Maintenance of normocalcemia by continuous infusion of the synthetic bovine parathyroid hormone (1–34) in parathyroidectomized rats

Ibrahim, Muawia M.; Forte, Leonard R.; Thomas, Mary L.

doi:10.1007/bf02411303

Cited by 13 publications

(5 citation statements)

References 12 publications

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“…In a second report, acute infusion of 1.0 gg of bPTH (1-84) into TPTX rats induced a rise in the serum calcium from -6-8 mg/dl (34). In a third report, the design of which most closely approximates the current design, hypocalcemic TPTX rats infused by osmotic minipumps with bPTH (1-34) at a rate of 0.5 ,ug/h developed hypercalcemia (13-15 mg/dl) by day 3 (18). Animals infused with 0.17 ug/h developed hypercalcemia in the 11 .0-mg/dl range, and animals receiving 0.6 ,g/h showed no calcemic response.…”

Section: Discussionmentioning

confidence: 80%

Synthetic human parathyroid hormone-like protein stimulates bone resorption and causes hypercalcemia in rats.

Stewart¹,

Mangin²,

Wu³

et al. 1988

J. Clin. Invest.

167

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Parathyroid hormone-like adenylate cyclase-stimulating proteins (hACSPs) have been implicated as one of the calcemic, bone-resorbing agents in patients with humoral hypercalcemia of malignancy. We report the synthesis of an amino-terminal hACSP fragment, Tyr' hACSP (1-36) amide. The synthetic hACSP is a potent agonist of renal membrane adenylate cyclase (K., 1.7 X 10-"') and of bone cell adenylate cyclase (K. 1 X 10-9 M). It is a potent bone-resorbing agent in vitro, stimulating 45Ca release from fetal rat long bones at a concentration of 10-' M. When infused via osmotic minipumps into rats, it is also a potent calcemic factor in vivo, inducing a rise in serum calcium from (mean ± SD) 10.6 ± 0.6 to 19.7 ± 3.2 mg/dl when infused at 1.4 pg/h and from 9.9 ± 0.7 to 11.4 ± 1.2 mg/dl when infused at 0.14 ,ug/h.These findings indicate that biologically active hACSP fragments can be synthesized. One such synthetic peptide possesses the in vitro and in vivo bioactivities demonstrated in native, tumor-derived hACSPs. It is also a potent calcemic, bone-resorbing agent.

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Section: Discussionmentioning

confidence: 80%

Synthetic human parathyroid hormone-like protein stimulates bone resorption and causes hypercalcemia in rats.

Stewart¹,

Mangin²,

Wu³

et al. 1988

J. Clin. Invest.

167

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“…The PTH-Cys solution was placed in osmotic minipumps (Alzet, no. 2002) delivering 1-34 PTH at a rate of 1 UI/hour (0.475 μg/h), reproducing "normal" conditions (1,31). The effectiveness of the PTH supplementation was subsequently assessed by blood ionized Ca measurement.…”

Section: Animal Studiesmentioning

confidence: 99%

PTH-independent regulation of blood calcium concentration by the calcium-sensing receptor

Loupy¹,

Ramakrishnan²,

Wootla³

et al. 2012

J. Clin. Invest.

180

171

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Tight regulation of calcium levels is required for many critical biological functions. The Ca 2+ -sensing receptor (CaSR) expressed by parathyroid cells controls blood calcium concentration by regulating parathyroid hormone (PTH) secretion. However, CaSR is also expressed in other organs, such as the kidney, but the importance of extraparathyroid CaSR in calcium metabolism remains unknown. Here, we investigated the role of extraparathyroid CaSR using thyroparathyroidectomized, PTH-supplemented rats. Chronic inhibition of CaSR selectively increased renal tubular calcium absorption and blood calcium concentration independent of PTH secretion change and without altering intestinal calcium absorption. CaSR inhibition increased blood calcium concentration in animals pretreated with a bisphosphonate, indicating that the increase did not result from release of bone calcium. Kidney CaSR was expressed primarily in the thick ascending limb of the loop of Henle (TAL). As measured by in vitro microperfusion of cortical TAL, CaSR inhibitors increased calcium reabsorption and paracellular pathway permeability but did not change NaCl reabsorption. We conclude that CaSR is a direct determinant of blood calcium concentration, independent of PTH, and modulates renal tubular calcium transport in the TAL via the permeability of the paracellular pathway. These findings suggest that CaSR inhibitors may provide a new specific treatment for disorders related to impaired PTH secretion, such as primary hypoparathyroidism.

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“…S EVERAL STUDIES HAVE TAKEN advantage of a parathyroid hormone (PTH) infusion device to produce continuously elevated PTH conditions either in normal or thyroparathyroidectomized (TPTX) animals. (1)(2)(3)(4)(5)(6)(7) Five days of PTH infusion studies in TPTX animals produced many of the characteristics of human primary hyperparathyroidism (PHPT): modest hypercalcemia and hypophosphatemia, renal loss of phosphate, elevated 1,25-dihydroxyvitamin D [1,25(OH 2 )D] and increased bone turnover. (6,7) Longer periods, 2-4 weeks, of PTH infusion in rats induce significant bone loss mimicking lower bone mass observed in patients with PHPT.…”

Section: Introductionmentioning

confidence: 99%

“…(1)(2)(3)(4)(5)(6)(7) Five days of PTH infusion studies in TPTX animals produced many of the characteristics of human primary hyperparathyroidism (PHPT): modest hypercalcemia and hypophosphatemia, renal loss of phosphate, elevated 1,25-dihydroxyvitamin D [1,25(OH 2 )D] and increased bone turnover. (6,7) Longer periods, 2-4 weeks, of PTH infusion in rats induce significant bone loss mimicking lower bone mass observed in patients with PHPT. (1)(2)(3)(4)(5) PTH given as pulsatile delivery for longer than 2 h/day or in continuous fashion for a total of 6 days gave rise to abnormalities observed in patients with chronic PHPT, including peritrabecular marrow fibrosis and focal bone resorption.…”

Section: Introductionmentioning

confidence: 99%

Skeletal Effects of Parathyroid Hormone Infusion in Ovariectomized Rats With or Without Estrogen Repletion

Shen

Birchman

Lindsay

2000

Journal of Bone and Mineral Research

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We employed skeletally matured rats to study changes in biochemical markers of bone turnover, bone mineral density (BMD), and bone biomechanics produced by continuous elevation of parathyroid hormone (PTH) in estrogen-deplete and -replete rodents. Ninety-six 7-month-old virgin female rats were divided randomly into 12 groups (n = 8) and treated as follows. One group was killed on the day of surgery. The remaining groups were either bilaterally ovariectomized (Ovx) or sham-operated and left untreated for 8 weeks, at which point, two groups, one sham and one Ovx, were killed. The remaining nine groups were treated for 2 weeks or 4 weeks. One sham and two Ovx groups received subcutaneous implants of Alzet miniosmotic pumps with vehicle for PTH. Two Ovx groups were given pumps with vehicle as well as a subcutaneous implant of 17beta-estradiol, which delivered 10 microg/kg per day. Two Ovx groups were implanted with rat PTH(1-34) in Alzet miniosmotic pumps, which delivered 30 microg PTH/kg per day. Two Ovx groups were implanted with both estradiol pellets and PTH-loaded pumps. One group of Ovx animals from each treatment was killed after 2 weeks and the other after 4 weeks. Biochemical markers of bone turnover, serum osteocalcin and urinary free pyridinoline, BMD, and mechanical strength of excised bones were measured. As expected, there was a significant increase in N-terminal PTH and serum calcium levels in all PTH infusion groups. Both serum osteocalcin and urinary pyridinoline showed a rapid increase within the first 2 weeks of the PTH infusion and remained elevated at week 4. In estrogen-replete groups, osteocalcin increased by week 2 of PTH infusion but pyridinoline did not increase until week 4. BMD of the distal and proximal femur showed the expected decrease 8 weeks after ovariectomy but did not exhibit any further changes during the 4 weeks of treatment with vehicle. Four weeks of PTH infusion in Ovx animals resulted in BMD loss at the midshaft, distal, and proximal regions of the femur. Estrogen repletion by itself, beginning 8 weeks after ovariectomy, produced no change in BMD at any site when compared with from Ovx vehicle-treated rats. Estrogen repletion in PTH-infused Ovx animals resulted in significant improvements of BMD comparable with sham-operated animals at all three femoral regions. The indentation test at the cancellous bone of the distal femur, three-point bending test at the midshaft femur, and cantilever bending test at the femoral neck showed that the changes in mechanical strength in these sites were consistent to the changes found in BMD. Our results showed that (1) continuously elevated levels of PTH induced additional loss of BMD in estrogen-deficient animals beyond the rapid bone loss phase associated with ovariectomy, (2) estrogen repletion, given by implant, to PTH-infused Ovx animals, reversed these BMD changes increasing BMD to levels comparable with estrogen-sufficient rats, and (3) these changes were reflected in the mechanical strength determined at these sites. These results len...

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Maintenance of normocalcemia by continuous infusion of the synthetic bovine parathyroid hormone (1–34) in parathyroidectomized rats

Cited by 13 publications

References 12 publications

Synthetic human parathyroid hormone-like protein stimulates bone resorption and causes hypercalcemia in rats.

Synthetic human parathyroid hormone-like protein stimulates bone resorption and causes hypercalcemia in rats.

PTH-independent regulation of blood calcium concentration by the calcium-sensing receptor

Skeletal Effects of Parathyroid Hormone Infusion in Ovariectomized Rats With or Without Estrogen Repletion

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