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J Clin Endocrinol Metab. 2019 May 14. pii: jc.2019-00563. doi: 10.1210/jc.2019-00563. [Epub ahead of print]

Treatment of Primary Aldosteronism with mTORC1 Inhibitors.

Author information

1
Department of Endocrinology, Diabetes and Metabolism, University Hospital Basel and Department of Biomedicine, University of Basel, Basel, Switzerland.
2
ESH Hypertension Center of Excellence, Medical Outpatient Department and Cardiology, University Hospital Basel, Basel, Switzerland.
3
Clinic of Endocrinology and Diabetology, Kantonsspital Baselland, Liestal, Switzerland.
4
Department of Pharmaceutical Sciences, University of Basel, Basel, Switzerland.
5
Klinik für Endokrinologie, Diabetologie und Klinische Ernährung, Universitätsspital Zürich, Zürich, Switzerland.
6
Medizinische Klinik und Poliklinik IV, Klinikum der Universität München, Munich, Germany.
7
Biozentrum, University of Basel, Basel, Switzerland.

Abstract

CONTEXT:

mTORC1 activity is often increased in the adrenal cortex of patients with primary aldosteronism and mTORC1 inhibition decreases aldosterone production in adrenocortical cells, suggesting the mTORC1 pathway as a possible target for treatment of primary aldosteronism.

OBJECTIVE:

To investigate the effect of mTORC1 inhibition on adrenal steroid hormones and hemodynamic parameters in mice and in patients with primary aldosteronism.

DESIGN:

(i) Plasma aldosterone, corticosterone and angiotensin II were measured in mice treated for 24 hours with vehicle or rapamycin. (ii) Plasma aldosterone levels after a saline infusion test, plasma renin, 24-hour urine steroid hormone metabolome and hemodynamic parameters were measured during an open-label study in 12 patients with primary aldosteronism before and after two-weeks of treatment with everolimus and after a two-week washout period.

MAIN OUTCOME MEASURES:

(i) Change in plasma aldosterone levels. (ii) Change in other steroid hormones, renin, angiotensin II and hemodynamic parameters.

RESULTS:

Treatment of mice with rapamycin significantly decreased plasma aldosterone levels (P = 0.007). Overall, treatment of primary aldosteronism patients with everolimus significantly decreased blood pressure (P < 0.05) and increased renin levels (P = 0.001) but did not lead to a significant reduction in aldosterone levels. However, prominent reduction of aldosterone levels upon everolimus treatment was observed in 4 out of 12 patients.

CONCLUSION:

In mice, mTORC1 inhibition was associated with reduced plasma aldosterone levels. In patients with primary aldosteronism, mTORC1 inhibition was associated with improved blood pressure and renin suppression. In addition, mTORC1 inhibition appeared to reduce plasma aldosterone in a subset of patients.

PMID:
31087053
DOI:
10.1210/jc.2019-00563

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