Renin inhibitor aliskiren improves impaired nitric oxide Bioavailability and protects against atherosclerotic changes
Renin inhibitor aliskiren improves impaired nitric oxide Bioavailability and protects against atherosclerotic changes
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DOI：
10.1161/hypertensionaha.108.111120
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发表时间：
2008-09-01
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;Tsujioka, Hiroto;Akasaka, Takashi
我们研究了阿利吉仑，一种直接的肾素抑制剂，是否能提高NO的生物利用度，并防止自发性动脉粥样硬化的变化。我们还研究了阿利吉仑和缬沙坦（一种血管紧张素II受体阻滞剂）联合治疗对上述结果的影响。Watanabe遗传性高血压兔用溶剂（对照）、阿利吉仑、缬沙坦或阿利吉仑加缬沙坦治疗8周。然后，测定乙酰胆碱诱导的NO产生作为内皮保护功能的替代指标，并测定超氧化物和血管过氧亚硝酸盐。采用高效液相色谱荧光检测法测定主动脉节段中的四氢生物蝶呤。通过组织学定量斑块面积。在所有试验组中，响应于主动脉内乙酰胆碱输注的血浆NO浓度的增加显著大于对照组。阿利吉仑+缬沙坦联合治疗使乙酰胆碱诱导的NO增加6.2 nmol/ L，显著高于阿利吉仑或缬沙坦单独治疗。对照组的血管超氧化物和过氧亚硝酸盐水平均显着高于阿利吉伦或缬沙坦组，而阿利吉伦+缬沙坦组的血管超氧化物和过氧亚硝酸盐水平均显着低于阿利吉伦或缬沙坦组。在阿利吉仑+缬沙坦联合治疗后观察到最高的四氢生物蝶呤水平。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。用直接的肾素抑制剂治疗对内皮功能和动脉粥样硬化变化有保护作用。此外，与直接的肾素抑制剂和血管紧张素II受体阻滞剂的共同治疗对两者都有相加的保护作用。
We investigated whether aliskiren, a direct renin inhibitor, improves NO bioavailability and protects against spontaneous atherosclerotic changes. We also examined the effects of cotreatment with aliskiren and valsartan, an angiotensin II receptor blocker, on the above-mentioned outcomes. Watanabe heritable hyperlipidemic rabbits were treated with vehicle ( control), aliskiren, valsartan, or aliskiren plus valsartan for 8 weeks. Then, acetylcholine- induced NO production was measured as a surrogate index of endothelium protective function, and both superoxide and vascular peroxynitrite were measured. Tetrahydrobiopterin in aortic segments was assessed by high- performance liquid chromatography with fluorescence detection. Plaque area was quantified by histology. Increase in plasma NO concentration in response to intra- aortic acetylcholine infusion was significantly greater in all of the test groups than in controls. Aliskiren + valsartan cotreatment increased acetylcholine- induced NO by 6.2 nmol/ L, which was significantly higher than that with either aliskiren or valsartan alone. Vascular superoxide and peroxynitrite levels were both significantly higher in controls and significantly lower in the aliskiren + valsartan group than in the aliskiren or valsartan group. The highest tetrahydrobiopterin levels were observed after aliskiren + valsartan cotreatment. Histology of the thoracic aorta revealed that the plaque area was significantly decreased with combination therapy compared with monotherapy. Treatment with a direct renin inhibitor has protective effects on endothelial function and atherosclerotic changes. Furthermore, cotreatment with a direct renin inhibitor and an angiotensin II receptor blocker has additive protective effects on both.