Alamandin and especially melatonin attenuate pulmonary arterial hypertension induced by monocrotalin.

BACKGROUND: Despite the available treatments, pulmonary arterial hypertension (PAH) prognosis is poor. OBJECTIVES: We aimed to investigate the effects of the alamandine (ALA), melatonin (MEL), and ALA + MEL in PAH. METHODS: The rats were randomly divided into Control (n = 10), monocrotaline (MCT) (n = 12), ALA (n = 12), MEL (n = 12), and ALA + MEL (n = 12) groups. PAH was induced by MCT. The ALA, MEL, and ALA + MEL groups received 50 µg/kg/day ALA, 10 mg/kg/day MEL, and ALA + MEL, respectively, for 35 days. Echocardiographic and hemodynamic measurements and tissue analyses (morphometric, histopathological, ELISA, and western blot) were performed. RESULTS: Monotherapies, especially MEL, reduced the right ventricular (RV) systolic pressure. Only MEL increased the pulmonary artery acceleration time. MCT increased the RV/left ventricle (LV) + interventricular septum (IVS) ratio. While ALA and ALA + MEL slightly decreased the RV/(LV + IVS), MEL significantly restored it. MCT increased the tunica intima-media (TIM) thickness, PCNA and α-SMA of pulmonary arterioles, histopathological score (HS) (inflammatory infiltration etc.) of the lung, and RV. All treatments reduced the TIM thickness (especially MEL), PCNA, and α-SMA. All treatments significantly decreased the HS of the lung; however, MEL and ALA + MEL produced greater benefits. All treatments attenuated the HS of RV. MCT caused a significant increase in lung lysyl oxidase (LOX) activity. All treatments restored the LOX; however, MEL and ALA + MEL provided greater improvement. While lung Nrf-2 was increased in MCT-treated rats, MEL reduced it. CONCLUSION: ALA, MEL, and ALA + MEL attenuate PAH and protect RV via antiproliferative, anti-remodeling, antihypertrophic, anti-inflammatory, and free radical scavenging (only MEL) capabilities. Overall, MEL produced the best outcomes.

Activation of the Mas receptors by AVE0991 and MrgD receptor using alamandine to limit the deleterious effects of Ang II-induced hypertension.

The MrgD receptor agonist, alamandine (ALA) and Mas receptor agonist, AVE0991 have recently been identified as protective components of the renin-angiotensin system. We evaluated the effects of ALA and AVE0991 on cardiovascular function and remodeling in angiotensin (Ang) II-induced hypertension in rats. Sprague Dawley rats were subject to 4-week subcutaneous infusions of Ang II (80 ng/kg/min) or saline after which they were treated with ALA (50 µg/kg), AVE0991 (576 µg/kg), or ALA+AVE0991 during the last 2 weeks. Systolic blood pressure (SBP) and heart rate (HR) values were recorded with tail-cuff plethysmography at 1, 15, and 29 days post-treatment. After euthanization, the heart and thoracic aorta were removed for further analysis and vascular responses. SBP significantly increased in the 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 -9, NADPH oxidase-4, and lysyl oxidase levels were comparable among groups. ALA, AVE0991, and the drug combination produced antihypertensive effects and alleviated vascular responses. The inflammatory and oxidative stress related to cardiac MCP-1 and CYP-A levels decreased in 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. Our experimental data showed the combination of ALA and AVE0991 was found beneficial in Ang II-induced hypertension in rats by reducing SBP, oxidative stress, inflammation, and improving vascular responses.

Pharmacological agents under investigation in the treatment of coronavirus disease 2019 and the importance of melatonin.

Coronavirus disease 2019 (COVID-19) is a life-threatening infectious respiratory disease caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). COVID-19 pandemic causing morbidities and even deaths worldwide revealed that there is urgent need to find pharmacological agents or vaccines. Although there are a lot of agents under investigation, there is no approved agent for the prevention or treatment of the COVID-19 yet. Treatment of patients remains mainly supportive as well as compassionate use of the agents under investigation. It is well established that excessive inflammatory and immune response and oxidative injury play a critical role in the pathogenesis of COVID-19. In this review, we aimed to update knowledge about pathogenesis, clinical features, and pharmacological treatment of COVID-19 and review the potential beneficial effects of ancient antioxidant, anti-inflammatory, and immunomodulatory molecule melatonin for prevention and treatment of COVID-19.