AJP - Heart Information on EB 2010
HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS
QUICK SEARCH:   [advanced]


     

Am J Physiol Heart Circ Physiol 290: H286-H294, 2006; doi:10.1152/ajpheart.00535.2005
0363-6135/06 $8.00
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 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 Web of Science (16)
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Vidal, A.
Right arrow Articles by Weber, K. T.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Vidal, A.
Right arrow Articles by Weber, K. T.

Calcium paradox of aldosteronism and the role of the parathyroid glands

Alex Vidal,1 Yao Sun,1 Syamal K. Bhattacharya,3 Robert A. Ahokas,4 Ivan C. Gerling,2 and Karl T. Weber1

Divisions of 1Cardiovascular Diseases and 2Endocrinology, Department of Medicine, and Departments of 3Surgery and 4Obstetrics and Gynecology, University of Tennessee Health Science Center, Memphis, Tennessee

Submitted 20 May 2005 ; accepted in final form 19 August 2005


   ABSTRACT
TOP
 ABSTRACT
MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 GRANTS
 REFERENCES
 
The hypercalciuria and hypermagnesuria that accompany aldosteronism contribute to a fall in plasma ionized extracellular Ca2+ and Mg2+ concentrations ([Ca2+]o and [Mg2+]o). Despite these losses and the decline in extracellular levels of these cations, total intracellular and cytosolic free Ca2+ concentration ([Ca2+]i) is increased and oxidative stress is induced. This involves diverse tissues, including peripheral blood mononuclear cells (PBMC) and plasma. The accompanying elevation in plasma parathyroid hormone (PTH) and reduction in bone mineral density caused by aldosterone (Aldo)-1% NaCl treatment (AldoST) led us to hypothesize that Ca2+ loading and altered redox state are due to secondary hyperparathyroidism (SHPT). Therefore, we studied the effects of total parathyroidectomy (PTx). In rats receiving AldoST, without or with a Ca2+-supplemented diet and/or PTx, we monitored urinary Ca2+ and Mg2+ excretion; plasma [Ca2+]o, [Mg2+]o, and PTH; PBMC [Ca2+]i and H2O2 production; plasma {alpha}1-antiproteinase activity; total Ca2+ and Mg2+ in bone, myocardium, and rectus femoris; and gp91phox labeling in the heart. We found that 1) the hypercalciuria and hypermagnesuria and decline (P < 0.05) in plasma [Ca2+]o and [Mg2+]o that occur with AldoST were not altered by the Ca2+-supplemented diet alone or with PTx; 2) the rise (P < 0.05) in plasma PTH with AldoST, with or without the Ca2+-supplemented diet, was prevented by PTx; 3) increased (P < 0.05) PBMC [Ca2+]i and H2O2 production, increased total Ca2+ in heart and skeletal muscle, and fall in bone Ca2+ and Mg2+ and plasma {alpha}1-antiproteinase activity with AldoST were abrogated (P < 0.05) by PTx; and 4) gp91phox activation in right and left ventricles at 4 wk of AldoST was attenuated by PTx. AldoST is accompanied by SHPT, with parathyroid gland-derived calcitropic hormones being responsible for Ca2+ overload in diverse tissues and induction of oxidative stress. SHPT plays a permissive role in the proinflammatory vascular phenotype.

aldosterone; magnesium; oxidative and nitrosative stress; parathyroid hormone

ALDOSTERONISM, defined as chronic, inappropriate (relative to dietary Na+) elevations in plasma aldosterone (Aldo), is accompanied by a proinflammatory phenotype characterized by oxidative and nitrosative stress, immune cell activation, vascular remodeling by invading inflammatory cells, and bone loss (3, 18, 31, 66, 87, 90). Mechanisms responsible for the vascular phenotype have been under investigation for some time. Aldo-salt treatment (AldoST)-induced elevations in arterial pressure have been considered and found to be noncontributory. This conclusion is based on multiple lines of evidence. 1) Systemic hypertension poses a hemodynamic overload on the left ventricle and aorta over the short term while sparing the atria, right ventricle, and pulmonary artery. On the other hand and given the in-parallel arrangement of the right and left heart created by a common coronary circulation, a circulating factor gains access to the entire heart as well as to the great vessels via their vasovasorum. Vascular lesions are found throughout the right and left atria and ventricles and the adventitia of the aorta and pulmonary artery (13, 57, 74, 86, 93). This is not the case for elevations in arterial pressure caused by an occlusive band around the abdominal aorta below the renal arteries, where renal ischemia does not occur with activation of the renin-angiotensin-Aldo system (13). 2) Vascular lesions do not appear when spironolactone, an Aldo receptor antagonist, is coadministered in a small (nondepressor) dose, which does not prevent the AldoST-induced elevation in arterial pressure, or in a larger (depressor) dose (12, 25, 54, 56, 57, 61, 66, 75). 3) Although they prevent a rise in arterial pressure, nonspecific vasoactive agents do not prevent vascular lesions (53, 57). Hypertension has also been considered to cause oxidative stress in the left ventricle and aorta (9, 33, 43, 83). However, such evidence has been found in the normotensive right ventricle (87) and in postcapillary venules (63), where elevations in arterial pressure are not expected. Additionally, an altered redox state is not seen with comparable elevations in arterial pressure induced by exogenous norepinephrine (43). Thus multiple lines of evidence have linked AldoST-induced vascular remodeling and oxidative stress to a circulating factor, rather than hemodynamic effects. Activated immune cells appear to represent this circulating factor (see below).

Aldosteronism in rats is accompanied by increased urinary and fecal excretion of Ca2+ and Mg2+, which contributes to a fall in plasma ionized concentrations of Ca2+ and Mg2+ (17, 18). Despite these losses and the fall in extracellular levels of these divalent cations, total intracellular and cytosolic free Ca2+ concentrations ([Ca2+]i) each rise, and oxidative stress is induced (2, 3, 17). This involves diverse tissues, including peripheral blood mononuclear cells (PBMC). A Ca2+ overload of PBMC with an accompanying induction of oxidative stress has been considered to be responsible for the activation of these cells (2, 3, 17, 31), which can be prevented by a Ca2+ channel blocker (2). Furthermore, an antioxidant abrogates vascular invasion by inflammatory cells (2, 87).

In rats and humans with chronic mineralocorticoid excess (plus dietary Na+), the increase in urinary and fecal excretion of Ca2+ and Mg2+ (15, 17, 18, 30, 35, 50, 85) and fall in their plasma ionized concentrations lead, eventually, to a reduction in bone mineral density (17, 18). On the basis of this collective evidence, we have inferred that secondary hyperparathyroidism (SHPT) is responsible for the Ca2+ overload of PBMC (17). However, the evidence has been circumstantial. Plasma parathyroid hormone (PTH) levels are increased in rats receiving AldoST, and hyperparathyroidism (HPT) has been reported in patients with primary or secondary aldosteronism (24, 45, 70, 76, 80). More definitive proof of the pathophysiological role of the parathyroid glands is the aim of the present study. We therefore hypothesized that the parathyroid glands are responsible for the Ca2+ overload and oxidative and nitrosative stress that accompany aldosteronism. To this end, the effects of AldoST, with or without a Ca2+-supplemented diet, were studied in parathyroidectomized (PTx) rats, rats with intact parathyroid glands, and unoperated, untreated, age- and gender-matched controls.


   MATERIALS AND METHODS
TOP
 ABSTRACT
 MATERIALS AND METHODS
RESULTS
 DISCUSSION
 GRANTS
 REFERENCES
 
Animal model. Nine-week-old male Sprague-Dawley rats (Harlan Sprague Dawley, Indianapolis, IN) were anesthetized with an intramuscular injection of ketamine (87 mg/kg body wt) and xylazine (13 mg/kg body wt). A midline incision was made along the anterior neck, and subcutaneous fat and platysma muscles were carefully dissected. Submaxillary salivary glands were laterally displaced to expose the sternohyoid muscle, which was longitudinally dissected. The thyroid gland was isolated, and the parathyroid glands were located and excised under a dissecting microscope at x10 magnification. PTx was considered successful only in rats with serum Ca2+ <6.0 mg/dl (1.5 mmol/l) 48 h postoperatively. Within 48 h of PTx, some rats exhibited signs of hypocalcemia: 1 in 5 animals showed frequent muscle fasciculations; 1 in 10 had fasciculations and tetany; and 1 in 20 had seizures. After a single 1-ml dose of a 2% CaCl2 solution by gavage, the rats were able to consume a normal chow diet (Harlan Teklad 2215 Rodent Diet) supplemented with 2.5% CaCO3 and 1% lactose (Ca2+-supplemented diet) to enhance gastrointestinal Ca2+ absorption. Thereafter, they remained permanently free of these signs and symptoms associated with hypocalcemia. The standard laboratory chow contains 1.13% Ca2+, 0.94% phosphorus, 0.4% Na+, 1% K+, 0.24% Mg2+, and 2.99 IU/g vitamin D3.

Unoperated, untreated, age- and gender-matched rats served as controls (n = 32). On the same day, uninephrectomized rats received Aldo (0.75 µg/h) by implanted minipump (Alzet, Cupertino, CA) together with 1% NaCl-0.4% KCl in drinking water (AldoST) and standard laboratory chow. A separate group of rats was treated with AldoST and fed the Ca2+-supplemented diet, and another group of PTx rats was treated with AldoST and fed the Ca2+-supplemented diet. Experimental groups were studied at 1, 2, 4, and 6 wk on the basis of gaps in our knowledge for the specific time points not previously reported. Animals were anesthetized and killed, and blood, PBMC, hearts, and skeletal muscle were harvested. Each time point for treated animals consisted of five rats. The study was approved by the institution's Animal Care and Use Committee.

Urinary excretion of Ca2+ and Mg2+. Individual animals were placed in a metabolic cage for collection of urine on the day before they were killed and tissues were sampled. Urinary concentrations of Ca2+ and Mg2+ were determined with an atomic absorption spectrophotometer as previously reported (17, 18). Urinary excretion rates of Ca2+ and Mg2+ are expressed in micrograms per 24 h.

Plasma ionized extracellular Ca2+ and Mg2+ concentrations. Plasma ionized extracellular Ca2+ and Mg2+ concentrations ([Ca2+]o and [Mg2+]o) were determined by the direct ion-selective electrode technique with a Nova 8 Analyzer (Nova Biomedical, Waltham, MA) (2).

Plasma PTH. Plasma PTH was measured by the intact PTH immunoradiometric assay with a commercial kit (Nichols Institute Diagnostics, San Clemente, CA) as reported elsewhere (17).

PBMC intracellular Ca2+ concentration, H2O2 production, and plasma {alpha}1-antiproteinase activity. PBMC were isolated, and cytosolic free [Ca2+]i was measured as described previously (3) by a modification of the ratiometric method and the fluorescent molecular probe fura-2 (Molecular Probes, Eugene, OR). As reported previously, H2O2 production by PBMC was measured fluorometrically with 2',7'-dichlorofluorescin diacetate with a flow cytometer (FACS Caliber, Becton, Dickinson, Franklin Lakes, NJ) (3). Plasma {alpha}1-antiproteinase ({alpha}1-AP) activity was assessed using the {alpha}1-AP 410 assay system (Oxis Research, Portland, OR) (31).

Bone Ca2+ and Mg2+ concentrations. Total Ca2+ and Mg2+ concentrations in tibia were determined by atomic absorption spectrophotometry and expressed in micrograms per milligram of fat-free dry bone as reported previously (17, 18).

Myocardial and skeletal muscle Ca2+ and Mg2+. Microdeterminations for Ca2+ and Mg2+ were carried out in defatted ventricular tissue and rectus femoris muscle and are expressed as nanoequivalents per milligram of fat-free dry tissue as reported elsewhere (17).

Activation of gp91phox. Coronal cryostat sections (6 µm) of both ventricles were prepared for immunohistochemistry as previously reported (87). Sections were incubated with primary antibody to gp91phox at a dilution of 1:100. Negative controls were incubated with secondary antibody alone.

Statistical analysis. Values are means ± SE. Data were analyzed using analysis of variance. Significant differences between individual means were determined using Bonferroni's post hoc multiple comparisons test. Significance was assigned to P < 0.05.


   RESULTS
TOP
 ABSTRACT
 MATERIALS AND METHODS
 RESULTS
DISCUSSION
 GRANTS
 REFERENCES
 
Urinary Ca2+ and Mg2+ excretion. A marked increase in urinary Ca2+ and Mg2+ excretion above control levels was found at 6 wk of AldoST (Fig. 1). We previously demonstrated the presence of hypercalciuria and hypermagnesuria at 1, 2, and 4 wk of AldoST (17). AldoST with the Ca2+-supplemented diet or AldoST with PTx and the Ca2+-supplemented diet did not alter the augmented urinary losses of these divalent cations seen with AldoST.



View larger version (18K):
[in this window]
[in a new window]
  		Fig. 1. Urinary Ca2+ and Mg2+ excretion in controls (n = 5) and at 6 wk of aldosterone (Aldo) salt treatment (AldoST, n = 5), AldoST + Ca2+-supplemented diet (n = 5), and AldoST + Ca2+-supplemented diet + parathyroidectomy (PTx, n = 5). AldoST-induced hypercalciuria and hypermagnesuria was not altered by Ca2+-supplemented diet or prior PTx. Values are means ± SE. [Ca2+]o and [Mg2+]o, extracellular Ca2+ and Mg2+ concentrations. *P < 0.05 vs. controls.

 
Plasma ionized [Ca2+]o and [Mg2+]o. Plasma ionized [Ca2+]o and [Mg2+]o levels were reduced (P < 0.05) during AldoST compared with controls (Fig. 2): in controls, plasma [Ca2+]o was 0.98 ± 0.01 mmol/l (range 0.89–1.16) and plasma [Mg2+]o was 0.36 ± 0.01 mmol/l (range 0.32–0.40), and during 1–6 wk of AldoST, plasma [Ca2+]o was 0.82 ± 0.02 mmol/l (range 0.71–0.94) and plasma [Mg2+]o was 0.28 ± 0.01 mmol/l (range 0.24–0.33, P < 0.05 vs. controls). In AldoST rats fed the Ca2+-supplemented diet, plasma [Ca2+]o and [Mg2+]o were also reduced: 0.81 ± 0.02 and 0.29 ± 0.01 mmol/l, respectively (P < 0.05). PTx before AldoST was accompanied by a greater fall in plasma [Ca2+]o, to 0.73 ± 0.02 mmol/l (range 0.48–0.84), which was statistically less (P < 0.05) than in AldoST rats with intact parathyroid glands. This was due to a more marked fall in plasma [Ca2+]o (to <0.71 mmol/l) in six PTx AldoST rats. This exaggerated decline observed in plasma [Ca2+]o may be consistent with consumption of less of the Ca2+-supplemented diet and a decline in vitamin D stores. Reduced Ca2+ mobilization from bone and loss of PTH-driven renal formation of 1,25-dihydroxyvitamin D3, which serves to increase gastrointestinal absorption of Ca2+, result in a dependence on dietary Ca2+ after PTx.



View larger version (15K):
[in this window]
[in a new window]
  		Fig. 2. Significant decline in plasma ionized [Ca2+]o and [Mg2+]o induced by 1–6 wk of AldoST (n = 19) was not altered by Ca2+-supplemented diet (n = 16) or prior PTx (n = 18). Values are means ± SE. *P < 0.05 vs. controls (n = 32). {dagger}P < 0.05 vs. AldoST and AldoST + Ca2+.

 
Plasma PTH. The declines in plasma ionized [Ca2+]o and [Mg2+]o are important determinants of the parathyroid glands' secretion of such calcitropic hormones as PTH (51). An early, albeit declining, elevation in plasma PTH at 1–6 wk of AldoST, with or without the Ca2+-supplemented diet, was abrogated by prior PTx (Fig. 3).



View larger version (31K):
[in this window]
[in a new window]
  		Fig. 3. AldoST (n = 17) increased plasma parathyroid hormone (PTH) levels with (n = 18) or without (n = 20) Ca2+-supplemented diet. PTH levels are essentially undetectable after PTx (n = 19). AldoST increased cytosolic free Ca2+ concentration ([Ca2+]i) in peripheral blood mononuclear cells during AldoST with (n = 19) or without (n = 20) Ca2+-supplemented diet. Prior PTx (n = 18) prevented AldoST-induced increase in [Ca2+]i. Values are means ± SE. *P < 0.05 vs. controls (n = 20). Dash-dot and broken lines represent means ± SE for controls.

 
PBMC [Ca2+]i. Cytosolic free [Ca2+]i in PBMC was increased significantly at 2, 4, and 6 wk of AldoST, with or without dietary Ca2+ supplementation (Fig. 3). PTH promotes Ca2+ loading of lymphocytes and monocytes, which is prevented by Ca2+ channel blockade (2, 41). In support of the role of SHPT in promoting Ca2+ overload of PBMC, we demonstrate that prior PTx is preventive.

Oxidative stress. The Ca2+ overload of PBMC, both total intracellular and cytosolic free Ca2+ (17), is accompanied by an induction of oxidative and nitrosative stress in these cells. H2O2 production by PBMC was increased at 1 and 2 wk of AldoST, with or without a Ca2+-supplemented diet (Fig. 4). PTx prevents the induction of oxidative stress in PBMC. We previously reported that increased H2O2 production by PBMC persists over 4 wk of AldoST and can be prevented by a Ca2+ channel blocker or an antioxidant (2, 3).



View larger version (20K):
[in this window]
[in a new window]
  		Fig. 4. Oxidative and nitrosative stress in peripheral blood mononuclear cells and their stress-induced increase in H2O2 production and in blood as shown by a decrease in plasma {alpha}1-antiproteinase ({alpha}1-AP) activity during AldoST with (n = 19) or without (n = 20) Ca2+-supplemented diet. Effect was attenuated by prior PTx (n = 19). Values are means ± SE. *P < 0.05 vs. controls (n = 20). Dash-dot and broken lines represent means ± SE for controls.

 
The presence of oxidative and nitrosative stress systemically is evidenced by the fall in plasma {alpha}1-AP activity at 1 and 6 wk of AldoST (Fig. 4) and extends our previous observations at 4 wk of AldoST. The Ca2+-supplemented diet did not prevent this decline in plasma {alpha}1-AP activity. PTx prevented the decline in plasma {alpha}1-AP activity that accompanies AldoST, consistent with oxidative stress in diverse tissues.

Bone Ca2+ and Mg2+ concentrations. Reducton of Ca2+ and Mg2+ concentrations in tibia at 4 and 6 wk of AldoST is consistent with PTH-mediated bone resorption. The Ca2+-supplemented diet did not prevent the loss of bone Ca2+ and Mg2+. On the other hand, PTx with the Ca2+-supplemented diet prevented the loss of these minerals from tibia (Fig. 5).



View larger version (18K):
[in this window]
[in a new window]
  		Fig. 5. Decline in bone Ca2+ and Mg2+ concentrations in tibia induced by 4–6 wk of AldoST, with (n = 5) or without (n = 5) Ca2+-supplemented diet, was prevented by Ca2+-supplemented diet with prior PTx (n = 5). Values are means ± SE. FFDB, fat-free dry bone. *P < 0.05 vs. controls (n = 5).

 
Myocardial and skeletal muscle Ca2+ and Mg2+ concentrations. Ca2+ loading of myocardial tissue is found at 4–6 wk of AldoST, with or without supplemental dietary Ca2+ (Fig. 6). Prior PTx prevented this rise in intra- and extracellular or total Ca2+ in myocardial tissue. Total Mg2+ concentration in myocardial tissue was not altered during 4–6 wk of AldoST with or without dietary Ca2+ supplements or with prior PTx and Ca2+-supplemented diet.



View larger version (21K):
[in this window]
[in a new window]
  		Fig. 6. Increase in Ca2+ concentration in myocardial tissue induced by AldoST with (n = 5) or without (n = 5) Ca2+-supplemented diet was prevented by prior PTx (n = 5). Increase in Ca2+ concentration of rectus femoris induced by AldoST with (n = 5) or without (n = 5) Ca2+-supplemented diet was prevented by Ca2+-supplemented diet with prior PTx (n = 5). Cardiac and skeletal muscle Mg2+ concentrations were not altered (vs. controls) by either intervention (not shown). Values are means ± SE. FFDT, fat-free dry tissue. *P < 0.05 vs. controls (n = 5).

 
As in myocardial tissue, Ca2+ concentration was increased in the rectus femoris at 4–6 wk of AldoST, with or without supplemental dietary Ca2+, and was prevented by PTx (Fig. 6). Skeletal muscle Mg2+ concentration was not altered during AldoST with or without dietary Ca2+ supplements or PTx.

Activation of gp91phox. In coronal sections of right and left ventricles, gp91phox labeling was positive in a small number of cells in interstitial and perivascular spaces of control rats (Fig. 7). Inflammatory cells and myofibroblasts appear in the perivascular space of the intramural coronary vasculature of the right and left ventricles at 4–6 wk of AldoST (14, 87). At these sites, we found markedly increased gp91phox-positive cells (Fig. 7), which are primarily inflammatory cells and myofibroblasts. This remodeling was attenuated by PTx (Fig. 7).



View larger version (113K):
[in this window]
[in a new window]
  		Fig. 7. Immunohistochemical study of activation of gp91phox in coronal cryostat sections of ventricle. Top: control. Middle: gp91phox, a subunit of NADPH oxidase, activity (arrows) during AldoST. AldoST-induced gp91phox activity was not altered by Ca2+-supplemented diet (not shown). Bottom: AldoST-induced gp91phox activity was attenuated (arrow), but not prevented, by prior PTx.

 

   DISCUSSION
TOP
 ABSTRACT
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
GRANTS
 REFERENCES
 
Previously, we merely implicated SHPT in the Ca2+ paradox that accompanies aldosteronism. Use of total PTx in the present study offers direct evidence in support of this hypothesis and addresses the impact of the parathyroid gland and its calcitropic hormones on the Ca2+ loading of PBMC and cardiac and skeletal muscle, as well as the appearance of oxidative and nitrosative stress. Our study led to several major findings.

Hypercalciuria and hypermagnesuria were observed at 6 wk of AldoST. We previously found a comparable level of urinary Ca2+ and Mg2+ excretion at 1–4 wk of AldoST, along with even greater gastrointestinal wasting of these divalent cations (17, 18). Together, these sustained losses led to a fall in plasma ionized [Ca2+]o and [Mg2+]o, each of which is a potent stimulus to the parathyroid glands' release of calcitropic hormones (51). The decline in plasma [Ca2+]o and [Mg2+]o with 1–6 wk of AldoST was not prevented by our Ca2+-supplemented diet or the amount of vitamin D3 available in standard chow and produced endogenously (albeit not measured). These findings suggest that supplemental calcitriol, together with a diet supplemented with Ca2+ and Mg2+, may be required to regulate PTH secretion in SHPT (68, 81). Bone resorption alone, as reflected by the fall in bone Ca2+ and Mg2+, was unable to preserve extracellular homeostasis of Ca2+ and Mg2+. We did not monitor other well-known effects of PTH, such as urinary phosphate excretion and acidification (1, 36, 67). In future studies, the importance of PTH and 1,25-dihydroxyvitamin D3 in AldoST rats with PTx can be addressed by autotransplantation of cryopreserved parathyroid glands and calcitriol supplements, respectively. We previously reported that cotreatment with an aldosterone receptor antagonist, spironolactone, attenuates urinary and fecal losses of Ca2+ and Mg2+ and, thereby, prevents the fall in plasma [Ca2+]o and [Mg2+]o and loss of bone mineral density (17). A reduction in plasma ionized [Ca2+]o has also been observed in humans with primary aldosteronism and is corrected by spironolactone or adrenal surgery (70, 76).

The fall in plasma [Ca2+]o and [Mg2+]o is accompanied by an elevation in plasma PTH, which declines over time, consistent with the downregulation of the parathyroid glands' Ca2+-sensing receptor (21). Prior PTx eliminates the rise in plasma PTH that accompanies AldoST. Elevations in plasma PTH have been found in rats treated with deoxycorticosterone acetate (DOCA)-salt (94), and chemical evidence of SHPT is corrected by spironolactone or adrenal surgery in humans with primary aldosteronism (70, 76). As in SHPT, bone Ca2+ and Mg2+ each fall significantly at 4 and 6 wk of AldoST, consistent with our previous findings for bone mineral density and bone strength (17, 18). SHPT and bone loss have also been observed in patients with advanced congestive heart failure (CHF), where secondary aldosteronism is expected, together with the hypercalciuria and hypermagnesuria, which accompany chronic treatment with furosemide, a potent loop diuretic (6, 45, 80).

A significant increase in total Ca2+ concentration of PBMC at 1–4 wk of AldoST is associated with the SHPT found in rats with aldosteronism (17). The persistent rise in intracellular Ca2+ that accompanies downregulated PTH levels is related to increased membrane permeability to Ca2+ and increased expression of Ca2+ channels (26, 79, 88). Ca2+ channel expression is also increased with aldosteronism (7, 77). The Ca2+ loading of PBMC involves its initial distribution within organelles, such as mitochondria and endoplasmic reticulum (10, 60, 73). Mitochondria regulate cytosolic Ca2+ (22, 82). Their ability to sequester cytosolic Ca2+ at a 3-log concentration gradient provides mitochondria with the unique capacity to regulate intracellular Ca2+ during transient or passive Ca2+ ingress. Mitochondria and endoplasmic reticulum chaperone proteins regulate cytosolic Ca2+. Cytosolic free [Ca2+]i of lymphocytes and monocytes are increased after 1 wk. Total Ca2+ concentrations in myocardium and skeletal muscle are also increased, as shown here and reported previously for the heart (17). Others have documented a rise in intracellular Ca2+ in vascular tissue and platelets during chronic mineralocorticoid-salt treatment (32, 38, 40). This Ca2+ loading of tissues, against a background of Ca2+ loss and reduced extracellular Ca2+, has been termed a Ca2+ paradox (28). This rise in total intracellular Ca2+ concentration does not mandate an increase in Ca2+ availability given the presence of Ca2+ binding proteins. Here we demonstrate that PTx prevents this Ca2+ paradox in myocyte- and nonmyocyte-containing tissues. Ca2+ channel blockade prevents the Ca2+ loading of diverse tissues in humans and rats with SHPT (2, 41). PTx and diltiazem are likewise protective in dystrophic hamsters, where Ca2+ loading occurs in skeletal muscle and heart (10, 60). Calcitropic hormones, which are released by the parathyroid glands and may contribute to the Ca2+ paradox, include PTH and endothelin (ET)-1 (27). PTx does not allow us to distinguish whether either or both of these hormones contribute to Ca2+ loading. Future studies to address the role of ET-1 will involve an ET-1 receptor antagonist in AldoST rats.

The Ca2+ overload of PBMC is accompanied by an induction of oxidative stress in these cells and is reflected in their increased production of H2O2, as shown for 1 and 2 wk of AldoST and as previously reported at 4 wk of AldoST (2, 3). H2O2 participates in the signal transduction that leads to an activation of PBMC. As observed in the present study, prior PTx prevents the induction of oxidative stress in PBMC. Amlodipine, a Ca2+ channel blocker, and N-acetylcysteine, an antioxidant, prevent the rise in H2O2 production in PBMC (2). Mitochondria take up and accumulate Ca2+ and represent a rich source of reactive oxygen species. Mitochondrial Ca2+ uptake stimulates net production of reactive oxygen species through activation of membrane permeability transition, release of cytochrome c, respiratory inhibition, and release of antioxidants (84). Oxidative stress occurs in response to Ca2+ accumulation within these organelles and when antioxidant defenses are exhausted. Another example of oxidative stress induced by mitochondrial Ca2+ overload is found in cardiomyocytes after ischemia-reperfusion (23). In lymphocytes, H2O2 acts as an intracellular messenger involved in signal transduction and amplification to activate these cells in a manner that simulates antigen-antigen receptor binding (for review see Ref. 72).

Oxidative and nitrosative stress at a systemic level is evidenced by the fall in plasma {alpha}1-AP activity, an inverse correlate of oxidative and nitrosative stress, which we report here for 1 and 6 wk of AldoST. Together with our previous finding, these observations demonstrate the sustained nature of oxidative and nitrosative stress in AldoST rats (3). In the secondary aldosteronism that accompanies CHF, oxidative and nitrosative stress has been reported in such diverse tissues as skin, skeletal muscle, heart, PBMC, and plasma (16, 34, 55, 89). Plasma levels of 8-isoprostane and thiobarbituric acid-reactive substances are increased in rats with chronic mineralocorticoidism and can be prevented by spironolactone or tempol, a superoxide dismutase mimetic (37, 66, 90). Here, we show that PTx prevents the decline in plasma {alpha}1-AP activity that accompanies AldoST and is related to Ca2+ loading of diverse tissues.

Another major finding of the present study is oxidative stress in inflammatory cells that invade the intramural coronary vasculature of the right and left ventricles at 4 wk of AldoST and is expressed as increased gp91phox labeling in these cells. We previously reported labeling of these cells with 3-nitrotyrosine, a stable residue indicative of a reactive nitrogen intermediate, peroxynitrite (3, 87). As noted here, this evidence of oxidative and nitrosative stress within the heart was not prevented by a Ca2+-supplemented diet but was attenuated by PTx with the Ca2+-supplemented diet. Prior PTx has been reported to ameliorate the incidence and severity of cardiac and renal lesions that accompany DOCA-salt treatment (58). Prior PTx has been reported to ameliorate the incidence and severity of vascular lesions in the heart, kidneys, and/or cerebral vasculature in response to DOCA-salt treatment (58) and a high-salt diet in Dahl salt-sensitive rats (39) and in stroke-prone spontaneously hypertensive rats (46). NADPH oxidase activity has been found in the aorta and mesenteric vasculature in rats with mineralocorticoidism and is attenuated by apocynin, an NADPH oxidase inhibitor, tempol, or an ET (ETA) receptor antagonist (5, 37, 47, 62, 66, 90).

Our findings draw attention to a permissive role of the parathyroid glands in the vascular remodeling that accompanies AldoST. PTx attenuated, but did not completely prevent, these lesions. Other factors may also be operative. ETA receptor antagonists attenuate the appearance of oxidative and nitrosative stress and expression of adhesion molecules in the affected vasculature in rats with a chronic excess of mineralocorticoid (47, 66, 90). Extraparathyroid sources of ET-1 include the adrenal glands and endothelium. Circulating vasopressin is elevated during AldoST and DOCA-salt treatment and provides a stimulus to ET-1 synthesis (48), as does an associated deficiency of Mg2+ (8). An increase in plasma norepinephrine in DOCA-salt-treated rats may result from centrally mediated increases in peripheral sympathetic neuronal activity (20, 69). Elevations in substance P, a neurotransmitter, may also contribute to chronic mineralocorticoid excess because of reductions in plasma ionized [Mg2+]o (42, 92). This uncertainty notwithstanding, a direct and immediate effect of AldoST on the vasculature appears less likely. This is further evidenced in a rodent model with cardiac overexpression of Aldo synthase and increased tissue levels of Aldo, where vascular remodeling was not found (29). Future studies are needed to address these issues. Hemodynamic factors, on the other hand, have been discounted (for review see Ref. 91).

Several clinical correlations can be drawn from the present study. Increased urinary Ca2+ excretion, reduced plasma ionized Ca2+, elevated plasma levels of PTH, and increased cytosolic free [Ca2+]i are found in patients with low-renin essential hypertension (11, 59, 71). High dietary Na+, which suppresses renin and aldosterone, and elevated circulating aldosterone inappropriate for 1% dietary NaCl are each accompanied by hypercalciuria, which can lead to SHPT. As in rats with aldosteronism and SHPT, the paradoxical loading of cells with Ca2+ may explain the efficacy of Ca2+ channel blockers in reducing blood pressure and preventing oxidative stress (2, 52). These agents also protect against the immune cell activation that accompanies the SHPT of chronic renal failure (4). Evidence of SHPT, including elevated plasma PTH and ET-1 levels, osteopenia, and osteoporosis, is found in patients with CHF (6, 45, 80). Hypovitaminosis D has also been reported in CHF patients (80). This may further compromise Ca2+ homeostasis and is likely related to a lack of exposure to sunlight, which accompanies this chronic, symptomatic, and disabling disorder. The cytokine profile of primary and SHPT (i.e., elevated circulating levels of IL-6 and TNF-{alpha}) resembles the proinflammatory CHF phenotype (49). Loop diuretics, commonly used in these patients, will exaggerate the urinary Ca2+ and Mg2+ excretion found with aldosteronism, thus promoting further PTH release and greater bone loss (44). On the other hand, the combination of a thiazide diuretic and spironolactone reverses these losses and preserves bone health (78). The negative impact of non-K+-sparing diuretics on morbidity and mortality in patients with CHF has been called into question (19). On the other hand, Aldo receptor antagonists reduce mortality and morbidity when added to an angiotensin-converting enzyme inhibitor and loop diuretic, with or without {beta}-receptor blocker and digoxin (64, 65).


   GRANTS
TOP
 ABSTRACT
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 GRANTS
REFERENCES
 
This work was supported, in part, by National Heart, Lung, and Blood Institute Grant R01-HL-73043 (K. T. Weber) and Training Grant 2T 32-HL-07641 (A. Vidal).


   FOOTNOTES
 

Address for reprint requests and other correspondence: K. T. Weber, Division of Cardiovascular Diseases, Univ. of Tennessee Health Science Center, 920 Madison Ave., Suite 300, 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
 DISCUSSION
 GRANTS
 REFERENCES
 

  1. Agus ZS, Wasserstein A, and Goldfarb S. Disorders of calcium and magnesium homeostasis. Am J Med 72: 473–488, 1982.[CrossRef][Web of Science][Medline]
  2. Ahokas RA, Sun Y, Bhattacharya SK, Gerling IC, and Weber KT. Aldosteronism and a proinflammatory vascular phenotype. Role of Mg2+, Ca2+ and H2O2 in peripheral blood mononuclear cells. Circulation 111: 51–57, 2005.[Abstract/Free Full Text]
  3. Ahokas RA, 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.
  4. Alexiewicz JM, Smogorzewski M, Akmal M, Klin M, and Massry SG. Nifedipine reverses the abnormalities in [Ca2+]i and proliferation of B cells from dialysis patients. Kidney Int 50: 1249–1254, 1996.[Web of Science][Medline]
  5. Ammarguellat FZ, Gannon PO, Amiri F, and Schiffrin EL. Fibrosis, matrix metalloproteinases, and inflammation in the heart of DOCA-salt hypertensive rats: role of ETA receptors. Hypertension 39: 679–684, 2002.[Abstract/Free Full Text]
  6. Anker SD, 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][Web of Science][Medline]
  7. Bénitah JP and Vassort G. Aldosterone upregulates Ca2+ current in adult rat cardiomyocytes. Circ Res 85: 1139–1145, 1999.[Abstract/Free Full Text]
  8. Berthon N, Laurant P, Hayoz D, Fellmann D, Brunner HR, and Berthelot A. Magnesium supplementation and deoxycorticosterone acetate-salt hypertension: effect on arterial mechanical properties and on activity of endothelin-1. Can J Physiol Pharmacol 80: 553–561, 2002.[CrossRef][Web of Science][Medline]
  9. Beswick RA, Zhang H, Marable D, Catravas JD, Hill WD, and Webb RC. Long-term antioxidant administration attenuates mineralocorticoid hypertension and renal inflammatory response. Hypertension 37: 781–786, 2001.[Abstract/Free Full Text]
  10. Bhattacharya SK, Johnson PL, and Thakar JH. Reversal of impaired oxidative phosphorylation and calcium overloading in the in vitro cardiac mitochondria of CHF-146 dystrophic hamsters with hereditary muscular dystrophy. J Neurol Sci 120: 180–186, 1993.[CrossRef][Web of Science][Medline]
  11. Brickman AS, Nyby MD, von Hungen K, Eggena P, and Tuck ML. Calcitropic hormones, platelet calcium, and blood pressure in essential hypertension. Hypertension 16: 515–522, 1990.[Abstract/Free Full Text]
  12. Brilla CG, Matsubara LS, and Weber KT. Anti-aldosterone treatment and the prevention of myocardial fibrosis in primary and secondary hyperaldosteronism. J Mol Cell Cardiol 25: 563–575, 1993.[CrossRef][Web of Science][Medline]
  13. Brilla CG, Pick R, Tan LB, Janicki JS, and Weber KT. Remodeling of the rat right and left ventricle in experimental hypertension. Circ Res 67: 1355–1364, 1990.[Abstract/Free Full Text]
  14. Campbell SE, Janicki JS, and Weber KT. Temporal differences in fibroblast proliferation and phenotype expression in response to chronic administration of angiotensin II or aldosterone. J Mol Cell Cardiol 27: 1545–1560, 1995.[CrossRef][Web of Science][Medline]
  15. Cappuccio FP, Markandu ND, and MacGregor GA. Renal handling of calcium and phosphate during mineralocorticoid administration in normal subjects. Nephron 48: 280–283, 1988.[Web of Science][Medline]
  16. Cesselli D, 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]
  17. Chhokar VS, Sun Y, Bhattacharya SK, Ahokas RA, Myers LK, Xing Z, Smith RA, Gerling IC, and Weber KT. Hyperparathyroidism and the calcium paradox of aldosteronism. Circulation 111: 871–878, 2005.[Abstract/Free Full Text]
  18. Chhokar VS, Sun Y, Bhattacharya SK, Ahokas RA, Myers LK, Xing Z, Smith RA, Gerling IC, and Weber KT. Loss of bone minerals and strength in rats with aldosteronism. Am J Physiol Heart Circ Physiol 287: H2023–H2026, 2004.[Abstract/Free Full Text]
  19. Domanski M, Norman J, Pitt B, Haigney M, Hanlon S, and Peyster E. Diuretic use, progressive heart failure, and death in patients in the Studies of Left Ventricular Dysfunction (SOLVD). J Am Coll Cardiol 42: 705–708, 2003.[Abstract/Free Full Text]
  20. Drolet G, Bouvier M, and de Champlain J. Enhanced sympathoadrenal reactivity to haemorrhagic stress in DOCA-salt hypertensive rats. J Hypertens 7: 237–242, 1989.[CrossRef][Web of Science][Medline]
  21. Drueke TB. Modulation and action of the calcium-sensing receptor. Nephrol Dialysis Transplant 19 Suppl V: V20–V26, 2004.
  22. Duchen MR. Mitochondria and calcium: from cell signalling to cell death. J Physiol 529: 57–68, 2000.[Abstract/Free Full Text]
  23. Duchen MR. Roles of mitochondria in health and disease. Diabetes 53 Suppl 1: S96–S102, 2004.[Abstract/Free Full Text]
  24. Ferriss JB, Brown JJ, Cumming AM, Fraser R, Lever AF, Peacock M, and Robertson JI. Primary hyperparathyroidism associated with primary hyperaldosteronism. Acta Endocrinol (Copenh) 103: 365–370, 1983.[Abstract/Free Full Text]
  25. Fornes P, Richer C, Vacher E, Bruneval P, and Giudicelli JF. Losartan's protective effects in stroke-prone spontaneously hypertensive rats persist durably after treatment withdrawal. J Cardiovasc Pharmacol 22: 305–313, 1993.[Web of Science][Medline]
  26. Fraser CL, Sarnacki P, and Arieff AI. Calcium transport abnormality in uremic rat brain synaptosomes. J Clin Invest 76: 1789–1795, 1985.[CrossRef][Web of Science][Medline]
  27. Fujii Y, Tomic M, Stojilkovic SS, Iida T, Brandi ML, Ogino Y, and Sakaguchi K. Effects of endothelin-1 on Ca2+ signaling and secretion in parathyroid cells. J Bone Miner Res 10: 716–725, 1995.[Web of Science][Medline]
  28. Fujita T and Palmieri GM. Calcium paradox disease: calcium deficiency prompting secondary hyperparathyroidism and cellular calcium overload. J Bone Miner Metab 18: 109–125, 2000.[CrossRef][Web of Science][Medline]
  29. Garnier A, Bendall JK, Fuchs S, Escoubet B, Rochais F, Hoerter J, Nehme J, Ambroisine ML, De Angelis N, Morineau G, d'Estienne P, Fischmeister R, Heymes C, Pinet F, and Delcayre C. Cardiac specific increase in aldosterone production induces coronary dysfunction in aldosterone synthase-transgenic mice. Circulation 110: 1819–1825, 2004.[Abstract/Free Full Text]
  30. Gehr MK 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]
  31. Gerling IC, 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]
  32. Haller H, Thiede M, Lenz T, Ludersdorf M, Harwig S, Distler A, and Philipp T. Intracellular free calcium and ionized plasma calcium during mineralocorticoid-induced blood pressure increase in man. J Hypertens Suppl 3: S41–S43, 1985.[Medline]
  33. Haugen EN, Croatt AJ, and Nath KA. Angiotensin II induces renal oxidant stress in vivo and heme oxygenase-1 in vivo and in vitro. Kidney Int 58: 144–152, 2000.[CrossRef][Web of Science][Medline]
  34. Hill MF 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]
  35. Horton R and Biglieri EG. Effect of aldosterone on the metabolism of magnesium. J Clin Endocrinol Metab 22: 1187–1192, 1962.[Abstract/Free Full Text]
  36. Hulter HN and Peterson JC. Renal and systemic magnesium metabolism during chronic continuous PTH infusion in normal subjects. Metabolism 33: 662–666, 1984.[CrossRef][Web of Science][Medline]
  37. Iglarz M, Touyz RM, Viel EC, Amiri F, and Schiffrin EL. Involvement of oxidative stress in the profibrotic action of aldosterone. Interaction with the renin-angiotensin system. Am J Hypertens 17: 597–603, 2004.[Web of Science][Medline]
  38. Jones AW and Hart RG. Altered ion transport in aortic smooth muscle during deoxycorticosterone acetate hypertension in the rat. Circ Res 37: 333–341, 1975.[Abstract/Free Full Text]
  39. Kazda S, Grunt M, Hirth C, Preis W, and Stasch JP. Calcium antagonism and protection of tissues from calcium damage. J Hypertens Suppl 5: S37–S42, 1987.[CrossRef][Medline]
  40. Kh R, Khullar M, Kashyap M, Pandhi P, and Uppal R. Effect of oral magnesium supplementation on blood pressure, platelet aggregation and calcium handling in deoxycorticosterone acetate-induced hypertension in rats. J Hypertens 18: 919–926, 2000.[CrossRef][Web of Science][Medline]
  41. Klinger M, Alexiewicz JM, Linker-Israeli M, Pitts TO, Gaciong Z, Fadda GZ, and Massry SG. Effect of parathyroid hormone on human T cell activation. Kidney Int 37: 1543–1551, 1990.[Web of Science][Medline]
  42. Kohlmann O Jr, Ginoza M, Cezaretti ML, Zanella MT, Ribeiro AB, Tavares A, Ramos OL, Leeman SE, Gavras I, and Gavras H. Cardiovascular effects of a specific nonpeptide antagonist of substance P (NK-1) receptor in DOCA-salt hypertension. Hypertension 26: 1186–1189, 1995.[Abstract/Free Full Text]
  43. Laursen JB, Rajagopalan S, Galis Z, Tarpey M, Freeman BA, and Harrison DG. Role of superoxide in angiotensin II-induced but not catecholamine-induced hypertension. Circulation 95: 588–593, 1997.[Abstract/Free Full Text]
  44. Law PH, Sun Y, Bhattacharya SK, Chhokar VS, and Weber KT. Diuretics and bone loss in rats with aldosteronism. J Am Coll Cardiol 46: 142–146, 2005.[Abstract/Free Full Text]
  45. Lee AH, 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][Web of Science][Medline]
  46. Lenz P, Luckhaus G, Stasch JP, and Kazda S. Therapy of diseased stroke-prone spontaneously hypertensive rats with nimodipine. Stroke 21 Suppl 12: IV111–IV112, 1990.[Medline]
  47. Li L, Fink GD, Watts SW, Northcott CA, Galligan JJ, Pagano PJ, and Chen AF. Endothelin-1 increases vascular superoxide via endothelinA-NADPH oxidase pathway in low-renin hypertension. Circulation 107: 1053–1058, 2003.[Abstract/Free Full Text]
  48. Li L, Galligan JJ, Fink GD, and Chen AF. Vasopressin induces vascular superoxide via endothelin-1 in mineralocorticoid hypertension. Hypertension 41: 663–668, 2003.[Abstract/Free Full Text]
  49. Mann DL and Young JB. Basic mechanisms in congestive heart failure. Recognizing the role of proinflammatory cytokines. Chest 105: 897–904, 1994.[Free Full Text]
  50. Massry SG, 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.[Web of Science]
  51. Mayer GP and Hurst JG. Comparison of the effects of calcium and magnesium on parathyroid hormone secretion rate in calves. Endocrinology 102: 1803–1814, 1978.[Abstract/Free Full Text]
  52. McCarron DA, Morris CD, and Bukoski R. The calcium paradox of essential hypertension. Am J Med 82: 27–33, 1987.[Web of Science][Medline]
  53. Mervaala E, Müller DN, Schmidt F, Park JK, Gross V, Bader M, Breu V, Ganten D, Haller H, and Luft FC. Blood pressure-independent effects in rats with human renin and angiotensinogen genes. Hypertension 35: 587–594, 2000.[Abstract/Free Full Text]
  54. Mervaala EM, Müller DN, Park JK, Schmidt F, Löhn M, Breu V, Dragun D, Ganten D, Haller H, and Luft FC. Monocyte infiltration and adhesion molecules in a rat model of high human renin hypertension. Hypertension 33: 389–395, 1999.[Abstract/Free Full Text]
  55. Miyamoto M, Kishimoto C, Shioji K, Lee JD, Shimizu H, Ueda T, and Yodoi J. Cutaneous arteriolar thioredoxin expression in patients with heart failure. Circ J 67: 116–118, 2003.[CrossRef][Web of Science][Medline]
  56. Müller DN, Mervaala EM, Dechend R, Fiebeler A, Park JK, Schmidt F, Theuer J, Breu V, Mackman N, Luther T, Schneider W, Gulba D, Ganten D, Haller H, and Luft FC. Angiotensin II (AT1) receptor blockade reduces vascular tissue factor in angiotensin II-induced cardiac vasculopathy. Am J Pathol 157: 111–122, 2000.[Abstract/Free Full Text]
  57. Muller DN, Mervaala EM, Schmidt F, Park JK, Dechend R, Genersch E, Breu V, Löffler BM, Ganten D, Schneider W, Haller H, and Luft FC. Effect of bosentan on NF-{kappa}B, inflammation, and tissue factor in angiotensin II-induced end-organ damage. Hypertension 36: 282–290, 2000.[Abstract/Free Full Text]
  58. Nickerson PA and Conran RM. Parathyroidectomy ameliorates vascular lesions induced by deoxycorticosterone in the rat. Am J Pathol 105: 185–190, 1981.[Abstract]
  59. Oshima T and Young EW. Systemic and cellular calcium metabolism and hypertension. Semin Nephrol 15: 496–503, 1995.[Web of Science][Medline]
  60. Palmieri GM, Nutting DF, Bhattacharya SK, Bertorini TE, and Williams JC. Parathyroid ablation in dystrophic hamsters. Effects on Ca content and histology of heart, diaphragm, and rectus femoris. J Clin Invest 68: 646–654, 1981.[CrossRef][Web of Science][Medline]
  61. Park JB and Schiffrin EL. Cardiac and vascular fibrosis and hypertrophy in aldosterone-infused rats: role of endothelin-1. Am J Hypertens 15: 164–169, 2002.[CrossRef][Web of Science][Medline]
  62. Park YM, Park MY, Suh YL, and Park JB. NAD(P)H oxidase inhibitor prevents blood pressure elevation and cardiovascular hypertrophy in aldosterone-infused rats. Biochem Biophys Res Commun 313: 812–817, 2004.[CrossRef][Web of Science][Medline]
  63. Piqueras L, Kubes P, Alvarez A, O'Connor E, Issekutz AC, Esplugues JV, and Sanz MJ. Angiotensin II induces leukocyte-endothelial cell interactions in vivo via AT1 and AT2 receptor-mediated P-selectin upregulation. Circulation 102: 2118–2123, 2000.[Abstract/Free Full Text]
  64. Pitt B, Remme W, Zannad F, Neaton J, Martinez F, Roniker B, Bittman R, Hurley S, Kleiman J, and Gatlin M. Eplerenone, a selective aldosterone blocker, in patients with left ventricular dysfunction after myocardial infarction. N Engl J Med 348: 1309–1321, 2003.[Abstract/Free Full Text]
  65. Pitt B, Zannad F, Remme WJ, Cody R, Castaigne A, Perez A, Palensky J, and Wittes W. The effect of spironolactone on morbidity and mortality in patients with severe heart failure. Randomized Aldactone Evaluation Study Investigators. N Engl J Med 341: 709–717, 1999.[Abstract/Free Full Text]
  66. Pu Q, Neves MF, Virdis A, Touyz RM, and Schiffrin EL. Endothelin antagonism on aldosterone-induced oxidative stress and vascular remodeling. Hypertension 42: 49–55, 2003.[Abstract/Free Full Text]
  67. Quamme GA. Effect of furosemide on calcium and magnesium transport in the rat nephron. Am J Physiol Renal Fluid Electrolyte Physiol 241: F340–F347, 1981.[Abstract/Free Full Text]
  68. Ramirez JA, Goodman WG, Belin TR, Gales B, Segre GV, and Salusky IB. Calcitriol therapy and calcium-regulated PTH secretion in patients with secondary hyperparathyroidism. Am J Physiol Endocrinol Metab 267: E961–E967, 1994.[Abstract/Free Full Text]
  69. Reid JL, Zivin JA, and Kopin IJ. Central and peripheral adrenergic mechanisms in the development of deoxycorticosterone-saline hypertension in rats. Circ Res 37: 569–579, 1975.[Abstract/Free Full Text]
  70. Resnick LM and Laragh JH. Calcium metabolism and parathyroid function in primary aldosteronism. Am J Med 78: 385–390, 1985.[CrossRef][Web of Science][Medline]
  71. Resnick LM, Nicholson JP, and Laragh JH. Calcium metabolism in essential hypertension: relationship to altered renin system activity. Fed Proc 45: 2739–2745, 1986.[Web of Science][Medline]
  72. Reth M. Hydrogen peroxide as second messenger in lymphocyte activation. Nat Immun 3: 1129–1134, 2002.[CrossRef][Web of Science][Medline]
  73. Rizzuto R, Duchen MR, and Pozzan T. Flirting in little space: the ER/mitochondria Ca2+ liaison. Sci STKE re1, 2004.
  74. Robert V, Van Thiem N, Cheav SL, Mouas C, Swynghedauw B, and Delcayre C. Increased cardiac types I and III collagen mRNAs in aldosterone-salt hypertension. Hypertension 24: 30–36, 1994.[Abstract/Free Full Text]
  75. Rocha R, Rudolph AE, Frierdich GE, Nachowiak DA, Kekec BK, Blomme EA, McMahon EG, and Delyani JA. Aldosterone induces a vascular inflammatory phenotype in the rat heart. Am J Physiol Heart Circ Physiol 283: H1802–H1810, 2002.[Abstract/Free Full Text]
  76. Rossi E, 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][Web of Science][Medline]
  77. Rossier MF, Lesouhaitier O, Perrier E, Bockhorn L, Chiappe A, and Lalevée N. Aldosterone regulation of T-type calcium channels. J Steroid Biochem Mol Biol 85: 383–388, 2003.[CrossRef][Web of Science][Medline]
  78. Runyan AL, Chhokar VS, Sun Y, Bhattacharya SK, Runyan JW, and Weber KT. Bone loss in rats with aldosteronism. Am J Med Sci 330: 1–7, 2005.[CrossRef][Web of Science][Medline]
  79. Scoble JE, Cragoe EJ Jr, and Hruska KA. Na+-Ca2+ exchange and calcium permeability in canine basolateral membrane vesicles: the effects of dibutyryl cAMP and specific inhibitors. Biochim Biophys Acta 944: 233–241, 1988.[Medline]
  80. Shane E, 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][Web of Science][Medline]
  81. Silver J, Moallem E, Epstein E, Kilav R, and Naveh-Many T. New aspects in the control of parathyroid hormone secretion. Curr Opin Nephrol Hypertens 3: 379–385, 1994.[CrossRef][Medline]
  82. Smaili SS, Hsu YT, Youle RJ, and Russell JT. Mitochondria in Ca2+ signaling and apoptosis. J Bioenerg Biomembr 32: 35–46, 2000.[CrossRef][Web of Science][Medline]
  83. Somers MJ, Mavromatis K, Galis ZS, and Harrison DG. Vascular superoxide production and vasomotor function in hypertension induced by deoxycorticosterone acetate-salt. Circulation 101: 1722–1728, 2000.[Abstract/Free Full Text]
  84. Starkov AA, Chinopoulos C, and Fiskum G. Mitochondrial calcium and oxidative stress as mediators of ischemic brain injury. Cell Calcium 36: 257–264, 2004.[CrossRef][Web of Science][Medline]
  85. Suki WN, 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]
  86. Sun Y, Ramires FJA, and Weber KT. Fibrosis of atria and great vessels in response to angiotensin II or aldosterone infusion. Cardiovasc Res 35: 138–147, 1997.[Abstract/Free Full Text]
  87. Sun Y, 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]
  88. Suzuki H, Shibata H, Murakami M, Sato A, Naito M, Ichihara A, Matsumoto A, Tsujimoto G, Hirasawa A, Horie K, et al. Modulation of angiotensin II type 1 receptor mRNA expression in human blood cells: comparison of platelets and mononuclear leucocytes. Endocr J 42: 15–22, 1995.[Web of Science][Medline]
  89. Tsutsui H, 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]
  90. Virdis A, Neves MF, Amiri F, Viel E, Touyz RM, and Schiffrin EL. Spironolactone improves angiotensin-induced vascular changes and oxidative stress. Hypertension 40: 504–510, 2002.[Abstract/Free Full Text]
  91. Weber KT. From inflammation to fibrosis: a stiff stretch of highway. Hypertension 43: 716–719, 2004.[Free Full Text]
  92. Weglicki WB, 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][Web of Science][Medline]
  93. Young M, Fullerton M, Dilley R, and Funder J. Mineralocorticoids, hypertension, and cardiac fibrosis. J Clin Invest 93: 2578–2583, 1994.[Web of Science][Medline]
  94. Zikos D, 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]



This article has been cited by other articles:


Home page
 Cardiovasc ResHome page
I. Tastan, R. Schreckenberg, S. Mufti, Y. Abdallah, H. M. Piper, and K.-D. Schluter
Parathyroid hormone improves contractile performance of adult rat ventricular cardiomyocytes at low concentrations in a non-acute way
Cardiovasc Res, April 1, 2009; 82(1): 77 - 83.
[Abstract] [Full Text] [PDF]

Home page
 Cardiovasc ResHome page
K. T. Weber, W. B. Weglicki, and R. U. Simpson
Macro- and micronutrient dyshomeostasis in the adverse structural remodelling of myocardium
Cardiovasc Res, February 15, 2009; 81(3): 500 - 508.
[Abstract] [Full Text] [PDF]

Home page
 HypertensionHome page
B. P. Shapiro, T. E. Owan, S. Mohammed, M. Kruger, W. A. Linke, J. C. Burnett Jr, and M. M. Redfield
Mineralocorticoid Signaling in Transition to Heart Failure With Normal Ejection Fraction
Hypertension, February 1, 2008; 51(2): 289 - 295.
[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
 Am. J. Physiol. Heart Circ. Physiol.Home page
M. Thomas, A. Vidal, S. K. Bhattacharya, R. A. Ahokas, Y. Sun, I. C. Gerling, and K. T. Weber
Zinc dyshomeostasis in rats with aldosteronism. Response to spironolactone
Am J Physiol Heart Circ Physiol, October 1, 2007; 293(4): H2361 - H2366.
[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]

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 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 Web of Science (16)
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Vidal, A.
Right arrow Articles by Weber, K. T.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Vidal, A.
Right arrow Articles by Weber, K. T.

HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS
Visit Other APS Journals Online
Copyright © 2006 by the American Physiological Society.