In Situ Demonstration of Angiotensin-Dependent and Independent Pathways for Hyperaldosteronism During Chronic Extracellular Fluid Volume Depletion

Junji Takaya, Taiji Matsusaka, Hideyuki Katori, Masaaki Tamura, Yoichi Miyazaki, Toshio Homma and Iekuni Ichikawa

Department of Pediatrics (J.T., T.M., H.K., Y.M., I.I.), Department of Medicine (T.M., I.I.), and Department of Biochemistry (M.T.), Vanderbilt University School of Medicine, Nashville, Tennessee 37232; and Institute of Medical Science, Molecular and Cellular Nephrology (T.M.), Department of Pediatrics (T.H., I.I.), Tokai University, Isehara, Kanagawa 259-1193, Japan

Address all correspondence and requests for reprints to: Taiji Matsusaka, M.D., Ph.D., Institute of Medical Science, Molecular and Cellular Nephrology, Tokai University, Bohseidai, Isehara City, Kanagawa 259-1193, Japan. E-mail: taijim{at}is.icc.u-tokai.ac.jp


    ABSTRACT
 TOP
 ABSTRACT
 INTRODUCTION
 RESULTS
 DISCUSSION
 MATERIALS AND METHODS
 REFERENCES
 
In wild-type mice, 2-wk administration of losartan, an angiotensin (Ang) II type 1 (AT1) receptor antagonist, along with dietary sodium restriction, resulted in an elevation of plasma aldosterone greater than that seen with sodium restriction alone (2.75 ± 0.35 vs. 1.38 ± 0.16 ng/ml, P < 0.01). Plasma potassium increased in sodium-restricted, losartan-treated mice (6.0 ± 0.2 mEq/liter), while potassium remained unchanged in mice with sodium restriction alone.

To study the effect of Ang II on glomerulosa cells that may operate independently of plasma potassium in situ, we used chimeric mice made of cells with or without the intact AT1A gene (Agtr1a). When animals were fed a normal diet or chronically infused with Ang II, the aldosterone synthase mRNA was detectable only in Agtr1a+/+ but not Agtr1a-/- zona glomerulosa cells. After 2 wk of sodium restriction, plasma aldosterone increased (1.51 ± 0.27 ng/ml) and potassium remained on average at 4.5 ± 0.2 mEq/liter, with aldosterone synthase mRNA expressed intensively in Agtr1a+/+, but not detectable in Agtr1a-/- cells. Simultaneous sodium restriction and losartan treatment caused increases in plasma potassium (5.5 ± 0.1 mEq/liter) and aldosterone (1.84 ± 0.38 ng/ml), with both Agtr1a-/- and Agtr1a+/+ cells intensively expressing aldosterone synthase mRNA. Thus, aldosterone production is regulated by Ang II in the adrenal gland during chronic alterations in extracellular fluid volume when plasma potassium is maintained within the normal range. In the light of a previous observation that dietary potassium restriction superimposed on sodium restriction abolished secondary hyperaldosteronism in angiotensinogen null-mutant mice, the present findings demonstrate that when the renin-Ang system is compromised, plasma potassium acts as an effective alternative mechanism for the volume homeostasis through its capacity to induce hyperaldosteronism.


    INTRODUCTION
 TOP
 ABSTRACT
 INTRODUCTION
 RESULTS
 DISCUSSION
 MATERIALS AND METHODS
 REFERENCES
 
THE RENIN-ANGIOTENSIN (Ang) system has been thought to be the most important regulator for aldosterone synthesis during alterations in the extracellular fluid (ECF) volume. A few facts support this notion. Adrenal glomerulosa cells express high density of Ang II type 1 (AT1) receptor (1). Ang II increases mRNA and protein of aldosterone synthase, a rate-limiting enzyme for aldosterone production, and enhances aldosterone production in vitro and in vivo (2). Renin and Ang II are concurrently up-regulated during ECF volume depletion. Moreover, some short-term experiments showed that blockade of Ang II synthesis or AT1 receptor attenuates plasma aldosterone level and the expression of aldosterone synthase in the adrenal zona glomerulosa (3, 4, 5). Thus, the notion appeared well established that Ang II mediates aldosterone production, especially during dietary sodium restriction.

However, it has been documented repeatedly that administration of Ang I converting enzyme (ACE) inhibitors or AT1 antagonists in humans and animals fails to suppress plasma aldosterone levels (6, 7, 8, 9, 10, 11, 12, 13, 14, 15). In this regard, we previously showed that null-mutant mice for the angiotensinogen gene (Agt), which can generate no Ang II, were perfectly capable of achieving secondary hyperaldosteronism when they were placed on dietary sodium restriction (16). In these mice, plasma potassium was markedly elevated, and plasma aldosterone concentration was proportional to that of potassium. Superimposition of potassium restriction on sodium restriction to normalize plasma potassium levels led to an abolition of hyperaldosteronism in Agt-/- mice. These findings unequivocally indicate that the establishment of secondary hyperaldosteronism does not require an intact renin-Ang system and suggest that in the absence of Ang II, potassium plays an intermediary role in secondary hyperaldosteronism. Thus, despite the experimental observations suggesting otherwise, it now becomes conceivable that Ang II is not of vital importance to achieve secondary hyperaldosteronism, at least for animals that lack Ang II from the earliest embryonic stage.

In the present study, we first studied whether the above Ang-independent hyperaldosteronism can operate in wild-type mice carrying an intact renin-Ang system. In addition, we undertook a new experimental approach that allows us to study the direct effect of Ang II on glomerulosa cells operating independently of the systemic milieu including plasma potassium. The approach involved the use of chimeric mice made up with two genetically different cell types, one with and the other without the intact AT1A (the major subtype of AT1 receptor in mice) gene (Agtr1a). Within a given chimeric mouse, both types of cells are exposed to the same systemic milieu, and the different behavior between the two types of cells represents the local and direct action of Ang II in the adrenal gland. With this chimeric mouse system, we demonstrated in situ the direct action of Ang II for the first time in the chronic setting of ECF volume depletion. In addition, the chimeric mice served to unveil the existence of a separate mechanism for aldosterone production that plays a vitally important role in ECF volume homeostasis.


    RESULTS
 TOP
 ABSTRACT
 INTRODUCTION
 RESULTS
 DISCUSSION
 MATERIALS AND METHODS
 REFERENCES
 
Up-Regulation of Aldosterone Production During Sodium Restriction in the Presence of Pharmacological AT1 Inhibition
We first examined whether the Ang II-independent secondary hyperaldosteronism is observed in wild-type mice during dietary sodium restriction using a pharmacological intervention. Wild-type mice were placed on a low-sodium diet with or without an AT1 antagonist, losartan (100 mg/liter in drinking water). After 2 wk, plasma aldosterone concentration measured by RIA was markedly elevated in the losartan-untreated mice (1.38 ± 0.16 ng/ml) from the baseline values found in mice on normal diet (0.40 ± 0.066 ng/ml, P < 0.01). Simultaneous administration of losartan caused a greater increase in plasma aldosterone (2.75 ± 0.35 ng/ml, vs. 0.39 ± 0.075 ng/ml, P < 0.01) (Fig. 1Go). To validate the plasma aldosterone measurement by a RIA method, we used HPLC-atmospheric pressure chemical ionization-tandem mass spectrometry. This method revealed the same effect of losartan on plasma aldosterone level. The mean value in losartan-untreated mice was 1.31 ± 0.41 ng/ml and, upon administration of losartan, 2.00 ± 0.22 ng/ml. In addition, a significant correlation was observed between the values obtained by these two methods (r = 0.603, P < 0.001). Thus, pharmacological blockade of AT1 does not attenuate the degree of the secondary hyperaldosteronism but, instead, appears to have unmasked a more potent mechanism for aldosterone production during chronic sodium restriction.



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Figure 1. Secondary Hyperaldosteronism Occurs in Wild-Type Mice in the Presence of AT1 Blockade

Wild-type mice were fed either normal (Normal Na) or low-sodium (Low Na) diet for 2 wk with or without losartan in the drinking water (100 mg/liter). Plasma aldosterone (upper panel) and potassium (lower panel) were determined by RIA and flame photometry, respectively. A, P < 0.01 compared with normal Na; B, P < 0.01 compared with normal Na + losartan, and compared with low Na; C, P < 0.01 compared with normal Na + losartan.

 
After 2 wk of sodium restriction alone, plasma potassium level was increased slightly, on average, from 4.4 ± 0.1 mEq/liter to 4.9 ± 0.2 mEq/liter (Fig. 1AGo). In marked contrast, simultaneous administration of sodium restriction and losartan caused a prominent increase to 6.0 ± 0.3 mEq/liter. Losartan alone was without effect on plasma potassium (4.4 ± 0.1 mEq/liter). Thus, the increase in aldosterone during sodium restriction was not attenuated by the treatment of AT1 antagonist.

Generation of AT1A Intact-Deficient Chimeric Mice
To study the direct action of Ang II on glomerulosa cells that may operate independently of the systemic milieu, we generated chimeric mice that were made up with AT1A-deficient (Agtr1a-/-) and intact cells. We used ROSA26 transgenic (ROSA) mice as a source of AT1A-intact cells. Since ROSA mice ubiquitously express the lacZ transgene and have an intact Agtr1a gene, staining for ß-galactosidase should allow us to distinguish Agtr1a-/- and intact cells. ß-Galactosidase staining confirmed that all cells in the adrenal gland in ROSA mice, but not in Agtr1a-/- mice, intensely express the lacZ gene (Fig. 2Go, a and c). To study the expression of AT1 receptor in the adrenal gland of ROSA and Agtr1a-/- mice, we performed binding autoradiography using [125I-Sar1-Ile8]Ang in the presence of an AT2 antagonist, PD123319. The study confirmed that zona glomerulosa and zona fasciculata of ROSA mice intensely express AT1 receptor (Fig. 2bGo). Although Agtr1a-/- mice have an intact gene for AT1B receptor, the second subtype of AT1 receptor in mice, no binding signal was detectable in Agtr1a-/- mice (Fig. 2dGo).



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Figure 2. LacZ and AT1 Expression in the Adrenal Gland from ROSA (a and b), Agtr1a-/- (c and d), and Agtr1a-/-{leftrightarrow} ROSA Mice (e–h)

a, c, e, and g, LacZ and nuclear fast red staining. b, d, f, and h, [125I-Sar1-Ile8]Ang binding in the adjacent sections in the presence of an AT2 antagonist, PD123319. Panel g is a high magnification of the area marked by the rectangle in e. Panel h is a high magnification of the corresponding field of f. Note that the pattern of Ang binding completely overlaps that of lacZ-positive cells, with the most intense signal localized to the zona glomerulosa.

 
We next examined chimeric mice generated from Agtr1a-/- and ROSA embryos (Agtr1a-/-{leftrightarrow} ROSA). Each adrenal cell was either intensively stained or completely negative for lacZ in chimeric mice (Fig. 2Go, e and g). LacZ-stained or unstained glomerulosa and fasciculata cells clustered, forming continuous columns extending from the capsule toward the medulla, indicating that these cells derived from the common precursor cells. In contrast, lacZ-positive and -negative medullar cells distributed in a somewhat mixed pattern, unrelated to the clonal distribution of cortical cells.

To correlate the cellular expression pattern of the AT1 receptor and the lacZ gene in the adrenal gland of Agtr1a-/-{leftrightarrow} ROSA mice, we performed Ang binding autoradiography and lacZ staining in the adjacent sections. The pattern of Ang binding completely overlapped that of lacZ-positive cells, with the most intense signal localized to the zona glomerulosa (Fig. 2Go, e and f; g and h). No binding signal was observed in lacZ-negative cells. These results established that the positive and negative lacZ staining faithfully reflects the presence and absence of AT1 receptor in the adrenal gland of Agtr1a-/-{leftrightarrow} ROSA mice.

The Expression of Aldosterone Synthase mRNA in Agtr1a-/-{leftrightarrow} ROSA Mice
To examine the role of Ang II in aldosterone production, we performed in situ hybridization for aldosterone synthase mRNA in the adrenal gland of Agtr1a-/-{leftrightarrow} ROSA mice placed under various conditions. The genotype of adrenal cells was determined by lacZ staining in the adjacent sections.

In Agtr1a-/-{leftrightarrow} ROSA mice fed a normal sodium diet, aldosterone synthase mRNA was observed only in ROSA cells, but not in Agtr1a-/- cells, within the zona glomerulosa (Fig. 3Go, a and b). This demonstrates that aldosterone synthesis is dependent on Ang II in this condition.



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Figure 3. The Expression of Aldosterone Synthase mRNA in the Adrenal Gland of Agtr1a-/-{leftrightarrow} ROSA in Various Conditions (a–l) and Agtr1a+/+{leftrightarrow} ROSA Mice on Normal Na Diet (m and n)

The left panels (a, c, e, g, i, k, and m) are LacZ and nuclear fast red staining. The right panels (b, d, f, h, j, l, and n) are in situ hybridization for aldosterone synthase mRNA performed in the adjacent sections. a, b, m, and n, Normal sodium diet. c and d, Ang II infusion (1 ng/g body wt/min). e, f, g, and h, Low-sodium diet. i, j, k, and l, Low-sodium diet with losartan. Panels g, h, k, and l are high magnifications of panels e, f, i, and j, respectively. The magnified fields are shown by rectangles in e and i.

 
We also generated chimeric mice that were made up of ROSA cells and wild-type cells, i.e. both carrying intact Agtr1a gene (Agtr1a+/+{leftrightarrow} ROSA). Both lacZ-positive and negative zona glomerulosa equally expressed aldosterone synthase mRNA, confirming that ROSA cells in the zona glomerulosa express a similar level of aldosterone synthase mRNA to that in wild-type glomerulosa cells (Fig. 3Go, m and n).

We next examined the response to exogenous Ang II. Ang II (1 ng/g body wt/min) was infused for 2 wk into Agtr1a-/-{leftrightarrow} ROSA mice using an osmotic minipump. A significant expression of aldosterone synthase mRNA was found in ROSA glomerulosa cells, whereas no hybridization signal was observed in Agtr1a-/- glomerulosa cells (Fig. 3Go, c and d).

We then placed Agtr1a-/-{leftrightarrow} ROSA mice on a low-sodium diet. After 2 wk of sodium restriction, plasma potassium remained within a normal range (4.5 ± 0.2 mEq/liter). Aldosterone synthase mRNA was expressed selectively in ROSA glomerulosa cells, whereas no hybridization signal was observed in Agtr1a-/- glomerulosa cells (Fig. 3Go, e and f; g and h). This indicates that in the presence of an intact renin-Ang system, the expression of aldosterone synthase mRNA during sodium restriction is also dependent on Ang II, and the plasma potassium remains within normal range.

Finally, we placed Agtr1a-/-{leftrightarrow} ROSA mice on sodium restriction and simultaneously treated them with losartan for 2 wk. In these mice, the expression of aldosterone synthase mRNA was not confined to ROSA cells in the zona glomerulosa, but was also found in Agtr1a-/- cells (Fig. 3Go, i and j; k and l). Of note, in these chimeric mice, plasma potassium levels were significantly elevated to the range of 5.2–5.8 mEq/liter. These findings demonstrate that an increase in plasma potassium acts as an alternative mechanism for the secondary hyperaldosteronism independently of the renin-Ang system when the latter is compromised.


    DISCUSSION
 TOP
 ABSTRACT
 INTRODUCTION
 RESULTS
 DISCUSSION
 MATERIALS AND METHODS
 REFERENCES
 
In our previous study, we demonstrated that Agt null-mutant mice were perfectly capable of achieving secondary hyperaldosteronism during dietary sodium restriction (16). A similar phenomenon was observed in Agtr1a-/- mice (our unpublished data and Ref. 17). Of note, Agt-/- and Agtr1a-/- mice develop a few anomalies (18, 19). It therefore remained possible that this Ang II-independent hyperaldosteronism is a peculiar phenomenon unique to the mutant strains. The current study rules out this possibility and demonstrates that AT1 antagonist causes a higher degree of secondary hyperaldosteronism during chronic sodium restriction. The results are in contrast to previous studies showing that blockade of Ang II attenuated the increase in plasma aldosterone concentration or adrenal aldosterone synthase mRNA that was induced by sodium restriction (3, 4, 5). The results of the present study are, however, in accord with those of the study by Clauser et al. (6), who showed a lack of aldosterone suppression upon inhibition of Ang II in rats maintained on a sodium-free diet for 15 d.

Unlike humans, mice have two subtypes of AT1 receptor, AT1A and AT1B, which are encoded by Agtr1a and Agtr1b, respectively. RT-PCR analysis of total RNA extracted from a whole mouse adrenal gland showed that only 10% of AT1 mRNA is of Agtr1b origin (20, 21). Since the expression of AT1B is restricted to the zona glomerulosa (22), whereas AT1A is expressed in both zonae glomerulosa and fasciculata, it is conceivable that the relative contribution of AT1B in the zona glomerulosa may be more than 10% of total AT1 mRNA. In the current study, however, the Agtr1a-/- cells in the adrenal gland of Agtr1a-/-{leftrightarrow} ROSA chimeric mice showed no detectable Ang binding and aldosterone synthase mRNA, indicating that the amount of AT1B protein and its function are negligible in the adrenal gland of mice fed normal sodium diet. We chronically infused Ang II into Agtr1a-/-{leftrightarrow} ROSA chimeric mice. In this condition, aldosterone synthase mRNA was expressed selectively in ROSA cells in the zona glomerulosa, but Agtr1a-/- cells expressed no detectable aldosterone synthase mRNA. We concluded that the uniform expression of aldosterone synthase mRNA in Agtr1a-/-{leftrightarrow} ROSA mice fed low-sodium diet and treated with AT1 antagonist is ascribed not to the intact AT1B, but to a non-Ang II mechanism.

In the Agtr1a-/-{leftrightarrow} ROSA chimeric mice placed on normal or low-sodium diet, hybridization signals for aldosterone synthase mRNA were strictly confined to lacZ-positive, AT1A-intact cells. In these mice, plasma potassium was within the normal range. Clearly, therefore, aldosterone production is dependent on Ang II when plasma potassium is within the normal range. This is an unequivocal demonstration that the hyperaldosteronism secondary to chronic ECF volume depletion is dependent on Ang II.

In the present study, plasma potassium was elevated in both wild-type mice and chimeric mice placed on dietary sodium restriction with administration of AT1 antagonist. In our previous study, simultaneous restriction of potassium during sodium restriction nullified hyperaldosteronism in Agt-/- mice (16). Early studies have indicated that plasma potassium is also an important modulator of aldosterone synthesis (26). However, the effect of potassium on aldosterone synthesis has largely been attributed to the activation of the adrenal renin-angiotensin system (4). In this regard, our present findings provided evidence that the potassium-mediated pathway for aldosterone synthesis operates independently of angiotensin. We also demonstrated that blockade of angiotensin in sodium-restricted mice resulted in a greater increase in plasma aldosterone, suggesting that the potassium-mediated pathway is more potent than angiotensin-dependent stimulation of aldosterone synthesis in this setting.

Collectively, these data indicate that an increase in plasma potassium becomes the intermediary regulator of aldosterone synthesis, allowing successful achievement of secondary hyperaldosteronism during ECF volume depletion when the renin-Ang system is compromised.


    MATERIALS AND METHODS
 TOP
 ABSTRACT
 INTRODUCTION
 RESULTS
 DISCUSSION
 MATERIALS AND METHODS
 REFERENCES
 
Mice
Wild-type 9-wk-old C57BL/6 mice (The Jackson Laboratory, Bar Harbor, Maine) were used for the experiment studying the effect of losartan during sodium restriction. The number of mice used was 5 (normal-sodium diet), 14 (low-sodium diet), 5 (losartan), and 14 (low-sodium diet plus losartan).

Chimeric mice were generated by an aggregation method as previously described (23, 24). The mice used as embryo donors had a mixed genetic background of C57BL/6, 129/Ola, and ICR. Chimeric mice generated from Agtr1a-/- and ROSA26 transgenic (ROSA) embryos were designated as Agtr1a-/-{leftrightarrow} ROSA, and those from wild-type and ROSA embryos as Agtr1a+/+{leftrightarrow} ROSA. Chimeric mice thus produced had varying degrees of ROSA-derived cells ranging between 0 and 100%, and the contribution of ROSA cells in the adrenal gland was similar to that in the skin. Chimeric mice (7 to 26 wk of age) in which 40–90% of the skin was of ROSA origin were used in this study. The number of Agtr1a-/-{leftrightarrow} ROSA mice analyzed was 5 (normal sodium diet), 5 (Ang II infusion), 5 (low-sodium diet), and 4 (low-sodium diet plus losartan). Three Agtr1a+/+{leftrightarrow} ROSA mice were fed normal sodium diet and analyzed.

All animals were handled in accordance with the institutional animal care policy of the Vanderbilt University Medical School.

Dietary Sodium Restriction
Mice were fed either a low-sodium diet (0.02% Na, Ralston Purina Co., Battle Creek, MI) or normal chow (0.46% Na, 0.72% K) for 2 wk. Some mice fed a low-sodium diet were also treated with an AT1 antagonist, losartan (100 mg/liter in drinking water) (Merck & Co., Inc., West Point, PA), which was started 2 d before dietary sodium restriction. All mice had free access to food and tap water.

Chronic Ang II Infusion
Ang II (1.0 ng/g wt/min) was infused sc by osmotic minipump (model 2002; Alza Corp., Palo Alto, CA) for 2 wk.

Analysis of the Adrenal Gland
Adrenal glands were embedded in OCT compound and frozen at -70 C. Serial sections (12 µm) were taken alternatively for lacZ staining and Ang II binding or in situ hybridization for aldosterone synthase mRNA. For ß-galactosidase staining, sections were fixed in 2% glutaraldehyde for 5 min, rinsed in PBS, and incubated in a staining solution consisting of 0.01% sodium deoxycholate, 0.02% IGAEPAL-CA630, 1 mM MgCl2, 2 mM K3Fe(CN)6, 2 mM K4Fe(CN)6, 1 mg/ml X-Gal (Life Technologies, Inc., Gaithersburg, MD) in PBS at 37 C for 10 h. Ang binding autoradiography was performed using [125I-Sar1-Ile8]Ang in the presence of AT2 antagonist, PD123319, as described previously (23). In situ hybridization was performed as described previously (23), using a specific probe for mouse aldosterone synthase (a gift from Dr. Keith L. Parker, Duke University, Durham, NC) (25).

Measurement of Plasma Aldosterone
Trunk blood was collected into ice-cold tubes in the presence of EDTA (10 mM) and centrifuged, and the plasma was kept frozen at -70 C until measurement. Plasma aldosterone concentration was determined by two methods. One method was RIA utilizing a commercially available kit (Coat-A-Count, Diagnostic Products, Los Angeles, CA). The second method used HPLC-atmospheric pressure chemical ionization-tandem mass spectrometry. Chromatography was performed on a Vydac (Hesperia, CA) C18 reverse phase column (2.0 x 150 mm, 5 µm). The mobile phase consisted of methanol/water (80:20, vol/vol) delivered at a flow rate of 200 µl/min. A 100-µl aliquot of extracted sample was injected onto the column. A Finnigan TSQ7000 mass spectrometer (Thermo Quest, Manchester, UK) was used for quantitative mass spectrometric detection. An atmospheric pressure chemical ionization source was used in the negative-ionization mode. The corona needle current, heated capillary, and vaporizer temperature were set at 5.0 µA, 230 C, and 400 C, respectively.

Measurement of Plasma Potassium
Blood was collected from the tail artery into heparinized hematocrit capillary tubes to avoid hemolysis. Potassium concentration was measured with a flame photometer (Instrumentation Laboratory, Lexington, MA).

Statistical Analysis
Data were expressed as the mean ± SE. Statistical significance was assessed by using the unpaired t test and regression analysis. A value of P < 0.05 was considered significant.


    ACKNOWLEDGMENTS
 
The authors thank Mr. Eric F. Howard and Ms. Ellen Donnert for technical assistance.


    FOOTNOTES
 
This work was supported by NIH Grants DK-44757 and DK-37868, Research for the Future Program of Japan Society for the Promotion of Science, Japan Heart Foundation Research Grant, and the Mochida Memorial Foundation for Medical and Pharmaceutical Research.

Abbreviations: Ang, Angiotensin; AT1, Ang II type 1; ECF, extracellular fluid

Received for publication April 5, 2001. Accepted for publication August 16, 2001.


    REFERENCES
 TOP
 ABSTRACT
 INTRODUCTION
 RESULTS
 DISCUSSION
 MATERIALS AND METHODS
 REFERENCES
 

  1. Gasc JM, Shanmugam S, Sibony M, Corvol P 1994 Tissue-specific expression of type 1 angiotensin II receptor subtypes. An in situ hybridization study. Hypertension 24:531–537[Abstract]
  2. Quinn SJ, Williams GH 1988 Regulation of aldosterone secretion. Annu Rev Physiol 50:409–426[CrossRef][Medline]
  3. Aguilera G, Catt KJ 1978 Regulation of aldosterone secretion by the renin-angiotensin system during sodium restriction in rats. Proc Natl Acad Sci USA 75:4057–4061[Abstract]
  4. Tremblay A, Parker KL, Lehoux JG 1992 Dietary potassium supplementation and sodium restriction stimulate aldosterone synthase but not 11 ß-hydroxylase P-450 messenger ribonucleic acid accumulation in rat adrenals and require angiotensin II production. Endocrinology 130:3152–3158[Abstract]
  5. Kakiki M, Morohashi K, Nomura M, Omura T, Horie T 1997 Regulation of aldosterone synthase cytochrome P450 (CYP11B2) and 11ß-hydroxylase cytochrome P450 (CYP11B1) expression in rat adrenal zona glomerulosa cells by low sodium diet and angiotensin II receptor antagonists. Biol Pharm Bull 20:962–968[Medline]
  6. Clauser E, Gonzalez MF, Bouhnik J, Corvol P, Menard J 1983 The effects of converting enzyme inhibitors on plasma angiotensinogen and plasma aldosterone in sodium-depleted rats. J Hypertens Suppl 1:37–40[Medline]
  7. Duprez DA, De Buyzere ML, Rietzschel ER, Taes Y, Clement DL, Morgan D, Cohn JN 1998 Inverse relationship between aldosterone and large artery compliance in chronically treated heart failure patients. Eur Heart J 19:1371–1376[Abstract/Free Full Text]
  8. MacFadyen RJ, Lee AF, Morton JJ, Pringle SD, Struthers AD 1999 How often are angiotensin II and aldosterone concentrations raised during chronic ACE inhibitor treatment in cardiac failure? Heart 82:57–61[Abstract/Free Full Text]
  9. Pedersen EB, Bech JN, Nielsen CB, Kornerup HJ, Hansen HE, Spencer ES, Solling J, Jensen KT 1997 A comparison of the effect of ramipril, felodipine and placebo on glomerular filtration rate, albuminuria, blood pressure and vasoactive hormones in chronic glomerulonephritis. A randomized, prospective, double-blind, placebo-controlled study over two years. Scand J Clin Lab Invest 57:673–81[Medline]
  10. Rietzschel E, Duprez DA, De Buyzere ML, Clement DL 2000 Inverse relation between aldosterone and venous capacitance in chronically treated congestive heart failure [published erratum appears in Am J Cardiol 2000 Aug 15;86(4):484]. Am J Cardiol 85:977–980[CrossRef][Medline]
  11. Sato A, Suzuki Y, Shibata H, Saruta T 2000 Plasma aldosterone concentrations are not related to the degree of angiotensin-converting enzyme inhibition in essential hypertensive patients. Hypertens Res 23:25–31[Medline]
  12. Staessen J, Lijnen P, Fagard R, Verschueren LJ, Amery A 1981 Rise in plasma concentration of aldosterone during long-term angiotensin II suppression. J Endocrinol 91:457–465[Abstract]
  13. Struthers AD 1995 Aldosterone escape during ACE inhibitor therapy in chronic heart failure. Eur Heart J 16(Suppl N):103–106
  14. Ueno H, Takata M, Tomita S, Oh-hashi S, Yasumoto K, Inoue H 1997 The effects of long-term treatment on left ventricular hypertrophy in patients with essential hypertension: relation to changes in neurohumoral factors. J Cardiovasc Pharmacol 30:643–648[CrossRef][Medline]
  15. Borghi C, Boschi S, Ambrosioni E, Melandri G, Branzi A, Magnani B 1993 Evidence of a partial escape of renin-angiotensin-aldosterone blockade in patients with acute myocardial infarction treated with ACE inhibitors. J Clin Pharmacol 33:40–45[Abstract/Free Full Text]
  16. Okubo S, Niimura F, Nishimura H, Takemoto F, Fogo A, Matsusaka T, Ichikawa I 1997 Angiotensin-independent mechanism for aldosterone synthesis during chronic extracellular fluid volume depletion. J Clin Invest 99:855–860[Abstract/Free Full Text]
  17. Oliverio MI, Best CF, Smithies O, Coffman TM 2000 Regulation of sodium balance and blood pressure by the AT(1A) receptor for angiotensin II. Hypertension 35:550–554[Abstract/Free Full Text]
  18. Niimura F, Labosky PA, Kakuchi J, Okubo S, Yoshida H, Oikawa T, Ichiki T, Naftilan AJ, Fogo A, Inagami T, Hogan BLM, Ichikawa I 1995 Gene targeting in mice reveals a requirement for angiotensin in the development and maintenance of kidney morphology and growth factor regulation. J Clin Invest 96:2947–2954[Medline]
  19. Oliverio MI, Delnomdedieu M, Best CF, Li P, Morris M, Callahan MF, Johnson GA, Smithies O, Coffman TM 2000 Abnormal water metabolism in mice lacking the type 1A receptor for ANG II. Am J Physiol Renal Physiol 278:F75–F82
  20. Nishimura H, Matsusaka T, Fogo A, Kon V, Ichikawa I 1997 A novel in vivo mechanism for angiotensin type 1 receptor regulation. Kidney Int 52:345–355[Medline]
  21. Burson JM, Aguilera G, Gross KW, Sigmund CD 1994 Differential expression of angiotensin receptor 1A and 1B in mouse. Am J Physiol 267:E260–E267
  22. Chen X, Li W, Yoshida H, Tsuchida S, Nishimura H, Takemoto F, Okubo S, Fogo A, Matsusaka T, Ichikawa I 1997 Targeting deletion of angiotensin type 1B receptor gene in the mouse. Am J Physiol 272:F299–F304
  23. Matsusaka T, Katori H, Inagami T, Fogo A, Ichikawa I 1999 Communication between myocytes and fibroblasts in cardiac remodeling in angiotensin chimeric mice. J Clin Invest 103:1451–1458[Abstract/Free Full Text]
  24. Takaya J, Matsusaka T, Ichikawa I 2000 Production and use of chimeric mice. In: Donna WD, ed. Methods in molecular medicine: angiotensin protocol. Totowa, NJ: Humana Press, Inc.; 41–51
  25. Domalik LJ, Chaplin DD, Kirkman MS, Wu RC, Liu WW, Howard TA, Seldin MF, Parker KL 1991 Different isozymes of mouse 11ß-hydroxylase produce mineralocorticoids and glucocorticoids. Mol Endocrinol 5:1853–1861[Abstract]
  26. Boyd JE, Palmore WP, Mulrow PJ 1971 Role of potassium in the control of aldosterone secretion in the rat. Endocrinology 88:556–565[Medline]