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1 Max Delbrück Center for Molecular Medicine, 13092 Berlin; 3 Department of Clinical Pharmacology, University Hospital Benjamin Franklin, Free University Berlin, 12200 Berlin, Germany; and 2 Institut National de la Santé et de la Recherche Médicale Unité 331, 69675 Bron, France
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ABSTRACT |
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 TOP
 ABSTRACT
 INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
REFERENCES
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TGR(ASrAOGEN)680, a newly developed transgenic rat line with specific downregulation of astroglial synthesis of angiotensinogen, exhibits decreased brain angiotensinogen content associated with a mild diabetes insipidus and lower blood pressure. Autoradiographic experiments were performed on TGR(ASrAOGEN) (TG) and Sprague-Dawley (SD) control rats to quantify AT1 and AT2 receptor-binding sites in different brain nuclei and circumventricular organs. Dose-response curves for drinking response to intracerebroventricular injections of ANG II were compared between SD and TG rats.
In most of the regions inside the blood-brain barrier [paraventricular nucleus (PVN), piriform cortex, lateral olfactory tract (LOT), and lateral preoptic area (LPO)], AT1 receptor binding (sensitive to CV-11974) was significantly higher in TG compared with SD. In contrast, in the circumventricular organs investigated [subfornical organ (SFO) and area postrema], AT1 receptor binding was significantly lower in TG. AT2 receptors (binding sensitive to PD-123319) were detected at similar levels in the inferior olive (IO) of both strains. Angiotensin-binding sites sensitive to both CV-11974 and PD-123319 were detected in the LPO of SD rats and specifically upregulated in LOT, IO, and most notably PVN and SFO of TG. The dose-response curve for water intake after intracerebroventricular injections showed a higher sensitivity to ANG II of TG (EC50 = 3.1 ng) compared with SD (EC50 = 11.2 ng), strongly suggesting that the upregulation of AT1 receptors inside the blood-brain barrier of TG rats is functional.
Finally, we showed that downregulation of angiotensinogen synthesized by astroglial cells differentially regulates angiotensin receptor subtypes inside the brain and in circumventricular organs.
antisense; angiotensin receptor subtypes
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INTRODUCTION |
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TOP
ABSTRACT
INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
REFERENCES
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THE PRESENCE OF A SEPARATE and distinct renin-angiotensin system (RAS) within the brain has been documented for more than 20 years. ANG II receptors are expressed within the blood-brain barrier in discrete loci associated with cardiovascular, body fluid, and neuroendocrine regulation (17, 22). Although the neuromodulatory role of ANG II starts to be well defined in vitro, a clear delineation between specific roles of circulating and intracerebral angiotensin active peptides is still a matter of debate, mostly because of the action of plasma RAS on the central nervous system through the circumventricular organs that lack the blood-brain barrier. Moreover, angiotensinogen is the only known ANG II precursor, and in the brain, glial cells are the major cell type expressing it, whereas ANG II is primarily of neuronal localization (3, 12, 15, 24, 26). The mismatch in location of the various components of a brain angiotensin system has led to the concept of volume transmission (3).
Very little is known about the factors involved in the regulation of brain ANG II receptors. In the periphery, an elevated ANG II level caused by sodium depletion or renal artery stenosis is associated with a diminished vasopressor response to intravenous infusion of ANG II related to a downregulation of the number of ANG II receptors. Conversely, reduced peripheral ANG II level by sodium loading or nephrectomy is associated with an enhanced vasoconstrictor response to peripheral administration of ANG II (7).
As far as ANG II receptors in the brain are concerned, the role of ANG II in the regulation of its own receptors is controversial. Chronic subcutaneous infusion of ANG II in rats was shown to increase the number of ANG II binding sites in neuronal membranes from the diencephalon (33). This effect would be indirect because ANG II does not cross the blood-brain barrier and would represent an action of ANG II on its receptor regulation in central structures opposite to that reported in the periphery. Other investigators reported that intracerebroventricular infusion of ANG II did not affect ANG II-receptor density or binding affinity in either the hypothalamus-thalamus-septum-midbrain or the brain stem, and thus it was concluded that brain ANG II receptors are unresponsive to increased ANG II levels in the cerebrospinal fluid (25). In the brain stem of angiotensinogen knockout mice, no change in AT1 receptor mRNA was found, however, it was clearly upregulated in a variety of peripheral organs (27).
TGR(ASrAOGEN) (TG) is a recently developed transgenic rat derived from Sprague-Dawley (SD) rats expressing an antisense RNA targeted against the 5' region of angiotensinogen mRNA under the control of the glial cell-specific glial fibrillary acidic protein promoter (23). This leads to a colocalized expression of angiotensinogen antisense RNA and angiotensinogen RNA in glial cells, the major site of angiotensinogen synthesis in the brain (3, 26). Angiotensinogen protein concentration determined by ELISA was reduced to ~10% in medulla, pons, hypothalamus, thalamus, and cerebellum compared with SD control rats. Angiotensinogen plasma concentrations and plasma renin activity were not affected as well as plasma sodium and potassium concentrations, indicating that the plasma renin-angiotensin-aldosterone system was not affected by the transgene (2, 23). Basal systolic and diastolic blood pressure were significantly lower than in SD animals, and plasma vasopressin was decreased leading to diabetes insipidus (2, 23).
Because the angiotensinogen decrease in TG occurs specifically in the brain, we expected a differential regulation of ANG II receptors in brain regions inside the blood-brain barrier and in circumventricular organs, which are accessible to circulating ANG II.
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MATERIALS AND METHODS |
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TOP
ABSTRACT
INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
REFERENCES
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Animals. Twelve-to-sixteen-week-old homozygous transgenic TG rats of the line 680 were kindly provided by Dr. Ursula Ganten (Max Delbrueck Center for Molecular Medicine, Berlin-Buch, Germany). SD Hanover rats were obtained from Moellegard Breeding & Research Center. This rat strain was the one used for the generation of the transgenic animals (23). Rats were housed in single cages under controlled conditions (temperature: 23°C, light from 6 AM to 6 PM) and had free access to standard rat laboratory diet and tap water ad libitum. The studies were performed according to the Guiding Principles in the Care and Use of Animals, corresponding to American Physiological Society guidelines.
Tissue preparation and receptor binding.
Rats were anesthetized with ether and intracardially perfused with
ice-cold PBS, pH 7.4. Brains were removed, immediately frozen in
isopentane at 
30°C, and stored at 80°C. Coronal sections (thickness 12 µm) were cut in a cryostat at 20°C and thaw-mounted on gelatin-coated cold glass slides. For each region of interest, we
made three to five consecutive sets of six coronal slices and used the
first and the last slices for conventional eosin staining.
Radioligand binding.
Slide-mounted sections were thawed to room temperature and preincubated
for 30 min at 22°C in 50 mM Tris · HCl buffer, pH 7.4, containing 150 mM NaCl, 5 mM EDTA, 20 µM bestatin (Boehringer, Mannheim), and 0.1% bovine serum albumin. Subsequently, consecutive sections were incubated for 2 h in fresh buffer with 300 pM
125I-labeled Sar1,Ile8-ANG II, a
concentration close to the Kd value
(28), to label ANG II binding sites (total binding).
AT1 and AT2 receptor subtypes were determined
by incubation with 300 pM 125I-labeled
Sar1,Ile8-ANG II in the presence of 10 µM
CV-11974 to specifically displace AT1 binding and in the
presence of 10 µM PD-123319 to specifically displace AT2
binding. Earlier experiments indicated that such concentrations of
antagonists will totally displace ANG II binding from AT1
and AT2 receptors, respectively (30).
Nonspecific binding was determined in the presence of both 10 µM
CV-11974 and 10 µM PD-123319, which totally prevented
125I-labeled Sar1,Ile8-ANG II
binding. Sections were then washed three times, 2 min each, in ice-cold
50 mM Tris · HCl buffer, pH 7.4, followed by a 30-s wash in
ice-cold distilled water and dried under a stream of cool air. The
labeled sections were apposed several times against 3H-Hyperfilm
(Amersham Buchler, Braunschweig, Germany) in X-ray cassettes for 1 to 3 days to have each region of interest in unsaturating conditions
together with an 125I-labeled standard microscale
(Amersham) at 20°C and then developed with D19 Kodak developer for
4 min at 4°C. Films were scanned with 1,200-dpi resolution and
subjected to computerized microdensitometry using National Institutes
of Health Image software on an Apple Macintosh
computer. Each region of interest was circumscribed manually; optical densities were measured, subsequently normalized with
the 125I-labeled standard curve and finally transformed
into femtomole per milligram protein. All data are expressed as
means ± SE of three TG and four SD rats with three to five slices
per region and per rat.
Intracerebroventricular ANG II injections. A detailed description for the procedure of stereotaxic injection in rats is given in Kawasaki et al. (10). Briefly, while rats were under chloral hydrate anesthesia (4%), a stainless steel guide cannula (25 gauge) was inserted stereotaxically in the right lateral cerebral ventricle through a small hole drilled into the skull (1.4 mm lateral and 0.9 mm posterior to bregma and 4.5 mm below the skull) (16). The cannula was fixed with jewelers' screws and dental cement and then closed with a dummy cannula. After surgery, rats were allowed to recover for 7 days. For each injection, the dummy cannula closing the implanted guide cannula was removed from the conscious rat; a 27-gauge internal cannula was inserted into the guide cannula and connected to a Hamilton 5-µl microsyringe via a 30-cm polyethylene tube. Rats were allowed to accommodate for 1 h before ANG II dissolved in isotonic saline was injected at doses of (ng) 0.1, 1, 10, and 100 in random order with a total volume of 5 µl. One injection only was given per day. Five microliters of isotonic NaCl vehicle were administered as control injections. The 3-h water intake was measured after each single injection. The basal unstimulated 24-h water intake was assessed for 2 days just before the first injection.
Statistics. Drinking responses to ANG II were compared between six TG and nine SD rats with the use of a two-way analysis of variance followed by post hoc analysis with the Newman-Keuls test. Dose-response curves were fitted to a four-parameter logistic equation with the Sigmaplot software. Fifty-percent effective dose (ED50) and maximal effect were compared with an unpaired Student's t-test. Receptor densities and 24-h water intake were compared with the unpaired Student's t-test. All results are expressed as means ± SE. The level for statistical significance was set at P < 0.05.
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RESULTS |
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TOP
ABSTRACT
INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
REFERENCES
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ANG II receptor-binding autoradiography.
ANG II receptors were markedly expressed and discretely distributed in
the adult rat brain. Nonspecific binding was <10% of total binding in
all examined brain areas and most often reached the level of the
background value of the film (Figs. 1,
2, 3, and
4).
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Water and salt intake.
The 24-h water intake in TG under basal conditions before
intracerebroventricular injections was slightly elevated without reaching statistical significance (46.4 ± 2.8 in TG vs. 40.8 ± 3.6 ml/24 h in SD). In both rat strains, a dose-response curve to
graded intracerebroventricular injections of ANG II was obtained (Fig.
5). The dose response was significantly
shifted to the left (P < 0.001) for TG. A
four-parameter logistic fitting of the dose-response data confirmed the
right shift with a significantly lower ED50 in TG compared
with SD control rats (3.12 ± 1.4 ng vs. 11.2 ± 5.4 ng,
P < 0.05). The calculated basal, Emax, and slopes were similar for both strains (Fig. 5).
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DISCUSSION |
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TOP
ABSTRACT
INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
REFERENCES
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Our results clearly show that in different forebrain areas inside the blood-brain barrier, the ANG II binding is significantly higher in AOGEN AS RNA-expressing transgenic rats compared with SD control rats. Moreover, AT1 receptor binding in the SFO and in the AP, which are both regions accessible to circulating ANG II, is downregulated compared with SD rats. The dose-response curve for drinking response to intracerebroventricular ANG II is significantly shifted to the left. These results allow us to conclude 1) decreased AOGEN synthesized by glial cells regulates neuronal AT1 receptor expression, 2) glial cell-derived AOGEN regulates differentially AT1 receptors inside the blood-brain barrier and in circumventricular organs, and 3) the increased receptor labeling is paralleled by an increased drinking response to ANG II, strongly suggesting its functional significance.
The expression pattern of ANG II binding sites fits well to that determined in other quantitative autoradiographic studies. Those structures that were shown to mediate the major ANG II effects in body fluid homeostasis and cardiovascular regulation (PVN, SFO, AP, NTS, MnPO) contain almost exclusively AT1 receptors, which is consistent with a number of autoradiographic studies (19, 29, 30). The IO is the only structure where significant ANG II binding could be observed in the presence of CV-11974. Again, this is in line with other autoradiographic experiments (18-20, 29). It should be mentioned that different autoradiographic studies found varying relative amounts of ANG II binding in different brain regions that seem to depend also on the radioligand used (34).
Almost all examined forebrain areas exhibit higher ANG II binding in TG compared with SD rats, whereas ANG II binding in circumventricular organs is decreased in both the SFO and AP. Whether the variations in receptor labeling result from variations in receptor density or receptor affinity cannot definitely be clarified with the data obtained in this set of experiments. Nevertheless, the use of the ANG II antagonist 125I-labeled Sar1,Ile8-ANG II as radioligand should decrease the possibility of detecting higher amounts of high-affinity G protein-coupled receptors.
So far, the reports of regulation of central ANG II receptors by ANG II
are controversial. Although chronic subcutaneous infusion of ANG II in
rats has been shown to increase the number of ANG II binding sites in
neuronal membranes from the diencephalon (32), it can be
argued that an upregulation of central ANG II receptors by circulating
ANG II might be, in part, interpreted as a secondary phenomenon after
increased aldosterone release (22), because mineralocorticoids induce an increase in the number of ANG II receptors
in discrete brain regions (11, 33).
Intracerebroventricular infusion of ANG II over 6 days (500 ng · µl
1 · h1) has been
reported not to affect central ANG II receptor expression (25), but again it can be speculated that with a dose of
500 ng · µl1 · h1, ANG II
leaks into the peripheral circulation and would thereby stimulate
aldosterone release. Aldosterone can cross the blood-brain barrier, and there, as discussed above, it is assumed to upregulate ANG
II receptors that would interfere with the direct effects of the
intracerebroventricularly infused ANG II. Moreover, the very high
nonphysiological doses used in these studies should have increased
blood pressure and possibly opened the blood-brain barrier. In
conclusion, to our knowledge, this is the first study demonstrating
that binding to brain ANG II receptors is regulated by angiotensin
generated from glial cell-derived angiotensinogen.
The decrease in ANG II binding in the AP and SFO is unexpected. Because it was shown that the circulating components of the RAS are not altered in the TG rats (2, 23), these alterations in receptor labeling can only result from the decreased brain angiotensinogen. It can thus be postulated that central angiotensinogen exerts a positive regulation on AT1 receptor binding in these regions.
Interestingly, in four forebrain regions (LPO, PVN, LOT, SFO) in TG, 20 to 40% of the total binding can be inhibited by both CV-11974 and PD-123319, whereas such a phenomenon is only marginally found in the LPO region of the SD. This might be due to a loss of selectivity due to the high concentration of competitors. But there are reports about central and peripheral pharmacological effects of ANG II being inhibited by both AT1 and AT2 antagonists that were interpreted either as a permissive effect of AT2 receptors on the binding of ANG II to AT1 receptors (6, 13, 21, 28) or an action of PD-123319 through the AT1B ANG II receptor subtype (5, 14). However, this observation, which implies a modification of the selectivity of the receptors in the transgenic animals, requires further experiments to be clarified.
Graded intracerebroventricular injections of ANG II were followed by a significant dose-dependent increased drinking response in TG compared with SD rats. The increased drinking response to intracerebroventricular ANG II administration correlates very well with the observed upregulation of AT1 receptors inside the blood-brain barrier in TG. Brain regions characterized by a higher expression of AT1 receptors, like the MnPO, have been shown to be involved in the ANG II-mediated induction of thirst (9, 17). Because the SFO AT1 receptors can also participate in this response, their decreased expression in the TG rats can prevent part of this increased drinking response to intracerebroventricular ANG II. Thus it seems very likely that the demonstrated upregulation of AT1 receptors in different brain regions of the forebrain is responsible for the enhanced responsiveness of neural circuits controlling water intake to ANG II, and it counteracts the decreased binding in the SFO region. Previous studies in spontaneously hypertensive rats (SHR) have demonstrated an attenuation of the elevated water and salt intake and decreased blood pressure after prevention of local ANG II formation with intracerebroventricular infusion of captopril or antisense oligonucleotides directed toward angiotensinogen or AT1 receptor mRNAs (4, 8, 31). The decreases in blood pressure as well as water and salt intake in these experiments were achieved by blocking the endogenous central RAS, supporting the view that centrally generated ANG II is a main factor leading to high blood pressure and exaggerated salt appetite in SHR. In normotensive Wistar-Kyoto and SD rats, there is also evidence for a role of central ANG II in drinking behavior. Intracerebroventricular injections of ANG II or renin caused increased salt appetite and drinking of water. Both renin-induced intakes were diminished by intracerebroventricular injection or infusion of angiotensin-converting enzyme inhibitors captopril or saralasin (1), indicating that the renin-induced effects on water and salt intake are mediated mainly by ANG II.
It can be concluded that the observed hypersensitivity to intracerebroventricular administered ANG II in TG is a consequence of the decreased central synthesis of angiotensinogen as the only known precursor of ANG II in vivo (22) and the resulting upregulation of AT1 receptors in the brain regions inside the blood-brain barrier.
Perspectives
With the use of transgenic rats with a brain-specific inhibition of angiotensinogen expression, we have addressed a specific aspect of the still unsolved question whether the brain RAS works independently from the circulating RAS or whether it is mainly regulated by peripheral angiotensins acting via circumventricular organs. The very clear differentiation between upregulated AT1 receptors inside the brain and nonaffected or downregulated AT1 receptors in circumventricular organs is a strong argument for the hypothesis of an independent brain RAS in the control of fluid homeostasis. Moreover, the fact that angiotensinogen originating from glial cells modulates ANG II receptors in neurons argues in favor of the proposed volume transmission operating in the brain (3). Future experiments will have 1) to define more precisely whether only AT1 or also other ANG II receptor subpopulations are subject to regulation by brain-borne angiotensinogen and 2) to clarify the meaning of our observation of ANG II binding sites sensitive to both CV-11974 and PD-123319. The transgenic animals with specific knock down of brain angiotensinogen used in this study can be a suitable tool to address these questions.| |
ACKNOWLEDGEMENTS |
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This work was supported by a grant of the Deutsche Forschungsgemeinschaft to M. Bader. G. Bricca was supported by fellowships of the Alexander von Humboldt Stiftung and the Fondation pour la Recherche Médicale.
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FOOTNOTES |
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Address for reprint requests and other correspondence: G. Bricca, Institut National de la Santé et de la Recherche Médicale Unité 331, 22 Ave. du Doyen Lépine, 69675 Bron, France (E-mail: bricca{at}lyon151.inserm.fr).
The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
Received 29 March 2000; accepted in final form 8 September 2000.
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REFERENCES |
|---|
|
TOP
ABSTRACT
INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
REFERENCES
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|---|
1.
Avrith, DB,
and
Fitzsimons JT.
Renin-induced sodium appetite: effects on sodium balance and mediation by angiotensin in the rat.
J Physiol
337:
479-496,
1983
2.
Baltatu, O,
Silva JA,
Ganten D,
and
Bader M.
The brain renin-angiotensin system modulates angiotensin II induced hypertension and cardiac hypertrophy.
Hypertension
35:
409-412,
2000
3.
Bunneman, B,
Fuxe K,
Bjelke B,
and
Ganten D.
The brain renin-angiotensin system and its possible involvement in volume transmission.
In: Volume Transmission in the Brain: Novel Mechanism for Neural Transmission, edited by Fuxe K,
and Agnati F.. New York: Raven, 1991, p. 131-158.
4.
Di Nicolantonio, R,
Hutchinson JS,
and
Mendelsohn FAO
Exaggerated salt appetite of spontaneously hypertensive rats is decreased by central angiotensin-converting enzyme blockade.
Nature
298:
846-848,
1982[Medline].
5.
Ernsberger, P,
Zhou J,
Damon TH,
and
Douglas JG.
Angiotensin II receptor subtypes in cultured rat renal mesengial cells.
Am J Physiol Renal Fluid Electrolyte Physiol
263:
F411-F416,
1992
6.
Galaverna, O,
Polidori C,
Sakai RR,
Liénard F,
Chow SY,
and
Fluharty SJ.
Blockade of central angiotensin type 1 and 2 receptors suppresses adrenalectomy-induced NaCl intake in rats.
Regul Pept
66:
47-50,
1996[ISI][Medline].
7.
Gunther, S,
Gimbrone MA, Jr,
and
Alexander RW.
Regulation by angiotensin II of its receptors in resistance blood vessels.
Nature
287:
230-232,
1980[Medline].
8.
Gyurko, R,
Wielbo D,
and
Phillips MI.
Antisense inhibition of AT1 receptor mRNA and angiotensinogen mRNA in the brain of spontaneously hypertensive rats reduces hypertension of neurogenic origin.
Regul Pept
49:
167-174,
1993[ISI][Medline].
9.
Johnson, AK,
and
Thunhorst RL.
The neuroendocrinology of thirst and salt appetite: visceral sensory signals and mechanisms of central integration.
Front Neuroendocrinol
18:
292-353,
1997[ISI][Medline].
10.
Kawasaki, H,
Takasaki K,
and
Furukawa T.
Exaggerated pressor response to centrally administered renin in freely moving, spontaneously hypertensive rats.
Eur J Pharmacol
138:
321-357,
1987.
11.
King, SJ,
Harding JW,
and
Moe KE.
Elevated salt appetite and brain binding of angiotensin II in mineralocorticoid-treated rats.
Brain Res
448:
140-149,
1988[ISI][Medline].
12.
Lenkei, Z,
Palkovits M,
Corvol P,
and
Llorens-Cortes C.
Expression of angiotensin type-1 (AT1) and type-2 (AT2) receptor mRNAs in the adult rat brain: a functional neuroanatomical review.
Front Neuroendocrinol
18:
383-439,
1997[ISI][Medline].
13.
Liénard, F,
Thornton SN,
Martial FP,
Mousseau MC,
and
Nicolaidis S.
Angiotensin II receptor subtype antagonists can both stimulate and inhibit salt appetite in rats.
Regul Pept
66:
87-94,
1996[ISI][Medline].
14.
Madhun, ZT,
Ernsberger P,
Ke FC,
Zhou J,
Hopfer U,
and
Douglas JG.
Signal transduction mediated by angiotensin II receptor subtypes expressed in rat mesengial cells.
Regul Pept
44:
149-157,
1993[ISI][Medline].
15.
Mungall, BA,
Shinkel TA,
and
Sernia C.
Immunocytochemical localization of angiotensinogen in the fetal and neonatal rat brain.
Neuroscience
67:
505-524,
1995[ISI][Medline].
16.
Paxinos, G,
and
Watson C.
The Rat Brain in Stereotaxic Coordinates (2nd Ed.). Sydney: Academic, 1986.
17.
Phillips, MI.
Functions of angiotensin in the central nervous system.
Annu Rev Physiol
49:
413-435,
1987[ISI][Medline].
18.
Rowe, BP,
Grove KL,
Saylor DL,
and
Speth RC.
Angiotensin II receptor subtypes in the rat brain.
Eur J Pharmacol
186:
339-342,
1990[ISI][Medline].
19.
Rowe, BP,
Grove KL,
Saylor DL,
and
Speth RC.
Discrimination of angiotensin II receptor subtype distribution in the rat brain using non-peptidic receptor antagonists.
Regul Pept
33:
45-53,
1991[ISI][Medline].
20.
Rowe, BP,
Saylor DL,
and
Speth RC.
Analysis of angiotensin II receptor subtypes in individual rat brain nuclei.
Neuroendocrinology
55:
563-573,
1992[ISI][Medline].
21.
Rowland, NE,
and
Fregly MJ.
Brain angiotensin AT-2 receptor antagonism and water intake.
Brain Res Bull
32:
391-394,
1993[ISI][Medline].
22.
Saavedra, JM.
Brain and pituitary angiotensin.
Endocr Rev
13:
329-380,
1992[ISI][Medline].
23.
Schinke, M,
Baltatu O,
Böhm M,
Peters J,
Rascher W,
Bricca G,
Lippoldt A,
Ganten D,
and
Bader M.
Blood pressure reduction and diabetes insipidus in transgenic rats deficient in brain angiotensinogen.
Proc Natl Acad Sci USA
96:
3975-3980,
1999
24.
Sernia, C.
Location and secretion of brain angiotensinogen.
Regul Pept
57:
1-18,
1995[ISI][Medline].
25.
Singh, R,
Husain A,
Ferrario CM,
and
Speth RC.
Rat brain angiotensin II receptors: effects of intracerebroventricular angiotensin II infusion.
Brain Res
303:
133-139,
1984[ISI][Medline].
26.
Stornetta, RL,
Hawelu-Johnson CL,
Guyenet PG,
and
Lynch KR.
Astrocytes synthesize angiotensinogen in brain.
Science
242:
1444-1446,
1988
27.
Tamura, K,
Yokoyama N,
Sumida Y,
Fujita T,
Chiba E,
Tamura N,
Kobayashi S,
Kihara M,
Murakami K,
Horiuchi M,
and
Umemura S.
Tissue-specific changes of type 1 angiotensin II receptor and angiotensin-converting enzyme mRNA in angiotensinogen gene-knockout mice.
J Endocrinol
160:
401-408,
1999[Abstract].
28.
Toney, GM,
and
Porter JP.
Functionnal roles of brain AT1 and AT2 receptors in the central angiotensin II pressor response in conscious young spontaneously hypertensive rats.
Brain Res Dev Brain Res
19:
193-199,
1993.
29.
Tsutsumi, K,
and
Saavedra JM.
Characterization and development of angiotensin II receptor subtypes (AT1 and AT2) in rat brain.
Am J Physiol Regulatory Integrative Comp Physiol
261:
R209-R216,
1991
30.
Tsutsumi, K,
Viswanathan M,
Strömberg C,
and
Saavedra JM.
Type-1 and type-2 angiotensin II receptors in fetal rat brain.
Eur J Pharmacol
198:
89-92,
1991[ISI][Medline].
31.
Wielbo, D,
Sernia C,
Gyurko R,
and
Phillips MI.
Antisense inhibition of hypertension in the spontaneously hypertensive rat.
Hypertension
25:
314-319,
1995
32.
Wilson, KM,
Sumners C,
and
Fregly MJ.
Effects of increased circulating angiotensin II (AII) on fluid exchange and binding of AII in the brain.
Brain Res Bull
20:
493-501,
1988[ISI][Medline].
33.
Wilson, KM,
Sumners C,
Hataway S,
Hataway S,
and
Fregly MJ.
Mineralocorticoids modulate central angiotensin II receptors in rats.
Brain Res
382:
87-96,
1986[ISI][Medline].
34.
Wright, JW,
and
Harding JW.
Brain angiotensin receptor subtypes in the control of physiological responses.
Neurosci Biobehav Rev
18:
21-53,
1994[ISI][Medline].
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 M. Sherrod, D. R. Davis, X. Zhou, M. D. Cassell, and C. D. Sigmund Glial-specific ablation of angiotensinogen lowers arterial pressure in renin and angiotensinogen transgenic mice Am J Physiol Regulatory Integrative Comp Physiol, December 1, 2005; 289(6): R1763 - R1769. [Abstract] [Full Text] [PDF]
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 S. O. Kasper, C. S. Carter, C. M. Ferrario, D. Ganten, L. F. Ferder, W. E. Sonntag, P. E. Gallagher, and D. I. Diz Growth, metabolism, and blood pressure disturbances during aging in transgenic rats with altered brain renin-angiotensin systems Physiol Genomics, November 17, 2005; 23(3): 311 - 317. [Abstract] [Full Text] [PDF]
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O. Skott Body sodium and volume homeostasis Am J Physiol Regulatory Integrative Comp Physiol, July 1, 2003; 285(1): R14 - R18. [Full Text] [PDF]
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T. E. Lohmeier Neurohumoral regulation of arterial pressure in hemorrhage and heart failure Am J Physiol Regulatory Integrative Comp Physiol, October 1, 2002; 283(4): R810 - R814. [Full Text] [PDF]
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 M. Bader and D. Ganten It's Renin in the Brain: Transgenic Animals Elucidate the Brain Renin-Angiotensin System Circ. Res., January 11, 2002; 90(1): 8 - 10. [Full Text] [PDF]
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S. Morimoto, M. D. Cassell, T. G. Beltz, A. K. Johnson, R. L. Davisson, and C. D. Sigmund Elevated Blood Pressure in Transgenic Mice With Brain-Specific Expression of Human Angiotensinogen Driven by the Glial Fibrillary Acidic Protein Promoter Circ. Res., August 17, 2001; 89(4): 365 - 372. [Abstract] [Full Text] [PDF]
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