We found a match
Your institution may have access to this item. Find your institution then sign in to continue.
- Title
Aldosterone Synthase Inhibitor FAD286 Ameliorates Angiotensin II-Induced End-Organ Damage.
- Authors
Fiebeler, A.; Shagdarsuren, E.; Rong, S.; Al-Saadi, N.; Gapelyuk, A.; Dechend, R.; Schirdewan, A.; Wellner, M.; Jeng, A. Y.; Webb, R. L.; Luft, F. C.; Muller, D. N.
- Abstract
Objective: Aldosterone (Ald) and angiotensin (Ang) II both lead to end-organ damage. Ald is mainly produced in the adrenal gland; however, local synthesis in cardiovascular tissues has also been proposed. Systemic and local Ald concentrations depend on Ald synthase CYP11B2 activity. We tested the hypothesis that Ald synthase inhibition ameliorates Ang II-induced end-organ damage. We also investigated the role of locally-produced Ald on end-organ damage. Methods: We investigated untreated transgenic rats over expressing both the human renin and angiotensinogen genes (dTGR) and adrenalectomized dTGR (dTGR-ADX). Both groups were also treated with the Ald synthase inhibitor FAD286 (4 mg/kg/d in the diet from week 4). dTGR-ADX as well as dTGR-ADX + FAD286 received dexamethasone 12µg/kg/d (i.p.) and 1% NaCl. dTGR-salt served as control group in the ADX protocol. Results: Untreated dTGR developed hypertension, cardiac hypertrophy, albuminuria and a 40% mortality (5/13) at 7 weeks. FAD286 reduced mortality to 10% (1/10). FAD286 did not affect BP in week 5 and 6, but lowered BP (177 ± 6mmHg), compared to dTGR (200 ± 5mmHg), at week 7 (p < 0.05). FAD286 reduced albuminuria as well as T-cell and macrophage infiltration (p < 0.05). The dTGR-salt controls showed a 100% mortality at week 9. ADX lowered circulating Ald to undetectable levels and reduced mortality to 38% (8/21). Left ventricular (LV) mass, albuminuria, and cell infiltration were lower after ADX (p < 0.05), while BP was not reduced. Magnetocardiographic (MCG) measurements indicated that ADX diminished cardiac fibrosis. FAD286 plus ADX reduced mortality to 24% (5/21) at week 9. FAD286 diminished LV mass; MCG data suggested a further reduction in cardiac fibrosis. Macrophage and T-cell infiltration in FAD286-treated dTGR plus ADX was lower, compared to dTGR-ADX (p < 0.05). Conclusions: Ald plays a major role in the pathogenesis of Ang II-induced end-organ damage. In addition to the circulating Ald, locally produced Ald might also promote cardiac damage. Our results suggest that blocking the Ald synthase could be a novel therapeutic option for cardiovascular protection.
- Subjects
ALDOSTERONE; ANGIOTENSINS; ANGIOTENSIN II; GENE expression; ADRENAL glands; HYPERTENSION; ALBUMINURIA
- Publication
Kidney & Blood Pressure Research, 2004, Vol 27, Issue 5/6, p288
- ISSN
1420-4096
- Publication type
Article