Skip to main content
NCBI home page
The Journal of Clinical Investigation logoLink to The Journal of Clinical Investigation
. 1985 Aug;76(2):695–702. doi: 10.1172/JCI112023

Long-term control of plasma calcitriol concentration in dogs and humans. Dominant role of plasma calcium concentration in experimental hyperparathyroidism.

H N Hulter, B P Halloran, R D Toto, J C Peterson
PMCID: PMC423880  PMID: 3928683

Abstract

Despite great interest in the elevated circulating levels of calcitriol (1,25-[OH]2D) associated with the clinical syndrome of human primary hyperparathyroidism, the relative potencies of known and potential stimuli/suppressors of long-term calcitriol levels have not been evaluated in either clinical or experimentally induced hyperparathyroid states. Based on reports that aparathyroid animals exhibit suppressed plasma calcitriol concentration and that acute administration of parathyroid hormone (PTH) to both humans and experimental animals or to renal slices in vitro results in increased plasma calcitriol concentration/production rate, it might be predicted that a chronic experimental model of either hypercalcemic primary hyperparathyroidism or hypocalcemic secondary hyperparathyroidism would show increased plasma calcitriol concentration. Chronic alterations in plasma calcium concentration have not been implicated as modulating calcitriol levels in any species. Accordingly, we investigated the long-term response of plasma calcitriol concentration in states of sustained experimental primary and secondary hyperparathyroidism. Intact dogs (group I) undergoing continuous intravenous PTH infusion for 12 d developed sustained hypercalcemia and hypophosphatemia, and plasma calcitriol concentration decreased from 23 +/- 3 to 14 +/- 3 pg/ml (P less than 0.01). Subsequent chelator (EGTA)-induced chronic normalization of hypercalcemia during ongoing PTH infusion resulted in a large and sustained increase in plasma calcitriol concentration to supernormal levels, reversible during subsequent cessation of chelator infusion. In additional intact dogs (group II), chronic chelator-induced hypocalcemic secondary hyperparathyroidism resulted in a sustained increase in plasma calcitriol concentration despite hyperphosphatemia. In normal human subjects undergoing a 12-13-d continuous intravenous PTH infusion to result in sustained moderate hypercalcemia (12.0 +/- 0.2 mg/100 ml) and hypophosphatemia, plasma calcitriol concentration decreased significantly (P less than 0.01) as in group I dogs and was followed by reversal to normal levels in a recovery period. The present results provide strong evidence in both humans and dogs that during experimentally induced chronic PTH excess, alterations in plasma calcium concentration dictate the directional response of circulating calcitriol concentrations. The long-term potency of plasma calcium concentration as a modulator of calcitriol metabolism is sufficient to override opposing modulation by plasma phosphorus concentration and PTH.

Full text

PDF
695

Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Aarskog D., Aksnes L. Acute response of plasma 1,25-dihydroxyvitamin D to parathyroid hormone. Lancet. 1980 Feb 16;1(8164):362–363. doi: 10.1016/s0140-6736(80)90904-6. [DOI] [PubMed] [Google Scholar]
  2. Adams N. D., Gray R. W., Lemann J., Jr The effects of oral CaCO3 loading and dietary calcium deprivation on plasma 1,25-dihydroxyvitamin D concentrations in healthy adults. J Clin Endocrinol Metab. 1979 Jun;48(6):1008–1016. doi: 10.1210/jcem-48-6-1008. [DOI] [PubMed] [Google Scholar]
  3. Aksnes L., Aarskog D. Effect of parathyroid hormone on 1,25-dihydroxyvitamin D formation in type I pseudohypoparathyroidism. J Clin Endocrinol Metab. 1980 Dec;51(6):1223–1226. doi: 10.1210/jcem-51-6-1223. [DOI] [PubMed] [Google Scholar]
  4. Alexander R. L., Jr Evaluation of an automatic calcium titrator. Clin Chem. 1971 Dec;17(12):1171–1175. [PubMed] [Google Scholar]
  5. Armbrecht H. J., Wongsurawat N., Zenser T. V., Davis B. B. Effect of PTH and 1,25(OH)2D3 on renal 25(OH)D3 metabolism, adenylate cyclase, and protein kinase. Am J Physiol. 1984 Jan;246(1 Pt 1):E102–E107. doi: 10.1152/ajpendo.1984.246.1.E102. [DOI] [PubMed] [Google Scholar]
  6. Bikle D. D., Rasmussen H. The ionic control of 1,25-dihydroxyvitamin D3 production in isolated chick renal tubules. J Clin Invest. 1975 Feb;55(2):292–298. doi: 10.1172/JCI107932. [DOI] [PMC free article] [PubMed] [Google Scholar]
  7. Broadus A. E., Horst R. L., Lang R., Littledike E. T., Rasmussen H. The importance of circulating 1,25-dihydroxyvitamin D in the pathogenesis of hypercalciuria and renal-stone formation in primary hyperparathyroidism. N Engl J Med. 1980 Feb 21;302(8):421–426. doi: 10.1056/NEJM198002213020801. [DOI] [PubMed] [Google Scholar]
  8. Broadus A. E., Magee J. S., Mallette L. E., Horst R. L., Lang R., Jensen P. S., Gertner J. M., Baron R. A detailed evaluation of oral phosphate therapy in selected patients with primary hyperparathyroidism. J Clin Endocrinol Metab. 1983 May;56(5):953–961. doi: 10.1210/jcem-56-5-953. [DOI] [PubMed] [Google Scholar]
  9. DeLuca H. F. Vitamin D metabolism and function. Arch Intern Med. 1978 May 15;138(Spec No):836–847. [PubMed] [Google Scholar]
  10. Eisman J. A., Wark J. D., Prince R. L., Moseley J. M. Modulation of plasma 1,25-dihydroxyvitamin D in man by stimulation and suppression tests. Lancet. 1979 Nov 3;2(8149):931–933. doi: 10.1016/s0140-6736(79)92624-2. [DOI] [PubMed] [Google Scholar]
  11. Emmertsen K., Melsen F., Mosekilde L., Lund B., Lund B., Sørensen O. H., Nielsen H. E., Sølling H., Hansen H. H. Altered vitamin D metabolism and bone remodelling in patients with medullary thyroid carcinoma and hypercalcitoninemia. Metab Bone Dis Relat Res. 1982;4(1):17–23. doi: 10.1016/0221-8747(82)90004-2. [DOI] [PubMed] [Google Scholar]
  12. Fox J., Heath H., 3rd The "calcium clamp": effect of constant hypocalcemia on parathyroid hormone secretion. Am J Physiol. 1981 Jun;240(6):E649–E655. doi: 10.1152/ajpendo.1981.240.6.E649. [DOI] [PubMed] [Google Scholar]
  13. Fraser D. R. Regulation of the metabolism of vitamin D. Physiol Rev. 1980 Apr;60(2):551–613. doi: 10.1152/physrev.1980.60.2.551. [DOI] [PubMed] [Google Scholar]
  14. Garabedian M., Holick M. F., Deluca H. F., Boyle I. T. Control of 25-hydroxycholecalciferol metabolism by parathyroid glands. Proc Natl Acad Sci U S A. 1972 Jul;69(7):1673–1676. doi: 10.1073/pnas.69.7.1673. [DOI] [PMC free article] [PubMed] [Google Scholar]
  15. Gray R. W., Wilz D. R., Caldas A. E., Lemann J., Jr The importance of phosphate in regulating plasma 1,25-(OH)2-vitamin D levels in humans: studies in healthy subjects in calcium-stone formers and in patients with primary hyperparathyroidism. J Clin Endocrinol Metab. 1977 Aug;45(2):299–306. doi: 10.1210/jcem-45-2-299. [DOI] [PubMed] [Google Scholar]
  16. Halloran B. P., Schaefer P., Lifschitz M., Levens M., Goldsmith R. S. Plasma vitamin D metabolite concentrations in chronic renal failure: effect of oral administration of 25-hydroxyvitamin D3. J Clin Endocrinol Metab. 1984 Dec;59(6):1063–1069. doi: 10.1210/jcem-59-6-1063. [DOI] [PubMed] [Google Scholar]
  17. Henry H. L., Midgett R. J., Norman A. W. Regulation of 25-hydroxyvitamin D3-1-hydroxylase in vivo. J Biol Chem. 1974 Dec 10;249(23):7584–7592. [PubMed] [Google Scholar]
  18. Hove K., Horst R. L., Littledike E. T., Beitz D. C. Infusions of parathyroid hormone in ruminants: hypercalcemia and reduced plasma 1,25-dihydroxyvitamin D concentrations. Endocrinology. 1984 Mar;114(3):897–903. doi: 10.1210/endo-114-3-897. [DOI] [PubMed] [Google Scholar]
  19. Hughes M. R., Brumbaugh P. F., Hussler M. R., Wergedal J. E., Baylink D. J. Regulation of serum 1alpha,25-dihydroxyvitamin D3 by calcium and phosphate in the rat. Science. 1975 Nov 7;190(4214):578–580. doi: 10.1126/science.1188357. [DOI] [PubMed] [Google Scholar]
  20. Hulter H. N., Gustafson L. E., Bonner E. L., Jr, Toto R. D., Mackie S. Thyroid replacement in thyroparathyroidectomized dogs. Miner Electrolyte Metab. 1984;10(4):228–232. [PubMed] [Google Scholar]
  21. Hulter H. N., Ilnicki L. P., Harbottle J. A., Sebastian A. Impaired renal H+ secretion and NH3 production in mineralocorticoid-deficient glucocorticoid-replete dogs. Am J Physiol. 1977 Feb;232(2):F136–F146. doi: 10.1152/ajprenal.1977.232.2.F136. [DOI] [PubMed] [Google Scholar]
  22. Hulter H. N., Licht J. H., Glynn R. D., Sebastian A. Renal acidosis in mineralocorticoid deficiency is not dependent on NaCl depletion or hyperkalemia. Am J Physiol. 1979 Mar;236(3):F283–F294. doi: 10.1152/ajprenal.1979.236.3.F283. [DOI] [PubMed] [Google Scholar]
  23. Kawashima H., Torikai S., Kurokawa K. Calcitonin selectively stimulates 25-hydroxyvitamin D3-1 alpha-hydroxylase in proximal straight tubule of rat kidney. Nature. 1981 May 28;291(5813):327–329. doi: 10.1038/291327a0. [DOI] [PubMed] [Google Scholar]
  24. Kremer R., Goltzman D. Parathyroid hormone stimulates mammalian renal 25-hydroxyvitamin D3-1 alpha-hydroxylase in vitro. Endocrinology. 1982 Jan;110(1):294–296. doi: 10.1210/endo-110-1-294. [DOI] [PubMed] [Google Scholar]
  25. Lund B., Sørensen O. H., Lund B., Bishop J. E., Norman A. W. Stimulation of 1,25-dihydroxyvitamin D production by parathyroid hormone and hypocalcemia in man. J Clin Endocrinol Metab. 1980 Mar;50(3):480–484. doi: 10.1210/jcem-50-3-480. [DOI] [PubMed] [Google Scholar]
  26. Maierhofer W. J., Gray R. W., Adams N. D., Smith G. A., Lemann J., Jr Synthesis and metabolic clearance of 1,25-dihydroxyvitamin D as determinants of serum concentrations: a comparison of two methods. J Clin Endocrinol Metab. 1981 Sep;53(3):472–475. doi: 10.1210/jcem-53-3-472. [DOI] [PubMed] [Google Scholar]
  27. Portale A. A., Booth B. E., Halloran B. P., Morris R. C., Jr Effect of dietary phosphorus on circulating concentrations of 1,25-dihydroxyvitamin D and immunoreactive parathyroid hormone in children with moderate renal insufficiency. J Clin Invest. 1984 Jun;73(6):1580–1589. doi: 10.1172/JCI111365. [DOI] [PMC free article] [PubMed] [Google Scholar]
  28. Rader J. I., Baylink D. J., Hughes M. R., Safilian E. F., Haussler M. R. Calcium and phosphorus deficiency in rats: effects on PTH and 1,25-dihydroxyvitamin D3. Am J Physiol. 1979 Feb;236(2):E118–E122. doi: 10.1152/ajpendo.1979.236.2.E118. [DOI] [PubMed] [Google Scholar]
  29. Ribovich M. L., DeLuca H. F. Effect of dietary calcium and phosphorus on intestinal calcium absorption and vitamin D metabolism. Arch Biochem Biophys. 1978 May;188(1):145–156. doi: 10.1016/0003-9861(78)90367-3. [DOI] [PubMed] [Google Scholar]
  30. Trechsel U., Eisman J. A., Fischer J. A., Bonjour J. P., Fleisch H. Calcium-dependent, parathyroid hormone-independent regulation of 1,25-dihydroxyvitamin D. Am J Physiol. 1980 Aug;239(2):E119–E124. doi: 10.1152/ajpendo.1980.239.2.E119. [DOI] [PubMed] [Google Scholar]

Articles from Journal of Clinical Investigation are provided here courtesy of American Society for Clinical Investigation

RESOURCES