Gschwend Simone, Haug Marcel Bernhard, Nierhaus Marc, Schulz Angela, Vetter Roland, Kossmehl Peter, Orzechowski Hans-Dieter, Scholze Jürgen, Rothermund Lars, Kreutz Reinhold
Institut für Klinische Pharmakologie und Toxikologie, Charité Centrum für Therapieforschung, Germany.
Life Sci. 2009 Sep 9;85(11-12):431-7. doi: 10.1016/j.lfs.2009.07.006. Epub 2009 Jul 25.
In patients with renal disease the cardiovascular risk is greatly increased, and endothelial dysfunction is assumed to play a pivotal role in this process. Therefore we compared treatment effects of a beta-blocker with additional vasodilatory capacities (nebivolol) and a beta-blocker lacking these actions (metoprolol) on intrarenal and coronary vascular function in a rat model of renal failure with hypertension.
Renal failure was induced by 5/6-nephrectomy (Nx) and analyzed after 4 weeks in Wistar rats. Untreated Nx, Nx/nebivolol 6 mg/d (Nx-Nebi); Nx/metoprolol 60 mg/d (Nx-Meto) and sham-operated (Sham) animals were studied. Isolated small renal and coronary arteries were investigated for endothelium-dependent relaxation to acetylcholine (ACh) and for the contribution of the endothelial mediators NO and endothelium-derived hyperpolarizing factor (EDHF).
Systolic blood pressure (SBP) was significantly increased in Nx, Nx-Nebi, and Nx-Meto (168+/-5, 153+/-3, and 162+/-6 mmHg) compared to Sham (138+/-3 mmHg, p<0.05, respectively). The increase in albuminuria of Nx (120-fold vs. Sham, p<0.0001) was almost (-85%) normalized by nebivolol compared to Sham (p<0.05), whereas metoprolol induced no significant effect. Renal arteries showed significantly increased Ach-relaxation in Nx and Nx-Nebi (Emax 86+/-4% and 76+/-7%, p<0.05) due to an increase in EDHF-mediated dilation (Emax_EDHF 78+/-7% and 73+/-6%) compared to Sham (Emax 54+/-4% and Emax_EDHF 44+/-6%) and Nx-Meto (Emax 42+/-12% and Emax_EDHF 18+/-5%). ACh-relaxation in coronary arteries was similar between groups but the contribution of NO (relative to EDHF) was strongly increased by nebivolol.
The present findings offer an explanation of the nephroprotective effect of intrarenal endothelial function in renal failure.
肾病患者的心血管风险大幅增加，内皮功能障碍被认为在此过程中起关键作用。因此，我们在伴有高血压的肾衰竭大鼠模型中，比较了具有额外血管舒张能力的β受体阻滞剂（奈必洛尔）和缺乏这些作用的β受体阻滞剂（美托洛尔）对肾内和冠状动脉血管功能的治疗效果。
通过5/6肾切除术（Nx）诱导Wistar大鼠肾衰竭，并在4周后进行分析。研究了未治疗的Nx组、Nx/奈必洛尔6mg/d组（Nx-Nebi）、Nx/美托洛尔60mg/d组（Nx-Meto）以及假手术（Sham）组动物。对分离出的小肾动脉和冠状动脉进行研究，检测其对乙酰胆碱（ACh）的内皮依赖性舒张反应，以及内皮介质一氧化氮（NO）和内皮衍生超极化因子（EDHF）的作用。
与假手术组（138±3mmHg）相比，Nx组、Nx-Nebi组和Nx-Meto组的收缩压（SBP）显著升高（分别为168±5、153±3和162±6mmHg，p<0.05）。与假手术组相比，Nx组的蛋白尿增加了120倍（p<0.0001），而奈必洛尔使其几乎恢复正常（与假手术组相比降低了85%，p<0.05），而美托洛尔未产生显著影响。与假手术组（Emax 54±4%和Emax_EDHF 44±6%）和Nx-Meto组（Emax 42±12%和Emax_EDHF 18±5%）相比，Nx组和Nx-Nebi组的肾动脉对ACh的舒张反应显著增强（Emax分别为86±4%和76±7%，p<0.05），这是由于EDHF介导的舒张作用增强（Emax_EDHF分别为78±7%和73±6%）。各组冠状动脉对ACh的舒张反应相似，但奈必洛尔使NO（相对于EDHF）的作用显著增强。
本研究结果为肾衰竭时肾内内皮功能的肾保护作用提供了解释。
