(Hypertension. 1999;34:408-414.)
© 1999 American Heart Association, Inc.
Scientific Contributions |
Role of Angiotensin Receptor Subtypes in Mesenteric Vascular Proliferation and Hypertrophy
From the Department of Medicine, University of Melbourne, Austin & Repatriation Medical Centre (Repatriation Campus), Heidelberg West, Victoria, Australia.
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Abstract |
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Abstract—The aim of this study was to explore the regulation of angiotensin receptors after chronic infusion with angiotensin II (Ang II) and to clarify the relative roles of the angiotensin type 1 (AT1) and type 2 (AT2) receptors in the mediation of Ang II–induced mesenteric vascular hypertrophy. In male Sprague-Dawley rats, Ang II infusion at a dose of 58.3 ng/min by subcutaneous osmotic minipumps for 14 days led to increased mesenteric weight and wall:lumen ratio of the vessels and proliferation of smooth muscle cells. These vascular changes were attenuated by either valsartan, an AT1 receptor antagonist, at a dose of 30 mg · kg-1 · d-1 by gavage, or PD123319, an AT2 receptor antagonist, at a dose of 830 ng/min by intraperitoneally implanted osmotic minipumps. Ang II infusion was associated with hypertension, which was prevented by valsartan, but not PD123319. 125I-Sar1, Ile8 Ang II binding to mesenteric vasculature was increased after Ang II infusion. Valsartan treatment was associated with reduced Ang II binding to both receptor subtypes, whereas PD123319 was associated with reduced Ang II binding to only the AT2 receptor subtype. These findings suggest that the trophic and proliferative effects of Ang II on the mesenteric vasculature are mediated by both AT1 and AT2 receptors.
Key Words: angiotensin II • receptors, angiotensin • vascular proliferation • proliferating cell nuclear antigen
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Introduction |
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TopAbstractIntroductionMethodsResultsDiscussionReferences |
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The function of angiotensin receptors in vascular proliferation and hypertrophy has been an area of ongoing debate.1 Contradictory functions of angiotensin type 1 (AT1) and type 2 (AT2) receptors have been documented by several investigators both in vivo and in vitro. Angiotensin II (Ang II) may play a dual role in cultured smooth muscle and endothelial cells,2 with the growth promoting effects of Ang II mediated by the AT1 receptor, whereas the antiproliferative effects of Ang II occur via the AT2 receptor.3 4 5 However, several recent studies have suggested that the AT2 receptor may act in a different manner in certain contexts. For example, Ang II–induced increase in RNA synthesis in cultured A10 smooth muscle cells, a cell line without AT1 receptors, could be blocked by PD123319, an AT2 receptor antagonist, but not by losartan, an AT1 receptor antagonist, which suggests a potential trophic action of the AT2 receptor on smooth muscle cell growth.6
In vivo, the AT2 receptor antagonist CGP 42112A, has been reported to be more effective at the prevention of neointima formation in an injured carotid artery model than the AT1 receptor antagonist losartan.7 This finding was interpreted as an indicator that the AT2 receptor plays a predominant role in neointima formation after vascular injury.7 However, with a transgenic technique, overexpression of the AT2 receptor attenuates neointimal formation after balloon injury in the rat carotid artery.8
In the rat administered Ang II chronically, the relative roles of the AT1 and AT2 receptor in the mediation of vascular hypertrophy have been explored by several groups. Ang II–induced aortic hypertrophy and fibrosis was prevented by the AT2 receptor antagonist PD123319 but not by the AT1 receptor antagonist valsartan.9 However, the opposite results have been reported by another group.10
The difference in results between these studies is unexplained. In none of these chronic Ang II infusion studies was regulation of angiotensin receptors and in particular the AT2 receptor explored. Therefore, the aim of the present study was to assess the regulation of angiotensin receptors after chronic infusion of Ang II alone or with either an AT1 or AT2 receptor antagonist. In addition, the effects of these angiotensin receptor antagonists on Ang II–associated mesenteric vascular proliferation and hypertrophy were directly evaluated.
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Methods |
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Protocols
Adult male Sprague-Dawley rats (body weight 230 to 280 g) were bred and housed at the Biological Research Laboratory in the Austin and Repatriation Medical Center were used in this study. The protocols for animal experimentation and the handling of animals were in accordance with the principles established by the Animal Welfare Committee of the Austin and Repatriation Medical Center.
In protocol 1, 40 rats were randomly allocated into 4 groups (n=10/group) and treated for 14 days. Group 1 received a vehicle infusion of 0.15 mol/L sodium chloride and 1 mmol/L acetic acid via Alzet osmotic minipumps (Model 2002, Alzet Corp) implanted subcutaneously in the midscapular region. Animals were anesthetized with enflurane (Ethrane). Group 2 was infused with human Ang II (Auspep) at a concentration of 7 mg/mL. On the basis of the pumping rate of the minipumps (0.5 µL/h), Ang II was administered at a dose of 58.3 ng/min, a dose shown to induce hypertension and vascular hypertrophy.11 Group 3 received the Ang II infusion plus the AT1 receptor antagonist valsartan (provided by Dr Marc de Gasparo, Novartis, Basel, Switzerland) at a dose of 30 mg · kg-1 · d-1 by daily gavage; this dose reduces blood pressure in Sprague-Dawley rats.12 13 Group 4 was infused with Ang II subcutaneously and the AT2 receptor antagonist PD123319 (provided by Dr Joan Keiser, Parke-Davis, Ann Arbor, Mich) via an intraperitoneally implanted Alzet minipump (Model 2002). PD123319 was dissolved at a concentration of 100 mg/mL with sterile water. On the basis of the pumping rate of the minipumps (0.5 µL/h), PD123319 was administered at 830 ng/min. This dose is in the range used by other groups14 and is the maximal dose that could be achieved with this model of minipump in our laboratory.
In protocol 2, the effect of treatment with valsartan (n=6) or PD123319 (n=7) alone on mesenteric vasculature was evaluated in Sprague-Dawley rats. Valsartan and PD123319 were administered as in protocol 1. To explore the possible influence of intraperitoneal implantation of minipumps on mesenteric vasculature, an additional group was implanted intraperitoneally with minipumps that contained vehicle alone (n=7).
Systolic blood pressure (SBP) was measured by indirect tail-cuff plethysmography in prewarmed, unanesthetized animals as previously described.15 The animals were killed at day 14. Blood samples were collected from the tail vein of conscious rats before the animals were killed for the measurement of plasma renin activity (PRA).16
Animals were anesthetized by intravenous injection of pentobarbitone sodium at a dose of 60 mg/kg body wt (Boehringer Ingelheim). The mesenteric arteries (n=7/group, protocol 1) were perfused in vivo at arterial pressure via an intra-aortic cannula. The vessels were first flushed of blood with saline and then fixed with 2.5% glutaraldehyde.17 The mesenteric vessels were removed and stripped of surrounding fat, connective tissue, and veins.17 The vessels were weighed, fixed in 10% formalin, and paraffin-embedded by use of the standard procedures.
Autoradiography
Mesenteric arteries (n=3/group, protocol 1) were dissected and
placed into ice-cold saline and stripped of surrounding fat, connective
tissue, and veins. Tissue was then snap-frozen in liquid nitrogen and
stored at -80°C. Sections (20 µm thick) were cut on a
cryostat at -20°C, dehydrated overnight under reduced pressure at
4°C, and then stored at -80°C in sealed containers with
silica gel.
Autoradiographic localization of Ang II receptors was
performed as described previously.18 Briefly, Ang II
receptor binding sites were labeled with the analogue of Ang II,
125I-Sar(1), Ile(8) Ang II. The slide-mounted
sections were preincubated for 15 minutes in 10 mmol/L sodium
phosphate buffer (pH 7.4) followed by 1 hour of incubation in a fresh
volume of the same buffer that contained 0.2 µCi/mL (
90 pmol/L)
125I-Sar(1), Ile(8) Ang II, 0.2% BSA, and
0.3 mmol/L bacitracin. AT1 receptor binding
was determined by the binding that remained in the presence of the
AT2 receptor antagonist PD123319
(10-5 mol/L). AT2 receptor
binding was determined by the binding that remained in the presence of
the AT1 receptor antagonist Dup 753
(10-5 mol/L). Nonspecific binding was determined
in parallel incubations in the presence of 10-5
mol/L PD123319 and 10-5 mol/L Dup 753. After the
sections were incubated, they were washed 4 times for 1 minute each in
ice-cold buffer, dried under a stream of cold air, and exposed to Agfa
Scopix CR3B x-ray film at room temperature for 2 weeks. A set of
radioactivity standards was included in each cassette.
After the films were exposed, they were processed and the optical densities quantified by a microcomputer imaging device (MCID Imaging system) coupled to an IBM-AT computer. A calibration curve of optical density versus radioactivity density was constructed by the computer program with the radioactivity standards. This enabled conversion of the data into dpm/mm2.18 Binding densities were calculated as the difference between the total binding and nonspecific binding, respectively. The slides were then coated in photographic emulsion (Ilford K5) and stored for 4 weeks. Slides were developed in phenisol developer (Ilford K5), fixed, and stained with hematoxylin-eosin for light microscopy.
Immunohistochemistry
Four-micron paraffin sections of mesenteric artery were cut,
dehydrated, and used for immunohistochemistry. Endogenous
peroxidase was inactivated with 3% hydrogen peroxide
(H2O2) in methanol for 20
minutes, then blocked with a protein block agent for 20 minutes. The
sections of vessels were labeled with either a mouse anti-human
–smooth muscle actin antibody or cell nuclear antigen proliferating
(PCNA, DAKO A/S). The multi-link swine anti-goat, -mouse, and
-rabbit immunoglobulin (DAKO A/S) was used as the secondary
antibody; this was then followed by peroxidase-conjugated streptavidin.
Detection was accomplished by reaction with 3,3'-diaminobenzidine
tetrahydrochloride (Sigma Chemical Co).
Histomorphometery
Mesenteric vascular structure was assessed by quantitative
histomorphometry as previously described.13 17 A video
imaging system (Video Pro 32) and an associated online microscope and
computer were used to count the number of PCNA positive cells in a
manner similar to that described by Kato et al.19 In
brief, the cells that contained PCNA were counted manually in the
mesenteric media and adventitia. The areas of the media and adventitia
were also measured. PCNA positive cells were expressed as the cell
number per µm2. In the adventitia, only
those positively stained cells located within 40 µm of the
external elastic lamina were included.
Statistical Analysis
Data were analyzed by ANOVA by use of Statview SE
(Brainpower) on a Macintosh Computer. Comparisons of group means were
performed by Fisher's least significant difference method. Because PRA
did not have a normal distribution, this parameter was
analyzed after logarithmic transformation. Data are shown as
mean±SEM. P<0.05 was considered statistically
significant.
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Results |
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Protocol 1
Ang II–infused rats gained less weight than vehicle-treated animals. This influence of Ang II on body weight was prevented by co-administration of Ang II with valsartan, but not with PD123319 (Table 1). Ang II infusion was associated with hypertension during the experimental period, which was prevented by concomitant treatment with valsartan but not PD123319 (Table 1). Ang II infusion was associated with markedly reduced PRA levels. Valsartan treatment increased PRA levels to more than those observed with vehicle alone. Administration of PD123319 did not influence the effect of Ang II on PRA (Table 1).
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Mesenteric Vessel Structure
Mesenteric vessel weight and the mesenteric vessel weight to body
weight ratio were increased 
2-fold in Ang II infused rats compared
with vehicle treatment. These changes were attenuated by both valsartan
and PD123319 (Table 1). Ang II infusion resulted in a 50%
increase in the wall:lumen ratio of mesenteric arteries. The increase
in the wall:lumen ratio was reduced by 90% with valsartan and by 70%
with PD123319. No significant difference existed between treatment with
valsartan or PD123319 in terms of their effects on prevention of Ang
II–induced increases in mesenteric vascular weight or wall:lumen
ratios (Figure 1, top).
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P<0.05 vs Ang II infusion.
Proliferative Cell Nuclear Antigen
Ang II infusion resulted in increased PCNA staining in the
mesenteric vasculature, which was assessed by a 5-fold increase in PCNA
positive cells in the medial layer and a 2-fold increase in PCNA
positive cells in the adventitial layer compared with vehicle-infused
rats. Treatment of Ang II–infused rats with either valsartan or
PD123319 was associated with a decrease in PCNA positive cells to
vehicle-infused levels in both media and adventitia (Figure 1, middle and bottom; Figure 2).
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)
and cells in the adventitia (
In Vitro Autoradiography of Angiotensin
Receptors
In vehicle infused rats, both AT1 and
AT2 receptors were present in mesenteric
vessels. AT1 receptors were the predominant
subtype (88%). The density of Ang II binding sites was increased after
Ang II infusion, with a 70% increase in AT1 and
a 4-fold increase in AT2 receptor subtypes.
Treatment with valsartan was associated with a reduction in both
AT1 and AT2 receptor
binding. Administration of PD123319 was associated with a decrease in
the AT2 receptor, but not the
AT1 receptor subtype (Table 2, Figure 3). Binding sites for both
AT1 and AT2 receptors were
in the medial and adventitial layers (Figure 4A and 4B). The same distribution of
AT1 and AT2 receptors was
observed after Ang II infusion (Figure 4C and 4D).
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Protocol 2
Weight gain was similar among the various treatment groups,
and there was no significant difference when compared with control
animals (Table 3). Valsartan resulted in
a decrease in SBP and an increase in PRA over the experimental period.
PD123319 or implantation of the minipump
intraperitoneally did not significantly influence
blood pressure or PRA (Table 3).
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No significant difference existed in mesenteric vessel weight or the ratio of mesenteric vessel weight to body weight between the valsartan treated and control rats. Intraperitoneal administration of PD123319 or vehicle alone via the osmotic minipumps was associated with an increase in vessel weight and in the ratio of mesenteric vessel weight to body weight (Table 3). However, the wall:lumen ratio of mesenteric arteries was not affected by any of the treatments compared with control animals. There was no significant difference in the number of PCNA positive cells in medial or adventitial layers among the various treatment groups (Table 3).
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Discussion |
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The present study has confirmed and extended previous findings that Ang II infusion promotes the growth of smooth muscle cells and induces vascular hypertrophy in rats.11 19 Administration of both the AT1 and AT2 receptor antagonists was associated with attenuation of mesenteric vascular hypertrophy and smooth muscle cell proliferation. These results are consistent with findings obtained from cultured rat cardiac fibroblasts, in which Ang II–stimulated collagen synthesis was mediated by both AT1 and AT2 receptors.20 In cultured quiescent vascular smooth muscle cells, Ang II elevates the nuclear transcription factor–
B (NF-B), which is thought to
participate in the regulation of cell proliferation and vascular
damage.21 This occurs via stimulation of both
AT1 and AT2
receptors.21 In aortic smooth muscle cells, Ang
II–induced changes in nuclear calcium levels are mediated by both
AT1 and AT2
receptors.22 This increase in nuclear calcium is thought
to play a pivotal role in the mediation of the trophic response to Ang
II.22 Furthermore, in cultured mouse spleen lymphocytes,
the stimulatory effect of Ang II on proliferation has been shown to be
mediated by both angiotensin receptor
subtypes.23
In protocol 2, intraperitoneal implantation of
osmotic minipumps that delivered either PD123319 or vehicle was
associated with increased mesenteric vessel weight. This may be due to
a nonspecific reaction to the minipumps or to the fluid delivered from
the minipumps into the abdominal cavity. However, treatment with either
valsartan or PD123319 in normotensive rats did not influence vascular
structure. Consistent with these in vivo findings are in vitro
studies that indicate that AT1 and
AT2 receptor antagonists inhibit the
activation of NF- B in Ang II–stimulated smooth muscle
cells in culture but not in quiescent cells.21
This study suggests that blood pressure and PRA respond differently to the AT1 and AT2 antagonists in both Ang II–induced hypertension and in the normotensive physiological state. Furthermore, these findings confirm that the effects of Ang II on regulation of blood pressure and PRA are mediated by the AT1 receptor and not the AT2 receptor. Other studies have shown that the administration of PD123319 in the rat, even at a very high dose, has no effects on blood pressure, plasma Ang II levels, or cardiovascular hemodynamics.9 24 25 These findings have been interpreted as indicating that PD123319 does not act on the AT1 receptor. However, it has been suggested that high doses of PD123319 may act as an AT1 antagonist.26 In the present study, it is unlikely that PD 123319 acted as an AT1 receptor antagonist because in vitro autoradiographic assessment of Ang II binding suggested that PD123319 inhibited the AT2 receptor but did not act as an AT1 receptor antagonist on the mesenteric vasculature. Indeed, Macari et al14 have suggested that the concentration of PD123319 required to exert an effect on the AT1 receptor is >100 µmol/L, a concentration that is unlikely to have been achieved in the present study. The lack of effect on the AT1 receptor with doses similar to those used in the present study has been previously reported.9 Nevertheless, in view of the difference in the mode of administration of PD123319 in the various studies and the lack of detailed bioavailability data for this compound, one cannot totally exclude that at very high doses, possibly at the tissue level, this agent could interact with the AT1 receptor.
Ang II can also induce vascular hypertrophy without significantly raising blood pressure.11 27 The cause for this vascular hypertrophy, independent of systemic hypertension, remains unclear. The possibility that this involves activation of the AT2 receptor, with subsequent proliferative effects without influencing blood pressure, remains to be determined. Recently, Otsuka et al28 reported a significantly enhanced mRNA expression for the AT2 receptors in the aorta of spontaneously hypertensive rats (SHR). Treatment with the AT2 receptor antagonist PD123319 was associated not only with a decrease in mRNA expression for the AT2 receptor but also with a reduction in the medial cross-sectional area of the aorta.28 This provides evidence for a role for the AT2 receptor in the process of smooth muscle hypertrophy in the aorta from SHR.28 This reduction in vascular hypertrophy with an AT2 receptor antagonist is consistent with previous studies that used either the model of Ang II infusion9 or carotid artery injury.7
The regulation of angiotensin receptors and the relative balance of AT1 and AT2 receptors in the setting of elevated plasma Ang II levels has not been fully explored. With the use of radioligand binding studies, it has been shown that there is a similar distribution of AT1 and AT2 receptor subtypes in the vascular system, albeit in the normal physiological context.29 However, it has been suggested that after Ang II infusion, there is increased expression of the AT2 rather than the AT1 receptor in hypertrophied rat hearts.29 30 With the use of radioligand binding techniques, we have shown for the first time that both AT1 and AT2 binding sites are present in the mesenteric vasculature from the rat with the AT1 receptor being the predominant subtype. Upregulation of both AT1 and AT2 receptor subtypes in mesenteric vasculature was observed after Ang II infusion. This increase in receptor number is particularly evident with respect to the AT2 receptor subtype with a 4-fold increase after Ang II infusion. Upregulation of the AT2 receptor has been described in other pathological states including hypertension,31 diabetes,32 myocardial infarction,33 and ischemia.34 Recently, it has been shown that angiotensin II promotes expression of the AT1 receptor in the kidney.35 These findings are consistent with the present study that noted a increase in the AT1 receptor binding with angiotensin II infusion.
The reduction in AT1 receptor binding with valsartan and the decrease in AT2 receptor binding with PD123319 is consistent with the known effects of these antagonists on angiotensin receptors. However, valsartan treatment was also associated with a reduction in AT2 binding density. The reason for this reduction in AT2 receptor density by treatment with valsartan is unknown. Because valsartan therapy was associated with reduced vascular injury and vascular injury is associated with increased AT2 receptor density, it is possible that the decrease in AT2 receptor binding with valsartan occurred as a consequence of valsartan's action as a vasoprotective agent. It is unlikely that this effect of valsartan is at the level of AT2 receptor gene expression because it has been shown in the SHR that losartan does not affect vascular AT2 receptor gene expression.28 Because administration of either valsartan or PD123319 is associated with attenuation of vascular proliferation and hypertrophy, it is likely that both receptor subtypes are involved in the mediation of angiotensin II–induced vascular injury.
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Acknowledgments |
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This study was supported by a grant from the National Heart Foundation of Australia. The authors would like to thank Dr Marc de Gasparo from Novartis for providing valsartan, Dr Joan Keiser from Parke Davis for providing PD123319, Christian Jarvinen for animal care, and Melinda Rockell for measurements of PRA.
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Footnotes |
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Reprints to Mark E. Cooper, Associate Professor, Department of Medicine, University of Melbourne, Austin and Repatriation Medical Centre (Repatriation Campus), Heidelberg West, Victoria 3081, Australia.
Received March 17, 1999; first decision April 5, 1999; accepted May 19, 1999.
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References |
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TopAbstractIntroductionMethodsResultsDiscussionReferences |
|---|
1. Horiuchi M, Akishita M, Dzau VJ. Recent progress in angiotensin II type 2 receptor research in the cardiovascular system. Hypertension. 1999;33:613–621.
2. Stoll M, Steckelings UM, Paul M, Bottari SP, Metzger R, Unger T. The angiotensin AT2-receptor mediates inhibition of cell proliferation in coronary endothelial cells. J Clin Invest. 1995;95:651–657.
3.
Yamada T, Horiuchi M, Dzau VJ. Angiotensin
II type 2 receptor mediates programmed cell death. Proc Natl Acad
Sci U S A. 1996;93:156–160.
4. Tsuzuki S, Eguchi S, Inagami T. Inhibition of cell proliferation and activation of protein tyrosine phosphatase mediated by angiotensin II type 2 (AT2) receptor in R3T3 cells. Biochem Biophys Res Commun. 1996;228:825–830.[Medline] [Order article via Infotrieve]
5. Ozawa Y, Suzuki Y, Murakami K, Miyazaki H. The angiotensin II type 2 receptor primarily inhibits cell growth via pertussis toxin-sensitive G proteins. Biochem Biophys Res Commun. 1996;228:328–333.[Medline] [Order article via Infotrieve]
6. Saward L, Zahradka P. The angiotensin type 2 receptor mediates RNA synthesis in A10 vascular smooth muscle cells. J Mol Cell Cardiol. 1996;28:499–506.[Medline] [Order article via Infotrieve]
7.
Janiak P, Pillon A, Prost JF, Vilaine JP. Role of
angiotensin subtype 2 receptor in neointima
formation after vascular injury. Hypertension. 1992;20:737–745.
8.
Nakajima M, Hutchinson HG, Fujinaga M, Hayashida W,
Morishita R, Zhang L, Horiuchi M, Pratt RE, Dzau VJ. The
angiotensin II type 2 (AT2) receptor antagonizes the growth
effects of the AT1 receptor: gain-of-function study using gene
transfer. Proc Natl Acad Sci U S A. 1995;92:10663–10667.
9. Levy BI, Benessiano J, Henrion D, Caputo L, Heymes C, Duriez M, Poitevin P, Samuel JL. Chronic blockade of AT2-subtype receptors prevents the effect of angiotensin II on the rat vascular structure. J Clin Invest. 1996;98:418–425.[Medline] [Order article via Infotrieve]
10.
Li JS, Touyz RM, Schiffrin EL. Effects of AT1 and AT2
angiotensin receptor antagonists in
angiotensin II-infused rats. Hypertension. 1998;31:487–492.
11.
Griffin SA, Brown WC, MacPherson F, McGrath JC, Wilson
VG, Korsgaard N, Mulvany MJ, Lever AF. Angiotensin II
causes vascular hypertrophy in part by a non-pressor
mechanism. Hypertension. 1991;17:626–635.
12. Wu LL, Cox A, Roe CJ, Dziadek M, Cooper ME, Gilbert RE. Transforming growth factor ß1 and renal injury following subtotal nephrectomy in the rat: role of the renin-angiotensin system. Kidney Int. 1997;51:1553–1567.[Medline] [Order article via Infotrieve]
13. Cao Z, Hulthén UL, Allen T, Cooper ME. Angiotensin converting enzyme inhibition and calcium channel blockade attenuate streptozotocin-diabetes-associated mesenteric vascular hypertrophy independent of their hypotensive action. J Hypertens. 1998;16:793–799.[Medline] [Order article via Infotrieve]
14. Macari D, Bottari S, Whitebread S, De Gasparo M, Levens N. Renal actions of the selective angiotensin AT2 receptor ligands CGP 42112B and PD 123319 in the sodium-depleted rat. Eur J Pharmacol. 1993;249:85–93.[Medline] [Order article via Infotrieve]
15.
Buñag RD. Validation in awake rat of a tail-cuff
method for measurement of systolic blood pressure. J
Appl Physiol. 1973;34:279–282.
16. Mendelsohn F, Hutchinson J, Johnston CI. A review of plasma renin measurements and their clinical significance. Aust NZ J Med. 1971;1:86–93.[Medline] [Order article via Infotrieve]
17. Rumble JR, Cooper ME, Soulis T, Cox A, Wu L, Youssef S, Jasik M, Jerus G, Gilbet R. Vascular hypertrophy in experimental diabetes: role of advanced glycation end products. J Clin Invest. 1997;99:1016–1027.[Medline] [Order article via Infotrieve]
18. Mendelsohn FA, Millan M, Quirion R, Aguilera G, Chou ST, Catt KJ. Localization of angiotensin II receptors in rat and monkey kidney by in vitro autoradiography. Kidney Int Suppl. 1987;20:S40–S44.[Medline] [Order article via Infotrieve]
19.
Kato H, Hou J, Chobanian AV, Brecher P. Effect of
angiotensin II infusion and inhibition of nitric oxide
synthase on the rat aorta. Hypertension. 1996;28:153–158.
20. Brilla CG, Zhou G, Matsubara L, Weber KL. Collagen metabolism in cultured adult rat cardiac fibroblast: response to angiotensin II and aldosterone. J. Mol. Cell Cardiol. 1994;26:809–820.[Medline] [Order article via Infotrieve]
21.
Lorenzo O, Ruiz-Ortega M, Ortego J. Role of AT1 and AT2
receptors in angiotensin II-induced nuclear transcription
factor– B activation in cultured cells. J
Hypertens. 1998;16:S26. Abstract.
22.
Munzenmaier DH, Greene AS. Angiotensin II
mediates a sustained rise in nuclear and cytoplasmic calcium via
multiple receptor subtypes. Am J Physiol. 1995;269:H565–H570.
23. Kunert Radek J, Stepien H, Komorowski J, Pawlikowski M. Stimulatory effect of angiotensin II on the proliferation of mouse spleen lymphocytes in vitro is mediated via both types of angiotensin II receptors. Biochem Biophys Res Commun. 1994;198:1034–1039.[Medline] [Order article via Infotrieve]
24. Macari D, Whitebread S, Cumin F, De Gasparo M, Levens N. Renal actions of the angiotensin AT2 receptor ligands CGP 42112 and PD 123319 after blockade of the renin-angiotensin system. Eur J Pharmacol. 1994;259:27–36.[Medline] [Order article via Infotrieve]
25. Champion HC, Garrison EA, Estrada LS, Potter JM, Kadowitz PJ. Analysis of responses to angiotensin I and angiotensin I-(3–10) in the mesenteric vascular bed of the cat. Eur J Pharmacol. 1996;309:251–259.[Medline] [Order article via Infotrieve]
26. Timmermans PB, Wong PC, Chiu AT, Herblin WF, Benfield P, Carini DJ, Lee RJ, Wexler RR, Saye JA, Smith RD. Angiotensin II receptors and angiotensin II receptor antagonists. Pharmacol Rev. 1993;45:205–51.[Medline] [Order article via Infotrieve]
27. Lever AF. Slow developing pressor effect of angiotensin II and vascular structure. J Hypertens Suppl. 1993;11:S27–28.
28.
Otsuka S, Sugano M, Makino N, Sawada S, Hata T,
Niho Y. Interaction of mRNAs for angiotensin II type 1 and
type 2 receptors to vascular remodeling in spontaneously hypertensive
rats. Hypertension. 1998;32:467–472.
29.
Sechi LA, Griffin CA, Grady EF, Kalinyak JE, Schambelan
M. Characterization of angiotensin II receptor subtypes in
rat heart. Circ Res. 1992;71:1482–1489.
30.
Lopez JJ, Lorell BH, Ingelfinger JR, Weinberg EO,
Schunkert H, Diamant D, Tang SS. Distribution and function of cardiac
angiotensin AT1- and AT2-receptor subtypes in hypertrophied
rat hearts. Am J Physiol. 1994;267:H844–H852.
31.
Wu J, Edwards D, Berecek KH. Changes in renal
angiotensin II receptors in spontaneously hypertensive rats
by early treatment with the angiotensin converting enzyme
inhibitor captopril. Hypertension. 1994;23:819–822.
32. Sechi LA, Griffin CA, Schambelan M. The cardiac renin-angiotensin system in STZ-induced diabetes. Diabetes. 1994;43:1180–1184.[Abstract]
33. Smits JF, Passier RC, Nelissen Vrancken HJ, Cleutjens JP, Kuizinga MC, Daemen MJ. Does ACE inhibition limit structural changes in the heart following myocardial infarction? Eur Heart J. 1995;16 (suppl):46–51.
34. Wiemer G, Scholkens BA, Wagner A, Heitsch H, Linz W. The possible role of angiotensin II subtype AT2 receptors in endothelial cells and isolated ischemic rat hearts. J Hypertens Suppl. 1993;11:S234–S235.[Medline] [Order article via Infotrieve]
35. Cheng HF, Becker BN, Burns KD, Harris RC. Angiotensin II upregulates type-1 angiotensin II receptors in renal proximal tubule. J Clin Invest. 1995;95:2012–2019.
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 D. Perlegas, H. Xie, S. Sinha, A. V. Somlyo, and G. K. Owens ANG II type 2 receptor regulates smooth muscle growth and force generation in late fetal mouse development Am J Physiol Heart Circ Physiol, January 1, 2005; 288(1): H96 - H102. [Abstract] [Full Text] [PDF]
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 K. Savary, A. Michaud, J. Favier, E. Larger, P. Corvol, and J.-M. Gasc Role of the renin-angiotensin system in primitive erythropoiesis in the chick embryo Blood, January 1, 2005; 105(1): 103 - 110. [Abstract] [Full Text] [PDF]
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M. E. Mabrouk, Q. N. Diep, K. Benkirane, R. M. Touyz, and E. L. Schiffrin SAM68: a downstream target of angiotensin II signaling in vascular smooth muscle cells in genetic hypertension Am J Physiol Heart Circ Physiol, May 1, 2004; 286(5): H1954 - H1962. [Abstract] [Full Text] [PDF]
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 R. Candido, T. J. Allen, M. Lassila, Z. Cao, V. Thallas, M. E. Cooper, and K. A. Jandeleit-Dahm Irbesartan but Not Amlodipine Suppresses Diabetes-Associated Atherosclerosis Circulation, March 30, 2004; 109(12): 1536 - 1542. [Abstract] [Full Text] [PDF]
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X. Zhang, M. Lassila, M. E. Cooper, and Z. Cao Retinal Expression of Vascular Endothelial Growth Factor Is Mediated by Angiotensin Type 1 and Type 2 Receptors Hypertension, February 1, 2004; 43(2): 276 - 281. [Abstract] [Full Text] [PDF]
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B. I. Levy Can Angiotensin II Type 2 Receptors Have Deleterious Effects in Cardiovascular Disease?: Implications for Therapeutic Blockade of the Renin-Angiotensin System Circulation, January 6, 2004; 109(1): 8 - 13. [Full Text] [PDF]
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 B. Rizkalla, J. M. Forbes, M. E. Cooper, and Z. Cao Increased Renal Vascular Endothelial Growth Factor and Angiopoietins by Angiotensin II Infusion Is Mediated by Both AT1 and AT2 Receptors J. Am. Soc. Nephrol., December 1, 2003; 14(12): 3061 - 3071. [Abstract] [Full Text] [PDF]
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 S. Sarlos, B. Rizkalla, C. J. Moravski, Z. Cao, M. E. Cooper, and J. L. Wilkinson-Berka Retinal Angiogenesis Is Mediated by an Interaction between the Angiotensin Type 2 Receptor, VEGF, and Angiopoietin Am. J. Pathol., September 1, 2003; 163(3): 879 - 887. [Abstract] [Full Text] [PDF]
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Z. Cao, F. Bonnet, R. Candido, S. P. Nesteroff, W. C. Burns, H. Kawachi, F. Shimizu, R. M. Carey, M. de Gasparo, and M. E. Cooper Angiotensin Type 2 Receptor Antagonism Confers Renal Protection in a Rat Model of Progressive Renal Injury J. Am. Soc. Nephrol., July 1, 2002; 13(7): 1773 - 1787. [Abstract] [Full Text] [PDF]
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M. Naruse, A. Tanabe, A. Sato, S. Takagi, K. Tsuchiya, T. Imaki, and K. Takano Aldosterone Breakthrough During Angiotensin II Receptor Antagonist Therapy in Stroke-Prone Spontaneously Hypertensive Rats Hypertension, July 1, 2002; 40(1): 28 - 33. [Abstract] [Full Text] [PDF]
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 S. Phoon and L. G. Howes Forearm vasodilator response to angiotensin II in elderly women receiving candesartan: role of AT2- receptors Journal of Renin-Angiotensin-Aldosterone System, March 1, 2002; 3(1): 36 - 39. [Abstract] [PDF]
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R. Shimizu-Hirota, H. Sasamura, M. Mifune, H. Nakaya, M. Kuroda, M. Hayashi, and T. Saruta Regulation of Vascular Proteoglycan Synthesis by Angiotensin II Type 1 and Type 2 Receptors J. Am. Soc. Nephrol., December 1, 2001; 12(12): 2609 - 2615. [Abstract] [Full Text] [PDF]
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C. Berry, R. Touyz, A. F. Dominiczak, R. C. Webb, and D. G. Johns Angiotensin receptors: signaling, vascular pathophysiology, and interactions with ceramide Am J Physiol Heart Circ Physiol, December 1, 2001; 281(6): H2337 - H2365. [Abstract] [Full Text] [PDF]
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M. El Mabrouk, R. M. Touyz, and E. L. Schiffrin Differential ANG II-induced growth activation pathways in mesenteric artery smooth muscle cells from SHR Am J Physiol Heart Circ Physiol, July 1, 2001; 281(1): H30 - H39. [Abstract] [Full Text] [PDF]
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M. Burnier Angiotensin II Type 1 Receptor Blockers Circulation, February 13, 2001; 103(6): 904 - 912. [Full Text] [PDF]
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M. Mifune, H. Sasamura, R. Shimizu-Hirota, H. Miyazaki, and T. Saruta Angiotensin II Type 2 Receptors Stimulate Collagen Synthesis in Cultured Vascular Smooth Muscle Cells Hypertension, November 1, 2000; 36(5): 845 - 850. [Abstract] [Full Text] [PDF]
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 C. Chassagne, C. Adamy, P. Ratajczak, B. Gingras, E. Teiger, E. Planus, P. Oliviero, L. Rappaport, J.-L. Samuel, and S. Meloche Angiotensin II AT2 receptor inhibits smooth muscle cell migration via fibronectin cell production and binding Am J Physiol Cell Physiol, April 1, 2002; 282(4): C654 - C664. [Abstract] [Full Text] [PDF]
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