Rostafuroxin ameliorates endothelial dysfunction and oxidative stress in resistance arteries from deoxycorticosterone acetate-salt hypertensive rats: the role of Na+K+-ATPase/cSRC pathway
Rostafuroxin ameliorates endothelial dysfunction and oxidative stress in resistance arteries from deoxycorticosterone acetate-salt hypertensive rats: the role of Na+K+-ATPase/cSRC pathway
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DOI：
10.1097/hjh.0000000000000059
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发表时间：
2014-03-01
影响因子：
4.9
通讯作者：
Rossoni, Luciana V.
中科院分区：
文献类型：
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作者：
Wenceslau, Camilla F.;Rossoni, Luciana V.
目的：内源性哇巴因在高血压患者和实验模型中升高，并与死亡率升高相关。在这种情况下，它是合理的假设，一种新的抗高血压药物，抑制内源性哇巴因的有害影响可能是一个特定的药理学工具，用于高血压治疗。在这里，我们调查了rostafuroxin（罗斯塔），哇巴因抑制剂，收缩压，内皮功能障碍和氧化应激在脱氧皮质酮醋酸酯（DOCA）-salt.Methods和结果：高血压模型建立在单侧肾切除Wistar大鼠使用DOCA-盐。SBP稳定后，DOCA-盐大鼠分为两组：DOCA-盐（对照）和DOCA-盐处理罗斯塔（1 mg/kg/天管饲，3周）。采用尾袖法测量收缩压，并使用钢丝肌电描记器评估肠系膜阻力动脉（MRA）的血管功能。一氧化氮和活性氧的产生进行了研究。进行蛋白质印迹以定量蛋白质表达。我们的研究结果表明，罗斯塔治疗降低SBP，通过增强一氧化氮合成和生物利用度改善乙酰胆碱诱导的舒张，减少NAD（P）H氧化酶和环氧合酶-2产生的超氧阴离子，减少细胞质酪氨酸激酶Src磷酸化，而不改变DOCA盐大鼠MRA中Na（+）K（+_）ATP酶活性。本研究报告了内源性哇巴因在容量依赖性高血压中的关键作用。在DOCA-盐大鼠的MRA中，内源性哇巴因与Na+K+-ATP酶的结合导致下游c-SRC活化、氧化应激和内皮功能障碍。内源性哇巴因是治疗高血压的公认靶点，罗斯塔可能代表一种新的治疗方法。
Aims: Endogenous ouabain is elevated in patients and experimental models of hypertension and is associated with elevated mortality. In this context, it is reasonable to assume that a new antihypertensive drug that inhibits the deleterious effects of endogenous ouabain may be a specific pharmacological tool for hypertension treatment. Here, we investigated the effects of rostafuroxin (ROSTA), an ouabain inhibitor, on SBP, endothelial dysfunction and oxidative stress in deoxycorticosterone acetate (DOCA)-salt rats.Methods and results: A hypertensive model was established in uninephrectomized Wistar rats using DOCA-salt. After SBP stabilization, DOCA-salt rats were divided into two groups: DOCA-salt (control) and DOCA-salt treatment with ROSTA (1 mg/kg per day gavage, 3 weeks). The SBP was measured using the tail-cuff method, and vascular function was assessed in mesenteric-resistance arteries (MRAs) using a wire myograph. Nitric oxide and reactive oxygen species production were investigated. Western blot was performed to quantify protein expression. Our results indicated that ROSTA treatment decreased SBP, improved acetylcholine-induced relaxation via enhanced nitric oxide synthesis and bioavailability, decreased superoxide anion generation from NAD(P)H oxidase and cyclooxygenase-2 and reduced cytoplasmic tyrosine kinase Src phosphorylation without changes in Na(+)K(+_)ATPase activity in MRA from DOCA-salt rats.Conclusion: This study reports the critical role of endogenous ouabain in volume-dependent hypertension. In MRA from DOCA-salt rats, the binding of endogenous ouabain to Na+K+-ATPase results in downstream c-SRC activation, oxidative stress and endothelial dysfunction. Endogenous ouabain is a putative target for the treatment of hypertension, and ROSTA may represent a novel therapeutic approach.