Pflügers Archiv - European Journal of Physiology

, Volume 467, Issue 12, pp 2413–2421 | Cite as

Furosemide stimulation of parathormone in humans: role of the calcium-sensing receptor and the renin-angiotensin system

  • Marie-Eve Muller
  • Valentina Forni Ogna
  • Marc Maillard
  • Candice Stoudmann
  • Carole Zweiacker
  • Christiane Anex
  • Grégoire Wuerzner
  • Michel Burnier
  • Olivier Bonny
Integrative physiology


Interactions between sodium and calcium regulating systems are poorly characterized but clinically important. Parathyroid hormone (PTH) levels are increased shortly after furosemide treatment by an unknown mechanism, and this effect is blunted by the previous administration of a calcimimetic in animal studies. Here, we explored further the possible underlying mechanisms of this observation in a randomized crossover placebo-controlled study performed in 18 human males. Volunteers took either cinacalcet (60 mg) or placebo and received a 20 mg furosemide injection 3 h later. Plasma samples were collected at 15-min intervals and analyzed for intact PTH, calcium, sodium, potassium, magnesium, phosphate, plasma renin activity (PRA), and aldosterone up to 6 h after furosemide injection. Urinary electrolyte excretion was also monitored. Subjects under placebo presented a sharp increase in PTH levels after furosemide injection. In the presence of cinacalcet, PTH levels were suppressed and marginal increase of PTH was observed. No significant changes in electrolytes and urinary excretion were identified that could explain the furosemide-induced increase in PTH levels. PRA and aldosterone were stimulated by furosemide injection but were not affected by previous cinacalcet ingestion. Expression of NKCC1, but not NKCC2, was found in parathyroid tissue. In conclusion, our results indicate that furosemide acutely stimulates PTH secretion in the absence of any detectable electrolyte changes in healthy adults. A possible direct effect of furosemide on parathyroid gland needs further studies.


Mineral metabolism Calcium-sensing receptor Renin-angiotensin-aldosterone system Cinacalcet Furosemide 



This study was funded by a grant of the National Center of Competence in Research “Kidney Control of Homeostasis” of the Swiss National Science Foundation (to OB and MB).

Conflict of interest

There was no conflict of interest.

Supplementary material

424_2015_1714_MOESM1_ESM.pdf (25 kb)
Supplemental Figure S1 Area under the curve (AUC) of plasma PTH in the different subgroups over time (H0 to H6). A significant difference is noted between the AUC of plasma PTH in furosemide injected subjects on placebo as compared to other subgroups. The significantly higher value indicates that stimulation of PTH secretion under furosemide does not occur under cinacalcet. * denotes p < 0.05 compared to P/F+. (PDF 24 kb)
424_2015_1714_MOESM2_ESM.pdf (59 kb)
Supplemental Figure S2 Plasma sodium (panel A) and potassium (panel B) over time. Values of plasma sodium and potassium remain stable in all subgroups during the whole investigation day, which denies a role of these electrolytes in plasma PTH secretion. Furosemide was injected at time 0. Values are means ± SEM. (PDF 59 kb)


  1. 1.
    Brown EM, Jones P, Adragna N (1983) Effects of ouabain on [3H]ouabain binding, 86Rb uptake, cellular sodium and potassium, and parathyroid hormone secretion in dispersed bovine parathyroid cells. Endocrinology 113(1):371–378CrossRefPubMedGoogle Scholar
  2. 2.
    Brown EM, Watson EJ, Thatcher JG, Koletsky R, Dawson-Hughes BF, Posillico JT, Shoback DM (1987) Ouabain and low extracellular potassium inhibit PTH secretion from bovine parathyroid cells by a mechanism that does not involve increases in the cytosolic calcium concentration. Metab Clin Exp 36(1):36–42CrossRefPubMedGoogle Scholar
  3. 3.
    Brown JM, Williams JS, Luther JM, Garg R, Garza AE, Pojoga LH, Ruan DT, Williams GH, Adler GK, Vaidya A (2014) Human interventions to characterize novel relationships between the renin-angiotensin-aldosterone system and parathyroid hormone. Hypertension 63(2):273–280. doi: 10.1161/HYPERTENSIONAHA.113.01910 PubMedCentralCrossRefPubMedGoogle Scholar
  4. 4.
    Brunaud L, Germain A, Zarnegar R, Rancier M, Alrasheedi S, Caillard C, Ayav A, Weryha G, Mirallie E, Bresler L (2009) Serum aldosterone is correlated positively to parathyroid hormone (PTH) levels in patients with primary hyperparathyroidism. Surgery 146(6):1035–1041. doi: 10.1016/j.surg.2009.09.041 CrossRefPubMedGoogle Scholar
  5. 5.
    Castrop H, Lorenz JN, Hansen PB, Friis U, Mizel D, Oppermann M, Jensen BL, Briggs J, Skott O, Schnermann J (2005) Contribution of the basolateral isoform of the Na-K-2Cl- cotransporter (NKCC1/BSC2) to renin secretion. Am J Physiol Ren Physiol 289(6):F1185–F1192. doi: 10.1152/ajprenal.00455.2004 CrossRefGoogle Scholar
  6. 6.
    Coe FL, Canterbury JM, Firpo JJ, Reiss E (1973) Evidence for secondary hyperparathyroidism in idiopathic hypercalciuria. J Clin Invest 52(1):134–142. doi: 10.1172/JCI107156 PubMedCentralCrossRefPubMedGoogle Scholar
  7. 7.
    el-Hajj Fuleihan G, Klerman EB, Brown EN, Choe Y, Brown EM, Czeisler CA (1997) The parathyroid hormone circadian rhythm is truly endogenous—a general clinical research center study. J Clin Endocrinol Metab 82(1):281–286PubMedGoogle Scholar
  8. 8.
    Elmgreen J, Tougaard L, Leth A, Christensen MS (1980) Elevated serum parathyroid hormone concentration during treatment with high ceiling diuretics. Eur J Clin Pharmacol 18(4):363–364CrossRefPubMedGoogle Scholar
  9. 9.
    Fischer E, Hannemann A, Rettig R, Lieb W, Nauck M, Pallauf A, Bildingmaier M, Beuschlein F, Wallaschofski H, Reincke M (2014) A high aldosterone to renin ratio is associated with high serum parathyroid hormone concentrations in the general population. J Clin Endocrinol Metab 99(3):965–971. doi: 10.1210/jc.2013-3214 PubMedGoogle Scholar
  10. 10.
    Fujita T, Chan JC, Bartter FC (1984) Effects of oral furosemide and salt loading on parathyroid function in normal subjects. Physiological basis for renal hypercalciuria. Nephron 38(2):109–114CrossRefPubMedGoogle Scholar
  11. 11.
    Grant FD, Mandel SJ, Brown EM, Williams GH, Seely EW (1992) Interrelationships between the renin-angiotensin-aldosterone and calcium homeostatic systems. J Clin Endocrinol Metab 75(4):988–992PubMedGoogle Scholar
  12. 12.
    Haegeli L, Brunner-La Rocca HP, Wenk M, Pfisterer M, Drewe J, Krahenbuhl S (2007) Sublingual administration of furosemide: new application of an old drug. Br J Clin Pharmacol 64(6):804–809. doi: 10.1111/j.1365-2125.2007.03035.x PubMedCentralPubMedGoogle Scholar
  13. 13.
    Hufnagle KG, Khan SN, Penn D, Cacciarelli A, Williams P (1982) Renal calcifications: a complication of long-term furosemide therapy in preterm infants. Pediatrics 70(3):360–363PubMedGoogle Scholar
  14. 14.
    Imura A, Tsuji Y, Murata M, Maeda R, Kubota K, Iwano A, Obuse C, Togashi K, Tominaga M, Kita N, Tomiyama K, Iijima J, Nabeshima Y, Fujioka M, Asato R, Tanaka S, Kojima K, Ito J, Nozaki K, Hashimoto N, Ito T, Nishio T, Uchiyama T, Fujimori T, Nabeshima Y (2007) alpha-Klotho as a regulator of calcium homeostasis. Science 316(5831):1615–1618. doi: 10.1126/science.1135901 CrossRefPubMedGoogle Scholar
  15. 15.
    Isales CM, Barrett PQ, Brines M, Bollag W, Rasmussen H (1991) Parathyroid hormone modulates angiotensin II-induced aldosterone secretion from the adrenal glomerulosa cell. Endocrinology 129(1):489–495. doi: 10.1210/endo-129-1-489 CrossRefPubMedGoogle Scholar
  16. 16.
    Jespersen B, Pedersen EB, Charles P, Danielsen H, Juhl H (1989) Elevated angiotensin II and vasopressin in primary hyperparathyroidism. Angiotensin II infusion studies before and after removal of the parathyroid adenoma. Acta Endocrinol (Copenh) 120(3):362–368Google Scholar
  17. 17.
    Kim YG, Kim B, Kim MK, Chung SJ, Han HJ, Ryu JA, Lee YH, Lee KB, Lee JY, Huh W, Oh HY (2001) Medullary nephrocalcinosis associated with long-term furosemide abuse in adults. Nephrol Dial Transplant : Off Publ Eur Dial Transplant Assoc - Eur Ren Assoc 16(12):2303–2309CrossRefGoogle Scholar
  18. 18.
    Maillard MP, Tedjani A, Perregaux C, Burnier M (2009) Calcium-sensing receptors modulate renin release in vivo and in vitro in the rat. J Hypertens 27(10):1980–1987. doi: 10.1097/HJH.0b013e32832f0d22 CrossRefPubMedGoogle Scholar
  19. 19.
    Maniero C, Fassina A, Guzzardo V, Lenzini L, Amadori G, Pelizzo MR, Gomez-Sanchez C, Rossi GP (2011) Primary hyperparathyroidism with concurrent primary aldosteronism. Hypertension 58(3):341–346. doi: 10.1161/HYPERTENSIONAHA.111.173948 CrossRefPubMedGoogle Scholar
  20. 20.
    Maniero C, Fassina A, Seccia TM, Toniato A, Iacobone M, Plebani M, De Caro R, Calo LA, Pessina AC, Rossi GP (2012) Mild hyperparathyroidism: a novel surgically correctable feature of primary aldosteronism. J Hypertens 30(2):390–395. doi: 10.1097/HJH.0b013e32834f0451 CrossRefPubMedGoogle Scholar
  21. 21.
    Martuseviciene G, Hofman-Bang J, Clausen T, Olgaard K, Lewin E (2011) The secretory response of parathyroid hormone to acute hypocalcemia in vivo is independent of parathyroid glandular sodium/potassium-ATPase activity. Kidney Int 79(7):742–748. doi: 10.1038/ki.2010.501 CrossRefPubMedGoogle Scholar
  22. 22.
    Mazzocchi G, Aragona F, Malendowicz LK, Nussdorfer GG (2001) PTH and PTH-related peptide enhance steroid secretion from human adrenocortical cells. Am J Physiol Endocrinol Metab 280(2):E209–E213PubMedGoogle Scholar
  23. 23.
    Ortiz-Capisano MC, Ortiz PA, Garvin JL, Harding P, Beierwaltes WH (2007) Expression and function of the calcium-sensing receptor in juxtaglomerular cells. Hypertension 50(4):737–743. doi: 10.1161/HYPERTENSIONAHA.107.095158 CrossRefPubMedGoogle Scholar
  24. 24.
    Osorio AV, Alon MM, Nichols MA, Alon US (1998) Effect of age on furosemide-induced nephrocalcinosis in the rat. Biol Neonate 73(5):306–312CrossRefPubMedGoogle Scholar
  25. 25.
    Pattaragarn A, Fox J, Alon US (2004) Effect of the calcimimetic NPS R-467 on furosemide-induced nephrocalcinosis in the young rat. Kidney Int 65(5):1684–1689. doi: 10.1111/j.1523-1755.2004.00564.x CrossRefPubMedGoogle Scholar
  26. 26.
    Pirklbauer M, Mayer G (2011) The exchangeable calcium pool: physiology and pathophysiology in chronic kidney disease. Nephrol Dial Transplant : Off Publ Eur Dial Transplant Assoc - Eur Ren Assoc 26(8):2438–2444. doi: 10.1093/ndt/gfr207 CrossRefGoogle Scholar
  27. 27.
    Reichel H, Deibert B, Geberth S, Schmidt-Gayk H, Ritz E (1992) Frusemide therapy and intact parathyroid hormone plasma concentrations in chronic renal insufficiency. Nephrol Dial Transplant : Off Publ Eur Dial Transplant Assoc - Eur Ren Assoc 7(1):8–15Google Scholar
  28. 28.
    Rejnmark L, Vestergaard P, Heickendorff L, Andreasen F, Mosekilde L (2001) Loop diuretics alter the diurnal rhythm of endogenous parathyroid hormone secretion. A randomized-controlled study on the effects of loop- and thiazide-diuretics on the diurnal rhythms of calcitropic hormones and biochemical bone markers in postmenopausal women. Eur J Clin Investig 31(9):764–772CrossRefGoogle Scholar
  29. 29.
    Rosenberg J, Pines M, Hurwitz S (1987) Response of adrenal cells to parathyroid hormone stimulation. J Endocrinol 112(3):431–437CrossRefPubMedGoogle Scholar
  30. 30.
    Saarela T, Lanning P, Koivisto M, Paavilainen T (1999) Nephrocalcinosis in full-term infants receiving furosemide treatment for congestive heart failure: a study of the incidence and 2-year follow up. Eur J Pediatr 158(8):668–672CrossRefPubMedGoogle Scholar
  31. 31.
    Stote RM, Smith LH, Wilson DM, Dube WJ, Goldsmith RS, Arnaud CD (1972) Hydrochlorothiazide effects on serum calcim and immunoreactive parathyroid hormone concentrations. Studies in normal subjects. Ann Intern Med 77(4):587–591CrossRefPubMedGoogle Scholar

Copyright information

© Springer-Verlag Berlin Heidelberg 2015

Authors and Affiliations

  • Marie-Eve Muller
    • 1
  • Valentina Forni Ogna
    • 1
  • Marc Maillard
    • 1
  • Candice Stoudmann
    • 2
  • Carole Zweiacker
    • 1
  • Christiane Anex
    • 1
  • Grégoire Wuerzner
    • 1
  • Michel Burnier
    • 1
  • Olivier Bonny
    • 1
    • 2
  1. 1.Service of Nephrology and Hypertension, Department of MedicineLausanne University HospitalLausanneSwitzerland
  2. 2.Department of Pharmacology and ToxicologyUniversity of LausanneLausanneSwitzerland

Personalised recommendations