Article
An Aldosterone Synthase Inhibitor Ameliorates Angiotensin II-induced End-Organ Damage
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Published: | August 10, 2005 |
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Background: Aldosterone (Ald) and angiotensin (Ang) II both cause end-organ damage. Ald is mainly produced in the adrenals; however, local cardiac synthesis has been reported. Ald concentrations depend on Ald synthase (CYP11B2). We tested the hypothesis that removing Ald by inhibiting Cyp11B2 or by adrenalectomy ameliorates end-organ damage. Furthermore, we investigated whether or not local cardiac Ald is adrenal gland-dependent.
Method: We investigated the CYP11B2 inhibitor FAD286 and the consequences of adrenalectomy (ADX) in transgenic rats overexpressing both the human renin and angiotensinogen genes (dTGR). dTGR-ADX received dexamethasone and 1% salt. dTGR-salt served as control group in the ADX protocol.
Results: Untreated dTGR developed hypertension, cardiac, and renal damage and a 40% mortality (5/13) at 7 weeks. FAD286 reduced mortality to 10% (1/10), ameliorated cardiac hypertrophy, albuminuria, cell infiltration, and matrix deposition in heart and kidney. FAD286 had a minor effect on BP (177±6 mm Hg), compared to dTGR (200±5 mm Hg; p<0.05). Circulating and cardiac Ald levels were reduced in FAD286 and Los-treated dTGR. Adrenalectomy decreased circulating and cardiac Ald to barely detectable levels. At week 7, ADX-dTGR-salt had a 22% mortality compared to 73% in dTGR-salt. Both groups were similarly hypertensive (190±9 vs. 187±4 mm Hg). In contrast, cardiac hypertrophy index, albuminuria, cell, and matrix deposition were significantly reduced after ADX (p<0.05).
Conclusion: FAD286 ameliorates Ang II-induced renal and cardiac damage. Ald plays a key role in the pathogenesis of Ang II-induced end-organ damage. The Ald produced in the adrenals is main source for cardiac Ald.