eplerenone and 4-hydroxy-2-nonenal

Angiotensin II (Ang II) and aldosterone contribute to hypertension, oxidative stress and cardiovascular damage, but the contributions of aldosterone during Ang II-dependent hypertension are not well defined because of the difficulty to assess each independently. To test the hypothesis that during Ang II infusion, oxidative and nitrosative damage is mediated through both the mineralocorticoid receptor (MR) and angiotensin type 1 receptor (AT1), five groups of Sprague-Dawley rats were studied: (i) control; (ii) Ang II infused (80 ng/min × 28 days); (iii) Ang II + AT1 receptor blocker (ARB; 10 mg losartan/kg per day × 21 days); (iv) Ang II + mineralocorticoid receptor (MR) antagonist (Epl; 100 mg eplerenone/day × 21 days); and (v) Ang II + ARB + Epl (Combo; × 21 days). Both ARB and combination treatments completely alleviated the Ang II-induced hypertension, whereas eplerenone treatment only prolonged the onset of the hypertension. Eplerenone treatment exacerbated the Ang II-mediated increase in plasma and heart aldosterone 2.3- and 1.8-fold, respectively, while ARB treatment reduced both. Chronic MR blockade was sufficient to ameliorate the AT1-mediated increase in oxidative damage. All treatments normalized protein oxidation (nitrotyrosine) levels; however, only ARB and Combo treatments completely reduced lipid peroxidation (4-hydroxynonenal) to control levels. Collectively, these data suggest that receptor signalling, and not the elevated arterial blood pressure, is the principal culprit in the oxidative stress-associated cardiovascular damage in Ang II-dependent hypertension.

Topics: Adrenal Glands; Aldehydes; Angiotensin II; Angiotensin II Type 1 Receptor Blockers; Animals; Biomarkers; Blood Pressure; Disease Models, Animal; Drug Therapy, Combination; Eplerenone; Heart Diseases; Hypertension; Lipid Peroxidation; Losartan; Male; Mineralocorticoid Receptor Antagonists; Myocardium; Oxidative Stress; Rats, Sprague-Dawley; Renin-Angiotensin System; Signal Transduction; Spironolactone; Time Factors; Tyrosine

The aim of this study was to examine the effects of eplerenone on hepatic fibrosis induced by bile duct ligation (BDL) in rat. Low- (1.0 mg/kg body weight, BW) and high- (4.0 mg/kg BW) dose eplerenone was administered orally for 21 days immediately following BDL. Fibrosis was assessed by measuring the fibrotic area after Sirius red staining. Immunostaining for alpha-smooth muscle actin (SMA), 4-hydroxy-2-nonenal (4-HNE) and 8-hydroxy-2-deoxyguanosine (8-OHdG) was also carried out. Gene expression levels of procollagen-I, transforming growth factor-beta1 (TGF-beta1), connective tissue growth factor (CTGF), tissue inhibitor of metalloproteinases-1 (TIMP-1) and matrix metalloproteinase-13 (MMP-13) in the liver were examined by real-time reverse transcriptase polymerase chain reaction. Plasma angiotensin II (ATII) concentration was measured via radioimmunoassay. The area of hepatic fibrosis and alpha-SMA positivity in the high-dose group was significantly decreased compared with that in the BDL group, but not in the low-dose group. 8-OHdG-positive cells in the low- and high-dose groups were significantly decreased compared with those in the BDL group. Immunostaining of 4-HNE in the high-dose group was significantly lower compared with that in the BDL group. Furthermore, TIMP-1 mRNA levels in the low- and high-dose groups were lower than that in the BDL group. The expression of TGF-beta1, CTGF, procollagen-1 and MMP-13 showed no differences. Plasma ATII concentration in the high-dose group was significantly decreased. Eplerenone attenuated the development of BDL-induced hepatic fibrosis by reducing oxidative stress, suppressing activated hepatic stellate cells and decreasing plasma ATII levels. Eplerenone may prove useful as an alternative treatment for antifibrosis therapy.

Topics: 8-Hydroxy-2'-Deoxyguanosine; Aldehydes; Animals; Bile Ducts; Deoxyguanosine; Eplerenone; Gene Expression Regulation; Hydroxyproline; Immunohistochemistry; Ligation; Lipid Peroxidation; Liver Cirrhosis; Male; Mineralocorticoid Receptor Antagonists; Oxidative Stress; Rats; Rats, Wistar; RNA, Messenger; Spironolactone