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J Clin Invest. 1981 June; 67(6): 1753–1760.
PMCID: PMC370753

Reversal of Secondary Hyperparathyroidism by Cimetidine in Chronically Uremic Dogs


Chronic cimetidine therapy has been shown to suppress circulating concentrations of immunoreactive parathyroid hormone (iPTH) in hemodialysis patients. To evaluate the long-term metabolic effects of cimetidine treatment, we studied seven chronically uremic dogs for 20 wk. The dogs were studied under metabolic conditions before, during, and after cimetidine therapy. iPTH fell progressively in the five treated dogs from 536±70 μleq/ml (mean±SE) (nl < 100 μleq/ml) before treatment to 291±25 μleq/ml at 12 wk (P < 0.001) and 157±32 μleq/ml at 20 wk (P < 0.001). The control dogs showed no consistent change in iPTH. The fall in iPTH was not associated with a change in serum ionized calcium. However, serum phosphorus decreased from 5.7±0.9 mg/dl to 3.4±0.2 mg/dl by the 20th wk (P < 0.05). By contrast, the serum concentration of 1,25-dihydroxycholecalciferol increased in all treated dogs from 33.4±4.3 pg/ml to 51.8±2.4 pg/ml during treatment (P < 0.01). Calcium balance was negative in all seven dogs before cimetidine (−347±84 mg/72 h) and remained so in the control dogs; it became positive in the five treated dogs after 12 wk (1,141±409 mg/72 h) (P < 0.05). Phosphorus balance, 24-h fractional phosphate excretion, and creatinine clearance remained unchanged. Pooled samples of serum obtained during the control and 20th wk of therapy were fractionated by gel filtration and the eluates assayed for immunoreactivity. The decrease in iPTH was associated with a decrease in all the immunoreactive species, indicating suppression of parathyroid gland secretion.

These observations indicate that cimetidine suppressed circulating concentration of biologically active parathyroid hormone. A probable net decrease in the loss of phosphorus from bone to blood ensued, resulting in a fall in serum phosphorus. This may have stimulated synthesis of 1,25-dihydroxycholecalciferol and led to a positive calcium balance, thereby maintaining the serum ionized calcium concentration. The maintenance of phosphate balance, despite suppression of iPTH by cimetidine, indicates that factors other than hyperparathyroidism relate to phosphate homeostasis in chronically uremic dogs.

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Selected References

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  • Massry SG, Goldstein DA. The search for uremic toxin(s) "X" "X" = PTH. Clin Nephrol. 1979 Apr;11(4):181–189. [PubMed]
  • Slatopolsky E, Caglar S, Gradowska L, Canterbury J, Reiss E, Bricker NS. On the prevention of secondary hyperparathyroidism in experimental chronic renal disease using "proportional reduction" of dietary phosphorus intake. Kidney Int. 1972 Sep;2(3):147–151. [PubMed]
  • Kaplan MA, Canterbury JM, Gavellas G, Jaffe D, Bourgoignie JJ, Reiss E, Bricker NS. The calcemic and phosphaturic effects of parathyroid hormone in the normal and uremic dog. Metabolism. 1978 Dec;27(12):1785–1792. [PubMed]
  • Jacob AI, Lanier D, Jr, Canterbury J, Bourgoignie JJ. Reduction by cimetidine of serum parathyroid hormone levels in uremic patients. N Engl J Med. 1980 Mar 20;302(12):671–674. [PubMed]
  • Schultze RG, Shapiro HS, Bricker NS. Studies on the control of sodium excretion in experimental uremia. J Clin Invest. 1969 May;48(5):869–877. [PMC free article] [PubMed]
  • Canterbury JM, Gavellas G, Bourgoignie JJ, Reiss E. Metabolic consequences of oral administration of 24,25-dihydroxycholecalciferol to uremic dogs. J Clin Invest. 1980 Mar;65(3):571–576. [PMC free article] [PubMed]
  • Canterbury JM, Lerman S, Claflin AJ, Henry H, Norman A, Reiss E. Inhibition of parathyroid hormone secretion by 25-hydroxycholecalciferol and 24,25-dihydroxycholecalciferol in the dog. J Clin Invest. 1978 May;61(5):1375–1383. [PMC free article] [PubMed]
  • Canterbury JM, Reiss E. Multiple immunoreactive molecular forms of parathyroid hormone in human serum. 1. Proc Soc Exp Biol Med. 1972 Sep;140(4):1393–1398. [PubMed]
  • Canterbury JM, Bricker LA, Levey GS, Kozlovskis PL, Ruiz E, Zull JE, Reiss E. Metabolism of bovine parathyroid hormone. Immunological and biological characteristics of fragments generated by liver perfusion. J Clin Invest. 1975 Jun;55(6):1245–1253. [PMC free article] [PubMed]
  • Lambert PW, Syverson BJ, Arnaud CD, Spelsberg TC. Isolation and quantitation of endogenous vitamin D and its physiologically important metabolites in human plasma by high pressure liquid chromatography. J Steroid Biochem. 1977 Sep;8(9):929–937. [PubMed]
  • Lambert PW, Toft DO, Hodgson SF, Lindmark EA, Witrak BJ, Roos BA. An improved method for the measurement of 1,25-(OH)2D3 in human plasma. Endocr Res Commun. 1978;5(4):293–310. [PubMed]
  • Kaplan MA, Canterbury JM, Gavellas G, Jaffe D, Bourgoignie JJ, Reiss E, Bricker NS. Interrelations between phosphorus, calcium, parathyroid hormone, and renal phosphate excretion in response to an oral phosphorus load in normal and uremic dogs. Kidney Int. 1978 Sep;14(3):207–214. [PubMed]
  • Slatopolsky E, Caglar S, Pennell JP, Taggart DD, Canterbury JM, Reiss E, Bricker NS. On the pathogenesis of hyperparathyroidism in chronic experimental renal insufficiency in the dog. J Clin Invest. 1971 Mar;50(3):492–499. [PMC free article] [PubMed]
  • Reiss E, Canterbury JM, Kanter A. Circulating parathyroid hormone concentration in chronic renal insufficiency. Arch Intern Med. 1969 Oct;124(4):417–422. [PubMed]
  • Arnaud CD. Hyperparathyroidism and renal failure. Kidney Int. 1973 Aug;4(2):89–95. [PubMed]
  • Freitag J, Martin KJ, Hruska KA, Anderson C, Conrades M, Ladenson J, Klahr S, Slatopolsky E. Impaired parathyroid hormone metabolism in patients with chronic renal failure. N Engl J Med. 1978 Jan 5;298(1):29–32. [PubMed]
  • Martin KJ, Hruska KA, Freitag JJ, Klahr S, Slatopolsky E. The peripheral metabolism of parathyroid hormone. N Engl J Med. 1979 Nov 15;301(20):1092–1098. [PubMed]
  • Abe M, Sherwood LM. Regulation of parathyroid hormone secretion by adrenyl cyclase. Biochem Biophys Res Commun. 1972 Jul 25;48(2):396–401. [PubMed]
  • Brown EM, Gardner DG, Windeck RA, Aurbach GD. Relationship of intracellular 3',5'-adenosine monophosphate accumulation to parathyroid hormone release from dispersed bovine parathyroid cells. Endocrinology. 1978 Dec;103(6):2323–2333. [PubMed]
  • Levey GS, Klein I. Solubilized myocardial adenylate cyclase. Restoration of histamine responsiveness by phosphatidylserine. J Clin Invest. 1972 Jun;51(6):1578–1582. [PMC free article] [PubMed]
  • Dousa TP, Code CF. Effect of histamine and its methyl derivatives on cyclic AMP metabolism in gastric mucosa and its blockade by an H2 receptor antagonist. J Clin Invest. 1974 Jan;53(1):334–337. [PMC free article] [PubMed]
  • Avioli LV, Birge SJ, Slatopolsky E. The nature of vitamin D resistance of patients with chronic renal disease. Arch Intern Med. 1969 Oct;124(4):451–454. [PubMed]
  • Coburn JW, Koppel MH, Brickman AS, Massry SG. Study of intestinal absorption of calcium in patients with renal failure. Kidney Int. 1973 Apr;3(4):264–272. [PubMed]
  • Schiffl H, Binswanger U. Calcium ATPase and intestinal calcium transport in uremic rats. Am J Physiol. 1980 May;238(5):G424–G428. [PubMed]
  • Henry HL, Midgett RJ, Norman AW. Regulation of 25-hydroxyvitamin D3-1-hydroxylase in vivo. J Biol Chem. 1974 Dec 10;249(23):7584–7592. [PubMed]
  • Boyle IT, Gray RW, DeLuca HF. Regulation by calcium of in vivo synthesis of 1,25-dihydroxycholecalciferol and 21,25-dihydroxycholecalciferol. Proc Natl Acad Sci U S A. 1971 Sep;68(9):2131–2134. [PubMed]
  • Tanaka Y, Deluca HF. The control of 25-hydroxyvitamin D metabolism by inorganic phosphorus. Arch Biochem Biophys. 1973 Feb;154(2):566–574. [PubMed]
  • Ribovich ML, DeLuca HF. Effect of dietary calcium and phosphorus on intestinal calcium absorption and vitamin D metabolism. Arch Biochem Biophys. 1978 May;188(1):145–156. [PubMed]
  • Chertow BS, Baylink DJ, Wergedal JE, Su MH, Norman AW. Decrease in serum immunoreactive parathyroid hormone in rats and in parathyroid hormone secretion in vitro by 1,25-dihydroxycholecalciferol. J Clin Invest. 1975 Sep;56(3):668–678. [PMC free article] [PubMed]
  • Coburn JW, Brickman AS, Hartenbower DL, Norman AW. Intestinal phosphate absorption in normal and uremic man: effects of 1,25(OH)2-vitamin D3 and 1alpha(OH)-vitamin D3. Adv Exp Med Biol. 1977;81:549–557. [PubMed]
  • Birge SJ, Haddad JG. 25-hydroxycholecalciferol stimulation of muscle metabolism. J Clin Invest. 1975 Nov;56(5):1100–1107. [PMC free article] [PubMed]
  • Bonjour JP, Preston C, Fleisch H. Effect of 1,25-dihydroxyvitamin D3 on the renal handling of Pi in thyroparathyroidectomized rats. J Clin Invest. 1977 Dec;60(6):1419–1428. [PMC free article] [PubMed]
  • Swenson RS, Weisinger JR, Ruggeri JL, Reaven GM. Evidence that parathyroid hormone is not required for phosphate homeostasis in renal failure. Metabolism. 1975 Feb;24(2):199–204. [PubMed]

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