Aldosterone synthase inhibition for the treatment of hypertension and the derived mechanistic requirements for a new therapeutic strategy

Journal of Hypertension

Volumn 31, Issue 10, 2013, Pages 2085-2093

  Schumacher, Christoph D ^a   Steele, Ronald E ^b   Brunner, Hans R ^c  

^a NOVARTIS PHARMA AG   (Switzerland)

^b NONE

^c NONE   (Switzerland)

Author keywords

Aldosterone synthase; Endocrine; Feedback; Hypertension; Hypothalamo hypophyseal system

Indexed keywords

ALDOSTERONE; ALDOSTERONE SYNTHASE; ANTIHYPERTENSIVE AGENT; CORTICOTROPIN; CORTODOXONE; DEOXYCORTICOSTERONE; EPLERENONE; FADROZOLE; HYDROCORTISONE; LCI 699; OXYGENASE INHIBITOR; PLACEBO; POTASSIUM; SODIUM; STEROID 11BETA MONOOXYGENASE; UNCLASSIFIED DRUG;

ADRENAL GLAND; ALDOSTERONE BLOOD LEVEL; ARTICLE; BLOOD PRESSURE MONITORING; BLOOD PRESSURE REGULATION; BLOOD SAMPLING; CORTICOTROPIN BLOOD LEVEL; DOSE RESPONSE; ENZYME INHIBITION; ESSENTIAL HYPERTENSION; EXERCISE TEST; FEEDBACK SYSTEM; HUMAN; HYDROCORTISONE BLOOD LEVEL; HYPERTENSION; HYPOTHALAMUS HYPOPHYSIS ADRENAL SYSTEM; MULTICENTER STUDY (TOPIC); PHASE 2 CLINICAL TRIAL (TOPIC); PLASMA RENIN ACTIVITY; POTASSIUM BLOOD LEVEL; PRIMARY HYPERALDOSTERONISM; PRIORITY JOURNAL; RANDOMIZED CONTROLLED TRIAL (TOPIC); RENIN ANGIOTENSIN ALDOSTERONE SYSTEM; RESISTANT HYPERTENSION; SODIUM BLOOD LEVEL; STEROIDOGENESIS;

ADOLESCENT; ADRENAL GLANDS; ADULT; AGED; ALDOSTERONE; ALDOSTERONE SYNTHASE; ANTIHYPERTENSIVE AGENTS; BIOLOGICAL MARKERS; BLOOD PRESSURE; DESOXYCORTICOSTERONE; DOUBLE-BLIND METHOD; FEMALE; HUMANS; HYDROCORTISONE; HYPERALDOSTERONISM; HYPERTENSION; HYPOTHALAMUS; IMIDAZOLES; MALE; MIDDLE AGED; PROSPECTIVE STUDIES; PYRIDINES; RENIN-ANGIOTENSIN SYSTEM; STEROID 11-BETA-HYDROXYLASE; TREATMENT OUTCOME; YOUNG ADULT;

EID: 84884359989     PISSN: 02636352     EISSN: 14735598     Source Type: Journal    
DOI: 10.1097/HJH.0b013e328363570c     Document Type: Article

References (24)

1. Brunner HR, Laragh JH, Baer L, Newton MA, Goodwin FT, Krakoff LR, et al. Essential hypertension: renin and aldosterone, heart attack and stroke. N Engl J Med 1972; 286:441-449.
2. Pitt B, Zannad F, Remme WJ, Cody R, Castaigne A, Perez A, et al. The effect of spironolactone on morbidity and mortality in patients with severe heart failure. Randomized Aldactone Evaluation Study Investigators. N Engl J Med 1999; 341:709-717.
3. Pitt B, Remme W, Zannad F, Neaton J, Martinez F, Roniker B, et al. Eplerenone, a selective aldosterone blocker, in patients with left ventricular dysfunction after myocardial infarction. N Engl J Med 2003; 348:1309-1321; erratum 348: 2271.
4. Zannad F, McMurray JJ, Krum H, van Veldhuisen DJ, Swedberg K, Shi H, et al. Eplerenone in patients with systolic heart failure and mild symptoms. N Engl J Med 2011; 364:11-21.
5. Chai W, Danser AH. Why are mineralocorticoid receptor antagonists cardioprotective? Naunyn Schmiedebergs Arch Pharmacol 2006; 374:153-162.
6. Schiffrin EL. Effects of aldosterone on the vasculature. Hypertension 2006; 47:312-318.
7. Santen RJ, Brodie H, Simpson ER, Siiteri PJ, Brodie A. History of aromatase: saga of an important biological mediator and therapeutic target. Endocr Rev 2009; 30:343-375.
8. Browne LJ, Gude C, Rodriguez H, Steele RE, Bhatnager A. Fadrozole hydrochloride: a potent, selective, nonsteroidal inhibitor of aromatase for the treatment of estrogen-dependent disease. J Med Chem 1991; 34:725-736.
9. Lipton A, Harvey HA, Demers LM, Hanagan JR, Mulagha MT, Kochak GM, et al. A phase I trial of CGS 16949A. A new aromatase inhibitor. Cancer 1990; 65:1279-1285.
10. Menard J, Pascoe L. Can the dextroenantiomer of the aromatase inhibitor fadrozole be useful for clinical investigation of aldosterone-synthase inhibition? J Hypertens 2006; 24:993-997.
11. Hurwitz S, Cohen RJ, Williams GH. Diurnal variation of aldosterone and plasma renin activity: timing relation to melatonin and cortisol and consistency after prolonged bed rest. J Appl Physiol 2004; 96:1406-1414.
12. Orth DN, Kovacs WJ. The adrenal cortex. In Wilson JD, Foster DW, Kronenberg HM, Larsen PR, editors. Williams textbook of endocrinology, 9th ed Philadelphia, PA: WB Saunders; 1998. pp. 517-518.
13. Calhoun DA, White WB, Krum H, Guo W, Bermann G, Trapani A, et al. Effects of a novel aldosterone synthase inhibitor for treatment of primary hypertension: results of a randomized, double-blind, placeboand active-controlled phase 2 trial. Circulation 2011; 124:1945-1955.
14. Amar L, Azizi M, Menard J, Peyrard S, Watson C, Plouin PF. Aldosterone synthase inhibition with LCI699: a proof-of-concept study in patients with primary aldosteronism. Hypertension 2010; 56:831-838.
15. Andersen K, Hartman D, Peppard T, Hermann D, Van Ess P, Lefkowitz M, Trapani A. The effects of aldosterone synthase inhibition on aldosterone and cortisol in patients with hypertension: a phase II, randomized, double-blind, placebo-controlled, multicenter study. J Clin Hypertens (Greenwich) 2012; 14:580-587.
16. Karns AD, Bral JM, Hartmann D, Peppard T, Schumacher C. Study of aldosterone synthase inhibition as an add-on therapy in resistant hypertension. J Clin Hypertens (Greenwich) 2013; 15:186-192.
17. Trunet PF, Mueller PH, Girard F, Aupetit B, Bhatnagar AS, Zognbi F, et al. The effects of fadrozole hydrochloride on aldosterone secretion in healthy male subjects. J Clin Endocrinol Metab 1992; 74:571-576.
18. Dunn JF, Nisula BC, Rodbard D. Transport of steroid hormones: binding of 21 endogenous steroids to both testosterone-binding globulin and corticosteroid-binding globulin in human plasma. J Clin Endocrinol Metab 1981; 53:58-68.
19. Mendel CM. The free hormone hypothesis: a physiologically based mathematical model. Endocr Rev 1989; 10:232-274.
20. Rupprecht R, Reul JM, van Steensel B, Spengler D, Soder M, Berning B, et al. Pharmacological and functional characterization of human mineralocorticoid and glucocorticoid receptor ligands. Eur J Pharmacol 1993; 247:145-154.
21. Hellal-Levy C, Couette B, Fagart J, Souque A, Gomez-Sanchez C, Rafestin-Oblin M. Specific hydroxylations determine selective corticosteroid recognition by human glucocorticoid and mineralocorticoid receptors. FEBS Lett 1999; 464:9-13.
22. Biller BM, Grossman AB, Stewart PM, Melmed S, Bertagna X, Bertheret J, et al. Treatment of adrenocorticotropin-dependent Cushing's syndrome: a consensus statement. J Clin Endocrinol Metab 2008; 93:2454-2462.
23. Sonino N, Boscaro M. Medical therapy for Cushing's disease. Endocrinol Metab Clin North Am 1999; 28:211-222.
24. Demers LM, Melby JC, Wilson TE, Lipton A, Harvey HA, Santen RJ. The effects of CGS 16949A, an aromatase inhibitor on adrenal mineralocorticoid biosynthesis. J Clin Endocrinol Metab 1990; 70: 1162-1166.