title: Aldosterone synthase inhibition in hypertension.
abstract: Hypertension is an established risk factor for stroke, premature coronary artery disease and heart failure. Control of elevated blood pressure has been shown to result in significant reduction of cardiovascular risk. Aldosterone, the final product of the renin-angiotensin-aldosterone system (RAAS), not only causes salt and water reabsorbtion in the kidneys through its effect on the mineralocorticoid hormone receptor (MR), but also an MR-independent effect, not regulated by conventional MR blockade. Although many pharmacological agents target different levels of the RAAS cascade, these generally result in elevated renin concentration and plasma renin activity. This upstream feedback response subsequently results in elevated levels of angiotensin II, a potent vasoconstrictor and stimulus to aldosterone release. This aldosterone breakthrough counteracts the long-term blood pressure-lowering effect of these agents. Therefore the development of a new class of pharmacologic agents that directly inhibit the production of aldosterone may prove clinically useful in reducing aldosterone and thereby controlling elevated blood pressure.
authors.affiliation: Cardiovascular Research Center, Landspitali the University Hospital of Iceland, IS-101, Reykjavik, Iceland, andersen@landspitali.is.
authors.forename: Karl
authors.initials: K
authors.lastname: Andersen
mesh_terms: D000450:Aldosterone / Q000096:biosynthesis; D000818:Animals; D000959:Antihypertensive Agents / Q000627:therapeutic use*; D019405:Cytochrome P-450 CYP11B2 / Q000037:antagonists & inhibitors*; D004791:Enzyme Inhibitors / Q000627:therapeutic use*; D006801:Humans; D006973:Hypertension / Q000188:drug therapy* / Q000201:enzymology; D012084:Renin-Angiotensin System
chemical_list: D000959:Antihypertensive Agents; D004791:Enzyme Inhibitors; D000450:Aldosterone; D019405:Cytochrome P-450 CYP11B2
references.citation: Hypertension. 2005 Apr;45(4):766-72
references.pmid: 15699471
references.citation: Curr Opin Investig Drugs. 2009 Apr;10(4):319-26
references.pmid: 19337952
references.citation: N Engl J Med. 2003 Apr 3;348(14):1309-21
references.pmid: 12668699
references.citation: Hypertension. 2010 May;55(5):1137-42
references.pmid: 20351345
references.citation: J Int Med Res. 2001 Jan-Feb;29(1):13-21
references.pmid: 11277342
references.citation: Circulation. 2004 Jun 15;109(23):2857-61
references.pmid: 15173035
references.citation: J Clin Endocrinol Metab. 2010 Apr;95(4):1986-90
references.pmid: 20130077
references.citation: Circulation. 2011 Nov 1;124(18):1945-55
references.pmid: 21986283
references.citation: J Hypertens. 2009 Apr;27(4):680-91
references.pmid: 19516169
references.citation: Endocrinology. 2008 Jan;149(1):28-31
references.pmid: 17884944
references.citation: Eur Heart J. 2008 Sep;29(17):2171-9
references.pmid: 18586661
references.citation: N Engl J Med. 1999 Sep 2;341(10):709-17
references.pmid: 10471456
references.citation: J Hypertens. 2007 Apr;25(4):891-4
references.pmid: 17351384
references.citation: Circulation. 2005 Jun 14;111(23):3087-94
references.pmid: 15939810
references.citation: Hypertension. 2009 Jun;53(6):932-6
references.pmid: 19380612
references.citation: J Clin Endocrinol Metab. 2007 Nov;92(11):4472-5
references.pmid: 17726083
references.citation: J Clin Hypertens (Greenwich). 2013 Mar;15(3):186-92
references.pmid: 23458591
references.citation: Nat Clin Pract Nephrol. 2007 Sep;3(9):486-92
references.pmid: 17717561
references.citation: J Hypertens. 2007 Apr;25(4):747-50
references.pmid: 17351364
references.citation: Nat Rev Cardiol. 2010 Aug;7(8):431-41
references.pmid: 20567239
references.citation: Mol Cell Endocrinol. 2009 Mar 25;301(1-2):2-6
references.pmid: 19026715
references.citation: Am J Hypertens. 1997 Dec;10(12 Pt 1):1326-34
references.pmid: 9443767
references.citation: J Clin Hypertens (Greenwich). 2012 Sep;14(9):580-7
references.pmid: 22947355
references.citation: Kidney Int. 2004 Jul;66(1):1-9
references.pmid: 15200407
references.citation: J Lab Clin Med. 1992 Dec;120(6):893-901
references.pmid: 1453111
references.citation: Hypertension. 2003 Dec;42(6):1206-52
references.pmid: 14656957
references.citation: Lancet. 2002 Dec 14;360(9349):1903-13
references.pmid: 12493255
references.citation: Kidney Int. 2009 May;75(9):936-44
references.pmid: 19225557
references.citation: N Engl J Med. 2011 Jan 6;364(1):11-21
references.pmid: 21073363
references.citation: Bioorg Med Chem Lett. 2010 Aug 1;20(15):4324-7
references.pmid: 20615692
references.citation: Hypertension. 2001 Mar;37(3):845-50
references.pmid: 11244006
references.citation: Eur J Med Chem. 2003 Apr;38(4):363-6
references.pmid: 12750023
references.citation: J Clin Endocrinol Metab. 1992 Mar;74(3):571-6
references.pmid: 1531483
references.citation: N Engl J Med. 2004 Jul 1;351(1):33-41
references.pmid: 15229305
references.citation: Clin Sci (Lond). 2007 Sep;113(6):267-78
references.pmid: 17683282
references.citation: Hypertension. 2006 Mar;47(3):312-8
references.pmid: 16432039
references.citation: Clin J Am Soc Nephrol. 2006 Sep;1(5):940-51
references.pmid: 17699311
references.citation: Mol Endocrinol. 2013 Feb;27(2):315-24
references.pmid: 23322723
references.citation: Am J Hypertens. 2008 Sep;21(9):1055-61
references.pmid: 18583983
references.citation: Hypertension. 2010 Nov;56(5):831-8
references.pmid: 20837883
references.citation: BMJ. 2013 Jan 28;346:f360
references.pmid: 23358488
references.citation: Nat Rev Drug Discov. 2003 Mar;2(3):177-8
references.pmid: 12619638
references.citation: J Hum Hypertens. 2008 Aug;22(8):550-8
references.pmid: 18449201
references.citation: N Engl J Med. 2001 Nov 1;345(18):1291-7
references.pmid: 11794147