Effect of 1,25-Dihydroxyvitamin D<sub>3</sub>and Diltiazem on Tissue Calcium in Uremic Rat

Inagaki, Oshi; Nakagawa, Kiyohiko; Syono, Tadayasu; Nishian, Yoshihiko; Takenaka, Yosiaki; Takamitsu, Yoshihiro

doi:10.3109/08860229509037632

Cited by 6 publications

(5 citation statements)

References 19 publications

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“…In the present study, we have carefully characterized the orally adenine-dosed rats with respect to calcium and phosphate homeostasis to clarify their usefulness as a severe CKD model. Some of the clinical outcomes of active vitamin D 3 therapies for CKD patients have been noted in previous animal studies (Krog et al, 1984;Inagaki et al, 1995;Hirata et al, 2003). Hypercalcemic dosages of calcitriol and active vitamin D3 analogues were inhibitory for 2HPT in 5/6Nx rats.…”

Section: Introductionmentioning

confidence: 63%

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Vascular calcification and secondary hyperparathyroidism of severe chronic kidney disease and its relation to serum phosphate and calcium levels

Terai

Nara

Takakura

et al. 2009

British J Pharmacology

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Background and purpose:Various complications consequent on disordered calcium and phosphate homeostasis occur frequently in chronic kidney disease (CKD) patients. Particularly, vascular calcification has high morbidity and mortality rates. There is a clear need for a better CKD model to examine various aspects of this disordered homeostasis. Experimental approach: Oral dosing with adenine induced CKD in rats in only 10 days. Serum calcium, phosphate and parathyroid hormone were measured and calcification in aorta was assessed histologically. The effects of varying phosphorus content of diet or treatment with phosphate binders or active vitamin D3 on these parameters were examined. Key results: After adenine dosing, significant hyperphosphatemia, hypocalcemia and secondary hyperparathyroidism (2HPT) were observed during the experimental period of 15 weeks. Aortic calcification was detected in only some of the animals even at 15 weeks (~40%). Treatment with vitamin D3 for 18 days, even at a low dose (100 ng·kg -1 , 3-4 times week -1 , p.o), caused aortic calcification in all animals and increases in serum calcium levels up to the normal range. The vitamin D3-induced calcification was significantly inhibited by phosphate binders which lowered serum phosphate levels and the calcium ¥ phosphate product, although serum calcium levels were elevated. Conclusions: These data suggest that rats dosed orally with adenine provide a more useful model for analysing calcium/ phosphate homeostasis in severe CKD. Controlling serum calcium/phosphate levels with phosphate binders may be better than vitamin D3 treatment in hyperphosphatemia and 2HPT, to avoid vascular calcification.

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Section: Introductionmentioning

confidence: 63%

“…Some of the clinical outcomes of active vitamin D 3 therapies for CKD patients have been noted in previous animal studies (Krog et al. , 1984; Inagaki et al. , 1995; Hirata et al.…”

Section: Introductionmentioning

confidence: 83%

Vascular calcification and secondary hyperparathyroidism of severe chronic kidney disease and its relation to serum phosphate and calcium levels

Terai

Nara

Takakura

et al. 2009

British J Pharmacology

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“…The selected dose of calcitriol (Henley et al, 2005;Inagaki et al, 1995) clearly increased the susceptibility of vessels to VC, and to the associated pathogenic hemodynamic alterations (increased PWV, pulse pressure). Although this study did not elucidate the specific mechanism by which calcitriol increases the susceptibility of vessels to calcification, the findings did reveal that hallmark increases in FGF-23 and serum calcium could have played a significant role, consistent with previous work (Koleganova et al, 2009).…”

Section: Discussionmentioning

confidence: 94%

Magnesium Modifies the Impact of Calcitriol Treatment on Vascular Calcification in Experimental Chronic Kidney Disease

Zelt

McCabe

Svajger

et al. 2015

J Pharmacol Exp Ther

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Chronic kidney disease (CKD) patients are commonly treated with vitamin D analogs, such as calcitriol. Recent epidemiologic evidence revealed a significant interaction between vitamin D and magnesium, since an inverse relationship between vitamin D levels and mortality mainly occurs in patients with a high magnesium intake. The aim of the study was to assess the mechanisms involved by determining whether magnesium alone or combined with calcitriol treatments differentially impacts vascular calcification (VC) in male Sprague-Dawley rats with adenine-induced CKD. Treatment with moderate doses of calcitriol (80 mg/kg) suppressed parathyroid hormone to near or slightly below control levels. Given alone, this dose of calcitriol increased the prevalence of VC; however, when magnesium was given in combination, the severity of calcification was attenuated in the abdominal aorta (51% reduction), iliac (44%), and carotid arteries (46%) compared with CKD controls. The decreases in vascular calcium content were associated with a 20-50% increase in vascular magnesium. Calcitriol treatment alone significantly decreased TRPM7 protein (↓ to ∼11%), whereas the combination treatment increased both mRNA (1.7Â) and protein (6.8Â) expression compared with calcitriol alone. In summary, calcitriol increased VC in certain conditions, but magnesium prevented the reduction in TRPM7 and reduced the severity of VC, thereby increasing the bioavailable magnesium in the vascular microenvironment. These findings suggest that modifying the adverse effect profile of calcitriol with magnesium may be a plausible approach to benefiting the increasing number of CKD patients being prescribed calcitriol.

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“…Hypercalcemia is a common feature of severe or refractory SHPT and adds to the risk of vascular calcification that is already present in these patients because of high serum phosphorus levels. Calcitriol facilitates the absorption of calcium and phosphorus from the gastrointestinal tract, thus adding to the calcium and phosphorus load and increasing the risk of vascular calcifications still further (56,59,99). Hypercalcemia also limits the potential use of calcium-based phosphate binders for reducing hyperphosphatemia in SHPT.…”

Section: The Car and Management Of Shptmentioning

confidence: 99%

The calcium-sensing receptor: a key factor in the pathogenesis of secondary hyperparathyroidism

Rodriguez¹,

Nemeth²,

Martin³

2005

American Journal of Physiology-Renal Physiology

160

107

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Serum calcium levels are regulated by the action of parathyroid hormone (PTH). Major drivers of PTH hypersecretion and parathyroid cell proliferation are the hypocalcemia and hyperphosphatemia that develop in chronic kidney disease patients with secondary hyperparathyroidism (SHPT) as a result of low calcitriol levels and decreased kidney function. Increased PTH production in response to systemic hypocalcemia is mediated by the calcium-sensing receptor (CaR). Furthermore, as SHPT progresses, reduced expression of CaRs and vitamin D receptors (VDRs) in hyperplastic parathyroid glands may limit the ability of calcium and calcitriol to regulate PTH secretion. Current treatment for SHPT includes the administration of vitamin D sterols and phosphate binders. Treatment with vitamin D is initially effective, but efficacy often wanes with further disease progression. The actions of vitamin D sterols are undermined by reduced expression of VDRs in the parathyroid gland. Furthermore, the calcemic and phosphatemic actions of vitamin D mean that it has the potential to exacerbate abnormal mineral metabolism, resulting in the formation of vascular calcifications. Effective new treatments for SHPT that have a positive impact on mineral metabolism are clearly needed. Recent research shows that drugs that selectively target the CaR, calcimimetics, have the potential to meet these requirements.

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Effect of 1,25-Dihydroxyvitamin D₃and Diltiazem on Tissue Calcium in Uremic Rat

Cited by 6 publications

References 19 publications

Vascular calcification and secondary hyperparathyroidism of severe chronic kidney disease and its relation to serum phosphate and calcium levels

Vascular calcification and secondary hyperparathyroidism of severe chronic kidney disease and its relation to serum phosphate and calcium levels

Magnesium Modifies the Impact of Calcitriol Treatment on Vascular Calcification in Experimental Chronic Kidney Disease

The calcium-sensing receptor: a key factor in the pathogenesis of secondary hyperparathyroidism

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Effect of 1,25-Dihydroxyvitamin D3and Diltiazem on Tissue Calcium in Uremic Rat

Cited by 6 publications

References 19 publications

Vascular calcification and secondary hyperparathyroidism of severe chronic kidney disease and its relation to serum phosphate and calcium levels

Vascular calcification and secondary hyperparathyroidism of severe chronic kidney disease and its relation to serum phosphate and calcium levels

Magnesium Modifies the Impact of Calcitriol Treatment on Vascular Calcification in Experimental Chronic Kidney Disease

The calcium-sensing receptor: a key factor in the pathogenesis of secondary hyperparathyroidism

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Effect of 1,25-Dihydroxyvitamin D₃and Diltiazem on Tissue Calcium in Uremic Rat