AJP - Heart Fuel your research with LabChart
HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS
QUICK SEARCH:   [advanced]


     

Am J Physiol Heart Circ Physiol 287: H2023-H2026, 2004; doi:10.1152/ajpheart.00477.2004
0363-6135/04 $5.00
This Article
Right arrow Abstract Freely available
Right arrow Full Text (PDF)
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Right arrow Citation Map
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in ISI Web of Science
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via ISI Web of Science (14)
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Chhokar, V. S.
Right arrow Articles by Weber, K. T.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Chhokar, V. S.
Right arrow Articles by Weber, K. T.

Loss of bone minerals and strength in rats with aldosteronism

Vikram S. Chhokar,1 Yao Sun,1 Syamal K. Bhattacharya,3 Robert A. Ahokas,4 Linda K. Myers,5 Zhiqing Xing,6 Richard A. Smith,6 Ivan C. Gerling,2 and Karl T. Weber1

Divisions of 1Cardiovascular Diseases and 2Endocrinology, Department of Medicine; and Departments of 3Surgery, 4Obstetrics and Gynecology, 5Pediatrics, and 6Orthopaedic Surgery, University of Tennessee Health Science Center, Memphis, Tennessee 38163

Submitted 25 May 2004 ; accepted in final form 24 June 2004


   ABSTRACT
TOP
 ABSTRACT
MATERIALS AND METHODS
 RESULTS AND DISCUSSION
 GRANTS
 REFERENCES
 
Congestive heart failure (CHF) is a clinical syndrome with origins rooted in a salt-avid state largely mediated by effector hormones of the circulating renin-angiotensin-aldosterone system. Other participating neurohormones include catecholamines, endothelin-1, and arginine vasopressin. CHF is accompanied by a systemic illness of uncertain causality. Features include the appearance of oxidative/nitrosative stress and a wasting of tissues including bone. Herein we hypothesized that inappropriate (relative to dietary Na+) elevations in plasma aldosterone (Aldo) contribute to an altered redox state, augmented excretion of divalent cations, and in turn, a loss of bone minerals and strength. In uninephrectomized rats that received chronic Aldo and 1% NaCl treatment for 4–6 wk, we monitored plasma {alpha}1-antiproteinase activity, which is an inverse correlate of oxidative/nitrosative stress; plasma concentrations of ionized Mg2+ and Ca2+; urinary Mg2+ and Ca2+ excretion; and bone mineral composition and strength to flexure stress. Compared with controls, we found reductions in plasma {alpha}1-antiproteinase activity and ionized Mg2+ and Ca2+ together with persistently elevated urinary Mg2+ and Ca2+ excretion, a progressive loss of bone mineral density and content with reduced Mg2+ and Ca2+ concentrations, and a reduction in cortical bone strength. Thus the hypermagnesuria and hypercalciuria that accompany chronic Aldo-1% NaCl treatment contribute to the systemic appearance of oxidative/nitrosative stress and a wasting of bone minerals and strength.

aldosterone; congestive heart failure; peripheral blood mononuclear cells; antiproteinase; parathyroid hormone

CONGESTIVE HEART FAILURE (CHF), a clinical syndrome with characteristic signs and symptoms, arises from circulating renin-angiotensin-aldosterone system activation (38) and is accompanied by a systemic illness that includes oxidative/nitrosative stress in the heart, systemic organs, circulating immune cells, and blood (10, 20, 34, 37) and a catabolic state with wasting of lean tissue, fat, and bone (2, 3, 22, 32). Aldosteronism in rats, which is defined as inappropriate (relative to dietary Na+) and chronic elevations in plasma aldosterone (Aldo) comparable to those seen in CHF, ultimately leads to a proinflammatory coronary vascular phenotype with evidence of oxidative/nitrosative stress (e.g., 3-nitrotyrosine labeling) in invading inflammatory cells (36). These vascular lesions are preceded by an immunostimulatory state that involves activated peripheral blood mononuclear cells (PBMCs) and is induced by Ca2+ loading and transduced by reactive oxygen species in these cells (1, 16). Herein we hypothesized that enhanced urinary excretion of Mg2+ and Ca2+ accompanies chronic Aldo with 1% NaCl treatment (Aldost) and leads to yet another component of this illness, namely, bone wasting.


   MATERIALS AND METHODS
TOP
 ABSTRACT
 MATERIALS AND METHODS
RESULTS AND DISCUSSION
 GRANTS
 REFERENCES
 
Male 8-wk-old Sprague-Dawley rats (Harlan, IN) were used in this study, which was approved by the institution's Animal Care and Use Committee. Unoperated and untreated age- and gender-matched rats served as controls. Uninephrectomized rats received Aldo (0.75 µg/h) via implanted minipump (Alzet; Cupertino, CA) together with 1% NaCl and 0.4% KCl in drinking water (Aldost) and standard laboratory diet (Harlan Tekland 2215 Rodent Diet). Plasma {alpha}1-antiproteinase ({alpha}1-AP) was assessed using the {alpha}1AP-410 assay system (Oxis Research; Portland, OR; Ref. 16). Concentrations of plasma ionized Mg2+ and Ca2+ were determined via the direct ion-selective electrode technique using a Nova 8 Analyzer (Nova Biomedical; Waltham, MA).

For the study of urinary Mg2+ and Ca2+ excretion, each animal was placed in a minerally decontaminated and distilled-deionized water-rinsed metabolic cage and allowed to continue to drink water that contained 1% NaCl. Food was withheld during the 24-h period of urine collection. Urine was frozen for later determination of Mg2+ and Ca2+ quantities. After each use, the cages were manually cleaned with deionized water, and all nonmetallic parts were washed with diluted (~3 N) hydrochloric acid and rinsed again with distilled-deionized water. Urinary Mg2+ and Ca2+ concentrations were determined as reported previously (7) using an atomic absorption spectrophotometer. By multiplying the respective concentrations (in µg/ml) by the 24-h urine volumes (in ml/24 h), we calculated the urinary excretion rates (expressed in µg/24 h).

Bone mineral density (BMD) and bone mineral content (BMC) values were determined for excised, manually cleaned tibias and femurs via peripheral dual-energy X-ray absorptiometry using GE Lunar PIXImus2 (GE Healthcare; Fairfield, CT) as previously validated for rat leg bones (25). Quality control and calibration were carried out within 24 h before each scanning period. Total tibial concentrations of Mg2+ and Ca2+ were determined using the atomic absorption spectrophotometer (Ref. 1; expressed in µg/mg of fat-free dry bone).

An Instron Universal Test System (Instron; Canton, MA) was used for mechanical testing (12). Flexure stress of the femurs was determined by breaking the bones with three-point bending. The femurs broke in the middiaphyseal region, and data were recorded as flexure stress in megapascals.

Values are presented as means ± SE. Data were analyzed with ANOVA. Significant differences between individual means were determined using the post hoc Bonferroni multiple-comparisons test. Significance was assigned to P < 0.05.


   RESULTS AND DISCUSSION
TOP
 ABSTRACT
 MATERIALS AND METHODS
 RESULTS AND DISCUSSION
GRANTS
 REFERENCES
 
This study led to several major findings. The first is the presence of an altered redox state during Aldost. The {alpha}1-AP, which is a major inhibitor of serine proteinases, is inactivated by peroxynitrite and hypochlorous acid. In control rats, plasma {alpha}1-AP activity was 39.8 ± 2.1 µmol/min; it was significantly reduced (24.3 ± 1.2 µmol/min) at 4 wk Aldost. This decrease in plasma {alpha}1-AP activity is in keeping with the presence of reactive oxygen and nitrogen species at a systemic level (40). Although {alpha}1-AP is frequently used as a biomarker to assess the presence of such species, we would caution that other factor(s) (e.g., a deficiency in {alpha}1-AP production and secretion as seen in hepatic disease or damage) could, albeit unlikely, account for some of the decreased plasma activity we found with Aldost. The cellular origin of this altered redox state is not well understood and likely involves multiple tissues such as heart and skeletal muscle, which have been reported as sites of oxidative/nitrosative stress in CHF (10, 20, 34, 37). We have incriminated a role for immune cells, including members of the monocyte-phagocyte system based on the appearance of oxidative/nitrosative stress in both PBMCs and inflammatory cells that invade the intramural coronary vasculature during Aldost (1, 16, 36).

The pathogenic basis for the induction of oxidative/nitrosative stress in PBMCs during Aldost has been linked to the reduced cytosolic free Mg2+ concentration ([Mg2+]i) together with intracellular Ca2+ loading (1, 16) of these cells. In human lymphocytes, a Na+-dependent reduction in [Mg2+]i appears in response to incubation with physiological concentrations of Aldo (13). This response is abrogated by an Aldo receptor antagonist, a transcription inhibitor, as well as by a protein-synthesis inhibitor; a Na+/Mg2+ exchanger was implicated as the responsible mechanism (13). Lymphocyte [Mg2+]i is reduced in patients with primary aldosteronism (13). Findings in our study raise the prospect that additional factors could regulate intracellular concentrations of these PBMC cations (see below) and will need to be considered in future studies.

In control rats, the plasma ionized Mg2+ was 0.35 ± 0.02 mmol/l. At 4 wk of Aldost, the ionized Mg2+ was significantly reduced to 0.19 ± 0.02 mmol/l (P < 0.05). Likewise, the plasma ionized Ca2+ at 4 wk of Aldost (0.70 ± 0.02 mmol/l) was less than the level found in unoperated controls (0.96 ± 0.03 mmol/l; P < 0.05). These reductions in plasma ionized Mg2+ and Ca2+ accompanied the marked increase in 24-h urinary Mg2+ and Ca2+ excretion levels during Aldost (see Table 1). The observed hypermagnesuria and hypercalciuria was persistent over 4–6 wk of Aldost and represent a second major finding of this study. Short-term studies in rats, dogs, and humans using such mineralocorticoid hormones as either deoxycorticosterone or fludrocortisone together with dietary Na+ loading have each demonstrated the dietary Na+-dependent increment in urinary Ca2+ excretion that occurs within the terminal segment of the nephron (8, 15, 24, 35, 42). Similar findings have been noted in humans with primary aldosteronism (27). Others (6, 21, 29) have shown that such a regimen in rats and patients with primary aldosteronism increases the urinary excretion of Mg2+, which normalizes after surgical removal of diseased adrenal tissue. Although the stimulus for the hypermagnesuria and hypercalciuria is uncertain, it is not related to elevations in arterial pressure (24, 35) or the mineralocorticoid hormone per se in the absence of dietary Na+ (35); it appears despite enhanced secretion of parathyroid hormone (PTH; Ref. 6). In rats and humans, marked dietary salt loading alone (e.g., 8% NaCl) is accompanied by hypercalciuria (11, 17, 23, 31, 33). In either setting, an expansion of the extravascular space is considered to be the likely mechanism leading to increased urinary excretion of these divalent cations (24, 35), which may be facilitated by nitric oxide-mediated increments in medullary blood flow (18, 44).


View this table:
[in this window]
[in a new window]
  		Table 1. Daily urine volume and urinary Mg2+ and Ca2+ excretion in response to Aldost

 
A third and hitherto unreported finding is the adverse effect of Aldost on bone. Coincident with marked urinary loss of Mg2+ and Ca2+ are rapid and profound reductions in BMD and BMC of both the tibia and femur (see Table 2). This loss of bone minerals was sustained over 4–6 wk of Aldost. We found comparable reductions in tibial total Mg2+ and Ca2+ concentrations (see Table 3). At week 6 of Aldost, this amounted to nearly a 50% reduction in the concentration of these divalent cations. Similar reductions in bone Mg2+ concentration together with systemic evidence of oxidative stress have been observed with dietary Mg2+ deficiency (30, 39). In conjunction with reduced BMD and BMC, there was a decrease in bone strength during Aldost compared with controls (Fig. 1). Cortical bone strength, as measured by three-point bending of the middiaphyseal region of the femur, was significantly reduced at weeks 5 and 6 of Aldost. In this study, whole femoral BMD decreased by 22% and BMC by 32% at 6 wk of Aldost compared with controls. The BMD and BMC levels for tibial bones decreased even more dramatically (53% and 71%, respectively). The femur contains more cortical bone, which may account for its losing less BMD and BMC. The decrease in BMD and BMC for the tibias also indicated a decrease in the overall size of the bones. The three-point bending measurements at 6 wk of Aldost showed a 30% decrease in femoral cortical bone strength (middiaphyseal region) compared with control rats. This region is almost entirely cortical bone and is an area of slow turnover compared to trabecular bone. The 30% decrease in cortical bone strength shown here is dramatic. The compressive strength of trabecular bone is roughly proportional to the square of its apparent density (9, 19). If bone density decreases by a factor of 2, the compressive strength decreases by a factor of 4. It is difficult to know fracture threshold from a rat model; however, the decreases in BMD and bone strength shown in this study are remarkable.


View this table:
[in this window]
[in a new window]
  		Table 2. Tibial and femoral BMD and BMC in response to Aldost

 

View this table:
[in this window]
[in a new window]
  		Table 3. Tibial total Mg2+ and Ca2+ concentrations in response to Aldost

 


View larger version (11K):
[in this window]
[in a new window]
  		Fig. 1. Three-point bending data from isolated rat femurs. Rats received aldosterone (0.75 µg/h) together with 1% NaCl and 0.4% KCl in drinking water (Aldost). Data are means ± SD expressed in megapascals (MPa); n = 5 rats. *P < 0.05, statistically different from control.

 
The urinary loss of Mg2+ and Ca2+ that accompanied Aldost will have profound systemic effects that were not addressed in the present study. It can be assumed that the loss of these divalent cations and reductions in their plasma ionized concentrations would induce hormonal responses that attempt to maintain plasma Mg2+ and Ca2+ homeostasis. These responses would include enhanced PTH secretion and formation of biologically active vitamin D metabolites. As noted above, we found reduced concentrations of serum ionized Mg2+ and Ca2+ at 4 wk of Aldost; this would serve to upregulate PTH secretion. Others have shown that plasma ionized Ca2+ and total plasma Ca2+ concentrations are reduced in rats receiving deoxycorticosterone and salt treatment (5, 41, 42), serum PTH and urinary excretion of cAMP are increased, which is a marker of parathyroid activity, and the presence of urinary hydroxyproline, which is a marker of bone resorption (4, 5). Endocrine properties of circulating PTH may be involved in the loss of bone minerals (5). PTH regulates renal production of 1,25(OH)2D3, which would serve to enhance gastrointestinal absorption of Ca2+. Increased gastrointestinal Ca2+ absorption, mediated by 1,25(OH)2D3, accompanies the hypercalciuria induced by deoxycorticosterone and salt treatment of several weeks duration (42). These early compensatory responses, however, may not be adequate to preserve plasma ionized Ca2+ concentrations during prolonged Aldost, as we noted herein, and this would represent a continuous stimulus to increased PTH secretion. As such, hyperparathyroidism has been observed in association with primary aldosteronism (14). Improvements in serum ionized Ca2+ and circulating PTH levels occur after adrenal surgery in primary aldosteronism (28, 29). Additional studies are needed to systematically address these important issues including the role of these hormones in regulating PBMC Mg2+ and Ca2+.

The ramifications of this study to the secondary aldosteronism found in human CHF could explain, at least in part, the appearance of a systemic illness with altered redox state and tissue wasting, including bone. Our findings also raise the possibility that older patients who have CHF with aldosteronism may be at increased risk for bone fracture. The large and rapid decrease in BMD and bone strength makes investigation of Aldo and sodium in humans essential. Even short-term hyperaldosteronism in humans may have significant effects on osteoporosis and risk of fracture later in life. Also, the effects of drugs such as bisphosphonates, which are used to treat various bone metabolism disorders by reducing Ca2+ lost by bone, should be investigated for their effects in patients with CHF. Bone loss together with elevated PTH levels are often found in normocalcemic patients with advanced CHF who await cardiac transplantation (3, 22, 32). Increased circulating levels of PTH and PTH-related protein have also been observed in patients with treated heart failure of less-advanced severity (26, 43). The pathogenesis of this secondary hyperparathyroidism, albeit uncertain and likely multifactoral, has included considerations of dietary Ca2+ deficiency, prerenal azotemia, hypovitaminosis D, reduced cardiac output, and the use of furosemide, which is a potent loop diuretic that promotes the excretion of divalent cations (32). On the basis of the findings of our study, we suggest that the consequences of Aldo (together with dietary NaCl) on urinary Mg2+ and Ca2+ excretion could also be contributory.


   GRANTS
TOP
 ABSTRACT
 MATERIALS AND METHODS
 RESULTS AND DISCUSSION
 GRANTS
REFERENCES
 
This work was supported, in part, by National Institutes of Health Grants R01 HL-67888 (to Y. Sun), R01 DK-62403 (to I. C. Gerling), R24 RR-15373 (to I. C. Gerling), R01 HL-62229 (to K. T. Weber), and Training Grant GR HL-07641, which funded V. S. Chhokar.


   FOOTNOTES
 

Address for reprint requests and other correspondence: K. T. Weber, Division of Cardiovascular Diseases, Univ. of Tennessee Health Science Center, 920 Madison Ave., Third Floor, Memphis, TN 38163 (E-mail: KTWeber{at}utmem.edu)

The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.


   REFERENCES
TOP
 ABSTRACT
 MATERIALS AND METHODS
 RESULTS AND DISCUSSION
 GRANTS
 REFERENCES
 

  1. AhokasRA, Warrington KJ, Gerling IC, Sun Y, Wodi LA, Herring PA, Lu L, Bhattacharya SK, Postlethwaite AE, and Weber KT. Aldosteronism and peripheral blood mononuclear cell activation. A neuroendocrine-immune interface. Circ Res 93: e124–e135, 2003.[Abstract/Free Full Text]
  2. AnkerSD, Chua TP, Ponikowski P, Harrington D, Swan JW, Kox WJ, Poole-Wilson PA, and Coats AJS. Hormonal changes and catabolic/anabolic imbalance in chronic heart failure and their importance for cardiac cachexia. Circulation 96: 526–534, 1997.[Abstract/Free Full Text]
  3. AnkerSD, Clark AL, Teixeira MM, Hellewell PG, and Coats AJ. Loss of bone mineral in patients with cachexia due to chronic heart failure. Am J Cardiol 83: 612–615, 1999.[CrossRef][ISI][Medline]
  4. BerthelotA, Desplan C, Pernot F, and Gairard A. I. PTH and U. cAMP during mineralocorticoid hypertension in the rat. Horm Metab Res 10: 83–84, 1978.[ISI][Medline]
  5. BerthelotA, Pernot F, and Gairard A. Increase in urinary excretion of phosphates, hydroxyproline, and cAMP during acetate desoxycorticosterone + saline treatment in the rat. Arch Int Pharmacodyn Ther 235: 196–203, 1978.[ISI][Medline]
  6. BerthelotA, Pernot F, and Gairard A. Influence of the thyroid and parathyroid glands on magnesium metabolism during mineralocorticoid treatment (DOCA + NaCl) in the rat. Ann Nutr Metab 27: 349–354, 1983.[ISI][Medline]
  7. BhattacharyaSK and Williams JC. Modified method of urinary calcium and magnesium determinations by atomic absorption spectrophotometry using nitrous oxide-acetylene flame. Anal Lett 12: 397–414, 1979.
  8. CappuccioFP, Markandu ND, and MacGregor GA. Renal handling of calcium and phosphate during mineralocorticoid administration in normal subjects. Nephron 48: 280–283, 1988.[ISI][Medline]
  9. CarterDR and Hayes WC. Bone compressive strength: the influence of density and strain rate. Science 194: 1174–1176, 1976.[Abstract/Free Full Text]
  10. CesselliD, Jakoniuk I, Barlucchi L, Beltrami AP, Hintze TH, Nadal-Ginard B, Kajstura J, Leri A, and Anversa P. Oxidative stress-mediated cardiac cell death is a major determinant of ventricular dysfunction and failure in dog dilated cardiomyopathy. Circ Res 89: 279–286, 2001.[Abstract/Free Full Text]
  11. ChanEL and Swaminathan R. Effect of different amounts of sodium intake for 4 months on calcium metabolism in normal and oophorectomized rats. J Bone Miner Res 8: 1185–1189, 1993.[ISI][Medline]
  12. CombsNR, Kornegay ET, Lindemann MD, Notter DR, Wilson JH, and Mason JP. Calcium and phosphorus requirement of swine from weaning to market weight: II. Development of response curves for bone criteria and comparison of bending and shear bone testing. J Anim Sci 69: 682–693, 1991.[Abstract]
  13. DelvaP, Pastori C, Degan M, Montesi G, Brazzarola P, and Lechi A. Intralymphocyte free magnesium in patients with primary aldosteronism: aldosterone and lymphocyte magnesium homeostasis. Hypertension 35: 113–117, 2000.[Abstract/Free Full Text]
  14. FerrissJB, Brown JJ, Cumming AM, Fraser R, Lever AF, Peacock M, and Robertson JI. Primary hyperparathyroidism associated with primary hyperaldosteronism. Acta Endocrinol 103: 365–370, 1983.
  15. GehrMK and Goldberg M. Hypercalciuria of mineralocorticoid escape: clearance and micropuncture studies in the rat. Am J Physiol Renal Fluid Electrolyte Physiol 251: F879–F888, 1986.[Abstract/Free Full Text]
  16. GerlingIC, Sun Y, Ahokas RA, Wodi LA, Bhattacharya SK, Warrington KJ, Postlethwaite AE, and Weber KT. Aldosteronism: an immunostimulatory state precedes the proinflammatory/fibrogenic cardiac phenotype. Am J Physiol Heart Circ Physiol 285: H813–H821, 2003.[Abstract/Free Full Text]
  17. GouldingA and Campbell DR. Effects of oral loads of sodium chloride on bone composition in growing rats consuming ample dietary calcium. Miner Electrolyte Metab 10: 58–62, 1984.[ISI][Medline]
  18. GrangerJP, Kassab S, Novak J, Reckelhoff JF, Tucker B, and Miller MT. Role of nitric oxide in modulating renal function and arterial pressure during chronic aldosterone excess. Am J Physiol Regul Integr Comp Physiol 276: R197–R202, 1999.[Abstract/Free Full Text]
  19. HayesWC and Carter DR. Postyield behavior of subchondral trabecular bone. J Biomed Mater Res 10: 537–544, 1976.[CrossRef][ISI][Medline]
  20. HillMF and Singal PK. Antioxidant and oxidative stress changes during heart failure subsequent to myocardial infarction in rats. Am J Pathol 148: 291–300, 1996.[Abstract]
  21. HortonR and Biglieri EG. Effect of aldosterone on the metabolism of magnesium. J Clin Endocrinol Metab 22: 1187–1192, 1962.[ISI][Medline]
  22. LeeAH, Mull RL, Keenan GF, Callegari PE, Dalinka MK, Eisen HJ, Mancini DM, DiSesa VJ, and Attie MF. Osteoporosis and bone morbidity in cardiac transplant recipients. Am J Med 96: 35–41, 1994.[CrossRef][ISI][Medline]
  23. LemannJ Jr, Pleuss JA, Hornick L, and Hoffman RG. Dietary NaCl-restriction prevents the calciuria of KCl-deprivation and blunts the calciuria of KHCO3-deprivation in healthy adults. Kidney Int 47: 899–906, 1995.[ISI][Medline]
  24. MassrySG, Coburn JW, Chapman LW, and Kleeman CR. The effect of long-term desoxycorticosterone acetate administration on the renal excretion of calcium and magnesium. J Lab Clin Med 71: 212–219, 1968.
  25. NagyTR, Prince CW, and Li J. Validation of peripheral dual-energy X-ray absorptiometry for the measurement of bone mineral in intact and excised long bones of rats. J Bone Miner Res 16: 1682–1687, 2001.[CrossRef][ISI][Medline]
  26. OginoK, Ogura K, Kinugasa Y, Furuse Y, Uchida K, Shimoyama M, Kinugawa T, Osaki S, Kato M, Tomikura Y, Igawa O, Hisatome I, Bilezikian JP, and Shigemasa C. Parathyroid hormone-related protein is produced in the myocardium and increased in patients with congestive heart failure. J Clin Endocrinol Metab 87: 4722–4727, 2002.[Abstract/Free Full Text]
  27. RastegarA, Agus Z, Connor TB, and Goldberg M. Renal handling of calcium and phosphate during mineralocorticoid "escape" in man. Kidney Int 2: 279–286, 1972.[ISI][Medline]
  28. ResnickLM and Laragh JH. Calcium metabolism and parathyroid function in primary aldosteronism. Am J Med 78: 385–390, 1985.[CrossRef][ISI][Medline]
  29. RossiE, Sani C, Perazzoli F, Casoli MC, Negro A, and Dotti C. Alterations of calcium metabolism and of parathyroid function in primary aldosteronism, and their reversal by spironolactone or by surgical removal of aldosterone-producing adenomas. Am J Hypertens 8: 884–893, 1995.[CrossRef][ISI][Medline]
  30. RudeRK, Kirchen ME, Gruber HE, Meyer MH, Luck JS, and Crawford DL. Magnesium deficiency-induced osteoporosis in the rat: uncoupling of bone formation and bone resorption. Magnes Res 12: 257–267, 1999.[ISI][Medline]
  31. SellmeyerDE, Schloetter M, and Sebastian A. Potassium citrate prevents increased urine calcium excretion and bone resorption induced by a high sodium chloride diet. J Clin Endocrinol Metab 87: 2008–2012, 2002.[Abstract/Free Full Text]
  32. ShaneE, Mancini D, Aaronson K, Silverberg SJ, Seibel MJ, Addesso V, and McMahon DJ. Bone mass, vitamin D deficiency, and hyperparathyroidism in congestive heart failure. Am J Med 103: 197–207, 1997.[CrossRef][ISI][Medline]
  33. ShorttC and Flynn A. Effect of dietary lactose on salt-mediated changes in mineral metabolism and bone composition in the rat. Br J Nutr 66: 73–81, 1991.[CrossRef][ISI][Medline]
  34. SinghN, Dhalla AK, Seneviratne C, and Singal PK. Oxidative stress and heart failure. Mol Cell Biochem 147: 77–81, 1995.[CrossRef][ISI][Medline]
  35. SukiWN, Schwettmann RS, Rector FC Jr, and Seldin DW. Effect of chronic mineralocorticoid administration on calcium excretion in the rat. Am J Physiol 215: 71–74, 1968.[Free Full Text]
  36. SunY, Zhang J, Lu L, Chen SS, Quinn MT, and Weber KT. Aldosterone-induced inflammation in the rat heart. Role of oxidative stress. Am J Pathol 161: 1773–1781, 2002.[Abstract/Free Full Text]
  37. TsutsuiH, Ide T, Hayashidani S, Suematsu N, Shiomi T, Wen J, Nakamura K, Ichikawa K, Utsumi H, and Takeshita A. Enhanced generation of reactive oxygen species in the limb skeletal muscles from a murine infarct model of heart failure. Circulation 104: 134–136, 2001.[Abstract/Free Full Text]
  38. WeberKT. Aldosterone in congestive heart failure. N Engl J Med 345: 1689–1697, 2001.[Free Full Text]
  39. WeglickiWB, Mak IT, Stafford RE, Dickens BF, Cassidy MM, and Phillips TM. Neurogenic peptides and the cardiomyopathy of magnesium-deficiency: effects of substance P-receptor inhibition. Mol Cell Biochem 130: 103–109, 1994.[CrossRef][ISI][Medline]
  40. WhitemanM, Szabo C, and Halliwell B. Modulation of peroxynitrite- and hypochlorous acid-induced inactivation of alpha1-antiproteinase by mercaptoethylguanidine. Br J Pharmacol 126: 1646–1652, 1999.[CrossRef][ISI][Medline]
  41. WrightGL and Rankin GO. Concentrations of ionic and total calcium in plasma of four models of hypertension. Am J Physiol Heart Circ Physiol 243: H365–H370, 1982.[Abstract/Free Full Text]
  42. ZikosD, Langman C, Gafter U, Delahaye B, and Lau K. Chronic DOCA treatment increases Ca absorption: role of hypercalciuria and vitamin D. Am J Physiol Endocrinol Metab 251: E279–E284, 1986.[Abstract/Free Full Text]
  43. ZittermannA, Schleithoff SS, Tenderich G, Berthold HK, Korfer R, and Stehle P. Low vitamin D status: a contributing factor in the pathogenesis of congestive heart failure? J Am Coll Cardiol 41: 105–112, 2003.[Abstract/Free Full Text]
  44. ZouAP and Cowley AW Jr. Role of nitric oxide in the control of renal function and salt sensitivity. Curr Hypertens Rep 1: 178–186, 1999.[Medline]



This article has been cited by other articles:


Home page
 J Am Coll CardiolHome page
L. D. Carbone, J. D. Cross, S. H. Raza, A. J. Bush, R. J. Sepanski, S. Dhawan, B. Q. Khan, M. Gupta, K. Ahmad, R. N. Khouzam, et al.
Fracture Risk in Men With Congestive Heart Failure: Risk Reduction With Spironolactone
J. Am. Coll. Cardiol., July 8, 2008; 52(2): 135 - 138.
[Abstract] [Full Text] [PDF]

Home page
 Clin Med ResHome page
S. Alsafwah, S. P. LaGuardia, M. Arroyo, B. K. Dockery, S. K. Bhattacharya, R. A. Ahokas, and K. P. Newman
Congestive Heart Failure is a Systemic Illness: A Role for Minerals and Micronutrients
Clin. Med. Res., December 1, 2007; 5(4): 238 - 243.
[Abstract] [Full Text] [PDF]

Home page
 Cardiovasc ResHome page
Y. Sun, R. A. Ahokas, S. K. Bhattacharya, I. C. Gerling, L. D. Carbone, and K. T. Weber
Oxidative stress in aldosteronism
Cardiovasc Res, July 15, 2006; 71(2): 300 - 309.
[Abstract] [Full Text] [PDF]

Home page
 Am. J. Physiol. Heart Circ. Physiol.Home page
A. Vidal, Y. Sun, S. K. Bhattacharya, R. A. Ahokas, I. C. Gerling, and K. T. Weber
Calcium paradox of aldosteronism and the role of the parathyroid glands
Am J Physiol Heart Circ Physiol, January 1, 2006; 290(1): H286 - H294.
[Abstract] [Full Text] [PDF]

Home page
 J Am Coll CardiolHome page
P. H. Law, Y. Sun, S. K. Bhattacharya, V. S. Chhokar, and K. T. Weber
Diuretics and Bone Loss in Rats With Aldosteronism
J. Am. Coll. Cardiol., July 5, 2005; 46(1): 142 - 146.
[Abstract] [Full Text] [PDF]

Home page
 CirculationHome page
R. A. Ahokas, Y. Sun, S. K. Bhattacharya, I. C. Gerling, and K. T. Weber
Aldosteronism and a Proinflammatory Vascular Phenotype: Role of Mg2+, Ca2+, and H2O2 in Peripheral Blood Mononuclear Cells
Circulation, January 4, 2005; 111(1): 51 - 57.
[Abstract] [Full Text] [PDF]

This Article
Right arrow Abstract Freely available
Right arrow Full Text (PDF)
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Right arrow Citation Map
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in ISI Web of Science
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via ISI Web of Science (14)
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Chhokar, V. S.
Right arrow Articles by Weber, K. T.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Chhokar, V. S.
Right arrow Articles by Weber, K. T.

HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS
Visit Other APS Journals Online
Copyright © 2004 by the American Physiological Society.