Laboratory of Translational Physiology, Federal University of Espirito Santo, Vitoria, ES, Brazil.
Pharmaceutical Sciences Graduate Program, Vila Velha University, Vila Velha, ES, Brazil.
Vascul Pharmacol. 2020 Jan;124:106601. doi: 10.1016/j.vph.2019.106601. Epub 2019 Nov 2.
Arterial hypertension is a condition associated with endothelial dysfunction, accompanied by an imbalance in the production of reactive oxygen species (ROS) and NO. The aim of this study was to investigate and elucidate the possible mechanisms of sildenafil, a selective phosphodiesterase-5 inhibitor, actions on endothelial function in aortas from spontaneously hypertensive rats (SHR). SHR treated with sildenafil (40 mg/kg/day, p.o., 3 weeks) were compared to untreated SHR and Wistar-Kyoto (WKY) rats. Systolic blood pressure (SBP) was measured by tail-cuff plethysmography and vascular reactivity was determined in isolated rat aortic rings. Circulating endothelial progenitor cells and systemic ROS were measured by flow cytometry. Plasmatic total antioxidant capacity, NO production and aorta lipid peroxidation were determined by spectrophotometry. Scanning electron microscopy was used for structural analysis of the endothelial surface. Sildenafil reduced high SBP and partially restored the vasodilator response to acetylcholine and sodium nitroprusside in SHR aortic rings. Using selective inhibitors, our experiments revealed an augmented participation of NO, with a simultaneous decrease of oxidative stress and of cyclooxygenase-1 (COX-1)-derived prostanoids contribution in the endothelium-dependent vasodilation in sildenafil-treated SHR compared to non-treated SHR. Also, the relaxant responses to sildenafil and 8-Br-cGMP were normalized in sildenafil-treated SHR and sildenafil restored the pro-oxidant/antioxidant balance and the endothelial architecture. In conclusion, sildenafil reverses endothelial dysfunction in SHR by improving vascular relaxation to acetylcholine with increased NO bioavailability, reducing the oxidative stress and COX-1 prostanoids, and improving cGMP/PKG signaling. Also, sildenafil reduces structural endothelial damage. Thus, sildenafil is a promising novel pharmacologic strategy to treat endothelial dysfunction in hypertensive states reinforcing its potential role as adjuvant in the pharmacotherapy of cardiovascular diseases.
动脉高血压是一种与内皮功能障碍相关的病症，伴有活性氧（ROS）和 NO 生成失衡。本研究旨在探讨和阐明选择性磷酸二酯酶-5 抑制剂西地那非对自发性高血压大鼠（SHR）主动脉内皮功能的可能作用机制。将接受西地那非（40mg/kg/天，口服，3 周）治疗的 SHR 与未治疗的 SHR 和 Wistar-Kyoto（WKY）大鼠进行比较。通过尾套容积描记法测量收缩压（SBP），并在分离的大鼠主动脉环中测定血管反应性。通过流式细胞术测量循环内皮祖细胞和全身 ROS。通过分光光度法测定血浆总抗氧化能力、NO 产生和主动脉脂质过氧化。扫描电子显微镜用于内皮表面的结构分析。西地那非降低了 SHR 的高血压并部分恢复了乙酰胆碱和硝普钠对 SHR 主动脉环的舒张反应。使用选择性抑制剂，我们的实验表明，与未治疗的 SHR 相比，西地那非治疗的 SHR 中 NO 的参与增加，同时氧化应激和环氧化酶-1（COX-1）衍生的前列腺素的贡献减少，导致内皮依赖性血管舒张。此外，西地那非治疗的 SHR 中对西地那非和 8-Br-cGMP 的舒张反应正常化，西地那非恢复了促氧化剂/抗氧化剂平衡和内皮结构。总之，西地那非通过提高 NO 生物利用度改善血管对乙酰胆碱的舒张反应，降低氧化应激和 COX-1 前列腺素，改善 cGMP/PKG 信号转导，从而逆转 SHR 的内皮功能障碍。此外，西地那非还减少了结构内皮损伤。因此，西地那非是一种有前途的新型药理学策略，可用于治疗高血压状态下的内皮功能障碍，增强其在心血管疾病药物治疗中的潜在作用。
