Chronic DOCA treatment increases Ca absorption: role of hypercalciuria and vitamin D

Zikos, D.; Langman, Craig B.; Gafter, Uzi; Delahaye, B.; Lau, Kai

doi:10.1152/ajpendo.1986.251.3.e279

Cited by 13 publications

(17 citation statements)

References 12 publications

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“…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 ϩ loading have each demonstrated the dietary Na ϩ -dependent increment in urinary Ca 2ϩ 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).…”

Section: Resultsmentioning

confidence: 60%

Loss of bone minerals and strength in rats with aldosteronism

Chhokar¹,

Sun²,

Bhattacharya³

et al. 2004

American Journal of Physiology-Heart and Circulatory Physiology

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gestive 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 ϩ ) 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 ␣1-antiproteinase activity, which is an inverse correlate of oxidative/nitrosative stress; plasma concentrations of ionized Mg 2ϩ and Ca 2ϩ ; urinary Mg 2ϩ and Ca 2ϩ excretion; and bone mineral composition and strength to flexure stress. Compared with controls, we found reductions in plasma ␣1-antiproteinase activity and ionized Mg 2ϩ and Ca 2ϩ together with persistently elevated urinary Mg 2ϩ and Ca 2ϩ excretion, a progressive loss of bone mineral density and content with reduced Mg 2ϩ and Ca 2ϩ 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 ϩ ) 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 Ca 2ϩ loading and transduced by reactive oxygen species in these cells (1, 16). Herein we hypothesized that enhanced urinary excretion of Mg 2ϩ and Ca 2ϩ accompanies chronic Aldo with 1% NaCl treatment (Aldost) and leads to yet another component of this illness, namely, bone wasting. MATERIALS AND METHODSMale 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 untr...

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Section: Resultsmentioning

confidence: 60%

Loss of bone minerals and strength in rats with aldosteronism

Chhokar¹,

Sun²,

Bhattacharya³

et al. 2004

American Journal of Physiology-Heart and Circulatory Physiology

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“…31 Hypercalciuria accompanies the short-term treatment of man or animals with a mineralocorticoid plus dietary salt. [32][33][34][35][36][37] It is present in patients with primary aldosteronism, where it is accentuated by dietary Na + loading. 36,38 The increment in urinary Ca 2+ excretion, which occurs in the distal segment of the nephron, is dietary Na + dependent.…”

Section: Sodium: the Facilitator In Aldosteronismmentioning

confidence: 99%

“…32,33 A role for such metabolic derangements as polydipsia and metabolic alkalosis that accompany chronic mineralocorticoid/salt treatment have likewise been eliminated. 37 In both rats and man, marked Na + loading alone (for example, a 8% NaCl diet) is accompanied by hypercalciuria, SHPT with bone loss and a proinflammatory vascular phenotype. [42][43][44][45][46][47][48][49][50] The likely mechanism is thought to be related to an expansion of the extravascular space, resulting in decreased proximal tubular resorption and thereby increased distal delivery of Na + , Ca 2+ and Mg 2+ , with the mineralocorticoid promoting distal tubular Na + resorption without retarding Ca 2+ or Mg 2+ excretion.…”

Section: Sodium: the Facilitator In Aldosteronismmentioning

confidence: 99%

“…We indeed found elevated plasma PTH levels, consistent with SHPT, during weeks 1-4 ALDOST. Both serumionized [Ca 2+ ] o and total plasma Ca 2+ are reduced in response to deoxycorticosterone/salt treatment, 37 together with increased serum PTH and urinary excretion of cAMP, a biomarker of parathyroid activity. SHPT has been reported in patients with primary aldosteronism, 41,[55][56][57] where expected aberrations in serum-ionized and total Ca 2+ , together with elevations in PTH, were normalized by either adrenal surgery or Spiro.…”

Section: Sodium: the Facilitator In Aldosteronismmentioning

confidence: 99%

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From aldosteronism to oxidative stress: the role of excessive intracellular calcium accumulation

et al. 2010

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Inappropriately (relative to dietary Na + ) elevated plasma aldosterone concentrations (PAC), or aldosteronism, have been incriminated in both the appearance of the cardiometabolic syndrome (CMS) and its progressive nature. The deleterious dual consequences of elevated PAC and dietary Na + have been linked to several components of the CMS, including salt-sensitive hypertension. Moreover, their adverse consequences are considered to be synergistic, culminating in a pro-oxidant phenotype with oxidative injury involving the heart and systemic tissues, including peripheral blood mononuclear cells (PBMC). Our experimental studies in rats receiving aldosterone/salt treatment have identified a common pathogenic event that links aldosteronism to the induction of oxidative stress. Herein, we review these findings and the important role of excessive intracellular Ca 2+ accumulation (EICA), or intracellular Ca 2+ overloading, which occurs in the heart and PBMC, leading to, respectively, cardiomyocyte necrosis with a replacement fibrosis and an immunostimulatory state with consequent coronary vasculopathy. The origin of EICA is based on elevations in plasma parathyroid hormone, which are integral to the genesis of secondary hyperparathyroidism that accompanies aldosteronism and occurs in response to plasma-ionized hypocalcemia and hypomagnesemia whose appearance is the consequence of marked urinary and fecal excretory losses of Ca 2+ and Mg 2+ . In addition, we found intracellular Ca 2+ overloading to be intrinsically coupled to a dyshomeostasis of intracellular Zn 2+ , which together regulate the redox state of cardiac myocytes and mitochondria via the induction of oxidative stress and generation of antioxidant defenses, respectively. To validate our hypothesis, a series of site-directed, sequential pharmacological and/or nutriceutical interventions targeted along cellular-molecular cascades were carried out to either block downstream events leading to the pro-oxidant phenotype or to enhance antioxidant defenses. In each case, the interventions were found to be cardioprotective. These cumulative salutary responses raise the prospect that pharmacological agents and nutriceuticals capable of influencing extra-and intracellular Ca 2+ and Zn 2+ equilibrium could prevent adverse cardiac remodeling and thereby enhance the management of aldosteronism.

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“…This secondary hyperparathyroidism leads to bone resorption and increased renal and gastrointestinal absorption of Ca 2+ and Mg 2+ promoted by 1,25(OH)2D3. 6,9,10 Bone mineral density declines during the course of aldosterone/salt treatment and is accompanied by a reduction in bone strength to resist flexor stress. 6 Elevations in plasma PTH are accompanied by an excessive accumulation of intracellular Ca 2+ in such diverse tissues as heart, skeletal muscle and peripheral blood mononuclear cells.…”

Section: Chf: a Salt-avid Statementioning

confidence: 99%

Congestive Heart Failure is a Systemic Illness: A Role for Minerals and Micronutrients

Alsafwah¹,

LaGuardia²,

Arroyo³

et al. 2007

Clinical Medicine & Research

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Congestive heart failure (CHF) is a clinical syndrome that features a failing heart together with signs and symptoms arising from renal retention of salt and water, mediated by attendant neurohormonal activation, and which prominently includes the renin-angiotensin-aldosterone system. More than this cardiorenal perspective, CHF is accompanied by a systemic illness whose features include an altered redox state in diverse tissues and blood, an immunostimulatory state with proinflammatory cytokines and activated lymphocytes and monocytes, and a wasting of tissues that includes muscle and bone. Based on experimental studies of aldosteronism and clinical findings in patients with CHF, there is an emerging body of evidence that secondary hyperparathyroidism is a covariant of CHF. The aldosteronism of CHF predisposes patients to secondary hyperparathyroidism because of a chronic increase in Ca 2+ and Mg 2+ losses in urine and feces, with a fall in their serum ionized levels and consequent secretion of parathyroid hormone. Secondary hyperparathyroidism accounts for bone resorption and contributes to a fall in bone strength that can lead to nontraumatic fractures. The long-term use of a loop diuretic with its attendant urinary wasting of Ca 2+ and Mg 2+ further predisposes patients to secondary hyperparathyroidism and attendant bone loss. Aberrations in minerals and micronutrient homeostasis that includes Ca 2+ , Mg 2+ , vitamin D, zinc and selenium appear to be an integral component of pathophysiologic expressions of CHF that contributes to its systemic and progressive nature. This broader perspective of CHF, which focuses on the importance of secondary hyperparathyroidism and minerals and micronutrients, raises the prospect that dietary supplements could prove remedial in combination with the current standard of care.

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Chronic DOCA treatment increases Ca absorption: role of hypercalciuria and vitamin D

Cited by 13 publications

References 12 publications

Loss of bone minerals and strength in rats with aldosteronism

Loss of bone minerals and strength in rats with aldosteronism

From aldosteronism to oxidative stress: the role of excessive intracellular calcium accumulation

Congestive Heart Failure is a Systemic Illness: A Role for Minerals and Micronutrients

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