(Hypertension. 2000;36:495.)
© 2000 American Heart Association, Inc.
Scientific Contributions |
Cardiac Aldosterone Production in Genetically Hypertensive Rats
From the Second Department of Internal Medicine (Y.T., T.Y., M.D., H.M.), Department of Health Sciences (Y.T.), School of Medicine, Kanazawa University, Kanazawa, Japan; and Third Department of Internal Medicine (I.M.), Fukui Medical School, Fukui, Japan.
Correspondence to Yoshiyu Takeda, MD, Second Department of Internal Medicine, School of Medicine, Kanazawa University, 13-1 Takara-machi, Kanazawa 920, Japan. E-mail takeday{at}mhs.mp.kanazawa-u.ac.jp
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Abstract—Aldosterone is synthesized in extra-adrenal tissues, both blood vessels and brain. We undertook the present study to determine whether the rat heart produces aldosterone and to investigate the effects of adrenalectomy, ACE inhibition, and angiotensin II on aldosterone synthesis in the heart. To clarify the pathophysiological role of cardiac aldosterone in the hypertensive heart, we compared the synthesis of aldosterone in the hearts of stroke-prone spontaneously hypertensive rats (SHRSP) with that in Wistar-Kyoto rats. The effects of the aldosterone antagonist spironolactone on myocardial hypertrophy in adrenalectomized SHRSP were also studied. Isolated rat hearts were perfused for 2 hours, and the perfusate was analyzed with HPLC and mass spectrometry. The activity of aldosterone synthase was estimated on the basis of the conversion of [14C]deoxycorticosterone to [14C]aldosterone. The levels of aldosterone synthase gene (CYP11B2) mRNA were determined with competitive polymerase chain reaction. Aldosterone production, the activity of aldosterone synthase, and the expression of CYP11B2 mRNA were increased in hearts from adrenalectomized rats and rats treated with angiotensin II. ACE inhibitors decreased cardiac aldosterone synthesis. Cardiac aldosterone, aldosterone synthase activity, and CYP11B2 mRNA levels in hearts from 2- and 4-week-old SHRSP were significantly greater than those of age-matched Wistar-Kyoto rats. Spironolactone prevented cardiac hypertrophy in adrenalectomized SHRSP. These results suggest that the rat heart produces aldosterone and that endogenous cardiac aldosterone may affect cardiac function and hypertrophy in hypertension in rats.
Key Words: heart • rats, inbred strains • aldosterone • hypertrophy • cytochrome p450 • mRNA
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Introduction |
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Aldosterone receptors are present in cardiac myocytes, endocardial endothelial cells, and cardiac fibroblasts.1 The peripheral infusion of aldosterone in rats causes cardiac hypertrophy and cardiac fibrosis without increasing the blood pressure.2 In cultured neonatal rat fibroblasts or cardiomyocytes, aldosterone increases collagen synthesis and protein synthesis.3 4
Physiologically significant amounts of mineralocorticoids are believed to be synthesized only in the adrenal cortex. However, extra-adrenal steroid 21-hydroxylation and 11ß-hydroxylation occur in a variety of human tissues. Circulating progesterone is converted to deoxycorticosterone (DOC) and DOC sulfate in adult and fetal human extra-adrenal tissues.5 The extra-adrenal expression of steroid 21-hydroxylase and 11ß-hydroxylase by a benign testicular Leydig cell tumor has also been reported.6 We reported that aldosterone, synthesized in the vasculature, is in part controlled by angiotensin (Ang) II and participates in the development of vascular hypertrophy that correlates with Ang II concentration.7 8
We performed the present study to determine whether the rat heart produces aldosterone and to investigate the effects of adrenalectomy, ACE inhibitor, and Ang II on aldosterone synthesis, aldosterone synthase activity, and the expression of aldosterone synthase gene (CYP11B2) in the heart. Next, to clarify the pathophysiological roles of cardiac aldosterone in the hypertensive heart, we compared both aldosterone synthesis and the expression of CYP11B2 mRNA in the hearts of stroke-prone spontaneously hypertensive rats (SHRSP) and Wistar-Kyoto (WKY) rats. The effects of the aldosterone antagonist spironolactone on myocardial hypertrophy in adrenalectomized SHRSP were also studied.
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Methods |
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Animals
SHRSP/Izm (2, 4, and 9 weeks old, n=24; 3 weeks old, n=20) and WKY/Izm rats (2 and 4 weeks old, n=24; 9 weeks old, n=96) donated by the Disease Model Cooperative Research Association (Kyoto, Japan) were housed in metabolic cages with free access to tap water and normal rat chow (0.1 mmol/g Na+, 0.24 mmol/g K+; Nippon Charles River). Animals were maintained in a constant temperature environment, with 12-hour light/dark cycles.
Experimental Protocol
In the first study, male 9-week-old WKY rats were used. The
first group of animals (n=24) underwent bilateral adrenalectomy under
ether anesthesia and were allowed free access to 0.9% NaCl
as drinking water for 7 days. The control group (n=24) consisted of
sham-operated animals that were supplied 0.9% NaCl solution. The
second group of rats (n=24) was administered the ACE
inhibitor quinapril (0.3 mg/d PO; Parke-Davis Co, Ltd) for
14 days. The third group of rats (n=24) was administered Ang II (9
µg/h) via an implanted osmotic minipump for 2 weeks as previously
described.9 Age- and weight-matched WKY rats that were
allowed access to tap water were used as controls. We confirmed no
residual adrenal tissues after experiments at necropsy on visual
inspection.
In the second study, 2-, 4-, and 9-week-old SHRSP (n=24 in each group) and age-matched WKY rats were used for the heart perfusion studies. Eight rats from each group were used for the quantification of CYP11B2 mRNA. The blood pressure was determined according to the plethysmographic tail-cuff method as previously reported.10 Blood was collected from the tail vein as previously reported.10 Plasma concentrations of corticosterone and aldosterone were estimated with radioimmunoassay (RIA) after extraction with a Sep-Pak C18 cartridge (Waters).
In the third study, 3-week-old SHRSP (n=36) were used to clarify the relationship between cardiac aldosterone and cardiac hypertrophy in SHRSP. Twenty adrenalectomized SHRSP were fed a high-sodium diet (0.9% drinking solution), and 10 rats were subcutaneously administered spironolactone (20 mg · kg-1 · d-1) via an implanted osmotic minipump for 8 weeks as previously described.11 Ten adrenalectomized SHRSP treated with vehicle (polyethylene glycol) for 8 weeks were used as controls. Sixteen sham-operated SHRSP with (n=8) or without (n=8) spironolactone were fed a high-sodium diet. The carotid artery was cannulated and blood pressure was recorded with a pressure transducer connected to a polygraph (RM 600; Nihon-Koden). Arterial blood pressure was measured in a conscious and unrestricted state. Before the animals were killed, they were anesthetized with pentobarbital (100 mg/kg IP), intubated, and mechanically ventilated. The chest was opened via median sternotomy, and the heart and lungs were removed. The right and left (plus septum) ventricles were weighed. All procedures were performed according to guidelines from the American Physiological Society and were approved by the Animal Research Committee of Kanazawa University (permit 28078).
Isolated Perfused Heart
Rats were heparinized and anesthetized with
pentobarbital (100 mg/kg IP). Once the rat was deeply
anesthetized, the heart was removed via sternotomy and placed
in ice-cold Krebs-Ringer solution. The heart was cannulated immediately
via the aorta, and retrograde perfusion was performed in a Langendorff
apparatus under constant pressure (90 mm Hg) with
modified Krebs-Henseleit solution.12 The solution was
gassed with 95% O2/5% CO2
and adjusted to pH 7.4. Studies were started after a 20-minute
equilibration perfusion.
Identification of Aldosterone in the Perfusate
The perfusate was extracted with a Sep-Pak C18 cartridge
and subjected to reversed-phase HPLC using methanol/water (40:100%) as
the mobile phase at a flow rate of 1.5 mL/min for 60 minutes. The
retention times of 18-hydroxycorticosterone, aldosterone,
corticosterone, DOC, progesterone, and pregnenolone were 35, 32, 43,
49, 55, and 59 minutes, respectively. The fraction corresponding to
synthetic aldosterone was collected and analyzed
with gas chromatography/mass spectrometry (GC/MS) as
previously reported.7
Measurements of Aldosterone in the Perfusate
After 20 minutes of equilibration, the perfusate was
collected for 2 hours. The perfusate with tritiated
aldosterone (3000 cpm; Amersham Japan) added to determine
recovery was extracted with a Sep-Pak C18 cartridge before HPLC
separation as described earlier. The aldosterone
concentration in the perfusate was measured with RIA after HPLC
separation. At the end of the experiment, the heart was
homogenized in 10 mL Krebs-Ringer buffer solution in a
tissue grinder. Protein was assayed according to the method of
Bradford.13
Measurements of Aldosterone Synthase Activity in
the Heart
Aldosterone synthase activity was estimated on the
basis of the conversion of [14C]DOC to
[14C]aldosterone. Diced heart
tissues were homogenized in 2 mL Krebs’ buffer (without
BSA) with three 10-second bursts in a Ystral
homogenizer, and the homogenate was assayed
for protein colorimetrically. Steroid conversion rates
were assayed in triplicate by the addition of homogenate (1
mg protein) to 1 mL buffer containing 0.5 µmol/L (0.001 µCi)
[14C]DOC, 250 mmol/L sucrose, 25
µmol/L isocitrate, and 50 mmol/L Tris-HCl, pH 7.4. After 120
minutes of incubation at 37°C, the incubation medium was extracted on
a Sep-Pak C18 cartridge. The steroids were separated with
reversed-phase HPLC. The fraction that corresponded to DOC and
aldosterone was counted in a scintillation counter.
Quantification of CYP11B2 mRNA in the Heart
Eight rats from each group were used for quantification of
CYP11B2 mRNA in the heart. Rats were anesthetized and
decapitated, and the heart was immediately removed. The tissue was
weighed, frozen in liquid nitrogen, and stored at -80°C before
analysis. Total RNA from rat hearts was isolated with
guanidinium thiocyanate followed by centrifugation in a
cesium chloride solution. Quantification of CYP11B2 mRNA was performed
with the competitive polymerase chain reaction (PCR) method as
previously reported.14 Sequences for the sense and
antisense primers for CYP11B2 have been reported
previously.15 The intra-assay and interassay variabilities
of the competitive PCR were 12.5% and 13.8%, respectively. To test
the yield and the efficiency of the reverse transcriptase reaction, 1
µg total RNA was subjected to reverse transcription (RT) as
described, with 5 µmol/L [32P]dCTP (New
England Nuclear) added to the reaction as previously
reported.16
Southern Blot
The RT-PCR products from 10-µL aliquots were
electrophoresed on a 3% agarose gel and transferred to nylon
membranes. Hybridization was performed as previously
reported,17 with a specific oligoprobe for CYP11B2
(5'-GATGCCTGGGATGTCATCTC-3') that had been end-labeled with
[32P]ATP (6000 Ci/mmol, New England Nuclear)
with a 5'-end oligonucleotide labeling kit.
Northern Blot Analysis of 
1-III Collagen mRNA
Poly(A)+ RNAs (5 µg/lane) of rat hearts
from each experimental group were separated by formaldehyde/agarose gel
electrophoresis, transferred to a nylon membrane
(Hybond-N+; Amersham Japan), and hybridized with
32P-labeled oligonucleotide probe
specific for 1-III collagen cDNA.18 The filters were
washed, and radioactive bands were detected with
autoradiography. The hybridized signals were
analyzed with a BAS 2000 Bioimaging Analyzer (Fuji
Photo Film Co Ltd). For quantification of relative levels of expression
of 1-III collagen mRNA, the autoradiographic signals
were standardized to signals determined from ß-actin mRNA in each
preparation to control for amounts of RNA loaded per
lane.17
Data are expressed as the mean±SEM. Differences were assessed by 1-way ANOVA and multiple comparison tests. Statistical significance was accepted for a value of P<0.05.
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Results |
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Table 1 summarizes the data for plasma renin activity (PRA) and plasma aldosterone and corticosterone concentrations for each experimental group. PRA was significantly higher in adrenalectomized rats than in sham-operated rats. In adrenalectomized rats, plasma aldosterone was not detected in 1 mL plasma on RIA. Rats treated with an ACE inhibitor had significantly lower plasma aldosterone concentrations than control rats (P<0.05). The plasma aldosterone concentration was significantly higher in rats that received Ang II (P<0.05). There were no significant differences in the plasma corticosterone concentration between rats treated with ACE inhibitor, rats that received Ang II, and control rats.
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The HPLC elution profile for immunoreactive aldosterone in the perfusate showed 1 large peak with a retention time of 32 minutes that corresponded to synthetic aldosterone (Figure 1). The aliquot of the fraction with a retention time of 32 minutes was injected into a GC/MS system, and the mass spectra pattern was identical to that for synthetic aldosterone (Figure 1). The sensitivity of the assay of aldosterone was 30 fmol. The overall recovery was 70%, interassay variation was 13.5%, and intra-assay variation was 9.5%.
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Figure 2 shows the analysis of CYP11B2 mRNA levels with competitive PCR. An increase in the concentration of competitive template for CYP11B2 from 0 to 160x10-3 amol/µL progressively inhibited the amplification of endogenous CYP11B2 cDNA in heart and adrenal gland. When PCR was carried out in the absence of RT, bands were not seen at 297 bp. The expression of CYP11B2 mRNA was much lower in heart than in adrenal gland.
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Figure 3 summarizes the amount of aldosterone synthesized, the activity of aldosterone synthase, and the concentrations of CYP11B2 mRNA in the heart for each experimental group. Aldosterone production in rats treated with ACE inhibitor was significantly reduced compared with that of controls (10±2.5 versus 18±2.2 pmol · mg-1 · h-1, P<0.05). Aldosterone production was significantly increased in adrenalectomized rats (30±2.8 pmol · mg-1 · h-1) and rats treated with Ang II (38±3.1 pmol · mg-1 · h-1; P<0.05). Aldosterone synthase activity in hearts was significantly reduced with ACE inhibitor by 44% (P<0.05) and significantly increased with adrenalectomy (1.7-fold) and Ang II (2.1-fold) (P<0.05). The expression of CYP11B2 mRNA in hearts was significantly reduced with ACE inhibitor by 51% (P<0.05) and significantly increased with adrenalectomy (2.1-fold) and Ang II (2.9-fold) (P<0.05).
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Table 2 summarizes the body weight, ratio of heart weight to body weight, systolic blood pressure, heart rate, and plasma aldosterone and corticosterone concentration in SHRSP and WKY rats. The ratio of heart weight to body weight was significantly increased in 4- and 9-week-old SHRSP compared with WKY rats of the same age (P<0.05). The blood pressure in 9-week-old SHRSP was significantly higher than that in WKY rats (P<0.05). The plasma aldosterone concentration was significantly higher in 9-week-old SHRSP than in age-matched WKY rats (P<0.05). The plasma corticosterone concentration did not differ between groups.
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Figure 4 shows the amount of aldosterone synthesized, the activity of aldosterone synthase, and the concentrations of CYP11B2 mRNA in the hearts of SHRSP and WKY rats. Aldosterone production from hearts was significantly greater in 2- and 4-week-old SHRSP (36±3.2 and 30±2.9 pmol · mg-1 · h-1, respectively) than in age-matched WKY rats (19±1.9 and 17±1.9 pmol · mg-1 · h-1, respectively; P<0.05). Aldosterone synthase activity in hearts was 1.9- and 1.8-fold higher in 2- and 4-week-old SHRSP than in age-matched WKY rats (P<0.05). The expression of CYP11B2 mRNA in hearts was 2.2- and 2.3-fold higher in 2- and 4-week-old SHRSP than in age-matched WKY rats (P<0.05).
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Table 3 summarizes the mean blood
pressure, body weight, ratio of left or right ventricular
weight to body weight, and 1-III collagen gene expression in each
experimental rat. Spironolactone decreased blood pressure, although not
significantly, in both adrenalectomized and sham-operated SHRSP.
Treatment with spironolactone significantly decreased left
ventricular weight in both adrenalectomized and
sham-operated SHRSP (P<0.05) but did not affect right
ventricular weight. The effect of spironolactone on left
ventricular weight in adrenalectomized SHRSP was smaller
than that in sham-operated SHRSP. Levels of 1-III collagen
mRNA were significantly decreased in both ventricles of
adrenalectomized or sham-operated SHRSP treated with spironolactone
(P<0.05).
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Cardiac hypertrophy is regulated by ventricular pressure and volume loading. Perivascular fibrous tissue synthesis is associated with chronic elevations in circulating effector hormones of the renin-angiotensin-aldosterone system, not with arterial hypertension per se. The fibrosis that follows myocyte necrosis is associated with increased plasma Ang II concentration and myocardial K+ depletion that accompanies chronic mineralocorticoid excess.19
More than 30 years ago, Ilett and Lockett20 described an aldosterone-like substance produced by heart muscle. The detection of 3ß-hydroxysteroid dehydrogenase activity in rat heart also indicates the potential for steroid metabolism in cardiac tissue.21 We confirmed the existence of aldosterone in the perfusate of rat heart with GC/MS. In adrenalectomized rats, plasma aldosterone was not detected; however, the aldosterone concentration in the perfusate was increased compared with sham-operated controls. These results support the hypothesis that the appearance of aldosterone in the perfusate does not reflect uptake from plasma. The findings of the present study, together with the observation of CYP11B2 expression in the heart, confirm that heart can synthesize aldosterone de novo by expressing CYP11B2 and other enzymes essential for the final product aldosterone.
There is increasing evidence of the presence of a cardiac renin-angiotensin system with local angiotensin formation.22 Local angiotensin formation in the heart may contribute to the pathogenesis of cardiac hypertrophy, congestive heart failure, and tissue remodeling.23 We have reported that rat and human blood vessels produce aldosterone.7 14 Vascular aldosterone production is controlled by the renin-angiotensin system at the transcriptional level14 and participates in the development of hypertension in rats.17 In this study, treatment with an ACE inhibitor decreased both the synthesis of aldosterone and the activity of aldosterone synthase in the heart. Decreased expression of CYP11B2 mRNA in the heart with ACE inhibitor therapy also was observed. Ang II is an important regulator of adrenal mineralocorticoid biosynthesis and secretion. Chronic treatment with Ang II increased cardiac aldosterone synthesis, aldosterone synthase activity, and the expression of CYP11B2 mRNA. These results suggest that cardiac aldosterone synthesis is controlled in part by the renin-angiotensin system at the transcriptional level. Cardiac aldosterone synthesis may be regulated by both the systemic and local renin-angiotensin system. Silvestre et al24 also reported that Ang II and a low-sodium/high-potassium diet increased the myocardial production of aldosterone in rat.
The SHRSP is a useful animal model of hypertension-induced cardiac hypertrophy.25 The systemic and local renin-angiotensin systems are major pathophysiological factors in the development of hypertrophy in this model.26 Early, long-term treatment of SHRSP with ACE inhibitors increases cardiac contractility and coronary flow and prevents the development of cardiac hypertrophy.27 Long-term treatment with Ang II type 1 receptor (AT1) antagonists also prevents cardiac hypertrophy in SHRSP.28 In this study, cardiac aldosterone levels were increased in the young prehypertensive SHRSP. Increased levels of CYP11B2 mRNA and aldosterone synthase activity in hearts of SHRSP suggest that local synthesis of aldosterone is increased in the cardiovascular system.
Gohlke et al27 reported that doses of ACE
inhibitors that do not decrease blood pressure inhibit the
cardiac hypertrophy in SHRSP and suggested that the effects
of ACE inhibitors on cardiac function are independent of
their antihypertensive and antihypertrophic actions. Increased
expression of renin, angiotensinogen, ACE, and
AT1 mRNA in the hearts of SHRSP has been
reported.29 The amount of aldosterone produced
by the heart is very small compared with the amount of plasma or
adrenal aldosterone with CYP11B2 mRNA levels in the heart
100-fold lower than in adrenal gland. Such a ratio is comparable
to that of ACE mRNA, of which the total quantity is 
150-fold lower
in the heart than in the lung, one of the main sources of this
enzyme.30
Robert et al31 reported that aldosterone-induced cardiac fibrosis is independent of blood pressure. In the present study, spironolactone prevented cardiac hypertrophy and fibrosis in both SHRSP and adrenalectomized SHRSP. However, the effect of spironolactone on cardiac fibrosis was greater than that on left ventricular weight in adrenalectomized SHRSP. These results indicate that the effect of circulating aldosterone on cardiac hypertrophy is more important than the effect of cardiac aldosterone, but the latter may contribute more for fibrosis. Although CYP11B2 expression, aldosterone synthase activity, and aldosterone production by heart were increased in SHRSP compared with WKY rats, this was only the case in early life. However, the blood pressure of the 2 groups was the same during this time frame, and it was only after 9 weeks that there was a significant difference, at which time the 3 parameters of aldosterone production were equivalent. This would suggest that cardiac aldosterone influences cardiac hypertrophy during the first few weeks of life. Recently, Silvestre et al32 reported that cardiac aldosterone production is increased in rats after cardiac myocardial infarction and that such increase in myocardial aldosterone level may be involved in post–myocardial infarction ventricular fibrosis. Further study is necessary to clarify the pathophysiological role of the cardiac renin-angiotensin-aldosterone system in cardiovascular disease.
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Acknowledgments |
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This work was supported in part by grants-in-aid for scientific research from the Ministry of Education, Science and Culture, Japan and the Yamanouchi Foundation for Research on Metabolic Disorders.
Received March 27, 2000; first decision April 4, 2000; accepted May 2, 2000.
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 W. Chai, I. M. Garrelds, R. de Vries, and A.H. Jan Danser Cardioprotective Effects of Eplerenone in the Rat Heart: Interaction With Locally Synthesized or Blood-Derived Aldosterone? Hypertension, April 1, 2006; 47(4): 665 - 670. [Abstract] [Full Text] [PDF]
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 P. Ye, C. J. Kenyon, S. M. MacKenzie, A. S. Jong, C. Miller, G. A. Gray, A. Wallace, A. S. Ryding, J. J. Mullins, M. W. McBride, et al. The Aldosterone Synthase (CYP11B2) and 11{beta}-Hydroxylase (CYP11B1) Genes Are Not Expressed in the Rat Heart Endocrinology, December 1, 2005; 146(12): 5287 - 5293. [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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J. W. Funder Cardiac Synthesis of Aldosterone: Going, Going, Gone... ? Endocrinology, November 1, 2004; 145(11): 4793 - 4795. [Full Text] [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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 S. Nakamura, M. Yoshimura, M. Nakayama, T. Ito, Y. Mizuno, E. Harada, T. Sakamoto, Y. Saito, K. Nakao, H. Yasue, et al. Possible Association of Heart Failure Status With Synthetic Balance Between Aldosterone and Dehydroepiandrosterone in Human Heart Circulation, September 28, 2004; 110(13): 1787 - 1793. [Abstract] [Full Text] [PDF]
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N. Ahmad, D. G. Romero, E. P. Gomez-Sanchez, and C. E. Gomez-Sanchez Do Human Vascular Endothelial Cells Produce Aldosterone? Endocrinology, August 1, 2004; 145(8): 3626 - 3629. [Abstract] [Full Text] [PDF]
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 R. S. Vasan, J. C. Evans, M. G. Larson, P. W.F. Wilson, J. B. Meigs, N. Rifai, E. J. Benjamin, and D. Levy Serum Aldosterone and the Incidence of Hypertension in Nonhypertensive Persons N. Engl. J. Med., July 1, 2004; 351(1): 33 - 41. [Abstract] [Full Text] [PDF]
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D. H. Endemann, R. M. Touyz, M. Iglarz, C. Savoia, and E. L. Schiffrin Eplerenone Prevents Salt-Induced Vascular Remodeling and Cardiac Fibrosis in Stroke-Prone Spontaneously Hypertensive Rats Hypertension, June 1, 2004; 43(6): 1252 - 1257. [Abstract] [Full Text] [PDF]
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 M. Epstein Reply Nephrol. Dial. Transplant., May 1, 2004; 19(5): 1332 - 1332. [Full Text] [PDF]
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 F. K Shieh, E. Kotlyar, and F. Sam Aldosterone and cardiovascular remodelling: focus on myocardial failure Journal of Renin-Angiotensin-Aldosterone System, March 1, 2004; 5(1): 3 - 13. [Abstract] [PDF]
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 D. Fraccarollo, P. Galuppo, S. Hildemann, M. Christ, G. Ertl, and J. Bauersachs Additive improvement of left ventricular remodeling and neurohormonal activation by aldosterone receptor blockade with eplerenone and ACE inhibition in rats with myocardial infarction J. Am. Coll. Cardiol., November 5, 2003; 42(9): 1666 - 1673. [Abstract] [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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T. Ito, M. Yoshimura, S. Nakamura, M. Nakayama, Y. Shimasaki, E. Harada, Y. Mizuno, M. Yamamuro, M. Harada, Y. Saito, et al. Inhibitory Effect of Natriuretic Peptides on Aldosterone Synthase Gene Expression in Cultured Neonatal Rat Cardiocytes Circulation, February 18, 2003; 107(6): 807 - 810. [Abstract] [Full Text] [PDF]
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S. M MacKenzie, R. Fraser, J. M. Connell, and E. Davies Local renin-angiotensin systems and their interactions with extra-adrenal corticosteroid production Journal of Renin-Angiotensin-Aldosterone System, December 1, 2002; 3(4): 214 - 221. [Abstract] [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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 R. E. Booth, J. P. Johnson, and J. D. Stockand ALDOSTERONE Advan Physiol Educ, March 1, 2002; 26(1): 8 - 20. [Abstract] [Full Text] [PDF]
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Y. Takeda, T. Yoneda, M. Demura, M. Usukura, and H. Mabuchi Calcineurin Inhibition Attenuates Mineralocorticoid-Induced Cardiac Hypertrophy Circulation, February 12, 2002; 105(6): 677 - 679. [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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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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