Addition of eplerenone to an angiotensin-converting enzyme inhibitor effectively improves nitric oxide bioavailability
Addition of eplerenone to an angiotensin-converting enzyme inhibitor effectively improves nitric oxide bioavailability
复制标题
DOI：
10.1161/hypertensionaha.107.104299
复制
发表时间：
2008-03-01
期刊：
影响因子：
8.3
通讯作者：
Akasaka, Takashi
中科院分区：
文献类型：
--
作者：
Imanishi, Toshio;Ikejima, Hideyuki;Akasaka, Takashi
血管紧张素II和醛固酮都促进内皮功能障碍和动脉粥样硬化。我们研究了依普利酮（一种选择性醛固酮拮抗剂）和依那普利（一种血管紧张素转换酶抑制剂）联合应用对NO生物利用度和自发性动脉粥样硬化变化的影响。24只有心肌梗死倾向的Watanabe遗传性高血压兔用赋形剂（对照）、依普利酮（50 mg/kg/天）、依那普利（3 mg/kg/天）或依普利酮加依那普利治疗8周（每组n = 6）。治疗后，乙酰胆碱诱导的NO生成作为内皮保护功能的替代品进行测量，并测量血管过氧亚硝酸盐（超氧化物和NO的产物），以评估功能失调的内皮NO合酶活性。通过组织学定量斑块面积。主动脉内输注乙酰胆碱使血浆NO浓度增加，所有药物治疗组均显著高于对照组。依普利酮和依那普利，在组合中，增加乙酰胆碱诱导的NO由7.9 nM，这是显着高于依普利酮或依那普利单独。与依那普利或依普利酮组相比，对照组血管过氧亚硝酸盐显著较高（1.3 pmol/mg蛋白质），联合治疗组显著较低（0.4 pmol/mg蛋白质）。依普利酮和依那普利联合治疗后四氢生物蝶呤水平最高。胸主动脉的组织学显示，与单药治疗相比，联合治疗的斑块面积显著减少。选择性醛固酮拮抗剂和血管紧张素转换酶抑制剂的联合治疗通过降低亚硝化应激对内皮功能和动脉粥样硬化变化具有相加的保护作用。
Angiotensin II and aldosterone both promote endothelial dysfunction and atherosclerosis. We investigated the effect of a combination of eplerenone, a selective aldosterone antagonist, and enalapril, an angiotensin-converting enzyme inhibitor, on NO bioavailability and spontaneous atherosclerotic changes. Twenty-four myocardial infarction prone Watanabe heritable hyperlipidemic rabbits were treated with vehicle (control), eplerenone (50 mg/kg per day), enalapril ( 3 mg/kg per day), or eplerenone plus enalapril for 8 weeks (n = 6 in each group). After treatment, acetylcholine-induced NO production was measured as a surrogate for endothelium-protective function, and vascular peroxynitrite (a product of superoxide and NO) was measured to assess dysfunctional endothelial NO synthase activity. Plaque area was quantified by histology. Intra-aortic infusion of acetylcholine produced an increase in plasma NO concentration that was significantly higher with all of the drug treatments compared with the control. Eplerenone and enalapril, in combination, increased acetylcholine-induced NO by 7.9 nM, which was significantly higher than with either eplerenone or enalapril alone. Vascular peroxynitrite was significantly higher in the control group (1.3 pmol/mg of protein) and significantly lower with combination treatment (0.4 pmol/mg of protein) compared with the enalapril or eplerenone group. The highest tetrahydrobiopterin levels were observed after cotreatment with eplerenone and enalapril. Histology of the thoracic aorta showed a significantly decreased plaque area with combination therapy compared with monotherapy. Combined treatment with a selective aldosterone antagonist and an angiotensin-converting enzyme inhibitor has additive protective effects on endothelial function and on atherosclerotic changes via decreased nitrosative stress.