Treatment of Primary Aldosteronism With mTORC1 Inhibitors.
- Trinh B Department of Endocrinology, Diabetes and Metabolism, University Hospital Basel, and Department of Biomedicine, University of Basel, Basel, Switzerland.
- Hepprich M Department of Endocrinology, Diabetes and Metabolism, University Hospital Basel, and Department of Biomedicine, University of Basel, Basel, Switzerland.
- Betz MJ Department of Endocrinology, Diabetes and Metabolism, University Hospital Basel, and Department of Biomedicine, University of Basel, Basel, Switzerland.
- Burkard T European Society of Hypertension Centre of Excellence, Medical Outpatient Department, and Department of Cardiology, University Hospital Basel, Basel, Switzerland.
- Cavelti-Weder C Department of Endocrinology, Diabetes and Metabolism, University Hospital Basel, and Department of Biomedicine, University of Basel, Basel, Switzerland.
- Seelig E Department of Endocrinology, Diabetes and Metabolism, University Hospital Basel, and Department of Biomedicine, University of Basel, Basel, Switzerland.
- Meienberg F Clinic of Endocrinology and Diabetology, Kantonsspital Baselland, Liestal, Switzerland.
- Kratschmar DV Department of Pharmaceutical Sciences, University of Basel, Basel, Switzerland.
- Beuschlein F Klinik für Endokrinologie, Diabetologie und Klinische Ernährung, Universitätsspital Zürich, Zürich, Switzerland.
- Reincke M Medizinische Klinik und Poliklinik IV, Klinikum der Universität München, Munich, Germany.
- Odermatt A Department of Pharmaceutical Sciences, University of Basel, Basel, Switzerland.
- Hall MN Biozentrum, University of Basel, Basel, Switzerland.
- Donath MY Department of Endocrinology, Diabetes and Metabolism, University Hospital Basel, and Department of Biomedicine, University of Basel, Basel, Switzerland.
- Swierczynska MM Biozentrum, University of Basel, Basel, Switzerland.
- 2019-05-16
Published in:
- The Journal of clinical endocrinology and metabolism. - 2019
Adult
Aldosterone
Angiotensin II
Animals
Blood Pressure
Everolimus
Female
Hemodynamics
Humans
Hyperaldosteronism
Male
Mechanistic Target of Rapamycin Complex 1
Mice
Mice, 129 Strain
Mice, Inbred BALB C
Mice, Inbred C57BL
Middle Aged
Pilot Projects
Proof of Concept Study
Renin
Sirolimus
English
CONTEXT
Mammalian target of rapamycin complex 1 (mTORC1) activity is often increased in the adrenal cortex of patients with primary aldosteronism (PA), and mTORC1 inhibition decreases aldosterone production in adrenocortical cells, suggesting the mTORC1 pathway as a target for treatment of PA.
OBJECTIVE
To investigate the effect of mTORC1 inhibition on adrenal steroid hormones and hemodynamic parameters in mice and in patients with PA.
DESIGN
(i) Plasma aldosterone, corticosterone, and angiotensin II (Ang II) were measured in mice treated for 24 hours with vehicle or rapamycin. (ii) Plasma aldosterone levels after a saline infusion test, plasma renin, and 24-hour urine steroid hormone metabolome and hemodynamic parameters were measured during an open-label study in 12 patients with PA, before and after 2 weeks of treatment with everolimus and after a 2-week washout.
MAIN OUTCOME MEASURES
(i) Change in plasma aldosterone levels. (ii) Change in other steroid hormones, renin, Ang II, and hemodynamic parameters.
RESULTS
Treatment of mice with rapamycin significantly decreased plasma aldosterone levels (P = 0.007). Overall, treatment of PA patients with everolimus significantly decreased blood pressure (P < 0.05) and increased renin levels (P = 0.001) but did not decrease aldosterone levels significantly. However, prominent reduction of aldosterone levels upon everolimus treatment was observed in four patients.
CONCLUSION
In mice, mTORC1 inhibition was associated with reduced plasma aldosterone levels. In patients with PA, 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.
Mammalian target of rapamycin complex 1 (mTORC1) activity is often increased in the adrenal cortex of patients with primary aldosteronism (PA), and mTORC1 inhibition decreases aldosterone production in adrenocortical cells, suggesting the mTORC1 pathway as a target for treatment of PA.
OBJECTIVE
To investigate the effect of mTORC1 inhibition on adrenal steroid hormones and hemodynamic parameters in mice and in patients with PA.
DESIGN
(i) Plasma aldosterone, corticosterone, and angiotensin II (Ang II) were measured in mice treated for 24 hours with vehicle or rapamycin. (ii) Plasma aldosterone levels after a saline infusion test, plasma renin, and 24-hour urine steroid hormone metabolome and hemodynamic parameters were measured during an open-label study in 12 patients with PA, before and after 2 weeks of treatment with everolimus and after a 2-week washout.
MAIN OUTCOME MEASURES
(i) Change in plasma aldosterone levels. (ii) Change in other steroid hormones, renin, Ang II, and hemodynamic parameters.
RESULTS
Treatment of mice with rapamycin significantly decreased plasma aldosterone levels (P = 0.007). Overall, treatment of PA patients with everolimus significantly decreased blood pressure (P < 0.05) and increased renin levels (P = 0.001) but did not decrease aldosterone levels significantly. However, prominent reduction of aldosterone levels upon everolimus treatment was observed in four patients.
CONCLUSION
In mice, mTORC1 inhibition was associated with reduced plasma aldosterone levels. In patients with PA, 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.
- Language
-
- English
- Open access status
- bronze
- Identifiers
-
- DOI 10.1210/jc.2019-00563
- PMID 31087053
- Persistent URL
- https://sonar.ch/global/documents/209202
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