scholarly journals A Novel Calcium-Sensing Receptor Antagonist Transiently Stimulates Parathyroid Hormone Secretion in Vivo

Endocrinology ◽  
2005 ◽  
Vol 146 (4) ◽  
pp. 2015-2022 ◽  
Author(s):  
Brian J. Arey ◽  
Ramakrishna Seethala ◽  
Zhengping Ma ◽  
Aberra Fura ◽  
Jennifer Morin ◽  
...  
Keyword(s):  
Parathyroid Hormone ◽  
Receptor Antagonist ◽  
Hormone Secretion ◽  
Calcium Sensing Receptor ◽  
Calcium Sensing

scholarly journals Relationship between parathyroid calcium-sensing receptor expression and potency of the calcimimetic, cinacalcet, in suppressing parathyroid hormone secretion in an in vivo murine model of primary hyperparathyroidism

2005 ◽  
Vol 153 (4) ◽  
pp. 587-594 ◽  
Author(s):  
Takehisa Kawata ◽  
Yasuo Imanishi ◽  
Keisuke Kobayashi ◽  
Takao Kenko ◽  
Michihito Wada ◽  
...  
Keyword(s):  
Parathyroid Hormone ◽  
Primary Hyperparathyroidism ◽  
Secondary Hyperparathyroidism ◽  
Murine Model ◽  
Hormone Secretion ◽  
Suppressive Effect ◽  
Receptor Expression ◽  
Parathyroid Glands ◽  
Calcium Sensing Receptor ◽  
Calcium Sensing

Cinacalcet HCl, an allosteric modulator of the calcium-sensing receptor (CaR), has recently been approved for the treatment of secondary hyperparathyroidism in patients with chronic kidney disease on dialysis, due to its suppressive effect on parathyroid hormone (PTH) secretion. Although cinacalcet’s effects in patients with primary and secondary hyperparathyroidism have been reported, the crucial relationship between the effect of calcimimetics and CaR expression on the parathyroid glands requires better understanding. To investigate its suppressive effect on PTH secretion in primary hyperparathyroidism, in which hypercalcemia may already have stimulated considerable CaR activity, we investigated the effect of cinacalcet HCl on PTH-cyclin D1 transgenic mice (PC2 mice), a model of primary hyperparathyroidism with hypo-expression of CaR on their parathyroid glands. A single administration of 30 mg/kg body weight (BW) of cinacalcet HCl significantly suppressed serum calcium (Ca) levels 2 h after administration in 65- to 85-week-old PC2 mice with chronic biochemical hyperparathyroidism. The percentage reduction in serum PTH was significantly correlated with CaR hypo-expression in the parathyroid glands. In older PC2 mice (93–99 weeks old) with advanced hyperparathyroidism, serum Ca and PTH levels were not suppressed by 30 mg cinacalcet HCl/kg. However, serum Ca and PTH levels were significantly suppressed by 100 mg/kg of cinacalcet HCl, suggesting that higher doses of this compound could overcome severe hyperparathyroidism. To conclude, cinacalcet HCl demonstrated potency in a murine model of primary hyperparathyroidism in spite of any presumed endogenous CaR activation by hypercalcemia and hypo-expression of CaR in the parathyroid glands.

Association of Polymorphic Alleles of the Calcium-Sensing Receptor Gene with Parathyroid Hormone Secretion in Hemodialysis Patients

Nephron ◽  
2000 ◽  
Vol 85 (4) ◽  
pp. 317-323 ◽  
Author(s):  
Shozo Yano ◽  
Toshitsugu Sugimoto ◽  
Michiko Kanzawa ◽  
Tatsuo Tsukamoto ◽  
Tetsuya Hattori ◽  
...  
Keyword(s):  
Parathyroid Hormone ◽  
Receptor Gene ◽  
Hormone Secretion ◽  
Hemodialysis Patients ◽  
Calcium Sensing Receptor ◽  
Calcium Sensing ◽  
Calcium Sensing Receptor Gene

scholarly journals Calcium-Sensing Receptor Expression and Parathyroid Hormone Secretion in Hyperplastic Parathyroid Glands from Humans

2005 ◽  
Vol 16 (7) ◽  
pp. 2190-2197 ◽  
Author(s):  
Sagrario Cañadillas ◽  
Antonio Canalejo ◽  
Rafael Santamaría ◽  
Maria E. Rodríguez ◽  
Jose C. Estepa ◽  
...  
Keyword(s):  
Parathyroid Hormone ◽  
Hormone Secretion ◽  
Receptor Expression ◽  
Parathyroid Glands ◽  
Calcium Sensing Receptor ◽  
Calcium Sensing

scholarly journals The full-length calcium-sensing receptor dampens the calcemic response to 1α,25(OH)2 vitamin D3 in vivo independently of parathyroid hormone

2009 ◽  
Vol 297 (3) ◽  
pp. F720-F728 ◽  
Author(s):  
Ogo Egbuna ◽  
Steven Quinn ◽  
Lakshmi Kantham ◽  
Robert Butters ◽  
Jiang Pang ◽  
...  
Keyword(s):  
Parathyroid Hormone ◽  
Full Length ◽  
Wild Type ◽  
Calcium Sensing Receptor ◽  
Targeted Disruption ◽  
Deficient Diet ◽  
Calcium Sensing ◽  
Increased Sensitivity ◽  
Key Genes

1α,25(OH)2 vitamin D3 [1,25(OH)2D3] increases serum Ca2+ concentration in vivo, an action counteracted by activation of the Ca2+-sensing receptor (CaSR), which decreases parathyroid hormone (PTH) secretion and increases renal Ca2+ excretion. Relatively little is known of the role the CaSR plays in this response through its potentially direct actions in kidney, gut, and bone independently of PTH. We report PTH-independent roles of the CaSR in modulating the response to exogenous 1,25(OH)2D3 in mice with targeted disruption of both the CaSR and PTH genes (C−P−) compared with that in mice with disruption of the PTH gene alone (C+P−) or wild-type mice (C+P+). After intraperitoneal injection of 0.5 ng/g body wt 1,25(OH)2D3, peak calcemic responses were observed at 24 h in all three genotypes in association with 1) a greater increase in serum Ca2+ in C−P− mice than in the other genotypes on a Ca2+-replete diet that was attenuated by a Ca2+-deficient diet and pamidronate, 2) increased urinary Ca2+-to-creatinine ratios (UCa/Cr) in the C+P− and C+P+ mice but a lowered ratio in the C−P− mice on a Ca2+-replete diet, and 3) no increase in calcitonin (CT) secretion in the C+P+ and C+P− mice and a small increase in the C−P− mice. PTH deficiency had the anticipated effects on the expression of key genes involved in Ca2+ transport at baseline in the duodenum and kidney, and injection of 1,25(OH)2D3 increased gene expression 8 h later. However, the changes in the genes evaluated did not fully explain the differences in serum Ca2+ seen among the genotypes. In conclusion, mice lacking the full-length CaSR have increased sensitivity to the calcemic action of 1,25(OH)2D3 in the setting of PTH deficiency. This is principally from enhanced 1,25(OH)2D3-mediated gut Ca2+ absorption and decreased renal Ca2+ excretion, without any differences in bone-related release of Ca2+ or CT secretion among the three genotypes that could explain the differences in their calcemic responses.

scholarly journals Phosphate acts directly on the calcium-sensing receptor to stimulate parathyroid hormone secretion

2019 ◽  
Vol 10 (1) ◽  
Author(s):  
Patricia P. Centeno ◽  
Amanda Herberger ◽  
Hee-Chang Mun ◽  
Chialing Tu ◽  
Edward F. Nemeth ◽  
...  
Keyword(s):  
Parathyroid Hormone ◽  
Hormone Secretion ◽  
Phosphate Concentration ◽  
Wild Type ◽  
Calcium Sensing Receptor ◽  
Mediated Action ◽  
Calcium Sensing ◽  
Competitive Antagonism ◽  
Phosphate Sensing ◽  
Phosphate Sensor

Abstract Extracellular phosphate regulates its own renal excretion by eliciting concentration-dependent secretion of parathyroid hormone (PTH). However, the phosphate-sensing mechanism remains unknown and requires elucidation for understanding the aetiology of secondary hyperparathyroidism in chronic kidney disease (CKD). The calcium-sensing receptor (CaSR) is the main controller of PTH secretion and here we show that raising phosphate concentration within the pathophysiologic range for CKD significantly inhibits CaSR activity via non-competitive antagonism. Mutation of residue R62 in anion binding site-1 abolishes phosphate-induced inhibition of CaSR. Further, pathophysiologic phosphate concentrations elicit rapid and reversible increases in PTH secretion from freshly-isolated human parathyroid cells consistent with a receptor-mediated action. The same effect is seen in wild-type murine parathyroid glands, but not in CaSR knockout glands. By sensing moderate changes in extracellular phosphate concentration, the CaSR represents a phosphate sensor in the parathyroid gland, explaining the stimulatory effect of phosphate on PTH secretion.

scholarly journals Acute activation of the calcium-sensing receptor inhibits plasma renin activity in vivo

2010 ◽  
Vol 299 (4) ◽  
pp. R1020-R1026 ◽  
Author(s):  
Douglas K. Atchison ◽  
M. Cecilia Ortiz-Capisano ◽  
William H. Beierwaltes
Keyword(s):  
Parathyroid Hormone ◽  
Plasma Renin Activity ◽  
Plasma Renin ◽  
Renin Activity ◽  
Juxtaglomerular Cells ◽  
Calcium Sensing Receptor ◽  
Conscious Rats ◽  
Calcium Sensing ◽  
Anesthetized Rats

In vitro, the renin-secreting juxtaglomerular cells express the calcium-sensing receptor, and its activation with the calcimimetic cinacalcet inhibits renin release. To test whether the activation of calcium-sensing receptor similarly inhibits plasma renin activity (PRA) in vivo , we hypothesized that the calcium-sensing receptor is expressed in juxtaglomerular cells in vivo, and acutely administered cinacalcet would inhibit renin activity in anesthetized rats. Since cinacalcet inhibits parathyroid hormone, which may stimulate renin activity, we sought to determine whether cinacalcet inhibits renin activity by decreasing parathyroid hormone. Lastly, we hypothesized that chronically administered cinacalcet would inhibit basal and stimulated renin in conscious rats. Calcium-sensing receptors and renin were localized in the same juxtaglomerular cells using immunofluorescence in rat cortical slices fixed in vivo. Cinacalcet was administered acutely via intravenous bolus in anesthetized rats and chronically in conscious rats by oral gavage. Acute administration of cinacalcet decreased basal renin activity from 13.6 ± 2.4 to 6.1 ± 1.1 ng ANG I·ml−1·h−1 ( P < 0.001). Likewise, cinacalcet decreased furosemide-stimulated renin from 30.6 ± 2.3 to 21.3 ± 2.3 ng ANG I·ml−1·h−1 ( P < 0.001). In parathyroidectomized rats, cinacalcet decreased renin activity from 9.3 ± 1.3 to 5.2 ± 0.5 ng ANG I·ml−1·h−1 ( P < 0.05) similar to sham-operated controls (13.5 ± 2.2 to 6.6 ± 0.8 ng ANG I·ml−1·h−1, P < 0.05). Chronic administration of cinacalcet over 7 days had no significant effect on PRA under basal or stimulated conditions. In conclusion, calcium-sensing receptors are expressed in juxtaglomerular cells in vivo, and acute activation of these receptors with cinacalcet inhibits PRA in anesthetized rats, independent of parathyroid hormone.

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