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Effects of high salt intake on brain AT₁ receptor densities in Dahl rats

Hypertension Unit, University of Ottawa Heart Institute, and Departments of Cellular and Molecular Medicine and Medicine, University of Ottawa, Ottawa, Ontario, Canada K1Y 4W7

Submitted 14 August 2002 ; accepted in final form 1 July 2003

	ABSTRACT

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To assess effects of dietary salt on brain AT₁ receptor densities, 4-wk-old Dahl salt-sensitive (Dahl S) and salt-resistant (Dahl R) rats were fed a regular (101 µmol Na/g) or high (1,370 µmol Na/g)-salt diet for 1, 2, or 4 wk. AT₁ receptors were assessed by quantitative in vitro autoradiography. AT₁ receptor densities did not differ significantly between strains on the regular salt diet. The high-salt diet for 1 or 2 wk increased AT₁ receptor binding by 21–64% in the Dahl S rats in the subfornical organ, median preoptic nucleus, paraventricular nucleus, and suprachiasmatic nucleus. No changes were noted in the Dahl R rats. After 4 wk on a high-salt diet, increases in AT₁ receptor binding persisted in Dahl S rats but were now also noted in the paraventricular nucleus, median preoptic nucleus, and suprachiasmatic nucleus of Dahl R rats. At 4 wk on the diet, intracerebroventricular captopril caused clear decreases in blood pressure only in the Dahl S on the high-salt diet but caused largely similar relative increases in brain AT₁ receptor densities in Dahl S and R on the high-salt diet versus regular salt diet. These data demonstrate that high salt intake rapidly (within 1 wk) increases AT₁ receptor densities in specific brain nuclei in Dahl S and later (by 4 wk) also in Dahl R rats. Because the brain renin-angiotensin system only contributes to salt-induced hypertension in Dahl S rats, further studies are needed to determine which of the salt-induced increases in brain AT₁ receptor densities contribute to the hypertension and which to other aspects of body homeostasis.

brain renin-angiotensin system; salt-induced hypertension; angiotensin II; autoradiography

The activity of the RAS may be enhanced by the increased release of its active peptides as well as by the upregulation of specific receptors. In Dahl S rats, AT₁ receptor mRNA increased threefold in brain homogenates following 6 wk of a high-salt diet (21). A high-salt diet for 2–5 wk caused a marked increase in angiotensin-converting enzyme (ACE) mRNA and activity measured in hypothalamic and pons homogenates in Dahl S rats compared with Dahl salt-resistant (Dahl R) rats (27). These studies (22, 27) do not provide information on where the increases in expression occur in the brain, and AT₁ receptor mRNA increases may not accurately reflect changes in the functional receptor. Lesion studies indicate that certain hypothalamic areas mediate the salt-induced hypertension in Dahl S rats. Lesions of the anteroventral third ventricle region (5) or bilateral lesions of the PVN (4, 6) attenuated the salt-induced hypertension in this model. Lesions of the anteromedial hypothalamus, which included the PVN, SCh, and intervening periventricular tissue, prevented the development of hypertension in Dahl S rats on a high-salt diet (2, 4). Because these regions contain components of the brain RAS (7, 14), we hypothesized that in one or more of these areas changes in the activity of the brain RAS, specifically the above-mentioned increases in AT₁ receptors mRNA, may contribute to salt-induced hypertension in Dahl S rats. The objective of the present study was therefore to identify changes in AT₁ receptor density induced by high dietary salt intake within the brain areas involved in sodium homeostasis and cardiovascular regulation in Dahl S versus Dahl R rats.

	METHODS

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Male Dahl R and S rats (Harlan Sprague Dawley, Madison, WI; age 3–4 wk), were housed in a temperature-controlled environment at 24°C on a 12:12-h light-dark cycle, fed regular rat chow, and allowed tap water ad libitum for at least 3 days before entering the study. All experimental procedures were carried out in accordance with the guidelines of the Canadian Institutes of Health Research outlined in the "Guide for the Care and Use of Experimental Animals". All chemicals were purchased from Sigma (Oakville, Ontario, Canada) except where otherwise noted.

Dietary treatments. At 4 wk of age, rats were randomly assigned to receive either a regular salt (101 µmol Na/g) or a high-salt (1,370 µmol Na/g, Teklad; Madison, WI) diet for 1, 2, or 4 wk (5–6 rats/group at each time point, for a total of 66 Dahl S and 66 Dahl R rats). At these ages, Dahl S rats are in the developmental phase of salt-induced hypertension and exhibit attendant increases in hypothalamus and pons ACE activity (27). To exclude confounding influences of surgical stress on brain AT₁ receptor densities, blood pressures and AT₁ receptor binding were measured in separate, parallel in time, groups of rats.

Blood pressure and heart rate measurement. At the end of the dietary period, rats were anesthetized by halothane-oxygen inhalation, and a polyethylene catheter was inserted into the left carotid artery, tunneled subcutaneously, and exteriorized at the nape. After an overnight recovery period, resting mean arterial pressure (MAP) and heart rate (HR) were recorded using a data acquisition program (Dataquest LabPro, Data Science International; St. Paul, MN), which allowed online analysis of the pulsatile blood pressure signal from the arterial catheter (averages of 10-s periods, sampling rate 500 Hz). After an accommodation period of 30 min, resting MAP and HR were recorded for 30 min in conscious, freely moving animals. Mean values over these 30 min were used for statistical analysis.

Intracerebroventricular injection of captopril and blood pressure and HR measurement. Captopril was administered into the lateral ventricle to eliminate endogenous ANG II and thereby eliminate possible differences in receptor density caused by ANG II-induced endocytosis. An additional group of 20 rats (10 Dahl S and 10 Dahl R) had an intracerebroventricular cannula stereotaxically implanted (13) after 3 wk on a regular or high-salt diet. One week later, i.e., after 4 wk of the diet, conscious rats were all injected intracerebroventricularly with captopril (100 µg in 2 µl of artificial cerebral spinal fluid, repeated after 1 h). Blood pressure and HR were recorded for 2 h (see above), and then the rats were decapitated for autoradiography.

Quantitative in vitro ANG II receptor autoradiography. Procedures for quantitative assessment of ANG II binding by in vitro receptor autoradiography were performed according to a standard protocol (21, 26). Briefly, rats were decapitated, and the brains were removed rapidly, frozen in 2-methylbutane at –40°C, and stored at –20°C. All tissues were processed within a 1-wk period. Serial 20-µm-thick sections were cut on a cryostat, thaw mounted onto Superfrost Plus microscope slides (VWR; West Chester, PA), and dehydrated overnight in a desiccator at 4°C. Sections were preincubated in a buffer (10 mM sodium phosphate, 120 mM NaCl, and 5 mM disodium EDTA, pH 7.4) containing 0.2% bovine serum albumin for 15 min at 20°C. Sections were then incubated in the same buffer containing 0.2% bovine serum albumin, 0.5 mg/ml bacitracin, and ¹²⁵I-labeled Sar¹Ile⁸-ANG II (0.3 µCi/ml, Washington State University Peptide Radioiodination Service Centre; Pullman, WA) for 1 h. AT₁ receptor binding was determined by including PD-123319 (10^–5 M), an AT₂ receptor antagonist, to exclude AT₂ receptor binding. Nonspecific binding was determined in the presence of 1 µM ANG II. After four successive 1-min washes in ice-cold buffer to remove nonspecifically bound ligand, sections were air-dried and then exposed to Kodak Biomax MR film (Eastman Kodak; Rochester, NY) for 48 h alongside methylacrylate ¹²⁵I standards (Washington State University Peptide Radioiodination Service Center). Film was processed using a Kodak X-OMAT 270 RA automatic processor (Rochester, NY), and relative optical density within outlined the brain areas, heart, and kidneys was quantified by computerized densitometry following the calibration to relative optical densities of the ¹²⁵I standards using a computer-assisted image analysis system, AIS/C (Imaging Research; St. Catharines, Ontario, Canada). Specific binding density was determined by subtraction of nonspecific binding (2–5%) from total binding (expressed as fmol/mg wet weight of tissue). Animals were coded such that experimental groups were not known during densitometry.

The rat brain nuclei localization in sections was defined according to the rat brain atlas of Paxinos and Watson (17). The PVN, MnPO, and SCh were chosen to represent nuclei with significant numbers of AT₁ receptors inside the BBB, and the OVLT and SFO were chosen as nuclei outside the BBB playing a major role in sodium homeostasis and cardiovascular regulation. Densities of six to eight sections for a given nucleus were averaged to provide the AT₁ receptor density for this nucleus. In the 4-wk studies, the heart and kidneys were included to represent peripheral tissues that express an intrinsic RAS. For the heart, five sections in the mid one-third perpendicular to the long axis of the heart were obtained, and densities for each section were measured and then averaged for the left ventricle (LV) and right ventricle (RV). For the kidneys, 10 sagittal sections through the renal hilus were obtained, and densities for each section were measured and then averaged for the renal cortex and medulla separately.

Statistical analysis. Data are presented as means ± SE. All comparisons between groups were determined by a two-way analysis of variance followed by the Student-Newman-Keuls test where applicable. The level of significance was set at P < 0.05. For AT₁ receptor densities, absolute values were compared within strains on high salt versus regular salt intake and between strains on the same diet.

	RESULTS

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Resting hemodynamics. Resting MAP tended to be higher in Dahl S versus R rats on a regular salt diet from 4 to 8 wk of age (Table 1). MAP of Dahl S rats progressively increased on the high-salt diet with rats becoming severely hypertensive after 4 wk of the diet (Table 1). Resting HR did not change significantly between groups during the first 2 wk on the diet but increased significantly in Dahl S rats after 4 wk on the high-salt diet (Table 1). Body weight was similar in Dahl R and Dahl S rats on the regular salt diet. Dahl S rats on the high-salt diet gained significantly less weight than Dahl R rats on the same diet or either strain on regular salt diet (Table 1).

AT₁ receptor density in the central nervous system. In all groups, high densities of ¹²⁵I-labeled Sar¹Ile⁸-ANG II binding to AT₁ receptors were readily detected in the OVLT, SFO, PVN, MnPO, and SCh (Table 2 and Fig. 1). Table 2 shows the absolute AT₁ receptor densities in the different nuclei of Dahl S and R rats on the high or regular salt intake. Figure 2 shows the results on a high-salt diet expressed as a percentage of the regular salt diet. On the regular salt diet, Dahl S and R rats exhibited fairly similar densities in all nuclei studied. In Dahl R rats, the high salt intake for 1 or 2 wk did not change AT₁ receptor binding in all brain areas investigated. However, in Dahl R rats on the high-salt diet for 4 wk, AT₁ receptor densities were increased (22–30%) in the PVN, MnPO, and SCh (all inside the BBB) but not in the OVLT or SFO (outside the BBB, Table 2 and Figs. 1 and 2). Dahl S rats exhibited a different pattern of changes in binding. Significant increases in AT₁ receptor binding in the PVN, MnPO, and SCh were noted in Dahl S rats within 1 wk on the high-salt diet and persisted after 2 and 4 wk, compared with Dahl S rats on the regular salt intake (Table 2 and Figs. 1 and 2). After 1 and 2 wk on the high salt intake, most of these increases were also significant compared with Dahl R rats on the high salt intake (Table 2). After 4 wk, significantly higher densities persisted in the PVN, SCh, and MnPO of Dahl S versus Dahl R rats on the high-salt diet (Table 2). Dahl S rats also showed significant increases in AT₁ receptor binding in the SFO, particularly after 1 wk on the high-salt diet. In both Dahl R and S rats, high salt intake did not change AT₁ receptor densities in the OVLT (Table 2 and Fig. 2).

View larger version (108K): [in this window] [in a new window]   Fig. 1. Autoradiographs showing 125I-labeled Sar1Ile8-ANG II AT1 receptor binding density within representative brain nuclei of a Dahl salt-sensitive (Dahl S) and Dahl salt-resistant (Dahl R) rat on a regular (101 µmol Na/g) or high-salt (1,370 µmol Na/g) diet from 4 to 6 wk of age. Binding density is represented by computer-generated pseudocolor gradient beside the graphs. OVLT, organum vasculosum laminae terminalis; SFO, subfornical organ; MnPO, median preoptic nucleus; SCh, suprachiasmatic nucleus; PVN, paraventricular nucleus; SH, Dahl S rat on high-salt diet; SR, Dahl S rat on regular salt diet; RH, Dahl R rat on high-salt diet; RR, Dahl R rat on regular salt diet.

View larger version (18K): [in this window] [in a new window]   Fig. 2. AT1 receptor binding densities in brain nuclei of Dahl S and Dahl R rats on regular (101 µmol Na/g, R) or high-salt (1,370 µmol Na/g, H) diet from 4 to 5, 4 to 6, or 4 to 8 wk of age (1, 2, or 4 wk of diets, respectively). Results from Table 2 are presented as percentages of densities on high salt vs. on regular salt (set as 100%) in the same strain. Values are percentage means ± SE; n = 5–6 rats/group. *P < 0.05 vs. same strain on regular salt.

AT₁ receptor binding in peripheral organs. On the regular salt intake, the heart of both strains showed low AT₁ receptor densities (Table 3). The high-salt diet for 4 wk did not change AT₁ receptor binding in either the LV or RV (Table 3). On the regular salt intake, AT₁ receptor densities were significantly higher in the renal cortex of Dahl R versus Dahl S rats but similar in the medulla (Table 3). High salt intake decreased renal AT₁ receptor binding similarly in Dahl S and Dahl R rats by 17–22% in the medulla and a 30% in the cortex (Table 3).

AT₁ receptor binding after intracerebroventricular injection of captopril. Intracerebroventricular injection of captopril decreased heart rate (by 20 beats/min) and resting MAP (by 30 mmHg, P < 0.05) in the Dahl S rats on a high-salt diet for 4 wk (Fig. 3A). In Dahl S rats on the regular salt diet or Dahl R rats on either the high- or regular salt diet, resting MAP showed minor (5–10 mmHg, not significant) decreases after captopril (Fig. 3A).

View larger version (27K): [in this window] [in a new window]   Fig. 3. Effects of intracerebroventricular (icv) infusion of captopril (100 µg/2 µl of artificial spinal fluid at time = 0 and 60 min) on mean arterial pressure (MAP) (A) and AT1 receptor binding densities in brain nuclei (B) of Dahl S and Dahl R rats on a regular (101 µmol Na/g, R) or high-salt (1,370 µmol Na/g, H) diet from 4 to 8 wk of age. A: results are the changes vs. baseline. Values are means ± SE from 5 rats in each group. B: results are presented as percentage of densities on high salt vs. regular salt (set as 100%) in the same strain. *P < 0.05 vs. same strain on regular salt; aP < 0.05, S vs. R rats.

In both Dahl S and R rats on the high versus regular salt intake for 4 wk, after intracerebroventricular treatment with captopril, relative differences in AT₁ receptor densities in the brain nuclei studied were substantially larger (Fig. 3B) compared with the modest differences without captopril (Fig. 2). The extent of these differences was similar in both strains in the SFO, PVN, MnPO, and SCh. In the OVLT, after captopril, a high salt-induced increase in AT₁ receptor binding became apparent, and this increase was significantly larger in Dahl S versus Dahl R rats (Fig. 3B).

	DISCUSSION

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The present study demonstrates that a high dietary salt intake for 1–2 wk increases AT₁ receptor binding in the brain regions involved in sodium homeostasis, sympathetic activity, and blood pressure regulation in Dahl S rats but not Dahl R rats. After 4 wk on a high-salt diet, these increases in AT₁ receptor binding persist in Dahl S rats, whereas Dahl R rats now also show (more modest) increases of AT₁ receptor binding in the brain areas inside the BBB but not outside the BBB. After 4 wk on the high-salt diet, inhibition of ANG II formation in the brain by intracerebroventicular injection of the ACE inhibitor captopril results in more substantial differences in AT₁ receptor binding on high versus regular salt intake, similarly in the two strains. In contrast to the central nervous system, AT₁ receptor binding in the heart was not affected by high salt and decreased in the renal medulla and cortex of both strains.

The regulation of AT₁ receptors in brain areas involved in sodium homeostasis and cardiovascular regulation may be one of the critical components in regulating the activity of the brain RAS in response to salt. In SHR, high sodium intake for 4 wk increased AT₁ receptor binding in the hypothalamus, thalamus, and striatum (15) but resulted in a slight fall in normotensive Wistar-Kyoto rats. In Dahl rats, 6 wk of a high-salt diet caused a threefold increase in AT₁ receptor mRNA in whole brain homogenates of Dahl S rats but only a slight (30%) rise in the normotensive controls, Dahl R rats (22). Quantification of the AT₁ receptor mRNA reflects AT₁ receptor gene expression but may not represent the actual changes in the membrane-bound functional receptors. The rate of protein translation and the speed of internalization may also play important roles in the AT₁ receptor density on the cytoplasm membrane. ¹²⁵I-labeled Sar¹Ile⁸-ANG II binding to AT₁ receptors reflects binding at the cell membrane and therefore only AT₁ receptor density on the cell membrane. In the present study, we demonstrate increases in ¹²⁵I-labeled Sar¹Ile⁸-ANG II binding to AT₁ receptors in the PVN, MnPO, SCh, and SFO after 1 and 2 wk of a high-salt diet in Dahl S rats but not in their normotensive controls, Dahl R rats. After 4 wk of diets, high salt-induced increases in AT₁ receptor binding persisted in these brain regions of Dahl S rats and were now also detected, although to a less extent, in the PVN, MnPO, and SCh of Dahl R rats.

Strehlow et al. (22) also found a slight increase of mRNA expression (30%) in the brain of Dahl R rats after 6 wk on a high-salt diet. This finding is consistent with another study showing that, in normotensive rats, 3 wk of high salt intake caused a similar range (35%) of upregulation of AT_1a (but not AT_1b) receptor mRNA in decorticated brain homogenates (19). In the present study, we noticed an increase in AT₁ receptor binding in the PVN, MnPO, and SCh, but not the OVLT and SFO of Dahl R rats, after more a chronic (4 wk) high-salt diet. These results indicate that in normotensive Dahl R rats, a chronic high-salt diet also results in an increase of AT₁ receptor binding, but this increase occurs later and to a less extent compared with the Dahl S rats. The increase of AT₁ binding only in nuclei inside the BBB in Dahl R rats on a high-salt diet may reflect a subtype difference (10, 14) and/or different functions in these brain areas versus areas outside the BBB (i.e., OVLT and SFO). However, after captopril, these two areas also show higher AT₁ receptor densities in Dahl R on a high-salt diet versus regular salt diet (see below).

AT₁ receptors in the brain appear to be upregulated in response to its ligand as chronic intracerebroventricular infusion of ANG II in normotensive rats increases AT₁ receptor mRNA and protein in whole brain homogenates (18). In the whole hypothalamus, ANG II levels are decreased in Dahl S versus R rats on a regular salt intake and remain decreased on a high salt intake (27). However, such tissue levels do not exclude increased ANG II release in specific nuclei and thereby an increase in AT₁ receptor occupancy in vivo. The ANG II-AT₁ receptor complex may be internalized very fast (30 min) through receptor-mediated endocytosis (24, 25). It is therefore possible that the receptor density measured by in vitro autoradiography underestimates the actual increase in number of receptors because of increased internalization subsequent to enhanced angiotensin synthesis in specific brain regions. To assess this possibility, brain ANG II synthesis was blocked by intracerebroventricular administration of the ACE blocker captopril in Dahl S and R rats on high versus regular salt intake for 4 wk, when on a high-salt diet both strains show increased brain AT₁ receptor densities. After 2-h inhibition of the brain RAS, the amount of the membrane-bound receptor may increase relative to the extent of receptor turnover. Indeed, after 2 h of intracerebroventricularly administered captopril, the amount of membrane-bound receptor as assessed by in vitro ¹²⁵I-labeled Sar¹Ile⁸-ANG II differed more markedly in all brain regions in both strains on a high-salt diet relative to rats on a regular salt diet. Thus after the chronic (4 wk) high salt intake, the receptor turnover appears to be enhanced by the high salt intake in both Dahl S and R rats, and the actual increase in AT₁ receptors appears to be substantially more than that found without captopril (Fig. 3B vs. Fig. 2). Moreover, in two areas (OVLT and SFO) of Dahl R rats, differences are apparent only after captopril, suggesting that in these areas the increase in receptor turnover prevents an actual increase in membrane-bound receptors (as measured without captopril). The percent differences after captopril varied between regions, possibly reflecting varying increases in ANG II. Between strains, the percent differences on the high- versus regular salt diet after captopril were fairly similar. However, absolute densities are higher in Dahl S versus Dahl R rats (Table 2), and therefore the actual activity of the RAS in these nuclei is likely higher in the Dahl S versus Dahl R rats.

Functional studies (8, 23) have clearly established that the brain RAS, through AT₁ receptor activation, plays an essential role in the sympathoexcitation and development of hypertension in Dahl S rats on high-salt diet. The larger blood pressure response to intracerebroventricular captopril in the Dahl S rats on high salt intake is consistent with these previous studies. The early development of hypertension in Dahl S rats on a high-salt diet is indeed accompanied by a clear increase in AT₁ receptor densities in brain areas, which are involved in the regulation of sympathetic tone and cardiovascular function. Rapid upregulation by high salt of AT₁ receptor densities in specific brain regions of Dahl S rats may per se not be sufficient to increase the sympathetic tone and blood pressure (12) but will likely enhance responses to increased release of angiotensins (11). On the other hand, after more chronic high salt intake, AT₁ receptor densities also increased (although to a less extent) in these brain regions of Dahl R rats. Autoradiography is not sensitive enough to assess the actual cellular distribution of the AT₁ receptors in a given nucleus. Further studies are needed to assess whether AT₁ receptors playing a role in central regulation of sodium and water homeostasis are similarly increased by the high salt intake in the two strains, but AT₁ receptors involved in regulation of sympathetic activity, and thereby blood pressure, only increased in Dahl S rats. In situ hybridization and other functional approaches may provide further insight in this regard.

In contrast to salt-induced increases of AT₁ receptor mRNA (22) and AT₁ receptor binding in specific brain regions (the present study) in Dahl S and Dahl R rats, AT₁ receptor mRNA (22) and AT₁ receptor binding decreased in the renal medulla and cortex in both Dahl S and Dahl R rats. The intrinsic tissue RASs therefore appear to be regulated in a distinct and organ-specific manner in response to dietary salt (16, 20, 22).

Limitations of study. We did not study the possible functional implications of the changes in brain AT₁ receptors in Dahl S and R rats by high salt intake. The discussion on this aspect should be considered "speculative." Second, in the captopril experiment we did not include the four control (i.e., no captopril) groups and therefore do not know the extent per se of changes induced by captopril within each of the four groups (i.e., Dahl S and R rats on high vs. regular salt intake). However, the primary objective of this particular experiment was to assess whether relative differences in AT₁ receptor binding between rats on a high-diet salt versus regular salt diet would become larger after inhibition of endogenous ANG II formation.

In conclusion, salt-induced hypertension in Dahl S rats is accompanied by increased densities of AT₁ receptors in brain areas both inside and outside of the BBB. Such salt-induced increases in AT₁ receptors in these brain areas may reflect increased local release of angiotensins and may contribute to the development of salt-induced sympathetic hyperactivity and hypertension. However, more chronic high salt intake also increases AT₁ receptor densities in the same brain areas in Dahl R rats. It is possible that some of the AT₁ receptor populations assessed are part of the central pathways involved in sodium and water homeostasis in both strains and other populations are part of central pathways involved in regulation of sympathetic activity, only activated in the Dahl S rats.

	DISCLOSURES

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S. J. Veerasingham was supported by a traineeship of the Heart and Stroke Foundation of Canada. F. H. H. Leenen is a Career Investigator of the Heart and Stroke Foundation of Ontario, Canada. This study was supported by Operating Grant MT-11897 from the Canadian Institutes of Health Research.

	ACKNOWLEDGMENTS

 
We are grateful to Dr. B. Huang for excellent technical assistance, M. J. McKinley and B. J. Oldfield (both from Howard Florey Institute, Melbourne, Australia) for expert opinions, and F. A. O. Mendelsohn's group (Howard Florey Institute) for teaching S. J. Veerasingham the in vitro receptor autoradiography technique.

Present address of J. M. Wang: Dept. of Molecular Pharmacology and Toxicology, Pharmaceutical Science Center, University of Southern California, Los Angeles, CA 90089.

Present address of S. J. Veerasingham: Dept. of Physiology and Functional Genomics, College of Medicine, University of Florida, Gainesville, FL 32610.

	FOOTNOTES

 

Address for reprint requests and other correspondence: F. H. H. Leenen, Hypertension Unit, Univ. of Ottawa Heart Institute, 40 Ruskin St., Ottawa, Ontario, Canada K1Y 4W7 (E-mail: fleenen{at}ottawaheart.ca).

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.

	REFERENCES

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1. Allen AM, Zhuo J, and Mendelsohn FA. Localization and function of angiotensin AT₁ receptors. Am J Hypertens 13: 31S–38S, 2000.[Web of Science][Medline]
2. Azar S, Ernsberger P, Livingston S, Azar P, and Iwai J. Paraventricular-suprachiasmatic lesions prevent salt-induced hypertension in Dahl rats. Clin Sci (Lond) 61, Suppl 7: 49s–51s, 1981.
3. Dampney RA, Fontes MA, Hirooka Y, Horiuchi J, Potts PD, and Tagawa T. Role of angiotensin II receptors in the regulation of vasomotor neurons in the ventrolateral medulla. Clin Exp Pharmacol Physiol 29: 467–472, 2002.[Web of Science][Medline]
4. Ernsberger P, Azar S, and Azar P. The role of the anteromedial hypothalamus in Dahl hypertension. Brain Res Bull 15: 651–656, 1985.[Medline]
5. Goto A, Ganguli M, Tobian L, Johnson MA, and Iwai J. Effect of an anteroventral third ventricle lesion on NaCl hypertension in Dahl salt-sensitive rats. Am J Physiol Heart Circ Physiol 243: H614–H618, 1982.[Abstract/Free Full Text]
6. Goto A, Ikeda T, Tobian L, Iwai J, and Johnson MA. Brain lesions in the paraventricular nuclei and catecholaminergic neurons minimize salt hypertension in Dahl salt-sensitive rats. Clin Sci (Lond) 61, Suppl 7: 53s–55s, 1981.
7. Healy DP and Printz MP. Distribution of immunoreactive angiotensin II, angiotensin I, angiotensinogen and renin in the central nervous system of intact and nephrectomized rats. Hypertension 6: I130–I136, 1984.[Medline]
8. Huang BS and Leenen FH. Both brain angiotensin II and "ouabain" contribute to sympathoexcitation and hypertension in Dahl S rats on high salt intake. Hypertension 32: 1028–1033, 1998.[Abstract/Free Full Text]
9. Huang BS and Leenen FH. Brain "ouabain" and angiotensin II in salt-sensitive hypertension in spontaneously hypertensive rats. Hypertension 28: 1005–1012, 1996.[Abstract/Free Full Text]
10. Kakar SS, Riel KK, and Neill JD. Differential expression of angiotensin II receptor subtype mRNAs (AT_1A and AT_1B) in the brain. Biochem Biophys Res Commun 185: 688–692, 1992.[Web of Science][Medline]
11. Lazartigues E and Davisson RL. Renovascular hypertension is exacerbated in transgenic mice with brain-selective overexpression of angiotensin II (AT₁) receptors (Abstract). Hypertension 40: 381, 2002.
12. Lazartigues E, Dunlay SM, Loihl AK, Sinnayah P, Lang JA, Espelund JJ, Sigmund CD, and Davisson RL. Brain-selective overexpression of angiotensin (AT₁) receptors causes enhanced cardiovascular sensitivity in transgenic mice. Circ Res 90: 617–624, 2002.[Abstract/Free Full Text]
13. Leenen FH and Yuan B. Prevention of hypertension by irbesartan in Dahl S rats relates to central angiotensin II type 1 receptor blockade. Hypertension 37: 981–984, 2001.[Abstract/Free Full Text]
14. Lenkei Z, Corvol P, and Llorens-Cortes C. The angiotensin receptor subtype AT_1A predominates in rat forebrain areas involved in blood pressure, body fluid homeostasis and neuroendocrine control. Brain Res Mol Brain Res 30: 53–60, 1995.[Medline]
15. Mizuno K and Fukuchi S. A possible role of the brain angiotensin II receptor binding in development of hypertension. Jpn Circ J 45: 1111–1115, 1981.[Medline]
16. Nishimura M, Nanbu A, Ohtsuka K, Takahashi H, Iwai N, Kinoshita M, and Yoshimura M. Sodium intake regulates renin gene expression differently in the hypothalamus and kidney of rats. J Hypertens 15: 509–516, 1997.[Web of Science][Medline]
17. Paxinos G and Watson C. The Rat Brain in Stereotaxic Coordinates (2nd ed.). San Diego, CA: Academic, 1986.
18. Porter JP. Chronic intracerebroventricular infusion of angiotensin II increases brain AT₁ receptor expression in young rats. Brain Res Dev Brain Res 112: 293–295, 1999.[Medline]
19. Sandberg K, Ji H, and Catt KJ. Regulation of angiotensin II receptors in rat brain during dietary sodium changes. Hypertension 23: I137–I141, 1994.[Web of Science][Medline]
20. Schmid C, Castrop H, Reitbauer J, Della Bruna R, and Kurtz A. Dietary salt intake modulates angiotensin II type 1 receptor gene expression. Hypertension 29: 923–929, 1997.[Abstract/Free Full Text]
21. Song K, Allen AM, Paxinos G, and Mendelsohn FA. Mapping of angiotensin II receptor subtype heterogeneity in rat brain. J Comp Neurol 316: 467–484, 1992.[Web of Science][Medline]
22. Strehlow K, Nickenig G, Roeling J, Wassmann S, Zolk O, Knorr A, and Bohm M. AT1 receptor regulation in salt-sensitive hypertension. Am J Physiol Heart Circ Physiol 277: H1701–H1707, 1999.[Abstract/Free Full Text]
23. Teruya H, Muratani H, Takishita S, Sesoko S, Matayoshi R, and Fukiyama K. Brain angiotensin II contributes to the development of hypertension in Dahl-Iwai salt-sensitive rats. J Hypertens 13: 883–890, 1995.[Medline]
24. Wang JM, Baudhuin P, Courtoy PJ, and de Potter W. Conversion of angiotensin II into active fragments by an endosomal pathway in bovine adrenal medullary cells in primary culture. Endocrinology 136: 5274–5282, 1995.[Abstract]
25. Wang JM, Llona I, and de Potter WP. Receptor-mediated internalization of angiotensin II in bovine adrenal medullary chromaffin cells in primary culture. Regul Pept 53: 77–86, 1994.[Web of Science][Medline]
26. Wang JM, Tan J, and Leenen FHH. Central nervous system blockade by peripheral administration of AT₁ receptor blockers. J Cardiovasc Pharmacol 41: 593–599, 2003.[Web of Science][Medline]
27. Zhao X, White R, Huang BS, Van Huysse J, and Leenen FH. High salt intake and the brain renin-angiotensin system in Dahl salt-sensitive rats. J Hypertens 19: 89–98, 2001.[Web of Science][Medline]

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