A. Abbreviations, Adrenodoxin-adrenodoxin reductase; ACE: Angiotensin-converting enzyme; ACTH: Adrenocorticotropic hormone; ANCOVA: Analysis of covariance; Ang II: Angiotensin II; ANOVA: Analysis of variance

. Asis, Aldosterone synthase inhibitors; AUC: Area under curve; bpm: Beats per minute; BUN: Blood urea nitrogen; C Cr : Creatinine clearance; C max : Maximum plasma concentrations; CI: Confidence interval

H. Joffe and G. Adler, Effect of Aldosterone and Mineralocorticoid Receptor Blockade on Vascular Inflammation, Heart Failure Reviews, vol.101, issue.6, pp.31-37, 2005.
DOI : 10.1007/s10741-005-2346-0

B. Pitt, F. Zannad, W. Remme, R. Cody, A. Castaigne et al., The Effect of Spironolactone on Morbidity and Mortality in Patients with Severe Heart Failure, New England Journal of Medicine, vol.341, issue.10, pp.709-717, 1999.
DOI : 10.1056/NEJM199909023411001

B. Pitt, W. Remme, F. Zannad, J. Neaton, F. Martinez et al., Eplerenone, a Selective Aldosterone Blocker, in Patients with Left Ventricular Dysfunction after Myocardial Infarction, New England Journal of Medicine, vol.348, issue.14, pp.1309-1321, 2003.
DOI : 10.1056/NEJMoa030207

F. Zannad, J. Mcmurray, H. Krum, D. Van-veldhuisen, K. Swedberg et al., Eplerenone in Patients with Systolic Heart Failure and Mild Symptoms, New England Journal of Medicine, vol.364, issue.1, pp.11-21, 2011.
DOI : 10.1056/NEJMoa1009492

J. Laragh, Vasoconstriction-volume analysis for understanding and treating hypertension: The use of renin and aldosterone profiles, The American Journal of Medicine, vol.55, issue.3, pp.261-274, 1973.
DOI : 10.1016/0002-9343(73)90128-9

L. Ramsay, J. Hettiarachchi, R. Fraser, and J. Morton, Amiloride, spironolactone, and potassium chloride in thiazide-treated hypertensive patents, Clinical Pharmacology and Therapeutics, vol.27, issue.4, pp.533-543, 1980.
DOI : 10.1038/clpt.1980.75

T. Chun and J. Pratt, Nongenomic Renal Effects of Aldosterone: Dependency on NO and Genomic Actions, Hypertension, vol.47, issue.4, pp.636-637, 2006.
DOI : 10.1161/01.HYP.0000205225.88721.2c

A. Mihailidou and J. Funder, Nongenomic effects of mineralocorticoid receptor activation in the cardiovascular system, Steroids, vol.70, issue.5-7, pp.347-351, 2005.
DOI : 10.1016/j.steroids.2005.02.004

A. Struthers, Aldosterone escape during ACE inhibitor therapy in chronic heart failure, European Heart Journal, vol.16, issue.suppl N, pp.103-106, 1995.
DOI : 10.1093/eurheartj/16.suppl_N.103

J. Staessen, P. Lijnen, R. Fagard, L. Verschueren, and A. A. , RISE IN PLASMA CONCENTRATION OF ALDOSTERONE DURING LONG-TERM ANGIOTENSIN II SUPPRESSION, Journal of Endocrinology, vol.91, issue.3, pp.457-465, 1981.
DOI : 10.1677/joe.0.0910457

M. Taves, C. Gomez-sanchez, and K. Soma, Extra-adrenal glucocorticoids and mineralocorticoids: evidence for local synthesis, regulation, and function, AJP: Endocrinology and Metabolism, vol.301, issue.1, pp.11-24, 2011.
DOI : 10.1152/ajpendo.00100.2011

URL : http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3275156

J. Silvestre, C. Heymes, A. Oubenaissa, V. Robert, B. Aupetit-faisant et al., Activation of Cardiac Aldosterone Production in Rat Myocardial Infarction : Effect of Angiotensin II Receptor Blockade and Role in Cardiac Fibrosis, Circulation, vol.99, issue.20, pp.2694-2701, 1999.
DOI : 10.1161/01.CIR.99.20.2694

P. White, Aldosterone synthase deficiency and related disorders, Molecular and Cellular Endocrinology, vol.217, issue.1-2, pp.81-87, 2004.
DOI : 10.1016/j.mce.2003.10.013

J. Veldhuis and J. Melby, Isolated Aldosterone Deficiency in Man: Acquired and Inborn Errors in the Biosynthesis or Action of Aldosterone*, Endocrine Reviews, vol.2, issue.4, pp.495-517, 1981.
DOI : 10.1210/edrv-2-4-495

E. Meredith, G. Ksander, L. Monovich, J. Papillon, Q. Liu et al., Discovery and in Vivo Evaluation of Potent Dual CYP11B2 (Aldosterone Synthase) and CYP11B1 Inhibitors, ACS Medicinal Chemistry Letters, vol.4, issue.12, pp.1203-1207, 2013.
DOI : 10.1021/ml400324c

T. Hakki and R. Bernhardt, CYP17- and CYP11B-dependent steroid hydroxylases as drug development targets, Pharmacology & Therapeutics, vol.111, issue.1, pp.27-52, 2006.
DOI : 10.1016/j.pharmthera.2005.07.006

X. Bertagna, R. Pivonello, M. Fleseriu, Y. Zhang, P. Robinson et al., LCI699, a Potent 11??-hydroxylase Inhibitor, Normalizes Urinary Cortisol in Patients With Cushing's Disease: Results From a Multicenter, Proof-of-Concept Study, The Journal of Clinical Endocrinology & Metabolism, vol.99, issue.4, pp.1375-1383, 2014.
DOI : 10.1210/jc.2013-2117

D. Lasala, Y. Shibanaka, and A. Jeng, Coexpression of CYP11B2 or CYP11B1 with adrenodoxin and adrenodoxin reductase for assessing the potency and selectivity of aldosterone synthase inhibitors, Analytical Biochemistry, vol.394, issue.1, pp.56-61, 2009.
DOI : 10.1016/j.ab.2009.07.025

D. Rigel, F. Fu, M. Beil, C. Hu, G. Liang et al., Pharmacodynamic and Pharmacokinetic Characterization of the Aldosterone Synthase Inhibitor FAD286 in Two Rodent Models of Hyperaldosteronism: Comparison with the 11??-Hydroxylase Inhibitor Metyrapone, Journal of Pharmacology and Experimental Therapeutics, vol.334, issue.1, pp.232-243, 2010.
DOI : 10.1124/jpet.110.167148

J. Bohlender, A. Fukamizu, A. Lippoldt, T. Nomura, R. Dietz et al., High Human Renin Hypertension in Transgenic Rats, Hypertension, vol.29, issue.1, pp.428-434, 1997.
DOI : 10.1161/01.HYP.29.1.428

R. St-jacques, S. Toulmond, A. Auger, C. Binkert, W. Cromlish et al., Characterization of a stable, hypertensive rat model suitable for the consecutive evaluation of human renin inhibitors, Journal of the Renin-Angiotensin-Aldosterone System, vol.10, issue.3, pp.133-145, 2011.
DOI : 10.1177/1470320310392618

K. Gough, M. Hutchison, O. Keene, W. Byrom, S. Ellis et al., Assessment of Dose Proportionality: Report from the Statisticians in the Pharmaceutical Industry/Pharmacokinetics UK Joint Working Party, Therapeutic Innovation & Regulatory Science, vol.29, issue.3, pp.1039-1048, 1995.
DOI : 10.1177/009286159502900324

T. Cai, S. Stribling, X. Tong, L. Xu, T. Wisniewski et al., Rhesus monkey model for concurrent analyses of in vivo selectivity, pharmacokinetics and pharmacodynamics of aldosterone synthase inhibitors, Journal of Pharmacological and Toxicological Methods, vol.71, 2014.
DOI : 10.1016/j.vascn.2014.09.011

Q. Hu, L. Yin, and R. Hartmann, Aldosterone Synthase Inhibitors as Promising Treatments for Mineralocorticoid Dependent Cardiovascular and Renal Diseases, Journal of Medicinal Chemistry, vol.57, issue.12
DOI : 10.1021/jm401430e

T. Berl, S. Linas, G. Aisenbrey, and R. Anderson, On the Mechanism of Polyuria in Potassium Depletion, Journal of Clinical Investigation, vol.60, issue.3, pp.620-625, 1977.
DOI : 10.1172/JCI108813

A. Fiebeler, J. Nussberger, E. Shagdarsuren, S. Rong, G. Hilfenhaus et al., Aldosterone Synthase Inhibitor Ameliorates Angiotensin II-Induced Organ Damage, Circulation, vol.111, issue.23, pp.3087-3094, 2005.
DOI : 10.1161/CIRCULATIONAHA.104.521625

L. Min, M. Mogi, J. Li, J. Iwanami, M. Iwai et al., Aldosterone and Angiotensin II Synergistically Induce Mitogenic Response in Vascular Smooth Muscle Cells, Circulation Research, vol.97, issue.5, pp.434-442, 2005.
DOI : 10.1161/01.RES.0000180753.63183.95

A. Montezano, G. Callera, A. Yogi, Y. He, R. Tostes et al., Aldosterone and Angiotensin II Synergistically Stimulate Migration in Vascular Smooth Muscle Cells Through c-Src-Regulated Redox-Sensitive RhoA Pathways, Arteriosclerosis, Thrombosis, and Vascular Biology, vol.28, issue.8, pp.1511-1518, 2008.
DOI : 10.1161/ATVBAHA.108.168021

E. Gomez-sanchez, The mammalian mineralocorticoid receptor: tying down a promiscuous receptor, Experimental Physiology, vol.159, issue.1, pp.13-18, 2010.
DOI : 10.1113/expphysiol.2008.045914

L. Yin, Q. Hu, J. Emmerich, M. Lo, E. Metzger et al., Novel Pyridyl- or Isoquinolinyl-Substituted Indolines and Indoles as Potent and Selective Aldosterone Synthase Inhibitors, Journal of Medicinal Chemistry, vol.57, issue.12, pp.5179-5189, 2014.
DOI : 10.1021/jm500140c

M. Azizi, L. Amar, and J. Menard, Aldosterone synthase inhibition in humans, Nephrology Dialysis Transplantation, vol.28, issue.1, pp.36-43, 2013.
DOI : 10.1093/ndt/gfs388

S. Berger, M. Bleich, W. Schmid, T. Cole, J. Peters et al., Mineralocorticoid receptor knockout mice: Pathophysiology of Na+ metabolism, Proceedings of the National Academy of Sciences, vol.95, issue.16, pp.9424-9429, 1998.
DOI : 10.1073/pnas.95.16.9424

M. Bleich, R. Warth, M. Schmidt-hieber, A. Schulz-baldes, P. Hasselblatt et al., Rescue of the mineralocorticoid receptor knock-out mouse, Pfl???gers Archiv European Journal of Physiology, vol.438, issue.3, pp.245-254, 1999.
DOI : 10.1007/s004240050906

N. Makhanova, M. Sequeira-lopez, R. Gomez, H. Kim, and O. Smithies, Disturbed Homeostasis in Sodium-Restricted Mice Heterozygous and Homozygous for Aldosterone Synthase Gene Disruption, Hypertension, vol.48, issue.6, pp.1151-1159, 2006.
DOI : 10.1161/01.HYP.0000249902.09036.e7

O. Neil, R. Helman, and S. , Transport characteristics of renal collecting tubules: influences of DOCA and diet, Am J Physiol, vol.233, pp.544-558, 1977.

L. Peterson and F. Wright, Effect of sodium intake on renal potassium excretion, Am J Physiol, vol.233, pp.225-234, 1977.

D. Calhoun, W. White, H. Krum, W. Guo, G. Bermann et al., Effects of a Novel Aldosterone Synthase Inhibitor for Treatment of Primary Hypertension: Results of a Randomized, Double-Blind, Placebo- and Active-Controlled Phase 2 Trial, Circulation, vol.124, issue.18, pp.1945-1955, 2011.
DOI : 10.1161/CIRCULATIONAHA.111.029892

R. Brown, J. Quirk, and P. Kirkpatrick, Eplerenone, Nature Reviews Drug Discovery, vol.144, issue.3, pp.177-178, 2003.
DOI : 10.1038/nrd1039

A. Mihailidou, L. Loan, T. Mardini, M. Funder, and J. , Glucocorticoids Activate Cardiac Mineralocorticoid Receptors During Experimental Myocardial Infarction, Hypertension, vol.54, issue.6, pp.1306-1312, 2009.
DOI : 10.1161/HYPERTENSIONAHA.109.136242

R. Fischer, R. Dechend, A. Gapelyuk, E. Shagdarsuren, K. Gruner et al., Angiotensin II-induced sudden arrhythmic death and electrical remodeling, AJP: Heart and Circulatory Physiology, vol.293, issue.2, pp.1242-1253, 2007.
DOI : 10.1152/ajpheart.01400.2006

D. Young, Quantitative analysis of aldosterone's role in potassium regulation, Am J Physiol, vol.255, pp.811-822, 1988.

R. Kazlauskaite, A. Evans, C. Villabona, T. Abdu, A. B. Atkinson et al., Corticotropin Tests for Hypothalamic-Pituitary- Adrenal Insufficiency: A Metaanalysis, The Journal of Clinical Endocrinology & Metabolism, vol.93, issue.11, pp.4245-4253, 2008.
DOI : 10.1210/jc.2008-0710

W. Coppage, . Jr, D. Island, M. Smith, and G. Liddle, INHIBITION OF ALDOSTERONE SECRETION AND MODIFICATION OF ELECTROLYTE EXCRETION IN MAN BY A CHEMICAL INHIBITOR OF 11??-HYDROXYLATION*???, Journal of Clinical Investigation, vol.38, issue.12, pp.2101-2110, 1959.
DOI : 10.1172/JCI103988

G. Liddle, D. Island, E. Lance, and A. Harris, ALTERATIONS OF ADRENAL STEROID PATTERNS IN MAN RESULTING FROM TREATMENT WITH A CHEMICAL INHIBITOR OF 11 ??HYDROXYLATION, The Journal of Clinical Endocrinology & Metabolism, vol.18, issue.8, pp.906-912, 1958.
DOI : 10.1210/jcem-18-8-906

W. White, D. Calhoun, H. Krum, W. Guo, A. Trapani et al., BLOCKADE OF ALDOSTERONE PRODUCTION AS A NOVEL APPROACH TO THE MANAGEMENT OF HIGH BLOOD PRESSURE: EFFICACY AND TOLERABILITY OF THE ALDOSTERONE SYNTHASE INHIBITOR LCI699 IN PATIENTS WITH STAGE 1-2 HYPERTENSION, Journal of the American College of Cardiology, vol.55, issue.10, pp.61-582, 2010.
DOI : 10.1016/S0735-1097(10)60583-9

L. Amar, M. Azizi, J. Menard, S. Peyrard, C. Watson et al., Aldosterone Synthase Inhibition With LCI699: A Proof-of-Concept Study in Patients With Primary Aldosteronism, Hypertension, vol.56, issue.5, pp.831-838, 2010.
DOI : 10.1161/HYPERTENSIONAHA.110.157271

B. Biller, A. Grossman, P. Stewart, S. Melmed, X. Bertagna et al., Treatment of Adrenocorticotropin-Dependent Cushing???s Syndrome: A Consensus Statement, The Journal of Clinical Endocrinology & Metabolism, vol.93, issue.7, pp.2454-2462, 2008.
DOI : 10.1210/jc.2007-2734