aliskiren and Atrial-Remodeling

Atrial fibrillation (AF) is the most common type of arrhythmia. Atrial remodeling is a major factor to the AF substrate. The purpose of the study is to explore whether aliskiren (ALS) has a cardioprotective effect and its potential molecular mechanisms on atrial remodeling.. The electrophysiological changes were observed after 2-h pacing. The AERP shortened with increased AFi and ADT, which was attenuated by ALS (P < 0.05). After pacing for 2 weeks, oxidative stress and inflammation markers in the Paced group were significantly higher than those in the Sham group (P < 0.01) and were reduced by ALS treatment (P < 0.01). The reduced level of antioxidant enzymes caused by RAP was also found to be elevated in ALS-treated group (P < 0.01). The results of pathology and echocardiography showed that RAP can cause atrial enlargement, fibrosis (P < 0.01), and were attenuated in ALS treatment group. The PI3K/Akt signaling pathway were downregulated induced by RAP. ALS could upregulate the PI3K/Akt pathway expression (P < 0.05). Furthermore, the cardioprotective effects in structural remodeling of ALS were suppressed by WM.. ALS may offer cardioprotection in RAP-induced atrial remodeling, which may partly be ascribed to its anti-inflammatory and anti-oxidative stress action and the regulation of PI3K/Akt signaling pathway.

Topics: Amides; Animals; Atrial Remodeling; Dogs; Echocardiography; Female; Fumarates; Inflammation Mediators; Male; Oxidative Stress; Phosphatidylinositol 3-Kinases; Random Allocation; Signal Transduction; Wortmannin

Atrial fibrillation (AF) contributing to the increasing mortality risk is the most common disease in clinical practice. Owing to the side effects and relative inefficacy of current antiarrhythmic drugs, some research focuses on renin-angiotensin-aldosterone system (RAS) for finding out the new treatment of AF. The purpose of this study is to confirm whether aliskiren as a proximal inhibitor of renin, which completely inhibits RAS, has beneficial effects on atrial structural remodeling in AF. In this study, rapid atrial pacing was induced at 500 beats per minute for 2 weeks in a canine model. A different dose of aliskiren was given orally for 2 weeks before rapid atrial pacing. HE staining and Masson's staining were used for analysis of myocardial fibrosis. TGF-β1, signal pathways, and pro-inflammatory cytokines were shown for the mechanism of structural remodeling after the treatment of aliskiren. Serious atrial fibrosis was induced by rapid atrial pacing, followed by the elevated TGF-β1, upregulated MEK and ERK1/2, and increased inflammatory factors. Aliskiren could apparently improve myocardial fibrosis by reducing the expression of TGF-β1, inhibiting MEK and ERK1/2 signal pathways, and decreasing IL-18 and TLR4 in both serum and atrial tissue. In conclusion, aliskiren could prevent atrial structural remodeling from rapid atrial pacing for 2 weeks. Aliskiren may play a potential beneficial role in the treatment of AF induced by rapid atrial pacing.

Topics: Action Potentials; Amides; Animals; Anti-Arrhythmia Agents; Atrial Fibrillation; Atrial Remodeling; Cardiac Pacing, Artificial; Cytokines; Disease Models, Animal; Dogs; Extracellular Signal-Regulated MAP Kinases; Female; Fibrosis; Fumarates; Heart Atria; Heart Rate; Inflammation Mediators; Male; MAP Kinase Kinase 1; Renin; Signal Transduction; Transforming Growth Factor beta1

Aliskiren inhibits the activation of the renin-angiotensin system. Here, we investigated the effects of aliskiren on chronic atrial iron remodeling in the experimental canine model of rapid atrial pacing.. Twenty-eight dogs were assigned to sham (S), control paced (C), paced + aliskiren (10 mg Kg(-1) d(-1), A1), and paced + aliskiren (20 mg Kg(-1) d(-1), A2) groups. Rapid atrial pacing at 500 bpm was maintained for 2 weeks, while group S was not paced. Levels of serum angiotensin-converting enzyme and angiotensin II after pacing were determined by ELISA. Whole-cell patch-clamp technique, western blot, and RT-PCR were applied to assess atrial ionic remodeling.. The density of I CaL and I Na currents (pA/pF) was significantly lower in group C compared with group S (I CaL: -4.09 ± 1.46 vs. -6.12 ± 0.58,P < 0.05; I Na: 30.48 ± 6.08 vs. 46.31 ± 4.73, P < 0.05). However, the high dose of aliskiren elevated the density of I CaL and I Na currents compared with group C (I CaL: -6.23 ± 1.35 vs. -4.09 ± 1.46, P < 0.05; I Na: 58.62 ± 16.17 vs. 30.48 ± 6.08, P < 0.01). The relative mRNA and protein expression levels of Cav1.2 and Nav1.5α were downregulated in group C respectively (Cav1.2: 0.46 ± 0.08; Nav1.5α: 0.52 ± 0.08, P < 0.01; Cav1.2: 0.31 ± 0.03; Nav1.5α: 0.41 ± 0.04, P < 0.01;), but were upregulated by aliskiren.. Aliskiren has protective effects on atrial tachycardia-induced atrial ionic remodeling.

Topics: Amides; Angiotensin II; Animals; Atrial Remodeling; Calcium Channels, L-Type; Cardiac Pacing, Artificial; Dogs; Down-Regulation; Fumarates; Gene Expression; Heart Atria; Hemodynamics; NAV1.5 Voltage-Gated Sodium Channel; Renin; Up-Regulation