| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
Division of Endocrinology, G. V. (Sonny) Montgomery Veterans Affairs Medical Center (E.P.G.-S., C.E.G.-S.), and University of Mississippi Medical Center (E.P.G.-S., N.A., D.G.R., C.E.G.-S.), Jackson, Mississippi 39216
Address all correspondence and requests for reprints to: Dr. Elise Gomez-Sanchez, Research Service, G. V. (Sonny) Montgomery Veterans Affairs Medical Center, 1500 East Woodrow Wilson Drive (151), Jackson, Mississippi 39216. E-mail: elise.gomezsanchez{at}med.va.gov.
 |
Abstract |
|---|
 Top Abstract IntroductionMaterials and MethodsResultsDiscussionReferences |
|---|
|
Introduction |
|---|
|
TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
|---|
At about the same time that an expanded, nonepithelial cell role was being established for aldosterone, interest in the de novo extraadrenal synthesis of adrenal corticoids was revived by the demonstration in the brain of cytochrome P450 side-chain cleavage (P450scc) enzyme activity, which is required for the first step of steroid synthesis from cholesterol (8). Within a few years, mRNA for all enzymes of aldosterone synthesis had been described in the heart and vascular system (9, 10, 11, 12, 13, 14, 15). Species, strain, and pathophysiological differences have been partially responsible for confusion about the existence of aldosterone synthase message in the heart. Aldosterone synthase mRNA is expressed in some strains of rat, but not mouse heart, and although Wistar and spontaneously hypertensive (SHR) rat hearts express aldosterone synthase mRNA under basal and stimulated conditions, it was not found in Sprague Dawley rat hearts unless the rats were chronically treated with angiotensin II (16). mRNA for P450scc, 3ß-ol-dehydrogenase, 21-hydroxylase, and 11ß-hydroxylase, but not aldosterone synthase, were detected in healthy adult human heart samples using RT-PCR and Southern blotting at 100- to 10,000-fold lower concentrations than those found in the adrenal (9, 17). Although the healthy adult human heart appears not to express aldosterone synthase mRNA, fetal and failing adult hearts do (17, 18, 19).
Aldosterone production has been reported in cultured vascular endothelial cells (12), vascular smooth muscle cells, mesenteric artery, brain, and isolated perfused hearts (10, 11, 12, 14, 15, 20, 21, 22, 23, 24). Aldosterone release by the perfused heart has been reported to be increased by angiotensin II, ACTH, a low salt diet (LS), and heart failure and to be greater in stroke-prone spontaneously hypertensive rats (SHRsp), compared with Wistar-Kyoto (WKY) rats (10, 15, 22, 23). The release of aldosterone into the perfusate as well as the elevated content of aldosterone in rat heart homogenates have been interpreted as de novo synthesis. Two very similar studies in humans resulted in diametrically opposite results and conclusions. In both studies, plasma levels of aldosterone in the heart effluent (anterior interventricular vein and coronary sinus) were compared with those in the aortic root in patients with left ventricular dysfunction and in healthy controls. Mizuno et al. (25) reported that peripheral blood concentrations of aldosterone in CHF patients were not different from those in control subjects; however, aldosterone levels were significantly higher in the blood draining from the heart than that in that from the aortic root in patients with CHF, but not in control individuals. This study supports the idea that aldosterone synthesis is increased in the failing heart and that the therapeutic response to MR inhibition is due to blocking the effect of aldosterone synthesized within the heart. Tsutamoto et al. (26) also found that circulating levels of aldosterone in patients with cardiac dysfunction were not different from those in control subjects. However, the aldosterone concentrations in coronary sinus samples were lower than those in the aortic root in both patients with heart failure and normal controls, suggesting that the heart extracted aldosterone from the circulation. Administration of the MR antagonist spironolactone decreased the extraction of aldosterone from plasma in patients with CHF (27).
In addition to clinical inconsistencies, there are those of enzyme expression and kinetics that make the interpretation of studies in this area difficult. The concentration of mRNA for all steroidogenic enzymes in rat heart and vascular tissue is much lower than that in the adrenal. The combined mass of the heart, endothelial, and vascular smooth muscle cells is very large, certainly much greater than the cell mass of the zona glomerulosa. Therefore, a significant total amount of enzyme expression and aldosterone synthesis is conceivable. Reported conversion rates of tritiated deoxycorticosterone (DOC) to aldosterone and corticosterone in heart homogenates are as high as those in zona glomerulosa, even though expression of aldosterone synthase is 1000 times less (10, 15, 22, 23, 28, 29). With these conversion rates, it is difficult to explain why adrenalectomy results in undetectable plasma concentrations of corticosterone and aldosterone unless the heart does not release these steroids, or precursors are not available for synthesis.
The following studies were undertaken in the rat to revisit reported discrepancies about the content and level of production of aldosterone in the heart by comparing levels of aldosterone in plasma and hearts of healthy rats under physiological conditions that alter adrenal production of aldosterone and in adrenalectomized (ADX) rats. The establishment of a baseline production of aldosterone within the heart will make it possible to assess normal and aberrant regulation of heart aldosterone synthesis, the role heart aldosterone synthesis may play in disease, and potential therapeutic regimens to normalize production.
|
Materials and Methods |
|---|
|
TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
|---|
Aldosterone and corticosterone assays
Plasma (0.5 ml) was extracted with 5 ml dichloromethane, reconstituted in 200–250 µl ELISA buffer (20 mM sodium phosphate, 100 mM sodium chloride, 0.01% thimerosal, and 0.05% Tween 20), and 50 µl were used to measure aldosterone by ELISA using a specific monoclonal antibody and protocol produced and characterized by us, as previously described (30, 31). The reconstituted extract was diluted 1:100, and corticosterone was measured by ELISA using a sheep polyclonal antibody, as described by us (32). All assays were performed in triplicate, included blanks, and were run more than once for most experiments to assure reproducibility. Plasma DOC was measured by RIA (33) in 0.5 ml plasma extracted with 7% dichloromethane in hexane.
Measurement of aldosterone and corticosterone in the heart
The heart was weighed, and 5 ml water were added containing 4000 dpm tritiated aldosterone for estimation of recoveries. It was homogenized using a Polytron (Brinkmann Instruments, Westbury, NY), the homogenate was extracted with 25 ml dichloromethane, and the aqueous phase was removed. To clean the sample, the organic phase was passed through a silica gel column (Silica Gel Grade 62, Sigma-Aldrich Corp., St. Louis, MO) that had been prewashed with 5 ml dichloromethane, where the steroids were adsorbed. The steroids were then eluted with 5 ml dichloromethane containing 7% methanol. The organic extract was evaporated under vacuum and reconstituted in 250 µl ELISA buffer. A 50-µl aliquot was used for estimation of recoveries, and 50 µl were used in triplicate for the aldosterone assay. The sensitivity of the ELISA for aldosterone was 1 pg/well, and that for corticosterone was 10 pg/well. A dilution of 1:100 (vol/vol) was used for measurement of corticosterone in intact rats, and a 1:10 (vol/vol) dilution was used for ADX rats. Results were expressed as picograms per gram of tissue for aldosterone and nanograms per gram of tissue for corticosterone, and as picograms (aldosterone) and nanograms (corticosterone) of plasma per milliliter. Dichloromethane was screened and redistilled when necessary to obtain negligible background signals for the steroid ELISAs. Recoveries were measured, and values were corrected for each tissue sample. Heart tissue protein was also measured using the bicinchoninic acid method (Pierce Chemical Co., Rockford, IL) to be able to compare the present studies with those of previously reported. The protein content of rat hearts was 65 ± 10 (±SD) mg/g tissue (n = 10).
mRNA expression for the genes coding for aldosterone synthase and 11ß-hydroxylase (CY11B2 and CY11B1, respectively) was measured in the hearts and adrenal glands of female Wistar rats on NS (n = 3) and HS and LS (plus 0.15% KCl in the water) diets for 12 d (n = 10). Tissues were removed, frozen in liquid nitrogen, and stored at –70 C until RNA extraction. Polyadenylated [Poly(A)+] mRNA was extracted from tissues with the Micro Poly(A) Pure or Poly(A) Pure Kit (Ambion, Houston, TX). RNA pellets were resuspended in 0.1 mM EDTA and treated with deoxyribonuclease using the DNA-free kit and were filtered through Spin columns (Ambion). PCR primers and probes (Table 1
) were designed with Primer3 software (http://genome.wi.mit.edu/cgi-bin/primer/primer3_www.cgi). Annealing temperature was set at 60 C for primers and 70 C for probes during primer/probe design. For RT, 500 ng poly(A)+ RNA were heated at 65 C for 5 min with 250 ng random hexamers primers and 1 µl 10 mM deoxy-NTPs (U.S. Biochemical Corp., Cleveland, OH) in a final volume of 12 µl. Superscript II ribonuclease H– reverse transcriptase (Invitrogen Life Technologies, Inc., Carlsbad, CA) was used for RT reaction following the manufacturer’s protocol. SUPERase In RNase inhibitor (Ambion) was added at a concentration of 1 U/µl. The Multiplex Quantitative PCR was carried out in a final volume of 50 µl/well containing 1 µl RT product, 1x buffer provided with the polymerase, 6 mM MgCl2, 0.2 mM deoxy-NTPs, 0.2 mM of each primer and probe (see Table 1), and 2.5 U SureStart Taq DNA polymerase (Brilliant Quantitative PCR Core Reagent Kit, Stratagene, La Jolla, CA). The cycling conditions consist of one cycle of 10 min at 95 C to activate the hot start polymerase and 50 cycles of 15 sec at 95 C, 15 sec at 60 C, and 1 min at 72 C. The PCR was carried out in an i-Cycler thermal cycler (Bio-Rad Laboratories, Hercules, CA), and real-time data were collected during the extension phase of the PCR cycle. For the standard curve, PCR products were cloned in the pCR2.1 TOPO vector (Invitrogen Life Technologies, Inc.) and were diluted to add 10–108 molecules/PCR. Primers were synthesized by MWG Biotech International (High Point, NC) and Black hole quenched probes (Biosearch Technologies, Inc., Novato, CA).
|
|
Results |
|---|
|
TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
|---|
Figure 1 is a composite graph showing the effects of different sodium chloride intakes and adrenalectomy in 9-wk-old rats (n = 10) assigned to the following four groups: intact NS, intact LS for 16 d, intact HS for 16 d, and ADX-HS for 16 d, and ADX for 2 d before tissue harvest. Plasma aldosterone was significantly increased by 16 d of LS [5127.3 ± 502.9 (±SEM), pg/ml] compared with NS (336 ± 62.4 pg/ml; P < 0.000127), whereas HS lowered it to 56.6 ± 11.2 pg/ml (P < 0.01). Plasma aldosterone in ADX-HS rats was measurable (barely) in only one of 11 rats. Plasma corticosterone in this rat was below the level of detection, indicating that she was indeed ADX. Levels of aldosterone in the hearts of the adrenal-intact rats were: NS, 220.8 ± 32.6 pg/g; LS, 4906.4 ± 508.7 pg/g; and HS, 87.2: ±12.3 pg/g. The aldosterone concentration in the hearts of the ADX rats was consistently 14.5 ± 5.6 pg/g in six of 11 ADX rats. The levels of aldosterone in the NS, LS, and HS hearts were significantly different from those in ADX rats (P < 0.01), as were those in LS compared with HS hearts (P < 0.01). Plasma corticosterone was measurable in one ADX rat (not the animal in which aldosterone was measured) at just above the limit of detection. Dietary salt did not have a predictable or significant statistical effect on plasma corticosterone levels in the intact animals. Heart corticosterone levels in the ADX rats were not measurable. Those in intact-NS rats were significantly different from those in intact-HS (P < 0.01).
|
and 2.
|
summarizes an experiment in which 12-wk-old rats (n = 9 or 10 depending on the group) were randomly assigned to three groups. Groups II and III were ADX, and group III received a miniosmotic pump (ALZET) sc that was primed to deliver 0.2 µg/h aldosterone upon insertion. All three groups in this study received HS thereafter, because ADX animals require supplemental sodium to maintain health. Tissues were harvested on d 8. Plasma and heart aldosterone levels of the aldosterone-replaced ADX rats were not statistically different from those of the intact rats; both were significantly greater than those of ADX animals (for the comparison of heart aldosterone: ADX-HS vs. intact-HS, P < 0.0017; and ADX-HS vs. ADX-HS plus aldosterone, P < 0.01). Plasma and heart corticosterone levels in the intact group were significantly greater than those in both ADX groups; levels were undetectable in most and at the limit of detection in a few individuals (intact-HS vs. ADX-HS and ADX-HS plus aldosterone, P < 0.01 for both plasma and heart). In two separate experiments a large excess of DOC (5 mg) was administered sc 3 h before tissue collection in ADX rats to determine whether substrate was a limiting factor for extraadrenal-expressed 11ß-hydroxylase and aldosterone synthase enzymes. In one experiment there were eight rats per group ADX for 48 h before the study; in the other, nine rats per group were ADX for 7 d before receiving DOC. Plasma concentrations of DOC in untreated ADX rats were undetectable; the mean plasma DOC concentration in the rats receiving DOC injections was 41.2 ± 5 ng/ml. The aldosterone concentration in the hearts of ADX rats given no treatment was 26 ± 14 pg/g; that in ADX and DOC-treated rats was 39.67 ± 14.8 pg/g wet tissue weight. There was no statistical difference between the ADX and ADX plus DOC heart aldosterone concentrations.
|
Discussion |
|---|
|
TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
|---|
LS increased and HS decreased aldosterone levels in both plasma and heart of intact rats, as would be expected if aldosterone in the heart were derived from the circulation, or the regulation of its synthesis were the same or similar in the heart as in the adrenal. The present findings are consistent with reports that LS increases aldosterone released by the isolated perfused heart (10), but not those that chronic sodium loading increases it (22). The differences between plasma aldosterone in NS and HS animals in our studies were larger that those reported previously. This probably reflects our use of rat chow containing 0.28–0.3% NaCl, the amount found in standard growth and maintenance chows in this country [Purina (Ralston Purina, St. Louis, MO) and Teklad], instead of the chow containing 0.4–0.6% NaCl used by others (10, 22).
Female rats were used in these studies because they are less likely to have ectopic adrenal tissue than males, as adrenal cortex primordia not uncommonly accompany the migrating testes and acquire significant synthetic ability upon chronic ACTH stimulation (35). In these studies both plasma and heart corticosterone concentrations in ADX rats were undetectable in almost all rats.
The disappearance of aldosterone in plasma in the human is biexponential, with an initial phase of 29 min and a second phase of about 120 min (36). By interpolation from the metabolic clearance rate of aldosterone in the rat, the disappearance of aldosterone from the circulation should be similar to that in humans (34). Because there is no known mechanism for long-term sequestration or protection from degradation of aldosterone, our data confirm reports that the rat heart may synthesize aldosterone in vivo, but in significantly smaller amounts than reported previously. This is consonant with our finding of extremely low levels of expression of mRNA for aldosterone synthase and 11ß-hydroxylase.
The aldosterone synthase enzyme is a partial processing enzyme that successively hydroxylates DOC to produce corticosterone, 18-hydroxycorticosterone, and aldosterone. The production of the intermediates, corticosterone and 18-hydroxycorticosterone, is significantly greater than that of the final product, aldosterone (37, 38). Thus, one would expect that corticosterone should be easily measured in the hearts of ADX rats if aldosterone were being synthesized. The finding that aldosterone in the heart was detectable in approximately 30% of hearts from ADX rats suggests that the heart is capable of synthesizing a very small amount of aldosterone. However, the finding that corticosterone, present at approximately 400 times the concentration of aldosterone in the intact heart, becomes undetectable in hearts of ADX rats suggests that no significant synthesis of corticosteroids occurs in the heart.
Although the total amount of mRNA in the whole heart was a fraction of that in the adrenal, the mRNA for CYP11B2 was significantly greater in the hearts of LS, compared with HS, rats in our studies. An increase in angiotensin II associated with LS is a primary stimulus of adrenal production of aldosterone, and pharmacological amounts of exogenous angiotensin II were reported to increase the aldosterone content in heart as well as that in serum (10).
The rate-limiting steps in the adrenal synthesis of aldosterone are the transport of cholesterol mediated by the steroidogenic acute regulatory protein to the inner mitochondrial membrane, where it is acted upon by P450scc, and the conversion of DOC to aldosterone by the mitochondrial aldosterone synthase (39, 40). The rates of conversion of tritiated DOC to corticosterone and aldosterone by cardiac tissue have been reported to be as high as those by the adrenal zona glomerulosa, which expresses more than 1000 times more enzyme than the heart (10, 15, 22, 23). Unfortunately, documentation of the method for estimating this conversion rate was not described sufficiently to be reproduced (10, 23). We found no significant difference between the aldosterone content of hearts of ADX rats with no detectable plasma DOC or those with circulating values in excess of 40 ng/ml. This is consistent with our demonstration of very low levels of CYP11B2 expression in the heart, as well as reports that the mRNA for the other enzymes required for adrenal corticoid synthesis from cholesterol are expressed in rat hearts at concentrations several orders of magnitude less than those in the adrenal (9, 17).
Most aldosterone in the heart tissue of healthy rats is derived from the circulation. The use of MR antagonists in the treatment of heart failure has increased greatly and is expected to increase even more with the recent advent of new MR-selective antagonists with fewer side-effects (7). However, the MRs in some, if not most, nonepithelial tissues, notably the hippocampus and perhaps the healthy heart, are normally occupied by glucocorticoids. The effect of generalized long-term blockade of MR in patients is as yet unknown. Knowledge about the regulation of aldosterone content of heart tissue, regardless of the source, may offer a novel way of reducing it in the diseased organ without altering MR-mediated homeostasis elsewhere.
|
Footnotes |
|---|
Abbreviations: ADX, Adrenalectomized; CHF, congestive heart failure; DOC, deoxycorticosterone; HS, high salt diet; LS, low salt diet; MR, mineralocorticoid receptor; NS, normal salt diet; P450scc, cytochrome P450 side-chain cleavage; poly(A)+, polyadenylated.
Received March 8, 2004.
Accepted for publication July 28, 2004.
|
References |
|---|
|
TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
|---|
This article has been cited by other articles:
 |
|
 |
|
  R. M. Touyz and G. E. Callera A New Look at the Eye: Aldosterone and Mineralocorticoid Receptors As Novel Targets in Retinal Vasculopathy Circ. Res., January 2, 2009; 104(1): 9 - 11. [Full Text] [PDF]
|
|
|
|
 |
|
 L. Michea, A. Villagran, A. Urzua, S. Kuntsmann, P. Venegas, L. Carrasco, M. Gonzalez, and E. T. Marusic Mineralocorticoid Receptor Antagonism Attenuates Cardiac Hypertrophy and Prevents Oxidative Stress in Uremic Rats Hypertension, August 1, 2008; 52(2): 295 - 300. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. M. C. Connell, S. M. MacKenzie, E. M. Freel, R. Fraser, and E. Davies A Lifetime of Aldosterone Excess: Long-Term Consequences of Altered Regulation of Aldosterone Production for Cardiovascular Function Endocr. Rev., April 1, 2008; 29(2): 133 - 154. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 R. M. Ortiz, M. L. Graciano, J. J. Mullins, and K. D. Mitchell Aldosterone receptor antagonism alleviates proteinuria, but not malignant hypertension, in Cyp1a1-Ren2 transgenic rats Am J Physiol Renal Physiol, November 1, 2007; 293(5): F1584 - F1591. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 D. G. Romero, L. L. Yanes, A. F. de Rodriguez, M. W. Plonczynski, B. L. Welsh, J. F. Reckelhoff, E. P. Gomez-Sanchez, and C. E. Gomez-Sanchez Disabled-2 Is Expressed in Adrenal Zona Glomerulosa and Is Involved in Aldosterone Secretion Endocrinology, June 1, 2007; 148(6): 2644 - 2652. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. L. Onozato, A. Tojo, N. Kobayashi, A. Goto, H. Matsuoka, and T. Fujita Dual blockade of aldosterone and angiotensin II additively suppresses TGF-{beta} and NADPH oxidase in the hypertensive kidney Nephrol. Dial. Transplant., May 1, 2007; 22(5): 1314 - 1322. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 T. Ohtani, M. Ohta, K. Yamamoto, T. Mano, Y. Sakata, M. Nishio, Y. Takeda, J. Yoshida, T. Miwa, M. Okamoto, et al. Elevated cardiac tissue level of aldosterone and mineralocorticoid receptor in diastolic heart failure: beneficial effects of mineralocorticoid receptor blocker Am J Physiol Regulatory Integrative Comp Physiol, February 1, 2007; 292(2): R946 - R954. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 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]
|
|
|
|
|
|
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]
|
|
|
|
|
|
M. Yamamuro, M. Yoshimura, M. Nakayama, K. Abe, M. Shono, S. Suzuki, T. Sakamoto, Y. Saito, K. Nakao, H. Yasue, et al. Direct Effects of Aldosterone on Cardiomyocytes in the Presence of Normal and Elevated Extracellular Sodium Endocrinology, March 1, 2006; 147(3): 1314 - 1321. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
E. L. Schiffrin Effects of Aldosterone on the Vasculature Hypertension, March 1, 2006; 47(3): 312 - 318. [Full Text] [PDF]
|
|
|
|
|
|
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]
|
|
|
|
|
|
W. Chai, I. M. Garrelds, R. de Vries, W. W. Batenburg, J. P. van Kats, and A.H. Jan Danser Nongenomic Effects of Aldosterone in the Human Heart: Interaction With Angiotensin II Hypertension, October 1, 2005; 46(4): 701 - 706. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
T. Sugiyama, T. Yoshimoto, K. Tsuchiya, N. Gochou, Y. Hirono, T. Tateno, N. Fukai, M. Shichiri, and Y. Hirata Aldosterone Induces Angiotensin Converting Enzyme Gene Expression via a JAK2-Dependent Pathway in Rat Endothelial Cells Endocrinology, September 1, 2005; 146(9): 3900 - 3906. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
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]
|
|
|
|
 |
|
 J. M C Connell and E. Davies The new biology of aldosterone J. Endocrinol., July 1, 2005; 186(1): 1 - 20. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A. Fiebeler, J. Nussberger, E. Shagdarsuren, S. Rong, G. Hilfenhaus, N. Al-Saadi, R. Dechend, M. Wellner, S. Meiners, C. Maser-Gluth, et al. Aldosterone Synthase Inhibitor Ameliorates Angiotensin II-Induced Organ Damage Circulation, June 14, 2005; 111(23): 3087 - 3094. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 H.-P. Gaeggeler, E. Gonzalez-Rodriguez, N. F. Jaeger, D. Loffing-Cueni, R. Norregaard, J. Loffing, J.-D. Horisberger, and B. C. Rossier Mineralocorticoid versus Glucocorticoid Receptor Occupancy Mediating Aldosterone-Stimulated Sodium Transport in a Novel Renal Cell Line J. Am. Soc. Nephrol., April 1, 2005; 16(4): 878 - 891. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
I. Z. Jaffe and M. E. Mendelsohn Angiotensin II and Aldosterone Regulate Gene Transcription Via Functional Mineralocortocoid Receptors in Human Coronary Artery Smooth Muscle Cells Circ. Res., April 1, 2005; 96(6): 643 - 650. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
E. P. Gomez-Sanchez, J. Samuel, G. Vergara, and N. Ahmad Effect of 3{beta}-hydroxysteroid dehydrogenase inhibition by trilostane on blood pressure in the Dahl salt-sensitive rat Am J Physiol Regulatory Integrative Comp Physiol, February 1, 2005; 288(2): R389 - R393. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. W. Funder Cardiac Synthesis of Aldosterone: Going, Going, Gone... ? Endocrinology, November 1, 2004; 145(11): 4793 - 4795. [Full Text] [PDF]
|
|
| |||||||||||||||||||||||||||||||||||||||||||||
