The Calcimimetic NPS R-568 Decreases Plasma PTH in Rats with Mild and Severe Renal or Dietary Secondary Hyperparathyroidism

Fox, John; Lowe, Stacey H.; Conklin, Rebecca L.; Nemeth, Edward F.

doi:10.1385/endo:10:2:97

Cited by 48 publications

(31 citation statements)

References 27 publications

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“…Therefore, the discovery of other compounds, in addition to Ca 2C , that are able to influence CaR, created the possibility to modulate parathyroid secretion. Development of compounds, called calcimimetics, that activate CaR, enabled the suppression of PTH secretion in rats and humans (Steffey et al 1993, Fox et al 1999, Goodman et al 2000. Calcimimetic compounds have great potential as an innovative medical approach to manage primary hyperparathyroidism (Silverberg et al 1997) and secondary hyperparathyroidism in uraemia (Fox et al 1999, Goodman et al 2000.…”

Section: Introductionmentioning

confidence: 99%

Hypertensive effect of calcilytic NPS 2143 administration in rats

Rybczyńska

Lehmann²,

Jurska-Jasko³

et al. 2006

Journal of Endocrinology

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Secretion of parathormone (PTH), the main parathyroid hormone, which is under the control of the calcium sensing receptor, might be inhibited by calcimimetics and stimulated by calcilytics. Parathyroid glands also secrete parathyroid hypertensive factor. Recently, it was shown that calcimimetic NPS R-568 induced decreased blood pressure in spontaneously hypertensive rats (SHR) in the presence of parathyroid glands. Therefore, the aim of this study was to determine whether administration of the calcilytic NPS 2143 provoked an increase of mean arterial blood pressure (MAP) in normotensive rats. We used male Wistar rats anaesthetized with thiopental. Clearance experiments were performed and the effect of bolus, 1 mg/kg body weight i.v. of NPS 2143 on MAP in the presence and absence of thyroparathyroidectomy (TPTX) was monitored continuously. Calcilytic properties of NPS 2143 were confirmed directly by a significant (P!0$05) increase of plasma PTH concentration, and indirectly by a rise of plasma Ca 2C concentration and urinary fractional phosphate excretion (FE Pi). NPS 2143 administration markedly (P!0$05) increased MAP, calculated as the difference (D) in MAP between sequential measurements and the time of bolus injection of calcilytic. The observed increase of blood pressure in the NPS 2143 group was also significant (P!0$05) compared with the control group. Performance of TPTX prevented the hypertensive effect of NPS 2143. We conclude that NPS 2143 is responsible for increased blood pressure in rats in the presence of parathyroid glands.

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Section: Introductionmentioning

confidence: 99%

Hypertensive effect of calcilytic NPS 2143 administration in rats

Rybczyńska

Lehmann²,

Jurska-Jasko³

et al. 2006

Journal of Endocrinology

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“…Allosteric activators of the calcium sensing receptor, e.g., NPSR-568 (R-568), reduce PTH secretion in rats or patients with primary and secondary hyperparathyroidism (15)(16)(17)(18)(19)(20).…”

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confidence: 99%

Beneficial Effects of Calcimimetics on Progression of Renal Failure and Cardiovascular Risk Factors

Ogata¹,

Ritz²,

Odoni³

et al. 2003

Journal of the American Society of Nephrology

139

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Abstract. In renal failure, parathyroid hormone (PTH) is not only involved in the genesis of disturbed calcium/phosphate metabolism and ostitis fibrosa; it is also a permissive factor in the genesis of hypertension, cardiovascular damage, and dyslipidemia. The allosteric activator of the calcium sensing receptor NPSR-568 (R-568) has been shown to reduce the serum intact PTH (iPTH) concentration in uremic rats. It was the purpose of this study in subtotally nephrectomized (SNX) rats to compare pharmacologic abrogation of secondary hyperparathyroidism by R-568 with parathyroidectomy (PTX). The effects on progression of renal failure, BP, and lipid and structural parameters of kidney and heart were studied. Four groups of male SD-rats were studied: (1) sham-operated ϩ vehicletreated rats (controls); (2) SNX ϩ vehicle-treated rats (SNX); (3) parathyroidectomized SNX ϩ vehicle-treated rats (SNXϩPTX); and (4) SNX ϩ calcimimetic R-568 -treated rats (SNXϩR-568). R-568 (50 mol/kg per d) was administered by gavage. Eight weeks after SNX, serum creatinine concentration, urinary albumin excretion, BP, and serum LDL-cholesterol concentration were significantly lower in both R-568 -treated and parathyroidectomized SNX compared with vehicletreated SNX. In addition, structural abnormalities of the kidney (glomerulosclerosis, tubulointerstitial changes) and the heart (interstitial fibrosis, capillary length density, arteriolar wall thickness) were significantly less pronounced than in vehicletreated SNX. It is concluded that in experimental renal failure abrogation of hyperparathyroidism by administration of a calcimimetic or PTX similarly attenuates progression of renal failure. Furthermore, it interferes with the development of cardiovascular risk factors and cardiac remodeling.Secondary hyperparathyroidism (sHPT) is a known complication of chronic renal failure. Elevated concentrations of parathyroid hormone (PTH) play a role not only in the pathogenesis of renal bone disease (1,2), but also in the development of cardiovascular risk factors such as disturbed lipid metabolism (3,4), glucose intolerance (5), and hypertension (6 -8). Parathyroidectomy (PTX) attenuates progression of renal failure in subtotally nephrectomized rats (SNX) on a high protein (9) or high phosphate (10,11) diet. sHPT is also known to play an important role in the development of structural abnormalities of the heart in renal failure, including left ventricular hypertrophy, interstitial fibrosis, and arteriolar wall thickening of the heart (7,(12)(13)(14).Allosteric activators of the calcium sensing receptor, e.g., NPSR-568 (R-568), reduce PTH secretion in rats or patients with primary and secondary hyperparathyroidism (15-20).There is no information on whether calcimimetics also affect abnormalities of uremia other than calcemia, phosphatemia (21), PTH concentrations (22), and skeletal abnormalities (17).Therefore, it was the purpose of this study to compare the effects of the calcimimetic R-568 and of parathyroidectomy on progression of renal failure, ...

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“…Hyperparathyroïdie secondaire à l'urémie Un certain nombre de résultats ont été obtenus chez l'animal uré-mique [14][15][16][17][18][19]: le traitement par calcimimétique réduit l'hyper-REVUES SYNTHÈSE (10,4 ± 3,7 mg/k). À la dose de 3,3 mg/kg, la PTH atteint sa concentration plasmatique minimale à la 15 e minute; quant à l'hypocalcémie, sa survenue intervient souvent avant la 30 e minute aux doses de 10 mg/kg à 100 mg/kg, et persistante puisqu'elle est encore importante au terme des 24 heures.…”

Section: Calcimimétiques En Cliniqueunclassified

Calcimimétiques et traitement des hyper-parathyroïdies

Ureña¹

2004

Med Sci (Paris)

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The Calcimimetic NPS R-568 Decreases Plasma PTH in Rats with Mild and Severe Renal or Dietary Secondary Hyperparathyroidism

Cited by 48 publications

References 27 publications

Hypertensive effect of calcilytic NPS 2143 administration in rats

Hypertensive effect of calcilytic NPS 2143 administration in rats

Beneficial Effects of Calcimimetics on Progression of Renal Failure and Cardiovascular Risk Factors

Calcimimétiques et traitement des hyper-parathyroïdies

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