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Horm Metab Res 2017; 49(06): 466-471
DOI: 10.1055/s-0043-101821
Endocrine Research
© Georg Thieme Verlag KG Stuttgart · New York

The Aldosterone Synthase Inhibitor FAD286 is Suitable for Lowering Aldosterone Levels in ZDF Rats but not in db/db Mice

Anja Hofmann
1   Division of Vascular Endothelium and Microcirculation, Department of Medicine III, University Hospital Carl Gustav Carus Dresden, Technische Universität Dresden, Dresden, Germany
,
Coy Brunssen
1   Division of Vascular Endothelium and Microcirculation, Department of Medicine III, University Hospital Carl Gustav Carus Dresden, Technische Universität Dresden, Dresden, Germany
,
Mirko Peitzsch
2   Division of Clinical Neurochemistry, Institute of Clinical Chemistry and Laboratory Medicine, University Hospital Carl Gustav Carus Dresden, Technische Universität Dresden, Dresden, Germany
,
Mariya Balyura
3   Department of Medicine III, University Hospital Carl Gustav Carus Dresden, Technische Universität Dresden, Dresden, Germany
,
Jennifer Mittag
1   Division of Vascular Endothelium and Microcirculation, Department of Medicine III, University Hospital Carl Gustav Carus Dresden, Technische Universität Dresden, Dresden, Germany
,
Annika Frenzel
1   Division of Vascular Endothelium and Microcirculation, Department of Medicine III, University Hospital Carl Gustav Carus Dresden, Technische Universität Dresden, Dresden, Germany
,
Anett. Jannasch
4   Cardiac Surgery, Heart Center Dresden, Technische Universität Dresden, Dresden, Germany
,
Nicholas F. Brown
5   Cardio Metabolic Diseases, Boehringer Ingelheim Pharmaceuticals Inc., Ridgefield, CT, USA
,
Steven M. Weldon
5   Cardio Metabolic Diseases, Boehringer Ingelheim Pharmaceuticals Inc., Ridgefield, CT, USA
,
Kristina K. Gueneva-Boucheva
5   Cardio Metabolic Diseases, Boehringer Ingelheim Pharmaceuticals Inc., Ridgefield, CT, USA
,
Graeme Eisenhofer
2   Division of Clinical Neurochemistry, Institute of Clinical Chemistry and Laboratory Medicine, University Hospital Carl Gustav Carus Dresden, Technische Universität Dresden, Dresden, Germany
3   Department of Medicine III, University Hospital Carl Gustav Carus Dresden, Technische Universität Dresden, Dresden, Germany
,
Stefan R. Bornstein
3   Department of Medicine III, University Hospital Carl Gustav Carus Dresden, Technische Universität Dresden, Dresden, Germany
6   Endocrinology and Diabetes, Division of Diabetes & Nutritional Sciences, Rayne Institute, Denmark Hill Campus, Faculty of Life Sciences & Medicine, Kings College London, London, UK
,
Henning Morawietz
1   Division of Vascular Endothelium and Microcirculation, Department of Medicine III, University Hospital Carl Gustav Carus Dresden, Technische Universität Dresden, Dresden, Germany
3   Department of Medicine III, University Hospital Carl Gustav Carus Dresden, Technische Universität Dresden, Dresden, Germany
› Author Affiliations
Further Information

Publication History

received 10 November 2016

accepted 12 January 2017

Publication Date:
20 April 2017 (online)

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Abstract

Inhibition of aldosterone synthase is an alternative treatment option to mineralocorticoid receptor antagonism to prevent harmful aldosterone actions. FAD286 is one of the best characterized aldosterone synthase inhibitors to date. FAD286 improves glucose tolerance and increases glucose-stimulated insulin secretion in obese and diabetic ZDF rats. However, there is limited knowledge about the dose-dependent effects of FAD286 on plasma aldosterone, corticosterone, and 11-deoxycorticosterone in ZDF rats and in db/db mice, a second important rodent model of obesity and type 2 diabetes. In addition, effects of FAD286 on plasma steroids in mice and rats are controversial. Therefore, obese Zucker diabetic fatty (ZDF) rats and db/db mice were treated with FAD286 for up to 15 weeks and plasma steroids were evaluated using highly sensitive liquid chromatography-tandem mass spectrometry. In ZDF rats, FAD286 (10 mg/kg/d) treatment resulted in nearly complete disappearance of plasma aldosterone while corticosterone levels remained unaffected and those of 11-deoxycorticosterone were increased ~4-fold compared to vehicle control. A lower dose of FAD286 (3 mg/kg/d) showed no effect on plasma aldosterone or corticosterone, but 11-deoxycorticosterone was again increased ~4-fold compared to control. In contrast to ZDF rats, a high dose of FAD286 (40 mg/kg/d) did not affect plasma aldosterone levels in db/db mice although 11-deoxycorticosterone increased ~2.5-fold. A low dose of FAD286 (10 mg/kg/d) increased plasma aldosterone without affecting corticosterone or 11-deoxycorticosterone. In conclusion, the aldosterone synthase inhibitor, FAD286, lowers plasma aldosterone in obese ZDF rats, but not in obese db/db mice.

Key words

aldosterone synthase inhibition - steroid hormones - db/db mice - ZDF rats

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