| Aldosterone synthase inhibitor ameliorates angiotensin II-induced organ damage. | |
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MedLine Citation:
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PMID: 15939810 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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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. |
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Authors:
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Anette Fiebeler; Jürg Nussberger; Erdenechimeg Shagdarsuren; Song Rong; Georg Hilfenhaus; Nidal Al-Saadi; Ralf Dechend; Maren Wellner; Silke Meiners; Christiane Maser-Gluth; Arco Y Jeng; Randy L Webb; Friedrich C Luft; Dominik N Muller |
Publication Detail:
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Type: Journal Article; Research Support, Non-U.S. Gov't Date: 2005-06-06 |
Journal Detail:
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Title: Circulation Volume: 111 ISSN: 1524-4539 ISO Abbreviation: Circulation Publication Date: 2005 Jun |
Date Detail:
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Created Date: 2005-06-15 Completed Date: 2006-02-06 Revised Date: 2006-11-15 |
Medline Journal Info:
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Nlm Unique ID: 0147763 Medline TA: Circulation Country: United States |
Other Details:
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Languages: eng Pagination: 3087-94 Citation Subset: AIM; IM |
Affiliation:
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Medical Faculty of the Charité, HELIOS Klinikum-Berlin, Franz Volhard Clinic, Berlin, Germany. fiebeler@fvk-berlin.de |
Export Citation:
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APA/MLA Format Download EndNote Download BibTex |
| MeSH Terms | |
Descriptor/Qualifier:
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Adrenal Glands
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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 |
| Chemical | |
Reg. No./Substance:
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0/Aldosterone Antagonists; 0/Enzyme Inhibitors; 11002-13-4/Angiotensinogen; 11128-99-7/Angiotensin II; 114798-26-4/Losartan; 52-39-1/Aldosterone; EC 1.14.15.4/Aldosterone Synthase; EC 3.4.23.15/Renin |
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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