera V,
Cachofeiro V. Losartan reduces constrictor responses in
aortic rings from spontaneously hypertensive rats: role of nitric oxide
and angiotensin II type 2 receptors.
Hypertension. 1996;28:967–972.
32. Maeso R, Rodrigo E, Muñoz-García R, Navarro-Cid J, Ruilope LM, Cachofeiro V, Lahera V. Factors involved in the effects of losartan on endothelial dysfunction induced by aging in SHR. Kidney Int. 1998;54(suppl 68):S30–S35.
33. Cachofeiro V, Maeso R, Muñoz-García R, Lahera V. The potential role of nitric oxide in angiotensin II-receptor blockade. Blood Press. 1996;5(suppl 2):29–35.
34. Criscione L, Bradley WA, Buehlmayer P, Whitebread S, Glazer R, Lloyd P, Mueller P, de Gasparo M. Valsartan: preclinical and clinical profile of an antihypertensive angiotensin II antagonist. Drug Rev. 1995;13:230–250.
35.
Scheidegger KJ, Butler S, Witztum JL.
Angiotensin II increases macrophage-mediated
modification of low density lipoprotein via a
lipoxygenase-dependent pathway. J Biol
Chem. 1997;272:21609–21616.
36.
Keidar S, Brook JG, Aviram M. Angiotensin
II enhances lipid peroxidation of low-density lipoprotein. News
in Physiological Sciences. 1993;8:245–248.
37.
Barnes PJ, Karin M. Nuclear factor-kB. A pivotal
transcription factor in chronic inflammatory diseases. N
Engl J Med. 1977;336:1066–1071.
38. Bell L, Madri JA. Influence of the angiotensin system on endothelial and smooth muscle cell migration. Am J Pathol. 1990;137:7–12.[Abstract]
39. Heagerty AM. Angiotensin II: vasoconstrictor or growth factor? J Cardiovasc Pharmacol. 1991;18(suppl 2):S14–S19.
40.
Hernandez-Presa MA, Bustos C, Ortego M, Tunon J, Ortega
L, Egido J. ACE inhibitor quinapril reduces the
arterial expression of NF-kappa B-dependent proinflammatory
factors but not of collagen I in a rabbit model of
atherosclerosis. Am J Pathol.. 1998;153:1825–1837.
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  N. de las Heras, M. Ruiz-Ortega, M. Ruperez, D. Sanz-Rosa, M. Miana, P. Aragoncillo, S. Mezzano, V. Lahera, J. Egido, and V. Cachofeiro Role of connective tissue growth factor in vascular and renal damage associated with hypertension in rats. Interactions with angiotensin II Journal of Renin-Angiotensin-Aldosterone System, December 1, 2006; 7(4): 192 - 200. [Abstract] [PDF]
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 S. Sola, M. Q.S. Mir, F. A. Cheema, N. Khan-Merchant, R. G. Menon, S. Parthasarathy, and B. V. Khan Irbesartan and Lipoic Acid Improve Endothelial Function and Reduce Markers of Inflammation in the Metabolic Syndrome: Results of the Irbesartan and Lipoic Acid in Endothelial Dysfunction (ISLAND) Study Circulation, January 25, 2005; 111(3): 343 - 348. [Abstract] [Full Text] [PDF]
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M. T. Johnstone, A. S. Perez, I. Nasser, R. Stewart, A. Vaidya, F. Al Ammary, B. Schmidt, G. Horowitz, J. Dolgoff, J. Hamilton, et al. Angiotensin Receptor Blockade With Candesartan Attenuates Atherosclerosis, Plaque Disruption, and Macrophage Accumulation Within the Plaque in a Rabbit Model Circulation, October 5, 2004; 110(14): 2060 - 2065. [Abstract] [Full Text] [PDF]
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 A. A. Miyakawa, M. de Lourdes Junqueira, and J. E. Krieger Identification of two novel shear stress responsive elements in rat angiotensin I converting enzyme promoter Physiol Genomics, April 13, 2004; 17(2): 107 - 113. [Abstract] [Full Text] [PDF]
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 E. Cediel, D. Sanz-Rosa, M. P. Oubina, N. de las Heras, F. R. G. Pacheco, O. Vegazo, J. Jimenez, V. Cachofeiro, and V. Lahera Effect of AT1 receptor blockade on hepatic redox status in SHR: possible relevance for endothelial function? Am J Physiol Regulatory Integrative Comp Physiol, September 1, 2003; 285(3): R674 - R681. [Abstract] [Full Text] [PDF]
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 A. R. Brasier, A. Recinos III, and M. S. Eledrisi Vascular Inflammation and the Renin-Angiotensin System Arterioscler Thromb Vasc Biol, August 1, 2002; 22(8): 1257 - 1266. [Abstract] [Full Text] [PDF]
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 P.O. Lim and T.M. MacDonald Step test in hypertension QJM, November 1, 2000; 93(11): 703 - 705. [Full Text] [PDF]
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M. d. Gasparo, P. Hess, B. Nuesslein-Hildesheim, P. Bruneval, and J.-P. Clozel Combination of non-hypotensive doses of valsartan and enalapril improves survival of spontaneously hypertensive rats with endothelial dysfunction Journal of Renin-Angiotensin-Aldosterone System, June 1, 2000; 1(2): 151 - 158. [Abstract] [PDF]
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M. de Gasparo New basic science initiatives with the angiotensin II receptor blocker valsartan Journal of Renin-Angiotensin-Aldosterone System, June 1, 2000; 1(2_suppl): S3 - S5. [Abstract] [PDF]
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J. M Neutel Hypertension and its management: a problem in need of new treatment strategies Journal of Renin-Angiotensin-Aldosterone System, June 1, 2000; 1(2_suppl): S10 - S13. [Abstract] [PDF]
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