Investigation of the effects of alamandine and AVE0991 on cardiac remodeling, vascular proliferation, and vascular contraction-relaxation response in angiotensin II-induced experimental hypertension model

Aim: Mas-related G protein-coupled receptor agonist, alamandine (ALA) and Mas receptor agonist, AVE0991 have recently been identified as protective components of the renin‑angiotensin system. In this study, we evaluated the effects of ALA and AVE0991 on cardiovascular function and remodeling in angiotensin (Ang) II-induced hypertension. Material and Method: Sprague Dawley rats were subject to 4-week subcutaneous infusions of Ang II (80 ng/kg/min) or saline control after which they were treated with ALA (50 mcg/kg), AVE0991 (576 mcg/kg), or ALA+AVE0991 during last 2 weeks. Systolic blood pressure (BP) and heart rate (HR) values were recorded at 1, 15, and 29 days post-treatment using tail-cuff plethysmography. After euthanization, the heart and thoracic aorta were removed for subsequent biochemical and histopathological analysis and also for vascular responses. Results: Sistolic BP significantly increased in Ang II group when compared to the control group. Furthermore, Ang II also caused an increase in cardiac and aortic cyclophilin-A (CYP-A), monocyte chemoattractant protein-1 (MCP-1), and cardiomyocyte degeneration, but produced a decrease in vascular relaxation. HR, matrix metalloproteinase-2 and metalloproteinase-9, NADPH oxidase-4, and lysyl oxidase levels were comparable among groups. ALA, AVE0991, and the drug combination produced antihypertensive effects and alleviate vascular responses. The inflammatory and oxidant process related to MCP-1 and CYP-A levels, respectively, decreased in the hearts of the Ang II+ALA+AVE0991 group. Vascular but not cardiac angiotensin-converting enzyme-2 levels decreased with Ang II administration but were similar to the Ang II+ALA+AVE0991 group. Conclusion: Our experimental data showed the combination of ALA and AVE0991 was more effective on reducing sistolic BP, oxidative stress, inflammation, and vascular-relaxation responses than their single use in Ang II-induced hypertension.