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

  • Integrative physiology
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Abstract

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.

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Acknowledgements

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).

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There was no conflict of interest.

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    Authors and Affiliations

    1. Service of Nephrology and Hypertension, Department of Medicine, Lausanne University Hospital, Lausanne, Switzerland

      Marie-Eve Muller, Valentina Forni Ogna, Marc Maillard, Carole Zweiacker, Christiane Anex, Grégoire Wuerzner, Michel Burnier & Olivier Bonny

    2. Department of Pharmacology and Toxicology, University of Lausanne, Lausanne, Switzerland

      Candice Stoudmann & Olivier Bonny

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    1. Marie-Eve Muller
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    Correspondence to Olivier Bonny.

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    Marie-Eve Muller, Valentina Forni Ogna, Michel Burnier and Olivier Bonny contributed equally to this work.

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    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)

    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)

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    Muller, ME., Forni Ogna, V., Maillard, M. et al. Furosemide stimulation of parathormone in humans: role of the calcium-sensing receptor and the renin-angiotensin system. Pflugers Arch - Eur J Physiol 467, 2413–2421 (2015). https://doi.org/10.1007/s00424-015-1714-4

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