Department of Anesthesiology, Hospital General Universitario Gregorio Marañón, Madrid, Spain.
Department of Pharmacology and Toxicology, Faculty of Medicine, Universidad Complutense, Madrid, Spain.
Hypertens Res. 2019 Oct;42(10):1485-1494. doi: 10.1038/s41440-019-0257-z. Epub 2019 Apr 16.
Our group previously demonstrated that dronedarone induces regression of left ventricular hypertrophy in spontaneously hypertensive rats (SHRs). We assessed changes in vascular remodeling and oxidative stress following short-term use of this agent. The coronary artery was isolated from 10-month-old male SHRs treated with 100 mg kg dronedarone once daily for 14 days (SHR-D group), and age-matched untreated SHRs were used as hypertensive controls. We analyzed the geometry and composition of the artery and constructed dose-response curves for acetylcholine and serotonin (5-HT). We calculated a global score (OXY-SCORE) from plasma biomarkers of oxidative status: carbonyl levels, thiol levels, reduced glutathione levels, total antioxidant capacity, and superoxide anion scavenging activity. Finally, we analyzed asymmetric dimethylarginine (ADMA) concentrations in plasma. Dronedarone significantly decreased wall thickness (medial and adventitial layer thickness and cell count) and the cross-sectional area of the artery. Dronedarone significantly improved endothelium-dependent relaxation and reduced the contraction induced by 5-HT. The OXY-SCORE was negative in the SHR model group (suggesting an enhanced oxidative status) and was positive in the SHR-D group (suggesting enhanced antioxidant defense). Dronedarone significantly decreased the concentrations of ADMA. We conclude that dronedarone improves coronary artery remodeling in SHRs. The better global antioxidant status after treatment with dronedarone and decreased plasma ADMA levels could contribute to the cardiovascular protective effect of dronedarone.
我们的团队之前已经证明，决奈达隆可使自发性高血压大鼠（SHR）的左心室肥厚消退。我们评估了该药物短期使用后血管重构和氧化应激的变化。从 10 个月大的雄性 SHR 中分离出冠状动脉，这些 SHR 每天接受 100mg/kg 的决奈达隆治疗 14 天（SHR-D 组），并使用年龄匹配的未经治疗的 SHR 作为高血压对照。我们分析了动脉的几何形状和组成，并构建了乙酰胆碱和 5-羟色胺（5-HT）的剂量反应曲线。我们根据氧化状态的血浆生物标志物计算了一个总体评分（OXY-SCORE）：羰基水平、巯基水平、还原型谷胱甘肽水平、总抗氧化能力和超氧阴离子清除活性。最后，我们分析了血浆中不对称二甲基精氨酸（ADMA）的浓度。决奈达隆显著降低了壁厚度（中膜和外膜厚度和细胞计数）和动脉的横截面积。决奈达隆显著改善了内皮依赖性松弛，并降低了 5-HT 引起的收缩。在 SHR 模型组中，OXY-SCORE 为负（表明氧化状态增强），而在 SHR-D 组中为正（表明抗氧化防御增强）。决奈达隆显著降低了 ADMA 的浓度。我们得出结论，决奈达隆可改善 SHR 的冠状动脉重构。治疗后更好的整体抗氧化状态和降低的血浆 ADMA 水平可能有助于决奈达隆的心血管保护作用。
