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