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Departments of Medicine (R.R., I.K., M.R.O.-M., G.H.W., G.K.A.) and Pathology (H.G.R.), Brigham and Women’s Hospital, Harvard Medical School, Boston, Massachusetts 02115; and Department of Pharmacology, New York Medical College (C.T.S.), Valhalla, New York 10595
Address all correspondence and requests for reprints to: Gail K. Adler, M.D., Ph.D., Brigham and Women’s Hospital, 221 Longwood Avenue, Boston, Massachusetts 02115. E-mail: gadler{at}partners.org
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Abstract |
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 Top Abstract IntroductionMaterials and MethodsResultsDiscussionReferences |
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-nitro-L-arginine methyl
ester (L-NAME; nitric oxide synthesis inhibitor) to male rats drinking
1% saline caused hypertension, severe biventricular myocardial
necrosis, proteinuria, and fibrinoid necrosis of renal and cardiac
vessels. Removal of aldosterone by adrenalectomy or through
administration of the selective aldosterone antagonist eplerenone
markedly reduced the cardiac and renal damage without significantly
altering blood pressure. Aldosterone infusion in adrenalectomized,
glucocorticoid-replaced L-NAME/angiotensin II-treated animals
restored damage. Thus, we identified aldosterone as a critical
mediator of L-NAME/angiotensine II induced vascular damage through
mechanisms apparently independent of its effects on systolic blood
pressure. |
Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Although many studies have investigated the role of angiotensin II (Ang II) in mediating cardiovascular damage, relatively little attention has been paid to the role of aldosterone, the end product of the RAAS. However, there are data to suggest that aldosterone may play an important role in the pathogenesis of cardiovascular disease that is independent of Ang II. Patients with primary aldosteronism, in which Ang II levels are usually very low, have a higher incidence of left ventricular hypertrophy (14), albuminuria (15), and stroke (16, 17) than do patients with essential hypertension. A recent study performed in patients classified with New York Heart Association class III and IV cardiac failure showed a 30% reduction in morbidity and mortality with the addition of the aldosterone antagonist spironolactone to conventional therapy including ACE inhibitors, loop diuretics, and digoxin (18). This decrease occurred with an average dose of spironolactone (26 mg/day) that did not have significant hemodynamic effects.
Experimental animal data support a role for aldosterone in mediating cardiovascular injury in the kidney and brain. In the stroke-prone spontaneously hypertensive rat (SHRSP), a genetic model of spontaneous hypertension, administration of either spironolactone (19) or an ACE inhibitor (7, 8, 20) greatly attenuated renal and cerebral vascular damage (20, 21). Likewise, in the remnant kidney hypertensive rat, administration of aldosterone reversed the renal protection given by blockade of the RAAS with combined ACE inhibition/AT1 receptor antagonist treatment (22). Thus, in the kidney and brain, aldosterone may have deleterious effects on the vasculature that may be independent of other components of the RAAS.
An important pathological effect of aldosterone in the heart has been reported in experimental models of mineralocorticoid hypertension. In these studies prolonged (6- to 8-week) exposure to aldosterone was associated with the development of myocardial fibrosis (23, 24). Although a direct effect of aldosterone on collagen deposition was initially proposed, in vitro studies have not consistently demonstrated an effect of aldosterone in modulating collagen gene expression (25, 26). Thus, the mechanisms by which aldosterone participates in the establishment of myocardial injury are unclear.
To explore the role of aldosterone in mediating early cardiovascular
injury in the heart, we used an experimental model in rats that
combines elevated blood pressure, moderately high salt intake, an
activated RAAS, and suppressed nitric oxide production. This model
involves chronic inhibition of nitric oxide synthase with
N-nitro-L-arginine
methyl ester (L-NAME) for 14 days in 1% NaCl-drinking rats combined
with a 3-day infusion of Ang II on days 11–14. In previous studies,
administration of L-NAME alone for 4–6 weeks (27) or of
L-NAME for 17 days coupled with a short-term Ang II infusion
(28) caused the development of hypertension and myocardial
fibrosis. Under both of these conditions, cardiac damage could be
reduced by AT1 receptor antagonism. However, the role of aldosterone in
mediating this damage was not studied.
In the present experiments we determined the early pathological effects of mineralocorticoids on the heart and kidney by performing ablation/replacement experiments with aldosterone in the 14-day L-NAME/Ang II/NaCl model of cardiac injury. Specifically, we tested whether reduction of mineralocorticoids by either adrenalectomy or pharmacological antagonism with eplerenone, a selective aldosterone receptor blocker (29, 30), would prevent cardiac and renal damage in this model and whether aldosterone replacement in adrenalectomized rats would restore damage. In addition, we determined what type of cardiac damage was induced by the L-NAME/Ang II/NaCl treatment and compared these changes to those that occurred in the kidney.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Experimental protocol
Wistar rats were housed in individual metabolic cages and given
1% NaCl as drinking fluid ad libitum. Three days later,
rats were placed on one of five dosing protocols. Group 1 (NaCl; n
= 8) received 1% NaCl to drink. Group 2 (L-NAME/Ang II/NaCl; n =
8) received L-NAME for 14 days and 1% NaCl. On day 11 of L-NAME
treatment, an osmotic minipump containing Ang II was implanted in each
animal sc. Group 3 (L-NAME/Ang II/NaCl plus eplerenone; n = 8)
received L-NAME/Ang II/NaCl and eplerenone (100 mg/kg/day p.o., days 0
to 14). Eplerenone was dissolved in 0.5% methylcellulose and
administered twice a day by gavage. Two additional groups of
NaCl-drinking rats were adrenalectomized (ADX) 3 days before initiation
of L-NAME/Ang II treatment. Group 4 (L-NAME/Ang II/NaCl plus ADX;
n = 11) received glucocorticoid replacement with dexamethasone
starting immediately after the surgery. Group 5 (L-NAME/Ang II/NaCl
plus ADX/ALDO; n = 9) received in addition to dexamethasone,
aldosterone starting on day 0 simultaneously with L-NAME treatment.
Dexamethasone was dissolved in sesame oil and administered as a single
sc dose (12 µg/kg·day) every day. This dose of dexamethasone has
been reported to maintain normal weight gain, glomerular filtration
rate, and fasting plasma glucose and insulin levels in adrenalectomized
rats (31). The experiment was concluded on day 14 of
L-NAME treatment. Ang II and aldosterone were administered via Alzet
osmotic minipumps (models 2001 and 2002, respectively, Alza Corp., Palo Alto, CA), which were implanted sc at the nape of
the neck in animals anesthetized with isoflurane. The concentrations of
Ang II and aldosterone used to fill the pumps were calculated based on
the mean pump rate provided by the manufacturer, the body weight of the
animals on the day before implantation of the pumps, and the dose
planned. Ang II (human, 99% peptide purity) was purchased from
American Peptide Co. (Sunnyvale, CA) and administered at a
dose of 225 µg/kg·day as reported previously (28). The
dose of aldosterone (40 µg/kg·day) is approximately 50% lower than
the dose used previously in studies of aldosterone-induced
cardiovascular injury (23, 24). This lower dose induced
lesions in stroke-prone spontaneously hypertensive rats
(20). Dexamethasone, aldosterone, and L-NAME were
purchased from Sigma (St. Louis, MO). The concentration of
L-NAME in the drinking water was adjusted daily to provide a dose of 40
mg/kg·day based on the daily fluid intake and the body weight of the
rats.
Surgical procedure
Three days before initiation of L-NAME treatment, rats from
groups 4 and 5 were anesthetized with sodium pentobarbital (Nembutal,
Abbott Laboratories, North Chicago, IL; 60 mg/kg, ip).
Bilateral adrenalectomy was performed using a dorsolumbar approach,
making separate incisions on each side. Adrenalectomized animals
received 1% NaCl ad libitum to drink after the surgical
procedure. No postoperative deaths occurred.
Animals in all groups were handled and weighed daily and maintained in separate metabolic cages. Twenty-four-hour fluid intake, food intake, and urine output were measured daily. Systolic blood pressure was measured 3 days before initiation of L-NAME treatment and on days 1, 5, 9, and 13. On day 14 of L-NAME treatment, animals were decapitated, trunk blood was collected into chilled tubes containing EDTA, and the heart and kidneys were removed, blotted dry, and immediately weighed. The heart and the kidneys were stored in 10% phosphate-buffered formalin and later processed for light microscopic evaluation.
Assays and analyses
Systolic blood pressure was measured in awake animals by
tail-cuff plethysmography using a Natsume KN-210 manometer and
tachometer (Peninsula Laboratories, Inc., Belmont, CA).
Rats were warmed at 37 C for 10 min and allowed to rest quietly in a
Lucite chamber before measurement of blood pressure. Urinary protein
concentration was determined in urine collected on the last day of the
experiment using the sulfosalicylic acid turbidity method. Urinary
protein excretion was calculated as the product of the urinary
concentration times the urine output per 24 h. Plasma aldosterone
concentration was determined using a standard RIA kit from
Diagnostic Products (Los Angeles, CA). PRA was determined
by RIA detection of generated angiotensin I (DiaSorin, Inc., Stillwater, MN).
Histology
Hearts were stained with the collagen-specific dye Sirius red
for determination of fibrosis as reported previously (24).
Interstitial collagen was determined using an automated image analyzer.
The hearts were also stained with hematoxylin and eosin for light
microscopic analysis. Two or three sections of the heart were analyzed
for each animal. Sections were taken from different parts of the heart
and contained both right and left ventricles. A scale from 0–4 was
used to score the level of myocardial injury in each section, and an
average score for each animal was obtained. A score of 0 represented no
damage. A score of 1 represented the presence of myocytes demonstrating
early necrotic changes such as nuclear pyknosis or karyolysis,
noncontracting marginal wavy fibers, and eosinophilic staining of the
cytoplasm associated with the presence of scattered neutrophilic
infiltrates. A score of 2 was given when one clear area of necrosis
(loss of myocardial cells with heavy neutrophilic infiltrates) was
observed. An example of this type of lesion is shown in Fig. 3A
. When
two or more separate areas of necrosis were found (implicating the
presence of two different myocardial infarctions in the same heart),
but the areas were localized and compromised less than 50% of the
ventricular wall, the hearts received a score of 3. A score of 4 was
assigned to hearts that demonstrated extensive areas of necrosis
compromising more than 50% of either the left or the right
ventricle.
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Statistical analysis
Data were tested for normality using the Kolmogorov-Smirnov
test. Systolic blood pressure was analyzed using repeated measures
ANOVA for time and treatment group with post-hoc analysis
using Dunnett’s test for comparisons against control. One-way ANOVA
was used for normally distributed data with one grouping variable.
Post-hoc analysis was performed using Newman-Keuls multiple
comparison test. Data that were not normally distributed were analyzed
with the Kruskal-Wallis test. Subsequently, selected pairwise
comparisons were made using the exact Wilcoxon test. Data are reported
as the mean ± SE for normally distributed
data and as the median with upper and lower quartile values for data
that were not normally distributed.
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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).
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. L-NAME/Ang II/NaCl treatment
significantly reduced PRA in intact animals compared with that in
saline-drinking controls. The higher levels of PRA observed in
L-NAME/Ang II/NaCl-treated rats that were adrenalectomized was
prevented by the administration of aldosterone (Fig. 2A). Despite the
marked inhibition of PRA observed in adrenal-intact animals treated
with L-NAME/Ang II/NaCl or L-NAME/Ang II/NaCl plus eplerenone, plasma
aldosterone was similar to that in saline-drinking controls (Fig. 2B).
As anticipated, plasma aldosterone was reduced to undetectable levels
in adrenalectomized rats, whereas adrenalectomized, aldosterone-infused
rats had elevated aldosterone levels.
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are data
obtained at the end of the experiment. Body weight was not different
among the three groups of adrenal-intact animals. However, both groups
of adrenalectomized rats demonstrated significantly lower body weight
compared with adrenal-intact groups. The ratio between total heart
weight and total body weight was used as an index of cardiac
hypertrophy. The cardiac hypertrophy index was higher in all groups of
animals receiving L-NAME/Ang II/NaCl compared with that in
NaCl-drinking controls (Table 1). Both eplerenone treatment and
adrenalectomy significantly reduced cardiac hypertrophy compared with
that observed in L-NAME/Ang II/NaCl-treated rats. Infusion of
aldosterone reversed the effect of adrenalectomy on the cardiac
hypertrophy index and restored it to a level that was not different
from that in the L-NAME/Ang II/NaCl group.
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and 4). L-NAME/Ang II/NaCl-treated rats
developed vascular damage and myocardial necrosis. A representative
photomicrograph of these lesions is shown in Fig. 3A. Myocardial
necrosis was characterized by loss of cross-striation of myofibers,
homogenization of cytoplasm, loss of cellular membranes, pyknosis and
eventually karyolysis of nuclei, and influx of inflammatory cells,
including polymorphonuclear cells and monocytes. Fibrinoid necrosis was
present in small coronary arteries and arterioles (not shown). In
contrast, cardiac injury in response to treatment with L-NAME/Ang
II/NaCl was markedly reduced in those animals in which eplerenone was
chronically administered or adrenalectomy was performed (Figs. 3B and 4). These two groups demonstrated levels of myocardial necrosis similar
to those observed in the NaCl-drinking controls. The protective effect
of adrenalectomy was completely reversed by the addition of an
aldosterone infusion.
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, A and C, staining of adjacent sections
with hematoxylin eosin and Sirius red, respectively).
Renal damage
Urinary protein excretion (24 h) measured at the end of the 2-week
treatment period was normal in the NaCl group (Fig. 5). Treatment with L-NAME/Ang II/NaCl
markedly increased urinary protein excretion. Eplerenone treatment and
adrenalectomy prevented the development of proteinuria in animals
receiving L-NAME/Ang II/NaCl treatment. In contrast, administration of
aldosterone to adrenalectomized rats completely restored the effects of
L-NAME/Ang II/NaCl treatment on proteinuria.
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and 7). Although renal arteriopathy was not
found in kidneys from NaCl-drinking controls, animals receiving
L-NAME/Ang II/NaCl treatment demonstrated severe renal vascular damage
involving primarily arcuate and interlobular arteries and arterioles
(Fig. 6). These vessels demonstrated fibrinoid necrosis of the vascular
wall with medial thickening and proliferation of the perivascular
connective tissue. A few isolated glomeruli had areas of focal
thrombosis. Proteinaceous casts at the level of the distal tubules and
reabsorption protein granules in proximal tubules frequently were
observed in L-NAME/Ang II/NaCl-treated rats. Renal arteriopathy tended
to be reduced in animals receiving eplerenone treatment. However, this
60% reduction in damage compared with L-NAME/Ang II/NaCl-treated rats
did not reach statistical significance upon analysis of the
histopathological scores (P = 0.1). Adrenalectomy
significantly reduced renal arteriopathy induced by L-NAME/Ang II/NaCl
treatment to levels that were not significantly different from those in
NaCl-drinking controls (Fig. 7). As was observed in the heart, when
aldosterone was infused into adrenalectomized, L-NAME/Ang
II/NaCl-treated rats, damage in the kidneys was significantly
increased.
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Multiple studies in mineralocorticoid/salt hypertensive and renovascular hypertensive rats have suggested that aldosterone plays a critical role in the development of myocardial fibrosis (23, 24). These studies have led to the hypothesis that aldosterone has a direct effect on the synthesis of extracellular matrix proteins, which, under certain circumstances, may lead to the development of tissue fibrosis (23). However, studies attempting to show a direct effect of mineralocorticoids on extracellular matrix proteins have been inconclusive (25, 26). In the L-NAME/Ang II/NaCl model, aldosterone appears to play a critical role in the early development of vascular lesions in the small arteries and arterioles in the heart and kidney and in the development of myocardial necrosis. Myocardial interstitial fibrosis was not observed, nor was fibrosis observed in areas of myocardial damage. However, we anticipate that, as part of the reparative process, fibrosis would develop in these areas. Indeed, Hou and colleagues have shown that the L-NAME/Ang II treatment induces the expression of growth factors and extracellular matrix proteins in the heart (28). Based on the strong evidence that aldosterone provokes myocardial fibrosis when administered chronically in vivo (but not in vitro), and our present finding that aldosterone mediates early myocardial ischemic damage, we hypothesize that myocardial fibrosis is a consequence of aldosterone inducing vascular damage followed by myocardial ischemia/necrosis. Whether this effect is a direct effect of aldosterone interacting with mineralocorticoid receptors located in blood vessels (32) or in cardiomyocytes (33) or is an indirect effect mediated by other factors such as up-regulation of Ang II receptors (34, 35) or volume and electrolyte changes remains to be elucidated. Furthermore, it is not known whether eplerenone can antagonize the rapid, nongenomic effects of aldosterone.
The results of the present experiment are consistent with several studies examining the influence of mineralocorticoids on the vasculature of the kidney and brain. In the SHRSP, a genetic rat model that develops spontaneous malignant nephrosclerosis and stroke, thrombotic microangiopathy in the kidney and brain was reduced by adrenalectomy (36), spironolactone administration (19), or eplerenone administration (37). Adrenalectomy also reduced renal nephropathy in partially nephrectomized rats (38). Thus, there is accumulating evidence that aldosterone may be involved in the development of vascular damage in the brain, kidney, and heart. In the present study aldosterone antagonism by eplerenone was particularly beneficial in the heart compared with the kidney. This may reflect the greater vulnerability of the heart to ischemic injury and/or differences in the mechanisms of aldosterone-mediated injury in the two organs.
With L-NAME/NaCl treatment before the administration of Ang II, glucocorticoid-replaced adrenalectomized animals showed a more rapid increase in systolic blood pressure than did intact animals. The reason for this difference in blood pressure responsiveness is unclear, but could be related to the surgical procedure itself or to the lack of an adrenal factor. The present study design did not allow us to determine whether the presence of hypertension and/or elevated Ang II levels is a requirement for the development of aldosterone-mediated lesions. However, from our results it is clear that hypertension and high Ang II levels, in the absence of aldosterone, cause much less cardiovascular damage. This raises the question of whether some of the adverse cardiovascular effects traditionally attributed to Ang II may be mediated by aldosterone. In favor of the latter hypothesis is the fact that exogenous administration of aldosterone to hypertensive rats receiving ACE inhibition (20, 21) or combined ACE inhibition/AT1 antagonism (22) completely reverses the cardiovascular protection provided by suppression of the RAAS.
The beneficial effects of eplerenone or adrenalectomy were not related to reductions in systolic blood pressure. Other studies have shown a similar dissociation between blood pressure and end-organ damage induced under conditions of an activated RAAS. In the SHRSP, blockers of the RAAS prevented nephrosclerosis and stroke without reducing systolic blood pressure (8, 9, 10, 11, 19, 20). In uninephrectomized, aldosterone/salt-treated rats, lowering systolic blood pressure by the administration of a mineralocorticoid receptor antagonist (RU28328) into the cerebral ventricles prevented the development of hypertension, but not that of myocardial fibrosis (24). Similarly, hypertension, but not myocardial fibrosis, was prevented with hydralazine in L-NAME-treated rats, whereas blocking the RAAS with an AT1 receptor antagonist reduced both systolic blood pressure and cardiac injury (39). Taken together, the above observations suggest that activation of the RAAS can mediate cardiovascular injury through mechanisms that are independent of a rise in systolic blood pressure.
In conclusion, the present experiments show that L-NAME/Ang II/NaCl treatment is highly effective in inducing hypertension and end-organ damage at the level of the heart and the kidney. Manipulations that eliminate or antagonize aldosterone are effective in preventing such an effect, suggesting that the damaging cardiovascular effects of L-NAME/Ang II/NaCl treatment are mediated at least in part by aldosterone. Furthermore, as the removal of aldosterone did not appreciably alter systolic blood pressure, the damaging effect of aldosterone may be independent of its classic effect on sodium retention, volume expansion, and hypertension. Finally, our data suggest that the primary effect of aldosterone is not to promote fibrosis but to induce medial fibrinoid necrosis in small arteries and arterioles with subsequent tissue necrosis. Fibrosis may be a reparative process. Thus, this model of cardiac damage may provide a tool for beginning to understand the mechanisms by which aldosterone antagonism improves cardiac morbidity and mortality in patients with cardiac failure (18).
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Acknowledgments |
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Footnotes |
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2 Supported by a postdoctoral fellowship grant from the American
Heart Association-New England Affiliate (9920264T).
Received April 12, 2000.
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References |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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G. Fejes-Toth and A. Naray-Fejes-Toth Early Aldosterone-Regulated Genes in Cardiomyocytes: Clues to Cardiac Remodeling? Endocrinology, April 1, 2007; 148(4): 1502 - 1510. [Abstract] [Full Text] [PDF]
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J. Perez-Rojas, J. A. Blanco, C. Cruz, J. Trujillo, V. S. Vaidya, N. Uribe, J. V. Bonventre, G. Gamba, and N. A. Bobadilla Mineralocorticoid receptor blockade confers renoprotection in preexisting chronic cyclosporine nephrotoxicity Am J Physiol Renal Physiol, January 1, 2007; 292(1): F131 - F139. [Abstract] [Full Text] [PDF]
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D. A. Calhoun Aldosterone and Cardiovascular Disease: Smoke and Fire Circulation, December 12, 2006; 114(24): 2572 - 2574. [Full Text] [PDF]
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F. Beygui, J.-P. Collet, J.-J. Benoliel, N. Vignolles, R. Dumaine, O. Barthelemy, and G. Montalescot High Plasma Aldosterone Levels on Admission Are Associated With Death in Patients Presenting With Acute ST-Elevation Myocardial Infarction Circulation, December 12, 2006; 114(24): 2604 - 2610. [Abstract] [Full Text] [PDF]
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A. J. Rickard, J. W. Funder, P. J. Fuller, and M. J. Young The Role of the Glucocorticoid Receptor in Mineralocorticoid/Salt-Mediated Cardiac Fibrosis Endocrinology, December 1, 2006; 147(12): 5901 - 5906. [Abstract] [Full Text] [PDF]
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G. P. Rossi, F. Mantero, A. C. Pessina, and For the PAPY Study Investigators Response to Renal Function in Primary Aldosteronism: Is Glomerular Hyperfiltration a Hallmark of Primary Aldosteronism? Further Results from the Primary Aldosteronism Prevalence in Hypertension (PAPY) Study Hypertension, December 1, 2006; 48(6): e111 - e112. [Full Text] [PDF]
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J. Lepenies and M. Quinkler MR blockade in patients with chronic renal disease--not the more the merrier, but the earlier the better Nephrol. Dial. Transplant., November 1, 2006; 21(11): 3343 - 3344. [Full Text] [PDF]
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C. Guo, D. Martinez-Vasquez, G. P. Mendez, M. F. Toniolo, T. M. Yao, E. M. Oestreicher, T. Kikuchi, N. Lapointe, L. Pojoga, G. H. Williams, et al. Mineralocorticoid Receptor Antagonist Reduces Renal Injury in Rodent Models of Types 1 and 2 Diabetes Mellitus Endocrinology, November 1, 2006; 147(11): 5363 - 5373. [Abstract] [Full Text] [PDF]
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M. Epstein, G. H. Williams, M. Weinberger, A. Lewin, S. Krause, R. Mukherjee, R. Patni, and B. Beckerman Selective Aldosterone Blockade with Eplerenone Reduces Albuminuria in Patients with Type 2 Diabetes Clin. J. Am. Soc. Nephrol., September 1, 2006; 1(5): 940 - 951. [Abstract] [Full Text] [PDF]
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 G.-P. Sun, M. Kohno, P. Guo, Y. Nagai, K. Miyata, Y.-Y. Fan, S. Kimura, H. Kiyomoto, K. Ohmori, D.-T. Li, et al. Involvements of Rho-Kinase and TGF-beta Pathways in Aldosterone-Induced Renal Injury J. Am. Soc. Nephrol., August 1, 2006; 17(8): 2193 - 2201. [Abstract] [Full Text] [PDF]
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A. Turchin, C. Z. Guo, G. K. Adler, V. Ricchiuti, I. S. Kohane, and G. H. Williams Effect of Acute Aldosterone Administration on Gene Expression Profile in the Heart Endocrinology, July 1, 2006; 147(7): 3183 - 3189. [Abstract] [Full Text] [PDF]
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E. Y. M. Lam, J. W. Funder, D. J. Nikolic-Paterson, P. J. Fuller, and M. J. Young Mineralocorticoid Receptor Blockade But Not Steroid Withdrawal Reverses Renal Fibrosis in Deoxycorticosterone/Salt Rats Endocrinology, July 1, 2006; 147(7): 3623 - 3629. [Abstract] [Full Text] [PDF]
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M. P. Ponda and T. H. Hostetter Aldosterone Antagonism in Chronic Kidney Disease Clin. J. Am. Soc. Nephrol., July 1, 2006; 1(4): 668 - 677. [Full Text] [PDF]
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W. Zhao, R. A. Ahokas, K. T. Weber, and Y. Sun ANG II-induced cardiac molecular and cellular events: role of aldosterone Am J Physiol Heart Circ Physiol, July 1, 2006; 291(1): H336 - H343. [Abstract] [Full Text] [PDF]
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 K. Takebayashi, S. Matsumoto, Y. Aso, and T. Inukai Aldosterone Blockade Attenuates Urinary Monocyte Chemoattractant Protein-1 and Oxidative Stress in Patients with Type 2 Diabetes Complicated by Diabetic Nephropathy J. Clin. Endocrinol. Metab., June 1, 2006; 91(6): 2214 - 2217. [Abstract] [Full Text] [PDF]
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J. L. Grobe, A. P. Mecca, H. Mao, and M. J. Katovich Chronic angiotensin-(1-7) prevents cardiac fibrosis in DOCA-salt model of hypertension Am J Physiol Heart Circ Physiol, June 1, 2006; 290(6): H2417 - H2423. [Abstract] [Full Text] [PDF]
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S.-Y. Han, C.-H. Kim, H.-S. Kim, Y.-H. Jee, H.-K. Song, M.-H. Lee, K.-H. Han, H.-K. Kim, Y.-S. Kang, J.-Y. Han, et al. Spironolactone Prevents Diabetic Nephropathy through an Anti-Inflammatory Mechanism in Type 2 Diabetic Rats J. Am. Soc. Nephrol., May 1, 2006; 17(5): 1362 - 1372. [Abstract] [Full Text] [PDF]
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 N. C Shah, S. Pringle, and A. Struthers Aldosterone Blockade Over and Above ACE-Inhibitors in Patients with Coronary Artery Disease but without Heart Failure Journal of Renin-Angiotensin-Aldosterone System, March 1, 2006; 7(1): 20 - 30. [Abstract] [PDF]
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C. L. Laffer, R. J. Bolterman, J. C. Romero, and F. Elijovich Effect of Salt on Isoprostanes in Salt-Sensitive Essential Hypertension Hypertension, March 1, 2006; 47(3): 434 - 440. [Abstract] [Full Text] [PDF]
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 T. R. Marcy and T. L. Ripley Aldosterone antagonists in the treatment of heart failure Am. J. Health Syst. Pharm., January 1, 2006; 63(1): 49 - 58. [Abstract] [Full Text] [PDF]
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J. C. Aldigier, T. Kanjanbuch, L.-J. Ma, N. J. Brown, and A. B. Fogo Regression of Existing Glomerulosclerosis by Inhibition of Aldosterone J. Am. Soc. Nephrol., November 1, 2005; 16(11): 3306 - 3314. [Abstract] [Full Text] [PDF]
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K. Miyata, M. Rahman, T. Shokoji, Y. Nagai, G.-X. Zhang, G.-P. Sun, S. Kimura, T. Yukimura, H. Kiyomoto, M. Kohno, et al. Aldosterone Stimulates Reactive Oxygen Species Production through Activation of NADPH Oxidase in Rat Mesangial Cells J. Am. Soc. Nephrol., October 1, 2005; 16(10): 2906 - 2912. [Abstract] [Full Text] [PDF]
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Y. Nagai, K. Miyata, G.-P. Sun, M. Rahman, S. Kimura, A. Miyatake, H. Kiyomoto, M. Kohno, Y. Abe, M. Yoshizumi, et al. Aldosterone Stimulates Collagen Gene Expression and Synthesis Via Activation of ERK1/2 in Rat Renal Fibroblasts Hypertension, October 1, 2005; 46(4): 1039 - 1045. [Abstract] [Full Text] [PDF]
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M. Quinkler, D. Zehnder, K. S. Eardley, J. Lepenies, A. J. Howie, S. V. Hughes, P. Cockwell, M. Hewison, and P. M. Stewart Increased Expression of Mineralocorticoid Effector Mechanisms in Kidney Biopsies of Patients With Heavy Proteinuria Circulation, September 6, 2005; 112(10): 1435 - 1443. [Abstract] [Full Text] [PDF]
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 K. Rossing, K. J. Schjoedt, U. M. Smidt, F. Boomsma, and H.-H. Parving Beneficial Effects of Adding Spironolactone to Recommended Antihypertensive Treatment in Diabetic Nephropathy: A randomized, double-masked, cross-over study Diabetes Care, September 1, 2005; 28(9): 2106 - 2112. [Abstract] [Full Text] [PDF]
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M. K. Rude, T.-A. S. Duhaney, G. M. Kuster, S. Judge, J. Heo, W. S. Colucci, D. A. Siwik, and F. Sam Aldosterone Stimulates Matrix Metalloproteinases and Reactive Oxygen Species in Adult Rat Ventricular Cardiomyocytes Hypertension, September 1, 2005; 46(3): 555 - 561. [Abstract] [Full Text] [PDF]
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C. Xue and H. M. Siragy Local Renal Aldosterone System and Its Regulation by Salt, Diabetes, and Angiotensin II Type 1 Receptor Hypertension, September 1, 2005; 46(3): 584 - 590. [Abstract] [Full Text] [PDF]
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G. H. Williams Cardiovascular Benefits of Aldosterone Receptor Antagonists: What About Potassium? Hypertension, August 1, 2005; 46(2): 265 - 266. [Full Text] [PDF]
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D. G.A. Veliotes, A. J. Woodiwiss, D. A.J. Deftereos, D. Gray, O. Osadchii, and G. R. Norton Aldosterone Receptor Blockade Prevents the Transition to Cardiac Pump Dysfunction Induced by {beta}-Adrenoreceptor Activation Hypertension, May 1, 2005; 45(5): 914 - 920. [Abstract] [Full Text] [PDF]
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A. Nishiyama, L. Yao, Y. Fan, M. Kyaw, N. Kataoka, K. Hashimoto, Y. Nagai, E. Nakamura, M. Yoshizumi, T. Shokoji, et al. Involvement of Aldosterone and Mineralocorticoid Receptors in Rat Mesangial Cell Proliferation and Deformability Hypertension, April 1, 2005; 45(4): 710 - 716. [Abstract] [Full Text] [PDF]
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J. Connell Review: Aldosterone -- the future challenge in cardiovascular disease? The British Journal of Diabetes & Vascular Disease, November 1, 2004; 4(6): 370 - 376. [Abstract] [PDF]
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E. P. Gomez-Sanchez, N. Ahmad, D. G. Romero, and C. E. Gomez-Sanchez Origin of Aldosterone in the Rat Heart Endocrinology, November 1, 2004; 145(11): 4796 - 4802. [Abstract] [Full Text] [PDF]
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J. A.S. Muldowney III, S. N. Davis, D. E. Vaughan, and N. J. Brown NO Synthase Inhibition Increases Aldosterone in Humans Hypertension, November 1, 2004; 44(5): 739 - 745. [Abstract] [Full Text] [PDF]
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 C. E.L. Lim, K. I. Matthaei, A. C. Blackburn, R. P. Davis, J. E. Dahlstrom, M. E. Koina, M.W. Anders, and P. G. Board Mice Deficient in Glutathione Transferase Zeta/Maleylacetoacetate Isomerase Exhibit a Range of Pathological Changes and Elevated Expression of Alpha, Mu, and Pi Class Glutathione Transferases Am. J. Pathol., August 1, 2004; 165(2): 679 - 693. [Abstract] [Full Text] [PDF]
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M. C. Rebsamen, E. Perrier, C. Gerber-Wicht, J.-P. Benitah, and U. Lang Direct and Indirect Effects of Aldosterone on Cyclooxygenase-2 and Interleukin-6 Expression in Rat Cardiac Cells in Culture and after Myocardial Infarction Endocrinology, July 1, 2004; 145(7): 3135 - 3142. [Abstract] [Full Text] [PDF]
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 R. Bos, N. Mougenot, O. Mediani, P. M. Vanhoutte, and P. Lechat Potassium Canrenoate, an Aldosterone Receptor Antagonist, Reduces Isoprenaline-Induced Cardiac Fibrosis in the Rat J. Pharmacol. Exp. Ther., June 1, 2004; 309(3): 1160 - 1166. [Abstract] [Full Text] [PDF]
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 A. D Struthers and T. M MacDonald Review of aldosterone- and angiotensin II-induced target organ damage and prevention Cardiovasc Res, March 1, 2004; 61(4): 663 - 670. [Abstract] [Full Text] [PDF]
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T. L. Goodfriend and D. A. Calhoun Resistant Hypertension, Obesity, Sleep Apnea, and Aldosterone: Theory and Therapy Hypertension, March 1, 2004; 43(3): 518 - 524. [Abstract] [Full Text] [PDF]
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S. Arima, K. Kohagura, H.-L. Xu, A. Sugawara, A. Uruno, F. Satoh, K. Takeuchi, and S. Ito Endothelium-Derived Nitric Oxide Modulates Vascular Action of Aldosterone in Renal Arteriole Hypertension, February 1, 2004; 43(2): 352 - 357. [Abstract] [Full Text] [PDF]
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 T.R. Uhrenholt, J. Schjerning, P.B. Hansen, R. Norregaard, B.L. Jensen, G.L. Sorensen, and O. Skott Rapid Inhibition of Vasoconstriction in Renal Afferent Arterioles by Aldosterone Circ. Res., December 12, 2003; 93(12): 1258 - 1266. [Abstract] [Full Text] [PDF]
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E. M. Oestreicher, D. Martinez-Vasquez, J. R. Stone, L. Jonasson, W. Roubsanthisuk, K. Mukasa, and G. K. Adler Aldosterone and Not Plasminogen Activator Inhibitor-1 Is a Critical Mediator of Early Angiotensin II/NG-Nitro-l-Arginine Methyl Ester-Induced Myocardial Injury Circulation, November 18, 2003; 108(20): 2517 - 2523. [Abstract] [Full Text] [PDF]
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R. A. Ahokas, K. J. Warrington, I. C. Gerling, Y. Sun, L. A. Wodi, P. A. Herring, L. Lu, S. K. Bhattacharya, A. E. Postlethwaite, and K. T. Weber Aldosteronism and Peripheral Blood Mononuclear Cell Activation: A Neuroendocrine-Immune Interface Circ. Res., November 14, 2003; 93 (10): e124 - e135. [Abstract] [Full Text] [PDF]
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B. Pitt, N. Reichek, R. Willenbrock, F. Zannad, R. A. Phillips, B. Roniker, J. Kleiman, S. Krause, D. Burns, and G. H. Williams Effects of Eplerenone, Enalapril, and Eplerenone/Enalapril in Patients With Essential Hypertension and Left Ventricular Hypertrophy: The 4E-Left Ventricular Hypertrophy Study Circulation, October 14, 2003; 108(15): 1831 - 1838. [Abstract] [Full Text] [PDF]
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K. T Weber, Yao Sun, L. A Wodi, A. Munir, E. Jahangir, R. A Ahokas, I. C Gerling, A. E Postlethwaite, and K. J Warrington Toward a broader understanding of aldosterone in congestive heart failure Journal of Renin-Angiotensin-Aldosterone System, September 1, 2003; 4(3): 155 - 163. [Abstract] [PDF]
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S. Arima, K. Kohagura, H.-L. Xu, A. Sugawara, T. Abe, F. Satoh, K. Takeuchi, and S. Ito Nongenomic Vascular Action of Aldosterone in the Glomerular Microcirculation J. Am. Soc. Nephrol., September 1, 2003; 14(9): 2255 - 2263. [Abstract] [Full Text] [PDF]
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T. H. Hostetter and H. N. Ibrahim Aldosterone in Chronic Kidney and Cardiac Disease J. Am. Soc. Nephrol., September 1, 2003; 14(9): 2395 - 2401. [Abstract] [Full Text] [PDF]
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P. N. Chander, R. Rocha, J. Ranaudo, G. Singh, A. Zuckerman, and C. T. Stier Jr. Aldosterone Plays a Pivotal Role in the Pathogenesis of Thrombotic Microangiopathy in SHRSP J. Am. Soc. Nephrol., August 1, 2003; 14(8): 1990 - 1997. [Abstract] [Full Text] [PDF]
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I. C. Gerling, Y. Sun, R. A. Ahokas, L. A. Wodi, S. K. Bhattacharya, K. J. Warrington, A. E. Postlethwaite, and K. T. Weber Aldosteronism: an immunostimulatory state precedes proinflammatory/fibrogenic cardiac phenotype Am J Physiol Heart Circ Physiol, July 11, 2003; 285(2): H813 - H821. [Abstract] [Full Text] [PDF]
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 C. T. Stier Jr., P. N. Chander, L. Rosenfeld, and C. A. Powers Estrogen promotes microvascular pathology in female stroke-prone spontaneously hypertensive rats Am J Physiol Endocrinol Metab, July 1, 2003; 285(1): E232 - E239. [Abstract] [Full Text] [PDF]
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J. M. Flack, R. Peters, T. Shafi, H. Alrefai, S. A. Nasser, and E. Crook Prevention of Hypertension and Its Complications: Theoretical Basis and Guidelines for Treatment J. Am. Soc. Nephrol., July 1, 2003; 14(90002): S92 - 98. [Abstract] [Full Text] [PDF]
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 H. T. Yu Progression of Chronic Renal Failure Arch Intern Med, June 23, 2003; 163(12): 1417 - 1429. [Abstract] [Full Text] [PDF]
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J. S. Williams and G. H. Williams 50th Anniversary of Aldosterone J. Clin. Endocrinol. Metab., June 1, 2003; 88(6): 2364 - 2372. [Full Text] [PDF]
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P. C. White Aldosterone: Direct Effects on and Production by the Heart J. Clin. Endocrinol. Metab., June 1, 2003; 88(6): 2376 - 2383. [Full Text] [PDF]
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N. J. Brown Eplerenone: Cardiovascular Protection Circulation, May 20, 2003; 107(19): 2512 - 2518. [Abstract] [Full Text] [PDF]
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T.-Y. Chun, L. J. Bloem, and J. H. Pratt Aldosterone Inhibits Inducible Nitric Oxide Synthase in Neonatal Rat Cardiomyocytes Endocrinology, May 1, 2003; 144(5): 1712 - 1717. [Abstract] [Full Text] [PDF]
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A. J. Casal, J.-S. Silvestre, C. Delcayre, and A. M. Capponi Expression and Modulation of Steroidogenic Acute Regulatory Protein Messenger Ribonucleic Acid in Rat Cardiocytes and after Myocardial Infarction Endocrinology, May 1, 2003; 144(5): 1861 - 1868. [Abstract] [Full Text] [PDF]
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 J Song, I Narita, S Goto, N Saito, K Omori, F Sato, J Ajiro, D Saga, D Kondo, M Sakatsume, et al. Gender specific association of aldosterone synthase gene polymorphism with renal survival in patients with IgA nephropathy J. Med. Genet., May 1, 2003; 40(5): 372 - 376. [Full Text] [PDF]
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 J. M. Flack, S. Oparil, J. H. Pratt, B. Roniker, S. Garthwaite, J. H. Kleiman, Y. Yang, S. L. Krause, D. Workman, and E. Saunders Efficacy and tolerability of eplerenone and losartan in hypertensive black and white patients J. Am. Coll. Cardiol., April 2, 2003; 41(7): 1148 - 1155. [Abstract] [Full Text] [PDF]
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R. Alzamora, E. T. Marusic, M. Gonzalez, and L. Michea Nongenomic Effect of Aldosterone on Na+,K+-Adenosine Triphosphatase in Arterial Vessels Endocrinology, April 1, 2003; 144(4): 1266 - 1272. [Abstract] [Full Text] [PDF]
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M. J. Young, L. Moussa, R. Dilley, and J. W. Funder Early Inflammatory Responses in Experimental Cardiac Hypertrophy and Fibrosis: Effects of 11{beta}-Hydroxysteroid Dehydrogenase Inactivation Endocrinology, March 1, 2003; 144(3): 1121 - 1125. [Abstract] [Full Text] [PDF]
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S. I. McFarlane and J. R. Sowers Aldosterone Function in Diabetes Mellitus: Effects on Cardiovascular and Renal Disease J. Clin. Endocrinol. Metab., February 1, 2003; 88(2): 516 - 523. [Full Text] [PDF]
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A. Sato, K. Hayashi, M. Naruse, and T. Saruta Effectiveness of Aldosterone Blockade in Patients With Diabetic Nephropathy Hypertension, January 1, 2003; 41(1): 64 - 68. [Abstract] [Full Text] [PDF]
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R. Rocha, C. L. Martin-Berger, P. Yang, R. Scherrer, J. Delyani, and E. McMahon Selective Aldosterone Blockade Prevents Angiotensin II/Salt-Induced Vascular Inflammation in the Rat Heart Endocrinology, December 1, 2002; 143(12): 4828 - 4836. [Abstract] [Full Text] [PDF]
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R. Rocha, A. E. Rudolph, G. E. Frierdich, D. A. Nachowiak, B. K. Kekec, E. A. G. Blomme, E. G. McMahon, and J. A. Delyani Aldosterone induces a vascular inflammatory phenotype in the rat heart Am J Physiol Heart Circ Physiol, November 1, 2002; 283(5): H1802 - H1810. [Abstract] [Full Text] [PDF]
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H. Krum, H. Nolly, D. Workman, W. He, B. Roniker, S. Krause, and K. Fakouhi Efficacy of Eplerenone Added to Renin-Angiotensin Blockade in Hypertensive Patients Hypertension, August 1, 2002; 40(2): 117 - 123. [Abstract] [Full Text] [PDF]
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N. Yamamoto, H. Yasue, Y. Mizuno, M. Yoshimura, H. Fujii, M. Nakayama, E. Harada, S. Nakamura, T. Ito, and H. Ogawa Aldosterone Is Produced From Ventricles in Patients With Essential Hypertension Hypertension, May 1, 2002; 39(5): 958 - 962. [Abstract] [Full Text] [PDF]
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A. K.L. Banes and S. W. Watts Upregulation of Arterial Serotonin 1B and 2B Receptors in Deoxycorticosterone Acetate-Salt Hypertension Hypertension, February 1, 2002; 39(2): 394 - 398. [Abstract] [Full Text] [PDF]
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C. E. Gomez-Sanchez and E. P. Gomez-Sanchez Cardiac Steroidogenesis--New Sites of Synthesis, or Much Ado About Nothing? J. Clin. Endocrinol. Metab., November 1, 2001; 86(11): 5118 - 5120. [Full Text] [PDF]
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M. J. Young, C. D. Clyne, T. J. Cole, and J. W. Funder Cardiac Steroidogenesis in the Normal and Failing Heart J. Clin. Endocrinol. Metab., November 1, 2001; 86(11): 5121 - 5126. [Abstract] [Full Text] [PDF]
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J. H. Pratt, G. J. Eckert, S. Newman, and W. T. Ambrosius Blood Pressure Responses to Small Doses of Amiloride and Spironolactone in Normotensive Subjects Hypertension, November 1, 2001; 38(5): 1124 - 1129. [Abstract] [Full Text] [PDF]
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M. R. Ward, P. Kanellakis, D. Ramsey, J. Funder, and A. Bobik Eplerenone Suppresses Constrictive Remodeling and Collagen Accumulation After Angioplasty in Porcine Coronary Arteries Circulation, July 24, 2001; 104(4): 467 - 472. [Abstract] [Full Text] [PDF]
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P. N. Hopkins, S. C. Hunt, X. Jeunemaitre, B. Smith, D. Solorio, N. D.L. Fisher, N. K. Hollenberg, and G. H. Williams Angiotensinogen Genotype Affects Renal and Adrenal Responses to Angiotensin II in Essential Hypertension Circulation, April 23, 2002; 105(16): 1921 - 1927. [Abstract] [Full Text] [PDF]
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| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
| Endocrinology | Endocrine Reviews | J. Clin. End. & Metab. |
| Molecular Endocrinology | Recent Prog. Horm. Res. | All Endocrine Journals |
, NaCl;
, L-NAME/Ang II/NaCl; 
, L-NAME/Ang II/NaCl plus eplerenone; 
,
L-NAME/Ang II/NaCl plus adrenalectomy; 
, L-NAME/Ang II/NaCl plus
ADX/aldosterone. P < 0.01 in all groups
vs. NaCl. Values are the mean ± SE.
, The average histopathological
score for an animal. The horizontal bar represents the
median value for the group.
