Aldosterone synthase inhibitor ameliorates angiotensin II-induced organ damage.
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.


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.
Fiebeler
Anette
A
Medical Faculty of the Charité, HELIOS Klinikum-Berlin, Franz Volhard Clinic, Berlin, Germany. fiebeler@fvk-berlin.de
Nussberger
Jürg
J
Shagdarsuren
Erdenechimeg
E
Rong
Song
S
Hilfenhaus
Georg
G
Al-Saadi
Nidal
N
Dechend
Ralf
R
Wellner
Maren
M
Meiners
Silke
S
Maser-Gluth
Christiane
C
Jeng
Arco Y
AY
Webb
Randy L
RL
Luft
Friedrich C
FC
Muller
Dominik N
DN
D000311:Adrenal Glands / Q000378:metabolism; D000315:Adrenalectomy; D000450:Aldosterone / Q000032:analysis / Q000096:biosynthesis / Q000097:blood; D000804:Angiotensin II / Q000009:adverse effects*; D000808:Angiotensinogen / Q000235:genetics; D000818:Animals; D030801:Animals, Genetically Modified; D019405:Cytochrome P-450 CYP11B2 / Q000037:antagonists & inhibitors*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005355:Fibrosis / Q000209:etiology / Q000473:pathology; D006331:Heart Diseases / Q000209:etiology / Q000473:pathology / Q000517:prevention & control*; D006801:Humans; D007249:Inflammation / Q000209:etiology / Q000473:pathology; D007674:Kidney Diseases / Q000209:etiology / Q000473:pathology / Q000517:prevention & control; D019808:Losartan / Q000008:administration & dosage / Q000494:pharmacology; D000451:Mineralocorticoid Receptor Antagonists / Q000494:pharmacology*; D009206:Myocardium / Q000737:chemistry; D051381:Rats; D012083:Renin / Q000097:blood / Q000235:genetics
D004791:Enzyme Inhibitors; D000451:Mineralocorticoid Receptor Antagonists; D000808:Angiotensinogen; D000804:Angiotensin II; D000450:Aldosterone; D019405:Cytochrome P-450 CYP11B2; D012083:Renin; D019808:Losartan