Aldosterone synthase inhibitor ameliorates angiotensin II-induced organ damage

Details

Serval ID
serval:BIB_22470D330496
Type
Article: article from journal or magazin.
Collection
Publications
Institution
Title
Aldosterone synthase inhibitor ameliorates angiotensin II-induced organ damage
Journal
Circulation
Author(s)
Fiebeler  A., Nussberger  J., Shagdarsuren  E., Rong  S., Hilfenhaus  G., Al-Saadi  N., Dechend  R., Wellner  M., Meiners  S., Maser-Gluth  C., Jeng  A. Y., Webb  R. L., Luft  F. C., Muller  D. N.
ISSN
1524-4539 (Electronic)
Publication state
Published
Issued date
06/2005
Volume
111
Number
23
Pages
3087-94
Notes
Journal Article
Research Support, Non-U.S. Gov't --- Old month value: Jun 14
Abstract
BACKGROUND: Aldosterone and angiotensin (Ang) II both may cause organ damage. Circulating aldosterone is produced in the adrenals; however, local cardiac synthesis has been reported. Aldosterone concentrations depend on the activity of aldosterone synthase (CYP11B2). We tested the hypothesis that reducing aldosterone by inhibiting CYP11B2 or by adrenalectomy (ADX) may ameliorate organ damage. Furthermore, we investigated how much local cardiac aldosterone originates from the adrenal gland. METHODS AND RESULTS: We investigated the effect of the CYP11B2 inhibitor FAD286, losartan, and the consequences of ADX in transgenic rats overexpressing both the human renin and angiotensinogen genes (dTGR). dTGR-ADX received dexamethasone and 1% salt. Dexamethasone-treated dTGR-salt served as a control group in the ADX protocol. Untreated dTGR developed hypertension and cardiac and renal damage and had a 40% mortality rate (5/13) at 7 weeks. FAD286 reduced mortality to 10% (1/10) and ameliorated cardiac hypertrophy, albuminuria, cell infiltration, and matrix deposition in the heart and kidney. FAD286 had no effect on blood pressure at weeks 5 and 6 but slightly reduced blood pressure at week 7 (177+/-6 mm Hg in dTGR+FAD286 and 200+/-5 mm Hg in dTGR). Losartan normalized blood pressure during the entire study. Circulating and cardiac aldosterone levels were reduced in FAD286 or losartan-treated dTGR. ADX combined with dexamethasone and salt treatment decreased circulating and cardiac aldosterone to barely detectable levels. At week 7, ADX-dTGR-dexamethasone-salt had a 22% mortality rate compared with 73% in dTGR-dexamethasone-salt. Both groups were similarly hypertensive (190+/-9 and 187+/-4 mm Hg). In contrast, cardiac hypertrophy index, albuminuria, cell infiltration, and matrix deposition were significantly reduced after ADX (P<0.05). CONCLUSIONS: Aldosterone plays a key role in the pathogenesis of Ang II-induced organ damage. Both FAD286 and ADX reduced circulating and cardiac aldosterone levels. The present results show that aldosterone produced in the adrenals is the main source of cardiac aldosterone.
Keywords
Adrenal Glands/metabolism Adrenalectomy Aldosterone/analysis/biosynthesis/blood Aldosterone Antagonists/*pharmacology Aldosterone Synthase/*antagonists & inhibitors Angiotensin II/*adverse effects Angiotensinogen/genetics Animals Animals, Genetically Modified Enzyme Inhibitors/pharmacology Fibrosis/etiology/pathology Heart Diseases/etiology/pathology/*prevention & control Humans Inflammation/etiology/pathology Kidney Diseases/etiology/pathology/prevention & control Losartan/administration & dosage/pharmacology Myocardium/chemistry Rats Renin/blood/genetics
Pubmed
Web of science
Open Access
Yes
Create date
05/03/2008 16:39
Last modification date
20/08/2019 12:59
Usage data