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

Research output: Contribution to journalArticle

44 Scopus citations

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 < 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 subseqent 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 < 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.

Original languageEnglish (US)
Pages (from-to)695-702
Number of pages8
JournalJournal of Clinical Investigation
Volume76
Issue number2
DOIs
StatePublished - 1985

ASJC Scopus subject areas

  • Medicine(all)

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