Dias Ananda T, Leal Marcos A S, Zanardo Tadeu C, Alves Gisele M, Porto Marcella L, Nogueira Breno V, Gava Agata L, Campagnaro Bianca P, Pereira Thiago M C, Meyrelles Silvana S, Campos-Toimil Manuel, Vasquez Elisardo C
Laboratory of Translational Physiology, Health Sciences Center, Federal University of Espirito Santo, Vitoria, Brazil.
Department Morphological Sciences, Health Sciences Center, Federal University of Espirito Santo, Vitoria, ES, Brazil.
Curr Pharm Biotechnol. 2018;19(6):483-494. doi: 10.2174/1389201019666180625094704.
By acting on multiple targets and promoting diverse actions, angiotensin II (Ang II) plays a pivotal role in vascular function. Recent studies suggested that phosphodiesterase-5 (PDE-5) inhibitors exhibit therapeutic effects in cardiovascular diseases. Here, the effects of sildenafil on vascular disturbances were analyzed in a mouse model of Ang II-induced hypertension.
Male C57BL/6 mice were used as untreated animals (control) or infused with Ang II (1000 ηg/kg/min) for 28 days and treated with sildenafil (40 mg/kg/min) or vehicle (Ang II) during the last two weeks. After 4 weeks, the Ang II animals exhibited a high systolic blood pressure (186±3 mmHg vs. 127±3 mmHg for control mice), which was attenuated by sildenafil (163±7 mmHg). The mesenteric vessels from the Ang II animals revealed damage to the endothelial layer, an increase in the cross-section area (1.9-fold) and vascular cell production of peroxynitrite (512±13 a.u.), which was ameliorated in the Ang II-Sil group (1.2-fold and 400±17 a.u.). Analysis of the vascular responsiveness showed an increased contractility response to norepinephrine in Ang II animals (Rmax: 70%), which was abolished by sildenafil through increased nitric oxide (NO) bioavailability and decreased reactive oxygen species (ROS) and vasoconstrictor prostanoids.
Sildenafil attenuates the morphofunctional deleterious effects of Ang II on resistance vessels. The benefits of sildenafil seem to occur through restoring the balance of ROS/NO/eicosanoids. Therefore, this study opened new avenues for further clinical targeting of the treatment of cardiovascular diseases related to activation of the renin-angiotensin system.
通过作用于多个靶点并促进多种作用，血管紧张素II（Ang II）在血管功能中起关键作用。最近的研究表明，磷酸二酯酶-5（PDE-5）抑制剂在心血管疾病中具有治疗作用。在此，在Ang II诱导的高血压小鼠模型中分析了西地那非对血管紊乱的影响。
雄性C57BL/6小鼠用作未治疗动物（对照）或输注Ang II（1000 ng/kg/min）28天，并在最后两周用西地那非（40 mg/kg/min）或赋形剂（Ang II）治疗。4周后，Ang II组动物表现出高收缩压（对照小鼠为186±3 mmHg，而对照小鼠为127±3 mmHg），西地那非使其降低（163±7 mmHg）。来自Ang II组动物的肠系膜血管显示内皮细胞层受损，横截面积增加（1.9倍），过氧亚硝酸盐的血管细胞生成增加（512±13任意单位）；在Ang II-西地那非组中得到改善（分别为1.2倍和400±17任意单位）。血管反应性分析显示，Ang II组动物对去甲肾上腺素的收缩反应增加（最大反应：70%），西地那非通过增加一氧化氮（NO）生物利用度、降低活性氧（ROS）和血管收缩性前列腺素而消除了这种反应。
西地那非减轻了Ang II对阻力血管的形态功能有害影响。西地那非的益处似乎是通过恢复ROS/NO/类花生酸的平衡而产生的。因此，本研究为进一步临床靶向治疗与肾素-血管紧张素系统激活相关的心血管疾病开辟了新途径。
